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Neuropathology 

Neuropathology
Chapter:
Neuropathology
Author(s):

Johannes Attems

and Kurt A. Jellinger

DOI:
10.1093/med/9780199644957.003.0006
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This chapter mainly describes the neuropathological lesions of age-associated neurodegenerative diseases and the related pathological classifications of these, to assist the reader in interpreting neuropathological reports. It is beyond the scope of this chapter to provide a comprehensive review of the neuropathology of all neurodegenerative diseases. Cerebrovascular disease, which is common and strongly age-associated, is covered and the chapter also reviews the increasing evidence on cerebral multimorbidity, that is, the presence of multiple pathologies in post-mortem brains. It is now recognized that multimorbidity in the aged brain is rather the rule, while pure pathologies are the exception. Finally, we give a view on new and currently emerging neuropathological methods that should more accurately reflect the burden of pathology seen in post-mortem brains.

Neurodegeneration: General Considerations

Neurodegenerative diseases are characterized by progressive neuronal dysfunction with consecutive neuronal loss of specific populations of neurons that frequently involve distinct anatomically related systems. Thus, selective neuronal vulnerability is a characteristic feature of neurodegenerative diseases. It should be emphasized that diseases with known vascular, toxic, metabolic, infectious, or immunologically determined causes are by definition not classified as (primary) neurodegenerative diseases. The clinical presentation of neurodegenerative diseases depends on the system or region affected by the disease rather than on the molecular nature of the characteristic neuropathological lesion per se; e.g. severe neuronal loss in the substantia nigra will clinically present as parkinsonism irrespective of the associated neuropathological lesion that potentially could be aggregates of α‎-synuclein (Lewy bodies), hyperphosphorylated tau (neurofibrillary tangles), cerebrovascular lesions, or other pathologies. Admittedly, the most likely neuropathological lesion associated with clinical parkinsonism is α‎-synuclein deposition in the substantia nigra, in which case the neuropathological diagnosis would be Lewy body disease with brainstem preponderance, i.e. Parkinson’s disease (Dickson et al., 2009; Jellinger, 2011c). On the other hand, in patients with advanced Alzheimer’s disease (AD) the substantia nigra is often affected by tau pathology, resulting in clinical parkinsonism (Attems et al., 2007), and vascular lesions in the substantia nigra are well recognized as causing vascular parkinsonism, which is a rare form of parkinsonism (Jellinger, 2008).

What are the causes and mechanisms of neuronal dysfunction and cell death in neurodegeneration? Apoptosis or ‘programmed cell death’ is an attractive mechanism to explain selective neuronal vulnerability (Dickson, 2011), while the term necrosis refers to the morphological changes that take place in a living organism in response to a noxious stimulus that causes cell death. In the central nervous system (CNS), necrosis is commonly observed after trauma, infection, and infarction, conditions that by definition do not fall into the category of neurodegeneration.

Apoptosis, on the other hand, is regulated by extrinsic (receptor- mediated) or intrinsic (mitochondria-mediated) pathways that via the activation of caspases lead to degradation of both DNA and cytoskeletal proteins (Wyllie, 1997). In several neurodegenerative diseases, damage resulting from reactive oxygen species has been identified as a major cytopathological feature, suggesting that oxidative stress plays an important role in neurodegeneration (Sayre et al., 2001). Cells that fail to compensate for oxidative stress enter apoptosis (Perry et al., 1998). However, apoptosis leads to cell death within hours, while neurodegenerative diseases typically have a course of years, suggesting increased compensatory cellular response in neurodegeneration in living organisms. In addition, failure in the maintenance of mitochondria has been suggested to play a role in neurodegeneration (for review see Karbowski and Neutzner, 2012).

While the respective roles of apoptosis, oxidative stress, and mitochondria in neurodegeneration remain unclear, aggregation of misfolded proteins (that might be neurotoxic) is a well described and unifying feature of neurodegeneration. Various proteins (e.g. amyloid-β‎, tau) lose their native structure and form fibrils rich in β‎-sheets that accumulate intra- or extracellularly (for review see Jellinger, 2010, 2012a). Indeed, the nature of the respective misfolded protein in conjunction with the topographical localization of the affected regions is the basis for the classification of neurodegenerative diseases (Table 6.1).

Table 6.1 Major protein aggregates in neurodegenerative diseases

Disease

Protein aggregate

Characteristic form

Localization

Alzheimer’s disease

Tau (3R, 4R)

NFT, NT

Neuronal cell bodies (NFT) and processes (NT)

Aβ‎ (1–40, 1–42)

Aβ‎-plaque

Extracellular

Aβ‎ (1–40, 1–42) and tau (3R, 4R)

Neuritic plaque

Aβ‎, extracellular; tau, neuronal processes

Lewy body diseases

Parkinson’s disease

α‎-Synuclein

LB, LN

Neuronal cell bodies (LB) and processes (LN)

Dementia with Lewy bodies

α‎-Synuclein

LB, LN

Neuronal cell bodies (LB) and processes (LN)

Multiple system atrophy

α‎-Synuclein

GCI

Cytoplasm of glial cells

Frontotemporal lobar degeneration

Pick’s disease

Tau (3R)

Pick bodies

Neuronal cell bodies

Corticobasal degeneration

Tau (4R)

Astrocytic plaque

Distal segments of astrocytes

Progressive supranuclear palsy

Tau (4R)

Globose NFT

Neuronal cell body

Tau (4R)

Tufted astrocyte

Astrocytic cell body

Agyrophilic grain disease

Tau (4R)

Grains

Neuronal processes (dendrites)

Neurofibrillary tangle dominant dementia

Tau (3R, 4R)

NFT, NT

Neuronal cell bodies (NFT) and processes (NT)

FTLD-TDP

TDP-43

NCI (NII)

Neuronal cytoplasm (and nuclei)

FTLD-UPS

Ubiquitin

NCI (NII)

Neuronal cytoplasm (and nuclei)

FTLD-FUS

FUS protein

NCI (NII)

Neuronal cytoplasm (and nuclei)

FTLD-ni

None known

NA

NA

3R, 3 repeat tau; 4R, 4 repeat tau; FTLD, frontotemporal lobar degeneration (for various forms of FTLD see main text); GCI, glial cytoplasmic inclusions; LB, Lewy body; LN, Lewy neurite; NA, not applicable; NCI, neuronal cytoplasmic inclusion; NFT, neurofibrillary tangle; NII, neuronal intanuclear inclusions; NT, neuropil thread.

Despite considerable advances in our understanding of some patho-mechanisms that ultimately lead to sporadic age-associated neurodegeneration, the exact causes for protein accumulation await further elucidation and are likely to be multifactorial. However, in hereditary neurodegenerative diseases the mechanisms that cause accumulation of misfolded proteins are in most cases reasonably well understood, thereby providing helpful information to further our understanding of patho-mechanisms in sporadic neurodegeneration; e.g. in trisomy 21 (Down syndrome) an increased expression of the amyloid precursor protein (APP) that is encoded on chromosome 21 leads to increased production of amyloid-β‎ (Aβ‎) with consecutive formation of Aβ‎ plaques. However, another possibility for increased production of amyloid-β‎ in both sporadic and hereditary (e.g. mutations in presenilin genes 1 and 2) neurodegenerative diseases and ageing might be increased activity of β‎- and γ‎-secretase, which leads to the increased formation of amyloid-β‎ oligomers (for more details on amyloid processing see section Alzheimer’s disease).

On the other hand, a decrease in protein degradation /and/or elimination out of the brain may cause protein accumulation and aggregation; cellular protein degradation and clearance is mediated via both the ubiquitin-proteasome system (UPS; ubiquitin pathway) and the autophagy-lysosomal pathway (ALP). Failure of UPS and ALP might be caused by increasing amounts of proteins that overwhelm these systems /and/or malfunction of the systems themselves, both probably resulting in protein misfolding and aggregation. Similarly, reduced elimination out of the brain could lead to accumulation of the respective protein; the CNS is devoid of lymphatic vessels and solutes are partly transported out of the brain via drainage along the perivascular pathway, and impairment of the perivascular pathway has been suggested to result in Aβ‎ accumulation (Weller et al., 2009).

It is generally assumed that misfolded proteins exert neurotoxicity, but the underlying mechanisms are poorly understood. Misfolded proteins form soluble oligomers that aggregate into insoluble structures, and by using appropriate histochemical techniques and immunohistochemical antibodies these insoluble structures can be seen on microscopic examination. However, it is not clear if the soluble oligomers /and/or the insoluble microscopically visible aggregates are the neurotoxic species. This has important implications with respect to the interpretation of neuropathological findings regarding disease mechanisms, as neuropathology detects insoluble aggregated proteins but not the soluble oligomers. It has indeed been suggested that the formation of insoluble aggregates represents a protective mechanism, insofar as neurotoxic oligomers are ‘trapped’ in their aggregated form and thereby lose their neurotoxic property. Alternatively, the accumulation and aggregation of proteins might primarily be the result of synaptic /and/or cellular damage, rather than the cause for cell death.

In most age-associated neurodegenerative diseases the amount of pathology is crucial for the development of clinical symptoms. In particular, AD pathology is frequently present to a limited extent in brains of nondemented older people. It is therefore still a matter of discussion whether age-associated neurodegenerative diseases are a pure consequence of ageing rather than a distinct disease, or if age is an important risk factor but would not inevitably lead to the development of full-blown disease with overt clinical symptoms, even in individuals aged over 100 years.

Neurodegeneration per se usually does not lead to fatal brain lesions that would cause the death of a patient, but naturally can be considered as severe underlying disease that predisposes individuals to acquire potentially fatal diseases. Bronchopneumonia most frequently represents the immediate cause of death in AD (approximately 50%), while in patients with vascular dementia, cardiovascular disease has been shown to be the immediate cause of death in approximately 50% (Attems et al., 2005b).

Alzheimer’s Disease

AD is the most frequent neurodegenerative disease, accounting for 50–80% of dementias. Both prevalence and incidence increase with age; in 65- to 69-year-olds the prevalence is 1%, doubling with each subsequent 5-year increment. Above age 85 years prevalence rates range from 20% to 50%. Thereby, increasing age is the most important risk factor for AD (see Chapters 31 and 33 for details and other risk factors).

The neuropathological diagnosis of AD is based on the semiquantitative and topographical assessment of Aβ‎ plaques, neurofibrillary tangles/neuropil threads (NFT/NT), and neuritic plaques (NP). However, additional neuropathological lesions such as cerebral amyloid angiopathy (CAA) and granulovacuolar degeneration (GVD) are typically present, but the assessment of those lesions is not required for stating a neuropathological diagnosis, according to current diagnostic criteria. The loss of neurons (Gomez-Isla et al., 1996) and synapses (Terry et al., 1991) in AD has been shown to be more directly related to the severity of the cognitive deficit, but assessing neuronal and synaptic loss is technical and time consuming and it is currently not possible to evaluate those on a routine basis.

Neuropathology of AD

On gross examination, post-mortem brains of AD patients often appear relatively normal without striking pathological changes, and reduction in brain weight may be minimal. However, if present, the characteristic atrophy in AD involves the entorhinal cortex, hippocampus, amygdala, and olfactory bulb, as well as the inferior temporal, superior frontal, and middle frontal gyri (Halliday et al., 2003) (Fig. 6.1). In all of these areas, tau pathology predominates and atrophy in AD is not associated with the burden of Aβ‎ plaques (Josephs et al., 2008). Cerebral atrophy leads to enlargement of the ventricles (i.e. hydrocephalus internus e vacuo) and the cortical ribbon may be thin. The substantia nigra is well pigmented while the locus ceruleus might be pale and the cerebellum is normal.

Fig. 6.1Comparison between formalin-fixed brain slices of the left hemispheres (level of posterior hippocampus) of an aged nondemented individual (A) and an AD patient (B). Note the marked atrophy (thinning of the gyri and deepening of the sulci) in B, in particular hippocampal atrophy (arrow in B) with widening of the inferior horn of the second ventricle (asterisk in B). (Photographs by courtesy of Simon Fraser and Arthur Oakley.).

Fig. 6.1
Comparison between formalin-fixed brain slices of the left hemispheres (level of posterior hippocampus) of an aged nondemented individual (A) and an AD patient (B). Note the marked atrophy (thinning of the gyri and deepening of the sulci) in B, in particular hippocampal atrophy (arrow in B) with widening of the inferior horn of the second ventricle (asterisk in B). (Photographs by courtesy of Simon Fraser and Arthur Oakley.).

In AD, neuronal loss has been described, in particular in the nucleus basalis of Meynert, the amygdala, olfactory bulb with olfactory nucleus, locus ceruleus, and serotonergic raphe nuclei. Another important feature of AD is synaptic loss and there is strong evidence that synapses play a major pathophysiological role in AD (for review see Duyckaerts et al., 2009). Band-like spongiosis and reactive astrocytosis may be present in AD. Despite the fact that the aforementioned lesions are of pathophysiological importance for AD (neuronal and synaptic loss) or frequent findings (spongiosis), they are not used for neuropathological diagnostic purposes, which rely on the assessment of NFT/NT and Aβ‎ plaques including neuritic plaques.

Neurofibrillary tangles and neuropil threads

NFT and NT are aggregates of hyperphosphorylated microtubule- associated protein tau (MAP tau). MAP tau is particularly abundant in axons and its physiological function is primarily to stabilize microtubules. Six isoforms of MAP tau exist in the human brain and, based on the number of C terminal microtubule-binding repeat motifs, each 3 repeat (3R) and 4 repeat (4R) isoforms can be distinguished (for review see Mandelkow and Mandelkow, 2012). In a dephosphorylated state MAP tau binds to microtubules, while phosphorylation leads to detachment from microtubules. Under physiological conditions MAP tau is in a dynamic equilibrium, on and off the microtubules, but under pathological conditions (neurodegeneration) MAP tau is hyperphosphorylated, resulting in the disintegration of microtubules and aggregation of insoluble filaments/fibrils composed of hyperphosphorylated MAP tau (for review see Ballatore et al., 2007). NFT/NT are composed of aggregates of hyperphosphorylated MAP tau, while so-called pre-tangles represent nonaggregated hyper- or abnormally phosphorylated MAP tau and are considered to be precursors of NFT/NT. Importantly, the extent of NFT/NT in the neocortex has been shown to correlate with cognitive deficits (for review see Nelson et al., 2012).

Using appropriate immunohistochemical antibodies (e.g. AT8), both NFT and NT can be visualized for histological assessment (Fig. 6.2). Of note, in AD both 3R and 4R tau isoforms are present, while some tauopathies are characterized by the exclusive presence of either 3R or 4R tau (for details see section Frontotemporal lobar degenerations). NFT are located in neuronal cell bodies and NT in axons and dendrites, the latter appearing in immunohistochemically stained sections as immunopositive threads in the neuropil. It has been suggested recently that the amount of NT rather than NFT should be assessed for diagnostic purposes (Alafuzoff et al., 2008). NFT and NT are predominantly found in the hippocampus, the entorhinal cortex, and in layers III and VI of the isocortex. However, NFT and NT are also present in the olfactory bulb and subcortical nuclei, in particular the locus ceruleus, in early, preclinical stages of AD (Attems et al., 2005c, 2012; Braak et al., 2011).

Fig. 6.2 In AD, high amounts of neurofibrillary tangles and neuropil threads are seen in the hippocampus (A), among other regions (see main text). Arrows in B mark a neuronal cell body that comprises a neurofibrillary tangle, while ovals encircle some of the many neuropil threads in neuronal processes that are seen in this photomicrograph. CA1, CA2, and CA4 hippocampal cornu ammonis (Ammon’s horn) sectors 1, 2, and 3, respectively; GR, granule cell layer of the dentate gyrus. Immunohistochemistry with antibody against hyperphosphorylated tau AT8. Scale bars: A, 50 μ‎m; B, 10 μ‎m. (Modified from Montine et al., 2011.).

Fig. 6.2
In AD, high amounts of neurofibrillary tangles and neuropil threads are seen in the hippocampus (A), among other regions (see main text). Arrows in B mark a neuronal cell body that comprises a neurofibrillary tangle, while ovals encircle some of the many neuropil threads in neuronal processes that are seen in this photomicrograph. CA1, CA2, and CA4 hippocampal cornu ammonis (Ammon’s horn) sectors 1, 2, and 3, respectively; GR, granule cell layer of the dentate gyrus. Immunohistochemistry with antibody against hyperphosphorylated tau AT8. Scale bars: A, 50 μ‎m; B, 10 μ‎m. (Modified from Montine et al., 2011.).

It is generally assumed that in AD, NFT and NT primarily manifest in transentorhinal and entorhinal cortices and then gradually spread towards the hippocampus and isocortex (Braak and Braak, 1991), and this pattern is the basis for diagnostic Braak stages (see section Neuropathological diagnostic criteria for AD). However, recently pretangle material (i.e. hyperphosphorylated but nonaggregated tau) was found in the locus ceruleus in the majority of individuals under 30 years of age who were devoid of cortical tau pathology, suggesting that tau pathology begins in the locus ceruleus rather than the transentorhinal cortex (Braak and Del Tredici, 2011; Braak et al., 2011), but this is controversial (Attems et al., 2012).

Amyloid-β‎ plaques

Aβ‎ peptides (4 kDA) are generated by β‎- and γ‎-secretase cleavage of the transmembranous amyloid precursor protein (APP) and comprise peptides terminating at carboxyl terminus 40 (Aβ‎40) and 42 (Aβ‎42) (Glenner and Wong, 1984). Cerebral Aβ‎ depositions are a hallmark of AD, but in the majority of clinicopathological correlative studies, cerebral Aβ‎ load does not correlate with clinical dementia (Nelson et al., 2012). Nevertheless, most therapeutic approaches against AD target Aβ‎. This is mainly due to the so-called amyloid cascade hypothesis that postulates that an increase in Aβ‎ is the trigger for a series of events that ultimately lead to the formation of NFT/NT (Hardy and Higgins, 1992; Hardy and Selkoe, 2002). The observation that mutations in genes that lead to an increase in Aβ‎ (APP, presenilins) cause familial AD with tau pathology (NFT/NT), while mutations that lead to tau pathology cause familial tauopathies without Aβ‎, argue in favour of the ‘amyloid cascade hypothesis’. However, several observations suggest that the ‘amyloid hypothesis’ might not apply for sporadic, age-associated AD; in early stages of AD, Aβ‎ is mainly present in neocortical areas, while tau pathology is seen in the transentorhinal cortex, and a large autopsy study analyzing the prevalence of Aβ‎ and tau pathology as a function of age demonstrated that tau pathology precedes Aβ‎ (Duyckaerts and Hauw, 1997). Also, APP transgenic mice develop abundant Aβ‎ but no tau pathology (for review see Duyckaerts et al., 2009). However, the frequent co-occurrence of Aβ‎ and tau strongly suggests a mutual interaction that awaits further elucidation. Although both Aβ‎ and tau have been extensively studied with regard to their separate mode of toxicity (for review see Hardy, 2003), more recently light has been shed on their possible interactions and synergistic effects in AD, linking Aβ‎ and tau (Gotz et al., 2010; Ittner and Gotz, 2010).

While Aβ‎40 constitutes the majority of cerebral Aβ‎ (over 95%), Aβ‎42 is more aggregatable and hence believed to initiate the formation of oligomers, fibrils, and plaques (Naslund et al., 1994; Younkin, 1995; Masters and Beyreuther, 2011). Aβ‎ aggregates extracellularly and, using appropriate antibodies (e.g. 4G8 antibody), various morphological forms of Aβ‎ aggregates can be detected (Fig. 6.3). The main parenchymal Aβ‎ deposits are diffuse or focal. Diffuse Aβ‎ deposits are usually large (up to several 100 μ‎m) and show ill-defined borders; they are referred to as ‘lake-like’, ‘fleecy’, and ‘subpial band-like’. Aβ‎ plaques, on the other hand, are focal Aβ‎ deposits; ‘mature’, ‘classical’, and ‘neuritic’ plaques can be distinguished.

Fig. 6.3 Aβ‎ depositions in the neocortex (A–C) show different morphology: subpial band-like Aβ‎ (arrows in A1), fleecy Aβ‎ (arrowheads in B), and Aβ‎ plaques (C). Immunohistochemistry with Aβ‎ antibody 4G8. Scale bars: A, 500 μ‎m; B, 20 μ‎m; C, 50 μ‎m..

Fig. 6.3
Aβ‎ depositions in the neocortex (A–C) show different morphology: subpial band-like Aβ‎ (arrows in A1), fleecy Aβ‎ (arrowheads in B), and Aβ‎ plaques (C). Immunohistochemistry with Aβ‎ antibody 4G8. Scale bars: A, 500 μ‎m; B, 20 μ‎m; C, 50 μ‎m..

It should be emphasized that neuritic plaques contain—in addition to Aβ‎ aggregates—hyperphosphorylated tau in dystrophic neurites (Fig. 6.4). Neuritic plaques are strongly associated with AD, while other forms of parenchymal Aβ‎ deposits are frequently seen to a considerable extent in post-mortem brains of nondemented individuals (Jellinger and Attems, 2012) and, as mentioned above, their density does not correlate with clinical dementia (for review see Duyckaerts and Dickson, 2011). However, it has been suggested that Thal Aβ‎ phases 4 and 5 are correlated with clinical dementia (see section Neuropathological diagnostic criteria for AD).

Fig. 6.4 Neuritic plaques are a neuropathological hallmark lesion of AD and represent Aβ‎ plaques that contain tau in distended neuronal processes (i.e. dystrophic neurites). A–C are photomicrographs from adjacent histological sections. A, Gallyas silver stain visualizes both aggregated Aβ‎ and tau and is therefore ideal to detect neuritic plaques (ring in A1, neuritic plaque; arrow in A2, dystrophic neurite; arrowhead in A2, neurofibrillary tangle). On the other hand, the combined use of tau (B, antibody AT8) and Aβ‎ (C, antibody 4G8) immunohistochemistry on adjacent sections is also useful to detect neuritic plaques, as tau immunopositivity shows a plaquelike pattern (ring in B) and Aβ‎ immunostaining confirms the presence of Aβ‎ plaques (C). Scale bars: A, B, and C, 200 μ‎m..

Fig. 6.4
Neuritic plaques are a neuropathological hallmark lesion of AD and represent Aβ‎ plaques that contain tau in distended neuronal processes (i.e. dystrophic neurites). A–C are photomicrographs from adjacent histological sections. A, Gallyas silver stain visualizes both aggregated Aβ‎ and tau and is therefore ideal to detect neuritic plaques (ring in A1, neuritic plaque; arrow in A2, dystrophic neurite; arrowhead in A2, neurofibrillary tangle). On the other hand, the combined use of tau (B, antibody AT8) and Aβ‎ (C, antibody 4G8) immunohistochemistry on adjacent sections is also useful to detect neuritic plaques, as tau immunopositivity shows a plaquelike pattern (ring in B) and Aβ‎ immunostaining confirms the presence of Aβ‎ plaques (C). Scale bars: A, B, and C, 200 μ‎m..

Additional lesions in AD

Although the neuropathological diagnosis of AD solely relies on the assessment of both Aβ‎ and tau pathology, a variety of additional neuropathological lesions are usually present. Indeed, the presence of multiple pathologies in brains of elderly demented (and nondemented) individuals is not an exceptional finding and this is addressed in detail in the final section of this chapter on cerebral multimorbidity. However, there are some additional pathologies that are particularly frequent in AD; among those are cerebral amyloid angiopathy (CAA), cerebrovascular lesions, hippocampal sclerosis, and granulovacuolar degeneration (GVD) (for review see Duyckaerts and Dickson, 2011). Although GVD may be present in diseases other than AD, it is regarded as a primarily AD-related phenomenon and therefore described in the next section, while the other pathologies are described in their own respective sections.

Granulovacuolar degeneration

The term GVD describes vacuolar changes in the cytoplasm of neurons of the medial temporal lobe, in particular in pyramidal neurons of the hippocampus, often in association with NFT, but they have also been described in other regions (e.g. neocortex, amygdala). GVD has been reported to be more frequent in AD compared to controls and may be present in tauopathies (e.g. Pick’s disease, progressive supranuclear palsy). It has been demonstrated recently that GVD first develops in neurons of the CA1/CA2 hippocampal subfield and then expands in a predictable sequence into other brain regions, allowing for the distinction in five different stages (Thal et al., 2011). Importantly, these stages are related to AD pathology, pointing towards a role of GVD in AD pathogenesis.

Neuropathological diagnostic criteria for AD

With the progression of the disease, the major neuropathological lesions of AD progress stepwise, following a hierarchical pattern:

  1. 1. Braak neurofibrillary stages describe the progression of NFT/NT from the transentorhinal and entorhinal areas (stages I and II) to hippocampus (stage III), temporal cortex (stage IV) and finally other neocortical areas of which the occipital cortex (stages V and VI) is used for staging purposes (Braak and Braak, 1991; Braak et al., 2006).

  2. 2. Thal Aβ‎ phases describe the progression of parenchymal Aβ‎ depositions; in phase 1 the isocortex is involved, the hippocampus and entorhinal cortex in phase 2, striatum and diencephalic nuclei in phase 3, brainstem nuclei in phase 4, and finally the cerebellum and additional brainstem nuclei in phase 5; phases 4 and 5 are suggested to be correlated with clinical dementia (Thal et al., 2002b).

Several criteria for the neuropathological diagnosis of AD are in use:

  • Age-adjusted criteria of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) are based on the semiquantitative assessment of neuritic plaques (sparse, moderate, frequent) in middle frontal gyrus, superior/middle temporal gyri, and inferior parietal lobule (Mirra et al., 1991).

  • The National Institute of Aging Nancy and Ronald Reagan Institute Criteria (NIA-RI Criteria) give a probability that a clinical dementia has been caused by AD and are based on both CERAD criteria and Braak neurofibrillary stages: i.e. CERAD neg. and Braak neg., no probability; CERAD A and Braak I/II, low probability; CERAD B and Braak III/IV, medium probability; CERAD C and Braak V/VI, high probability (Hyman, 1998).

  • Recently, new NIA–Alzheimer’s Association guidelines that combine Thal Aβ‎ phases, Braak neurofibrillary stages, and CERAD criteria have been proposed (Hyman et al., 2012; Montine et al., 2012). According to these criteria, a neuropathological report should state the Aβ‎ plaque score (Thal et al., 2002b), Braak neurofibrillary stage (Braak and Braak, 1991, Braak et al., 2006), and CERAD neuritic plaque score (Mirra et al., 1993), which yield a combined ‘ABC score’. This ABC (Amyloid, Braak, CERAD) score should be stated regardless of clinical history, to reflect the amount of ‘Alzheimer Disease Neuropathologic Change’. Table 6.2 illustrates how each A, B, and C score is transformed to state the level of AD neuropathological change on a four-tiered scale: ‘Not, Low, Intermediate, and High’. The NIA-AA guidelines for the neuropathological assessment of AD await further validation.

Table 6.2 ABC criteria for the diagnosis of Alzheimer’s disease (AD)-related pathology. The level of AD neuropathological change is determined by assessing A, B, and C scores. A scores are related to Thal phase for Aβ‎-plaques (first column), B scores to neuritic Braak stages (bottom row), and C scores to Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) stages (last column)

Level of AD neuropathologic change

Thal phase

A

B

C

CERAD

for Aβ‎-plaques

0 or 1

2

3

0

0

Not

Not

Not

0

Neg

1 or 2

1

Low

Low

Low

0 or 1

Neg or A

1 or 2

1

Low

Intermediate

Intermediate

2 or 3

A or B

3

2

Low

Intermediate

Intermediate

any C

Neg or A to C

4 or 5

3

Low

Intermediate

Intermediate

0 or 1

Neg or A

4 or 5

3

Low

Intermediate

High

2 or 3

B or C

Braak 0–II

Braak III–IV

Braak V–VI

(Modified from Montine et al., 2011.)

Cerebral Amyloid Angiopathy

CAA is defined as the deposition of a congophilic material (i.e. positive staining with a Congo-red dye) in cerebral leptomeningeal and intracortical arteries, arterioles, capillaries, and, rarely, veins. CAA is also referred to as congophilic amyloid angiopathy (for review see Vinters, 1987; Attems et al., 2011a). CAA occurs in both hereditary or familial and sporadic forms. While the amyloid in sporadic, age-associated forms is predominantly composed of Aβ‎, the nature of amyloid depositions in hereditary forms is determined by the respective underlying mutation (e.g. A-Bri and cystatin C in BRI2 and cystatin C gene mutations, respectively). Sporadic CAA is frequently but not invariably present in AD and is often observed in older individuals without AD (Chui et al., 1992; Greenberg, 1998; Jellinger, 2002; Attems and Jellinger, 2004). CAA is considered a risk factor for nontraumatic intracerebral lobar haemorrhage (ICH) in the elderly and is present in 5–20% of all cases with ICH (Pezzini et al., 2009), but in large autopsy cohorts the prevalence of ICH in CAA cases was approximately 5%, being similar to cases without CAA (Attems et al., 2008). CAA may cause microbleeds (Greenberg et al., 2009) and in moderate to severe stages has been shown to be an independent risk factor for cognitive impairment (Matthews et al., 2009).

Histopathology of CAA

Aβ‎ is initially deposited in the outer parts of the vessel wall, but with increasing severity all layers of the vessel wall show Aβ‎ depositions accompanied by a loss of smooth muscle cells. In very severe stages of CAA the vascular architecture is disrupted, but endothelial cells are usually preserved (Fig. 6.5).

Fig. 6.5 Cerebral amyloid angiopathy (CAA) presents as Aβ‎ depositions in the walls of meningeal (arrows in A) and cortical (arrowheads in A) arteries, while capillary CAA refers to Aβ‎ depositions in the walls of capillaries (arrowheads in B). CAA may be the cause for nontraumatic intracerebral haemorrhage (ICH). Photomicrograph C shows an ICH (left upper part) in a patient with CAA; insets in C show photomicrographs of sections of the same block stained with anti-Aβ‎ antibody 4G8, demonstrating CAA in regions adjacent to the ICH, thereby suggesting that CAA might have been the cause for ICH in this case. A and B and insets in C, 4G8 immunohistochemistry; C, H/E. Scale bars: A and C, 500 μ‎m; B, 50 μ‎m..

Fig. 6.5
Cerebral amyloid angiopathy (CAA) presents as Aβ‎ depositions in the walls of meningeal (arrows in A) and cortical (arrowheads in A) arteries, while capillary CAA refers to Aβ‎ depositions in the walls of capillaries (arrowheads in B). CAA may be the cause for nontraumatic intracerebral haemorrhage (ICH). Photomicrograph C shows an ICH (left upper part) in a patient with CAA; insets in C show photomicrographs of sections of the same block stained with anti-Aβ‎ antibody 4G8, demonstrating CAA in regions adjacent to the ICH, thereby suggesting that CAA might have been the cause for ICH in this case. A and B and insets in C, 4G8 immunohistochemistry; C, H/E. Scale bars: A and C, 500 μ‎m; B, 50 μ‎m..

CAA may frequently show a patchy distribution and primarily affects leptomeningeal and cortical vessels of neocortical regions (Thal et al., 2003). The occipital lobe has been reported to be the site that is both most frequently and severely affected by CAA, followed by either frontal, temporal, or parietal lobes (Tomonaga, 1981; Vinters and Gilbert, 1983; Pfeifer et al., 2002; Attems et al., 2005a).

Aβ‎ depositions in the walls of capillaries are referred to as capillary CAA (capCAA) and usually present as strong staining lining capillary walls in sections stained with appropriate Aβ‎ antibodies. The presence of capCAA distinguishes two types of CAA: CAA-type 1 is characterized by the presence of capCAA and may show additional Aβ‎ depositions in noncapillary blood vessels, whereas in CAA-type 2, Aβ‎ depositions are restricted to leptomeningeal and cortical arteries, arterioles, and, rarely, veins without capillary involvement (Thal et al., 2002a). Of note, the frequency of the APOEε‎4-allele in CAA-type 1 is more that four times higher than in CAA-type 2 (Thal et al., 2002a). It has been shown recently that the presence of capCAA identifies a subtype of sporadic AD that is defined by characteristic neuropathological features and genotype-specific associations (Thal et al., 2010). Pericapillary Aβ‎ deposits are predominately composed of Aβ‎42 and are clustered in the glia limitans around capillaries and represent another type of capillary involvement (Attems et al., 2004, 2010).

As of today, no standardized neuropathological consensus criteria for the scoring of CAA have been established, but several methods have been published and are usually used to describe the severity of CAA in post-mortem brains (Vonsattel et al., 1991; Olichney et al., 1995; Thal et al., 2003; Attems et al., 2005a; Chalmers et al., 2009).

Hippocampal Sclerosis

Hippocampal sclerosis (HS) is defined as severe astrogliosis and neuronal loss in the CA1 region of the hippocampus, which neurons are particularly vulnerable to hypoxia, and in the subiculum. HS occurs in up to 26% of older individuals, frequently as an additional finding in AD, and is often accompanied by multiple small infarcts in other brain regions/and/or leucencephalopathy (Jellinger, 2007b). It has been shown that patients with HS are older than those without HS and had more coronary artery disease, suggesting that related occult hypoxic ischaemic episodes may represent pathogenic factors (Attems and Jellinger, 2006). On the other hand, transactivation-responsive (TAR) DNA-binding protein 43 (TDP-43) pathology was detected in up to 70% of cases with HS (Amador-Ortiz et al., 2007), and approximately 50% of frontotemporal lobar degeneration-TDP (see section FTLD with TDP-43 pathology) cases show HS. In a recent autopsy study, TDP-43 pathology was seen in 18% of cases with HS, and in 46% of cases with concomitantt AD pathology (Rauramaa et al., 2011). However, a causal link between HS and TDP-43 has not been demonstrated and their frequent co-occurence might rather reflect a mere coincidence of two relatively common pathologies (Davidson et al., 2011). It has been suggested that HS may incorporate different subtypes: HS with advanced age (HS-Aging), HS with seizures (HS-SZ), with tauopathies (HS-tau), with non-tauopathy frontotemporal dementia (HS-FTD), and with cerebrovascular diseases (HS-CVD) (Nelson et al., 2011).

Lewy Body Diseases

Lewy body diseases (LBD) comprise Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD) (McKeith et al., 2005). The characteristic neuropathological lesions of LBDs are Lewy bodies (LB) in neuronal somata and Lewy neurites (LN) in cell processes. LB and LN are composed of α‎-synuclein aggregates. α‎-Synuclein is a 140-amino acid residue protein that is a member of a family of proteins that include β‎- and γ‎-synucleins with unknown physiological function(s). α‎-Synuclein is a lipid binding protein (Goedert, 2001) located at presynaptic terminals in proximity to synaptic vesicles, and it has been suggested that its physiological function involves the modulation of synaptic transmission and neuronal plasticity (for review see Waxman and Giasson, 2009). In addition, α‎-synuclein might be a chaperone protein, an inhibitor of phospholipase D2, and an active participant in oxidative stress production, as well as being both neuroprotective and neurotoxic (for review see Spillantini, 2011). Under pathological conditions, phosphorylation of α‎-synuclein is enhanced (at Ser 129) and its aggregates are the main component of LB and LN that may in addition contain ubiquitin and α‎-B-crystallin, among others (for review see Jellinger, 2012c).

LB occur in two types (Fig. 6.6): (1) classical LB are spherical cytoplasmic inclusions 8–30 μ‎m in diameter with a hyaline eosinophilic core, concentric lamellar bands, and a narrow pale-stained halo that are predominantly seen in pigmented neurons of the substantia nigra, locus ceruleus, and dorsal motor nucleus of the vagus nerve; and (2) cortical LB are eosinophilic, rounded, angular, or reniform structures without a halo, which are seen in iso- and allocortical areas. Of note, while classical LB can be easily detected on routine H/E stained sections, cortical LB are not readily detected and immunohistochemistry for α‎-synuclein should be used to detect cortical LB and LN, the latter appearing as thin immunopositive threads in the neuropil (for review see Dickson et al., 2009; Jellinger, 2011c).

Fig. 6.6 Classical Lewy bodies in the substantia nigra (arrows in A and B) show a hyaline eosinophilic core and a narrow pale stained halo (B shows two Lewy bodies in one pigmented neuron). Degenerating pigmented neurons lose melanin (pigment incontinence) that may be incorporated by macrophages (C). On H/E sections, cortical Lewy bodies are rounded eosinophilic inclusions (D) in neuronal cell bodies that are readily detected with α‎-synuclein immunohistochemistry (E, arrowhead in E1) that also stains Lewy neurites as thread- and dot-like structures in the neuropil (E). A–D, H/E; E, α‎-synuclein immunohistochemistry. Scale bars: A, 50 μ‎m; B–D, 20 μ‎m; E, 200 μ‎m..

Fig. 6.6
Classical Lewy bodies in the substantia nigra (arrows in A and B) show a hyaline eosinophilic core and a narrow pale stained halo (B shows two Lewy bodies in one pigmented neuron). Degenerating pigmented neurons lose melanin (pigment incontinence) that may be incorporated by macrophages (C). On H/E sections, cortical Lewy bodies are rounded eosinophilic inclusions (D) in neuronal cell bodies that are readily detected with α‎-synuclein immunohistochemistry (E, arrowhead in E1) that also stains Lewy neurites as thread- and dot-like structures in the neuropil (E). A–D, H/E; E, α‎-synuclein immunohistochemistry. Scale bars: A, 50 μ‎m; B–D, 20 μ‎m; E, 200 μ‎m..

Parkinson’s disease

PD is one of the most frequent neurodegenerative movement disorders, with a mean age of onset between 55 and 65 years. The prevalence in the general population is estimated at 0.3%, but this increases with increasing age to 3% over 65 years. The four cardinal clinical features are Tremor at rest, Rigidity, Akinesia (or bradykinesia), and Postural instability (TRAP), often associated with gait disturbances and falls (Jankovic, 2008). However, PD can present with a variety of additional clinical features and various clinical subtypes have been described and the neuropathology underlying clinical variability in α‎-synucleinopathies (e.g., PD) has been reviewed recently (Halliday et al., 2011).

On macroscopic examination the most remarkable feature of PD is pallor of the substantia nigra and often the locus ceruleus. Histologically, abundant LB and LN are predominantly present in subcortical nuclei, e.g. substantia nigra, locus ceruleus, and dorsal motor nucleus of the vagal nerve. In particular, the substantia nigra pars compacta shows a severe depletion of pigmented/melanized (45–66%) and of dopaminergic (60–88%) neurons, particularly in an area projecting to the striatum (ventrolateral tier) (for review see Jellinger, 2011b, 2012b).

Dementia with Lewy bodies and Parkinson’s disease dementia

The distinction between DLB and PDD is primarily based on clinical data; in PDD the onset of extrapyramidal symptoms should precede dementia by 1 year. Neuropathologically a significantly more severe Aβ‎ plaque load in the striatum of DLB than in PDD patients has been observed (Jellinger and Attems, 2006; Halliday et al., 2011). However, on neuropathological post-mortem examination, clinical PDD might either present as DLB or as PD with an additional dementing disease such as AD, and consequently those latter cases are not strictly associated with DLB.

DLB is the second most common age-associated neurodegenerative dementia, accounting for up to 26% of dementias in specialized referral centres (for review see Ince, 2011). The clinical symptoms of DLB are dementia associated with core neuropsychiatric features of fluctuating cognitive function, visual hallucinations, and in up to 75% of cases mild parkinsonism (McKeith et al., 2005). For more detailed description of clinical findings in DLB, see Chapter 35.

Macroscopically, brains of DLB patients may appear normal or show diffuse cerebral atrophy that is indistinguishable from AD. The pigmentation of the substantia nigra varies from normal to pale and the locus ceruleus is usually depigmented. Histologically, DLB is characterized by abundant LB and LN in the neocortex, in particular the cingulate gyrus and the limbic system including the entorhinal cortex and hippocampus. Similar to AD, additional pathologies are usually present in DLB and those are discussed in the section Cerebral multimorbidity.

Neuropathological diagnostic criteria for Lewy body disease

Several neuropathological staging systems for LBD are in use:

  1. 1. Braak stages for α‎-synuclein-related pathology postulate that nuclei in the medulla oblongata (e.g. dorsal motor nucleus of the vagus nerve) become initially affected (stage 1) and pathology spreads gradually to the pons (locus ceruleus, stage 2), midbrain (substantia nigra, stage 3), entorhinal cortex and hippocampus (stage 4), and finally reaches the neocortex (stages 5 and 6) (Braak et al., 2003). Using this classification, PD would reach stage 3, while DLB should at least show stage 4.

  2. 2. The Newcastle–McKeith criteria for LBD (McKeith et al., 2005) distinguish between brainstem predominant (PD), limbic (transitional; DLB), and diffuse neocortical (DLB) types. These criteria differ from Braak stages insofar as they do not strictly postulate a stepwise progression of α‎-synuclein pathology from the medulla oblongata to pons, midbrain, limbic areas, and neocortex, and cases might show severe neocortical α‎-synuclein pathology with only minimal involvement of brainstem regions. Thereby this staging system questions the validity of the system proposed by Braak and colleagues (Braak et al., 2003).

  3. 3. Leverenz and colleagues (Leverenz et al., 2008) modified the Newcastle–McKeith criteria by adding an amygdala predominant type that may completely lack α‎-synuclein pathology in regions other than the amygdala. This amygdala predominant type frequently co-occurs with severe AD (e.g. in 24% of otherwise pure AD cases (Uchikado et al., 2006)).

Multiple System Atrophy

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized clinically by parkinsonism, cerebellar ataxia, autonomic dysfunction, and corticospinal signs. MSA primarily involves striatonigral and olivopontocerebellar structures (for review see Jellinger and Lantos, 2010; Holton et al., 2011). On macroscopic examination considerable atrophy of the cerebellum and pontine base is frequently observed and the atrophic putamen shows dark discoloration. The substantia nigra and locus ceruleus are depigmented. The characteristic neuropathological lesios of MSA are oligodendroglial α‎-synuclein cytoplasmic inclusions known as glial cytoplasmic inclusions (GCI or Papp-Lantos inclusions) that are associated with myelin depletion. α‎-Synuclein also accumulates in oligodendroglial nuclei as well as in the cytoplasm and nuclei of neurons (Fig. 6.7).

Fig. 6.7 In multiple system atrophy (MSA), aggregates of α‎-synuclein termed Papp-Lantos inclusions or glial cytoplasmic inclusions (arrows in B and C) are frequent in the oligodendroglia. Photomicrographs are taken from sections of the external capsule. A and B, α‎-synuclein immunohistochemistry; C, H/E. Scale bars: A, 500 μ‎m; B and C, 20 μ‎m..

Fig. 6.7
In multiple system atrophy (MSA), aggregates of α‎-synuclein termed Papp-Lantos inclusions or glial cytoplasmic inclusions (arrows in B and C) are frequent in the oligodendroglia. Photomicrographs are taken from sections of the external capsule. A and B, α‎-synuclein immunohistochemistry; C, H/E. Scale bars: A, 500 μ‎m; B and C, 20 μ‎m..

Frontotemporal Lobar Degenerations (Including Tauopathies)

Frontotemporal lobar degenerations (FTLD), the third or fourth most frequent cause of dementias, usually show a frontotemporal pronounced cerebral atrophy. Microscopically they are characterized by cellular inclusion bodies that are composed of tau or TDP-43 or a protein encoded by the fused in sarcoma gene (FUS) and/or ubiquitin or neurofilament and/or a basophilic substance (basophilic inclusion bodies). According to the predominant protein aggregates, the subtypes described in the following sections can be distinguished, but there are cases with overlapping pathology (Mackenzie et al., 2011; Goedert et al., 2012; Halliday et al., 2012; Seltman and Matthews, 2012). It should be mentioned that FTLD-tau are frequently listed in the group of tauopathies that additionally include diseases that are not characterized by atrophy of frontal /and/or temporal lesions, such as parkinsonism-dementia complex of Guam and postencephalic parkinsonism.

FTLD-tau

Pick’s disease (PiD)

Pick’s disease, although a well-known eponym, is a rare cause of frontotemporal dementia (less than 5% of cases), with behavioural abnormalities or with nonfluent progressive aphasia as the most common clinical presentation. Both sexes are equally affected, with an average age of onset at approximately 60 years and a disease duration of 8–10 years (for a review see Munoz et al., 2011). At post-mortem examination, the characteristic macroscopic feature is severe circumscribed atrophy of the frontal, temporal, and, sometimes, parietal lobes, while the motor and sensory cortices, posterior two-thirds of the superior temporal gyrus, and occipital cortex are preserved. The brainstem and cerebellum show no macroscopic abnormalities. Histologically the macroscopically atrophic areas as well as the deep grey matter and the brainstem, in particular monoaminergic nuclei, show neuronal loss and gliosis, which also affects atrophic subcortical white matter. Pick bodies—the neuropathological hallmark lesion of PiD—are large argyrophilic, neuronal, cytoplasmic, round inclusions predominately composed of 3R tau. Pick bodies are frequent in hippocampal pyramidal neurons of the CA1 sector, while CA2–4 and subiculum are less frequently involved. In other cortical areas, Pick bodies may occur less evenly distributed but in large clusters (Dickson, 2009; Munoz et al., 2011). Ballooned neurons, similar to the ones seen in corticobasal degeneration (CBD), may be present as well as tau immunoreactive glial lesions that, interestingly, are predominately composed of 4R tau (Zhukareva et al., 2002).

Corticobasal degeneration (CBD)

The clinical symptoms in CBD are highly variable, the most characteristic being the corticobasal syndrome with asymmetrical akinetic-rigid parkinsonism and cortical signs including apraxia, dystonia, and myoclonus. However, some autopsy series indicate that—although being characteristic—the corticobasal syndrome may not be the most common clinical presentation of CBD, as frontal-type dementia has been reported to be more frequent. No epidemiological data are available for the prevalence and incidence of CBD, but its incidence has been estimated to be less than 1 per 100,000 people per year. CBD is a disease of middle to late age with no gender predisposition and age being the only known risk factor (for a review see Dickson et al., 2011). Reflecting the broad spectrum of possible clinical presentations, the neuropathological findings in CBD are highly variable. However, the classical presentation shows asymmetrical atrophy of cortical gyri that is most marked in superior frontal and parietal parasagittal regions. Among other macroscopic features, a red-brown discoloration may be seen in the globus pallidus and the substantia nigra shows loss of neuromelanin pigment, while the locus ceruleus appears normal. The characteristic neuropathological finding of CBD is the accumulation of 4R tau in the neuropil and in astrocytes in the cortex, white matter, basal ganglia, thalamus, and brainstem. 4R tau may also be present in neurons, but the neuropathological hallmark lesion is the astrocytic plaque, which is not seen in other diseases (Dickson, 2009; Kouri et al., 2011). The astrocytic plaque represents 4R tau accumulation in distal segments of astrocytes, while the cell body is free of accumulation. This morphology is reminiscent of a neuritic plaque (ide nomen) but no Aβ‎ accumulation is present in astrocytic plaques. Astrocytic plaques predominately occur in the cortex, but can also be present in other regions such as the caudate and putamen. Swollen cortical neurons that are termed ballooned neurons are another neuropathological hallmark of CBD.

Progressive supranuclear palsy (PSP)

Symmetrical, akinetic-rigid parkinsonism with severe postural instability and supranuclear ophthalmoplegia are the typical clinical symptoms of progressive supranuclear palsy (PSP) (Steele–Richardson–Olszewski syndrome), but less frequent atypical presentations such as asymmetrical clinical syndromes (e.g. corticobasal syndrome) may be seen (Steele et al., 1964; Dickson et al., 2010). In the UK, the prevalence of PSP is estimated at approximately 5 per 100,000, with the mean age at onset ranging from 66– 69 years and in 44–61% of cases affecting females (Nath et al., 2001). The basal ganglia, subthalamic nucleus, and substantia nigra are primarily affected, and usually pathology in the cerebellar dentate nucleus is severe and associated with profound atrophy of the superior cerebellar peduncle (Dickson, 2009). The characteristic neuronal lesion is the globose NFT that is composed of 4R tau and occurs in brainstem nuclei and the nucleus basalis of Meynert, while in other regions NFTs may be flame-shaped. Immunohistochemistry for 4R tau also labels tuft-shaped astrocytes (tufted astrocytes) which are the most characteristic glial lesion in PSP (Yamada et al., 1992). In addition, 4R tau positive NT are seen in grey and white matter of both cortical and subcortical regions. The severity and distribution of tau pathology varies in the different subtypes of PSP (PSP, parkinsonism/PSP-P, Richardson’s syndrome, and atypical forms) (Dickson et al., 2011).

Argyrophilic grain disease

Argyrophilic grain disease (AGD) has a mean age of onset of approximately 80 years, with males and females affected equally. AGD is the most common sporadic tauopathy and is observed in up to 5% of late-onset dementia cases (Saito et al., 2002). However, AGD is a frequent finding in other neurodegenerative diseases and has been reported to be present in varying severity in up to 26% of AD cases (Fujino et al., 2005). Macroscopically the brain appears relatively normal with mild frontotemporal cortical atrophy, but severe atrophy of the ambient gyrus was described in late stages of the disease (Saito et al., 2002). In AGD, 4R tau aggregates occur in dendrites and present as comma- or grain-shaped structures in the neuropil of the medial temporal lobe, in particular in the hippocampus Ammon’s horn sector CA1 and prosubiculum (for review see Tolnay and Braak, 2011). In addition, 4R tau is present in oligodendroglia, referred to as coiled bodies, that may be present in other tauopathies but in AGD are a consistent finding in the white matter.

Neurofibrillary tangle dominant dementia

Neurofibrillary tangle dominant dementia (NFTD) is characterized by the presence of NFT/NT that contain both 3R and 4R tau, while Aβ‎ pathology is in 75% of cases completely absent or present to a very limited degree. Importantly, in NFTD, tau pathology is mostly confined to allocortical regions, corresponding to neurofibrillary Braak stage III, and rarely mild isocortical involvement is seen. NFTD accounts for 5 to 7% of late-onset dementias and differs from AD by later onset (80 years), shorter duration (5 years), less severe cognitive impairment, and the almost absence of APOEε‎4 genotype (Jellinger and Attems, 2007a). Recent studies showed absence of soluble Aβ‎ with the tau gene MAPT H1 haplotype, classifying it as a specific tauopathy independent of amyloid (Santa-Maria et al., 2012).

FTLD with TDP-43 pathology

FTLD with TDP-43 pathology (FTLD-TDP) may show any of the three major clinical variants of the frontotemporal dementia syndrome, including behavioural variant, progressive nonfluent aphasia, and semantic dementia (Cairns et al., 2007b). The clinical frontotemporal dementia syndrome accounts for 10–15% of all dementia cases, and some studies have shown that neuropathologically FTLD-TDP is present in 50% of cases with clinical frontotemporal dementia syndrome (Lipton et al., 2004; Neumann et al., 2006; Cairns et al., 2007b; Davidson et al., 2007). The mean age of onset of FTLD-TDP is approximately 60 years (33–89 years) with a mean disease duration of 8 years (2–18 years). Neuropathologically FTLD-TDPs are characterized by neuronal cytoplasmic inclusions (NCI) that consist of phosphorylated TDP-43. TDP-43 is involved in regulating transcription and alternative splicing (Buratti and Baralle, 2008), and physiologically TDP-43 is present in the nucleus but under pathological conditions such as FTLD-TDP is usually located in the cytoplasm (TDP-43 NCI in spinal motor neurons are a characteristic feature of amyotrophic lateral sclerosis). Macroscopically cerebral atrophy is variable, but frontal and temporal lobes are most frequently affected, sometimes with asymmetrical distribution. In addition to unspecific features of neurodegeneration, TDP-43 positive NCI and dystrophic neurites are usually seen in the frontotemporal neocortex and granule cell layer of the dentate gyrus (Cairns et al., 2007a) (Fig. 6.8). Neuronal intranuclear inclusions (NII) may also be present and, depending on the amount and distribution of NCI and DN as well as on the presence of NII, four neuropathological subtypes (types A, B, C, D) of FTLD-TDP have been described (Mackenzie et al., 2011).

Fig. 6.8 TDP-43 positive neuronal cytoplasmic inclusions (NCI, arrow in A1 and B) and thread-like structures (arrowhead in A1) are the characteristic neuropathological lesion for FTLD-TDP-43 and motor neuron disease (amyotrophic lateral sclerosis) but may be present as an unspecific feature in a variety of other diseases, including AD. Of note, under physiological conditions TDP-43 is present in neuronal nuclei (ring in B). Immunohistochemistry with antibody against (nonphosphorylated) TDP-43. Scale bars: A, 100 μ‎m; B, 20 μ‎m..

Fig. 6.8
TDP-43 positive neuronal cytoplasmic inclusions (NCI, arrow in A1 and B) and thread-like structures (arrowhead in A1) are the characteristic neuropathological lesion for FTLD-TDP-43 and motor neuron disease (amyotrophic lateral sclerosis) but may be present as an unspecific feature in a variety of other diseases, including AD. Of note, under physiological conditions TDP-43 is present in neuronal nuclei (ring in B). Immunohistochemistry with antibody against (nonphosphorylated) TDP-43. Scale bars: A, 100 μ‎m; B, 20 μ‎m..

FTLD-with ubiquitin positive inclusions (UPS)

Ubiquitin positive inclusions are the characteristic lesion of FTLD-UPS (ubiquitin-proteasome-system). It now appears that most cases of sporadic FTLD-UPS have FUS immunoreactive pathology, but the term FTLD-UPS is still appropriate for a familial form of FTLD, familial FTLD linked to chromosome 3 (FTD-3).

FTLD-FUS

FTLD-FUS are characterized by abnormal accumulation of the FUS protein as the most prominent pathology, and include atypical FTLD with ubiquinated inclusions (aFTLD-U), neuronal intermediate filament inclusion disease (NIFID), and basophilic inclusion body disease (BIBD) (Mackenzie et al., 2010). A more detailed description of FTLD-FUS is beyond the scope of this chapter (for comprehensive review see Cairns, 2011; Neumann and Mackenzie, 2011).

FTLD with no inclusions

The term FTLD-no inclusions (FTLD-ni) is used for FTLD cases that lack any histochemically and immunohistochemically detectable inclusions but otherwise show clinical features of dementia and nonspecific neuropathological changes (e.g. atrophy, neuronal loss). This type has previously been referred to as ‘dementia lacking distinctive histopathology’ (DLDH), but it is suggested that FTLD-ni replaces the term DLDH, as the latter suggest that pathological lesions are completely absent (Mackenzie et al., 2009).

Huntington’s Disease (HD)

Huntington’s disease is an autosomal dominant hereditary disease. HD belongs to the family of trinucleotide repeat diseases that are caused by expansions of pre-existing tandem repeat sequences with each of the diseases (e.g. myotonic dystrophy type 2, spinocerebellar ataxia) affecting different genes (for review see Clark, 2011). The gene for HD (huntingtin or HTT) is located on the short arm of chromosome 4 (4p16.3) and the mutation consists of an expanded repetition of the cytosine-adenine-guanine (CAG) trinucleotide (The Huntington’s Disease Collaborative Research Group, 1993). HD equally affects men and woman, age at diagnosis is on average 40 years, and the symptomatic prevalence ranges from 5–10 per 100,000 (Hedreen and Roos, 2011). The prodromal period of HD, which may be present for many years before diagnosis, is characterized by motor abnormalities (subtle involuntary movements and oculomotor dysfunction), while the typical symptoms of the disease include chorea and mental dysfunction, leading to dementia (Shoulson and Young, 2011). The brain in end-stage HD shows severe reduction in weight (900–1,000 g) mainly due to profound atrophy of the caudate nucleus and putamen, but the cerebral cortex, hippocampus, thalamus, and white matter are also affected (Shoulson and Young, 2011). Microscopically the basal ganglia show severe neuronal loss and gliosis, and on microscopic examination huntingtin or ubiquitin positive protein accumulations are frequently seen in cellular processes (neurites) and, to a lesser degree, as nuclear inclusion bodies (Hedreen and Roos, 2011; Shoulson and Young, 2011).

Prion Diseases

Prion diseases that are also known as transmissible spongiform encephalopathies (TSEs) are caused by a potentially infectious agens and thereby differ from other neurodegenerative diseases. The infectious agens is the prion protein that essentially consists of PrPSc which presents as aggregates of an abnormally folded β‎-sheet-rich isoform of a normal cellular protein, of largely unknown function (possible role in myelin maintenance), termed PrPC (for review see Aguzzi and Heikenwalder, 2006). Prion diseases occur in humans and animals. Human prion diseases encompass sporadic (sporadic Creutzfeldt–Jakob disease (sCJD) and fatal sporadic insomnia), inherited (familial CJD, Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia), and infectious forms (iatrogenic CJD, variant CJD (vCJD) and Kuru) (Parchi et al., 2011). Of note, as vCJD predominantly occurred in the UK, the country with the highest incidence of bovine spongiform encephalopathy (BSE, a bovine prion disease), the exposure to prion proteins due to past consumption has been suggested to cause vCJD in humans (Will et al., 1996). It is assumed that PrPSc is capable of inducing conformational conversion of PrPC into PrPSc, thereby leading to a spread of aggregated PrPSc in the CNS.

The most common form of prion disease in humans is sCJD, accounting for 85% of all CJD. No cause for sCJD has been identified and the typical clinical picture is rapidly progressive dementia with ataxia and myoclonus. The incidence of sCJD is between 1 and 2 cases per million per year and the mean age of onset is 65 years (for a review see Budka et al., 2011). On macroscopic examination the brain may appear normal but usually some degree of atrophy is present. Histologically sCJD is characterized by a triad of spongiform change, neuronal loss, and astrocytic as well as microglial gliosis. Spongiform change presents as diffuse or focal small round or oval vacuoles in the cerebral cortex (whole thickness or deep layers), subcortical grey matter (almost constantly in the head of the caudate nucleus), and cerebellar molecular layer. In addition, PrP immunohistochemistry should be used to confirm the diagnosis (Budka et al., 2011). A consensus classification of human prion disease subtypes allows reliable identification of molecular subtypes (Parchi et al., 2012).

Vascular Dementia (VaD)

Vascular dementia or vascular cognitive impairment (O’Brien et al., 2003) can be defined as acquired cognitive impairment caused by cerebrovascular disease. Due to the high variability of morphological findings and multifactorial pathogenesis of VaD, no generally accepted morphologic scheme for staging cerebrovascular lesions and no validated neuropathological criteria for VaD have been established to date (for review see Jellinger, 2007b, 2008). Therefore many aspects of VaD, such as prevalence, morphology, and pathogenesis, are a matter of ongoing discussions. VaD has, however, been suggested to be the cause for dementia in approximately 10% of cases. Clearly, cerebrovascular lesions can cause neuronal loss and—depending on the topographical localization—this process may lead to dementia.

The morphological substrates for VaD are extensive and only a brief and incomplete description can be provided here (for comprehensive reviews see Jellinger, 2007b; Grinberg and Thal, 2010).

Two types of vessel disorders can potentially cause VaD:

  1. 1. Atherosclerosis is a very common vessel disorder in the older person, frequently affecting large to medium sized arteries of the entire cardiovascular system. In the cranium it often affects the circle of Willis, and an important extracranial site—with respect to the development of cerebrovascular lesions—is the carotid arteries, in particular at the level of the carotid bifurcation. Atherosclerosis is initiated by thickening of the tunica intima (i.e. the innermost layer of a blood vessel), with subsequent accumulation of blood-derived lipids. This process is followed by splitting of the internal elastic lamina and finally cholesterol accumulation leads to the manifestation of atherosclerotic plaques that can calcify. Atherosclerosis causes narrowing of the arteries’ lumina, thereby reducing the blood supply for the supported region, but this is frequently compensated by a shift in blood flow towards collateral arteries (e.g. vertebral arteries for internal carotid arteries). On the other hand, rupture of atherosclerotic plaques often leads to thrombosis that results in either occlusion of the lumen or thromboembolism. Depending on the size of the embolus, thromboembolism may cause lesions that range from ‘silent infarcts’ to large cerebral infarcts with overt clinical symptoms.

  2. 2. Small vessel disease refers to pathological changes that affect small arteries and arterioles (Fig. 6.9). Small arteries may show morphological changes that are similar to atherosclerotic changes (i.e. microatheroma) and are termed ‘small vessel arteriosclerosis/atherosclerosis’. ‘Lipohyalinosis’ is used for asymmetric fibrosis/hyalinosis, while concentric hyaline thickening with lumen stenosis is termed ‘arteriosclerosis’. The latter is particularly common in the white matter and the main cause for white- and deep grey matter lesions, respectively.

Fig. 6.9 Small vessel disease is a frequent cause of white matter (WM) lesions. (A) Normal vessel and white matter; note the slight perivascular space that is regarded as an artifact; (B) mildly enlarged perivascular spaces; (C) considerable enlargement of the perivascular space accompanied by moderate demyelination of the WM (pallor in myelin staining); (D) severe WM lesions with enlarged perivascular spaces, WM pallor, and tissue loss; (E) normal artery; (F) artery with mild fibrosis; (G) artery with moderate fibrosis; (H) severe arteriolar fibrosis with acellular concentric thickening of the vessel wall (usually associated with hypertension). A–D, Luxol Fast Blue histochemistry (myelin stain); E–H, H/E. Scale bars: A and G, 50 μ‎m; B, C, D, and H, 100 μ‎m; E and F, 20 μ‎m. (Photomicrographs by courtesy of Kirsty McAleese.).

Fig. 6.9
Small vessel disease is a frequent cause of white matter (WM) lesions. (A) Normal vessel and white matter; note the slight perivascular space that is regarded as an artifact; (B) mildly enlarged perivascular spaces; (C) considerable enlargement of the perivascular space accompanied by moderate demyelination of the WM (pallor in myelin staining); (D) severe WM lesions with enlarged perivascular spaces, WM pallor, and tissue loss; (E) normal artery; (F) artery with mild fibrosis; (G) artery with moderate fibrosis; (H) severe arteriolar fibrosis with acellular concentric thickening of the vessel wall (usually associated with hypertension). A–D, Luxol Fast Blue histochemistry (myelin stain); E–H, H/E. Scale bars: A and G, 50 μ‎m; B, C, D, and H, 100 μ‎m; E and F, 20 μ‎m. (Photomicrographs by courtesy of Kirsty McAleese.).

White matter lesions (leukoaraiosis) are increasingly detected by modern neuroimaging methods (up to 60% in individuals over 60 years of age), frequently clinically asymptomatic, and in most cases related to small vessel disease of the white matter. The associated neuropathological findings include demyelination, axonal loss, and lacunar infarcts (usually small), most frequently in the frontal, parietal, and occipital white matter (Schmidt et al., 2011). Using special stains (e.g. Luxol Fast Blue), demyelination is indicated by a pallor in staining intensity and arterioles in these areas may show concentric thickening of the vessel wall and perivascular spaces that are filled with macrophages (of note, small perivascular spaces alone are not an indicator of small vessel disease but are an artifact caused by tissue processing; Fig. 6.9). Lacunes are cavities measuring 5–10 mm in diameter that are caused by either old (lacunar) infarcts or less frequently haemorrhages. In addition to the white matter, they occur in the basal ganglia (deep grey matter lesions) and, if severe, are the morphologic substrate of the so-called status lacunaris or état criblé.

Ischaemic brain infarcts are caused by insufficient blood supply frequently due to thromboembolism. After 6–12 h the neurons show signs of acute ischaemic cell injury (e.g. eosinophilic cytoplasm and shrunken nucleus) and between 24 and 48 h neutrophils appear that are replaced by macrophages after 48 h. Ten days after the infarction, the area is liquefied, resulting in the formation of a cavity (third week) that becomes intersected by vascular and connective tissue strand and surrounded by gliosis (scarring, Fig. 6.10). Haemorrhagic brain infarcts are characterized by secondary blood influx into the infarcted territory and microinfarcts refer to infarcts below 5 mm in diameter (for lacunar infarcts see above).

Fig. 6.10Old cystic infarct in the right frontal lobe in the territory of the middle cerebral artery (A; B, frontal plane). Scale bars: A, 50 mm; B, 20 mm..

Fig. 6.10
Old cystic infarct in the right frontal lobe in the territory of the middle cerebral artery (A; B, frontal plane). Scale bars: A, 50 mm; B, 20 mm..

Cerebral haemorrhages are larger than 10 mm in diameter. Causes for nontraumatic intracerebral haemorrhage include aneurysms of cerebral arteries, coagulation disorders, atherosclerosis, hypertension with small vessel disease, and CAA. Recently, cerebral microbleeds have gained wider attention as MRI detects small signal voids, indicating perivascular accumulation of haemosiderin/haemosiderin-laden macrophages that are presumed to reflect old cerebral microbleeds. Cerebral microbleeds are associated with CAA and, according to MRI studies, frequent in older people (e.g. 23.5% in Vernooij et al., 2008). However, microbleeds are rarely seen at neuropathological post-mortem examination and their true incidence is therefore controversial.

It is beyond the scope of this chapter to provide a comprehensive review of the many possible ways to classify cerebrovascular pathology and several articles are suggested for further reading (O’Brien et al., 2003; Kalaria et al., 2004; Jellinger, 2007b, 2008; Gorelick et al., 2011). As an example, a brief outline of the classification of VaD according to the underlying disease is now provided.

  1. 1. Large vessel disease: Atherosclerosis of extra- or intracranial arteries may cause thromboembolism or hypoperfusion that leads to single or multiple infarctions in the cerebral regions that receive blood supply by the respective artery. Cognitive impairment might result from tissue loss with a volume over 50 ml (Kalaria et al., 2004), or from smaller infarcts that are strategically placed affecting functionally important brain areas and neuronal circuits (‘strategic’ infarct dementia syndrome).

  2. 2. Small vessel disease: Small vessel disease affects small arteries and arterioles and includes arteriosclerosis/atherosclerosis, arteriolosclerosis, and lipohyalinosis (for review see Grinberg and Thal, 2010). Small vessel disease may cause ischaemic white matter damage and lacunar infarcts in the basal ganglia, both of which may present a morphological correlate for VaD.

  3. 3. Hypoxic damage: Hypoxic damage caused by cerebral hypoperfusion may lead to ischaemic-anoxic damage and hippocampal sclerosis (see section Hippocampal sclerosis).

Cerebral multimorbidity

It is becoming increasingly clear that the ageing brain is characterized by the presence of multiple pathologies rather than the characteristic neuropathological lesions of one single neurodegenerative disease only. Of particular importance is the frequent presence of confounding processes in the aged brain that coexist with AD, as, for example, cerebrovascular disease, LB pathology, AGD, TDP-43 pathology, and hippocampal sclerosis. Approximately two-thirds of aged human brains contain nonAD pathology (Nagy et al., 1997; Nelson et al., 2007; Schneider et al., 2007a; Davidson et al., 2011), which have, however, frequently been missed clinically and could not be identified without neuropathological examination using modern biochemical and molecular-biological analyses (for review see Jellinger, 2013).

A large autopsy study reported that 41.5% of clinically demented patients (n = 1,700, mean age 84.3 ± 6.0 years) fulfilled neuropathological criteria of pure AD, while AD with additional pathology was seen in 43.2%; 23.2% showed additional cerebrovascular pathology (e.g. infarcts, hippocampal sclerosis, lacunar state), 9.2% α‎-synuclein pathology, and 2.6% various other neuropathological lesions, while the remaining 15.3% did not show any AD pathology, including 10.7% of ‘pure’ vascular dementia and 5.5% other disorders (Jellinger and Attems, 2007b; Jellinger, 2011d).

Another large autopsy study across nine centres of the BrainNet Europe Consortium included neuropathological data of 3,303 cases (1,667, female; 1,636, male; mean age, 74.14 ± 12.07 years) that showed clinical dementia. Fifty three percent of cases showed mixed pathology, which was most frequently seen in LBD (PD, 92%; LBD, 61%), followed by cases with cerebrovascular pathology (65%), and AGD (61%), compared to AD (43%), PSP (22%), CBD (21%), FTLD (9%), and CJD (2%). The most frequent additional diagnoses in mixed cases was AD pathology in 89.6% (P 〈 0.01), followed by cerebrovascular pathology (52.6%), synucleinopathy (50%), and AGD (11.4%) (Kovacs et al., 2008).

The prevalence of mixed pathologies increases with age. In a consecutive autopsy series on 1,110 patients (64% female; mean age at death 83.3 ± 5.6 years, range 60–103 years, 90% over age 70), the prevalence of pure AD increased from 32.2% in the 7th decade to 45.1% in the 9th decade, while it decreased in the 10th decade to 39.2%. By contrast, the prevalence of AD with minor cerebrovascular lesions as well as mixed dementia (AD and vascular dementia) both increased from 7.8% and 0% in the 7th decade to 32.9% and 7.5% in the 10th decade, respectively (Jellinger and Attems, 2010b).

As already outlined neurodegenerative diseases are neuropathologically characterized by the presence of discrete lesions in a specific topographical pattern. However, data from many different autopsy studies point towards the presence of additional lesions in otherwise well-characterized cases, which fulfill the criteria for a single distinct disorder (Fig. 6.11):

Fig. 6.11Multiple pathologies in brains of older demented patients. Full arrows point towards the characteristic neuropathology of the respective disease, while dotted arrows point towards neuropathological lesions that are frequently seen in addition to the main pathological hallmark lesions. Approximate percentages are encircled. AD, Alzheimer’s disease; LBD, Lewy body diseases; FTLD-TDP, frontotemporal lobar degeneration with TDP-43 pathology; VaD, vascular dementia..

Fig. 6.11
Multiple pathologies in brains of older demented patients. Full arrows point towards the characteristic neuropathology of the respective disease, while dotted arrows point towards neuropathological lesions that are frequently seen in addition to the main pathological hallmark lesions. Approximate percentages are encircled. AD, Alzheimer’s disease; LBD, Lewy body diseases; FTLD-TDP, frontotemporal lobar degeneration with TDP-43 pathology; VaD, vascular dementia..

The high prevalence of multiple pathologies in brains of aged individuals could reflect the simultaneous presence of one single distinct neurodegenerative disease and age-related changes that are not directly associated with the primary neurodegenerative disease; e.g. the high prevalence of cerebrovascular lesions in AD brains of individuals aged 80+ probably mirrors the prevalence of age-associated vascular diseases in the aged per se, rather than suggesting causal relationships between AD and cerebrovascular lesions. The burdens of vascular and AD-type lesions are indeed considered to be independent of each other and are consistent with an additive (or even synergistic) effect of both types of lesions on cognitive impairment (Schneider et al., 2004; Jellinger and Attems, 2005; Jellinger, 2007a; Launer et al., 2008; Duyckaerts et al., 2009; Strozyk et al., 2010; Duyckaerts and Dickson, 2011). The thresholds for vascular and degenerative lesions in distinguishing ‘pure’ vascular dementia or AD from mixed cases have been critically discussed (Lee et al., 2000; Zekry et al., 2003; Gold et al., 2007). AD pathology alone more frequently accounts for dementia than both microscopic and macroscopic infarcts (Troncoso et al., 2008) and in advanced stages of AD concomitant small vascular lesions do not significantly influence the overall state and progression of cognitive decline; hence the severity and extent of AD pathology seems to overwhelm the effects of cerebrovascular disease (Lee et al., 2000; Bennett et al., 2005; Jellinger, 2007b, 2008). However, this does not preclude the possibility that cerebrovascular lesions exert an influence on AD pathology itself and it has been suggested that cerebrovascular lesions in AD lower the threshold for overt clinical dementia, i.e. less AD pathology is needed to cause clinical symptoms, if additional cerebrovascular pathology is present (Jellinger and Attems, 2003).

Another example of the simultaneous presence of a distinct neurodegenerative disease and age-associated change would be limited AD pathology (e.g. Braak stage III and Aβ‎-plaques) in DLB; here, AD pathology could be regarded as age-associated change that manifests independently of DLB. Similarly to the presumed impact of cerebrovascular lesions in AD, α‎-synuclein pathology in DLB might be aggravated by age-associated AD pathology.

In vitro studies demonstrated synergistic fibrillization of tau and α‎-syn (Giasson et al., 2003) and recent data from studies on transgenic (tg) mice indeed suggest a mutual interaction of Aβ‎, tau, and α‎-synuclein pathologies; Clinton and colleagues (Clinton et al., 2010) crossed 3xtg mice that develop both Aβ‎-plaques and tau pathology (Oddo et al., 2003) with mice that express the A53T mutation in α‎-synuclein (M83-h) (Giasson et al., 2002). At 12 months of age these so-called DLB-AD mice had significantly higher detergent soluble and insoluble Aβ‎40, detergent insoluble Aβ‎42, and insoluble tau levels than 3xtg mice, respectively. Moreover, detergent insoluble α‎-synuclein as well as detergent soluble α‎-synuclein phosphorylated at serine 129 levels were significantly higher in DLB-AD mice compared to M83-h mice. Taken together, these results suggest that Aβ‎, tau, and α‎-synuclein interact in vivo to promote the aggregation and accumulation of each other (Clinton et al., 2010).

Albeit directly comparable data on humans are not available, recent studies suggest similar interactions in human brains; e.g. in a study on PDD and PD cases, Compta and colleagues (Compta et al., 2011) found a significant correlation between Lewy body scores and NFT Braak stages. On the other hand, the considerable overlap between tau and α‎-synuclein pathologies could be explained by a mechanistic linkage between tauopathies and synucleinopathies; it has been suggested that reduced levels of proteasome 19S and 20S subunits facilitate abnormal deposition of both tau and α‎-synuclein (Wills et al., 2010; Jellinger, 2011a, 2012a).

Future Directions in Neuropathological Assessment

Currently, neuropathological assessment is based on semiquantitative scoring, usually on a four-tiered scale, e.g. 0, absent; 1, mild; 2, moderate; 3, severe. Frequently, the criteria for scoring one of those categories have been standardized, e.g. (Alafuzoff et al., 2008, 2009a, 2009b). While semiquantitative assessment allows for the statement of routine diagnoses, it provides only a rough estimation of the amount of pathology present. For example, we found that the area covered by immunopositivity for AT8 antibody (tau) in cases that were assigned the score ‘severe’ differs by nearly 100% between cases. In the 90+ study, a prospective longitudinal population-based study of ageing and dementia, the area covered by Aβ‎ immunopositivity in selected neocortical regions significantly correlated with the presence of clinical dementia (Robinson et al., 2011); of note, in most studies the extent of neocortical of Aβ‎ immunopositivity as assessed by semiquantitative scoring did not correlate with the presence of clinical dementia (for review see Duyckaerts et al., 2009). It is likely that new clinicopathological phenotypes could be identified by routinely assessing the amount of pathology in a more quantitative way. Indeed, in quantitatively assessing tau pathology in a large cohort (n = 889) of neuropathologically diagnosed AD cases, Murray and colleagues (Murray et al., 2011) recently found hippocampal sparing and limbic predominant subtypes of AD, that differed in clinical presentation, age at onset, disease duration, and rate of cognitive decline from typical AD. These data are confirmed in another large series of autopsy-confirmed AD cases where typical AD accounted for 82.5%, hippocampal-sparing and limbic-predominant forms for around 9% each (Jellinger, 2012d). Given that quantitative assessment of tau pathology alone in AD cases points towards new clinicopathological phenotypes, we believe that a more accurate, quantitative assessment of various neuropathological lesions is necessary to further elucidate possible mutual relationships between pathologies as well as their combined influence on the clinical picture. A deeper knowledge of underlying pathologies in age-associated neurodegeneration and cerebrovascular disorders is paramount to identify suitable targets for new therapeutic approaches.

Aguzzi, A. and Heikenwalder, M. (2006). Pathogenesis of prion diseases: current status and future outlook. Nature Reviews Microbiology, 4, 765–75.Find this resource:

Alafuzoff, I., et al. (2008). Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe Consortium. Brain Pathology, 18, 484–96.Find this resource:

Alafuzoff, I., et al. (2009a). Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium. Acta Neuropathologica, 117, 635–52.Find this resource:

Alafuzoff, I., et al. (2009b). Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathologica, 117, 309–20.Find this resource:

Amador-Ortiz, C., et al. (2007). TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Annals of Neurology, 61, 435–45.Find this resource:

Attems, J. and Jellinger, K.A. (2004). Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology — a pilot study. Acta Neuropathologica, 107, 83–90.Find this resource:

Attems, J. and Jellinger, K.A. (2006). Hippocampal sclerosis in Alzheimer disease and other dementias. Neurology, 66, 775.Find this resource:

Attems, J., Lintner, F., and Jellinger, K.A. (2004). Amyloid beta peptide 1–42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology. Acta Neuropathologica, 107, 283–91.Find this resource:

Attems, J., Jellinger, K.A., and Lintner, F. (2005a). Alzheimer’s disease pathology influences severity and topographical distribution of cerebral amyloid angiopathy. Acta Neuropathologica, 110, 222–31.Find this resource:

Attems, J., et al. (2005b). Cause of death in demented and non-demented elderly inpatients; an autopsy study of 308 cases. Journal of Alzheimer’s Disease, 8, 57–62.Find this resource:

Attems, J., Lintner, F., and Jellinger, K.A. (2005c). Olfactory involvement in aging and Alzheimer’s disease: an autopsy study. Journal of Alzheimer’s Disease, 7, 149–57.Find this resource:

Attems, J., Quass, M., and Jellinger, K.A. (2007). Tau and alpha-synuclein brainstem pathology in Alzheimer disease: relation with extrapyramidal signs. Acta Neuropathologica, 113, 53–62.Find this resource:

Attems, J., Lauda, F., and Jellinger, K.A. (2008). Unexpectedly low prevalence of intracerebral hemorrhages in sporadic cerebral amyloid angiopathy: an autopsy study. Journal of Neurology, 255, 70–6.Find this resource:

Attems, J., et al. (2010). Capillary CAA and perivascular Abeta-deposition: two distinct features of Alzheimer’s disease pathology. Journal of the Neurological Sciences, 299, 155–62.Find this resource:

Attems, J., et al. (2011). Review: s poradic cerebral amyloid angiopathy. Neuropathology and Applied Neurobiology, 37 (1), 75–93.Find this resource:

Attems, J., Thomas, A. and Jellinger, K. (2012). Correlations between cortical and subcortical tau pathology. Neuropathology and Applied Neurobiology, 38 (6), 582–90.Find this resource:

Ballatore, C., Lee, V.M., and Trojanowski, J.Q. (2007). Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nature Reviews Neuroscience, 8, 663–72.Find this resource:

Bennett, D. A., et al. (2005). Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology, 64, 834–41.Find this resource:

Braak, H. and Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica, 82, 239–59.Find this resource:

Braak, H. and Del Tredici, K. (2011). The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathologica, 121, 171–81.Find this resource:

Braak, H., et al. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 24, 197–211.Find this resource:

Braak, H., et al. (2006). Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathologica, 112, 389–404.Find this resource:

Braak, H., et al. (2011). Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. Journal of Neuropathology and Experimental Neurology, 70, 960–9.Find this resource:

Budka, H., et al. (2011). Sporadic Creutzfeldt-Jakob disease. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edn. Chichester: Wiley-Blackwell.Find this resource:

Buratti, E. and Baralle, F.E. (2008). Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Frontiers in Bioscience, 13, 867–78.Find this resource:

Cairns, N.J. (2011). Neuronal intermediate filament inclusion disease. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

Cairns, N.J., et al. (2007a). Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathologica, 114, 5–22.Find this resource:

Cairns, N.J., et al. (2007b). TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. American Journal of Pathology, 171, 227–40.Find this resource:

Chalmers, K., et al. (2009). Validation of international consensus criteria for the assessment of cerebral amyloid angiopathy in post-mortem brain. Proceedings of Sixth International Conference on Vascular Dementia, Barcelona.Find this resource:

    Chui, H.C. (2006). Vascular cognitive impairment: today and tomorrow. Alzheimer’s and Dementia, 2, 185–94.Find this resource:

    Chui, H.C., et al. (1992). Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer’s Disease Diagnostic and Treatment Centers. Neurology, 42, 473–80.Find this resource:

    Chui, H.C., et al. (2006). Cognitive impact of subcortical vascular and Alzheimer’s disease pathology. Annals of Neurology, 60, 677–87.Find this resource:

    Clark, H.B. (2011). Introduction to trinucleotide repeat disorders. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Clinton, L.K., et al. (2010). Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. Journal of Neuroscience, 30, 7281–9.Find this resource:

    Compta, Y., et al. (2011). Lewy- and Alzheimer-type pathologies in Parkinson’s disease dementia: which is more important? Brain, 134, 1493–505.Find this resource:

    Davidson, Y., et al. (2007). Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathologica, 113, 521–33.Find this resource:

    Davidson, Y.S., et al. (2011). TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s Syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathologica, 122, 703–13.Find this resource:

    Dickson, D.W. (2009). Neuropathology of non-Alzheimer degenerative disorders. International Journal of Clinical and Experimental Pathology, 3, 1– 23.Find this resource:

    Dickson, D.W. (2011). Introduction to neurodegeneration: the molecular pathology of dementia and movement disorders. In: Dickson, D.W. and Weller, R.O. (eds) Neurodeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Dickson, D.W., et al. (2009). Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurology, 8, 1150–7.Find this resource:

    Dickson DW, et al. (2010). Neuropathology of variants of progressive supranuclear palsy. Current Opinions in Neurology, 23, 394–400.Find this resource:

    Dickson, D.W., et al. (2011). Progressive supranuclear palsy and corticobasal degeneration. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Duyckaerts, C. and Dickson, D.W. (2011). Neuropathology of Alzheimer’s disease and its variants. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Duyckaerts, C. and Hauw, J.J. (1997). Prevalence, incidence and duration of Braak’s stages in the general population: can we know? Neurobiology of Aging, 18, 362–9 ; discussion 389 – 92.Find this resource:

    Duyckaerts, C., Delatour, B., and Potier, M.C. (2009). Classification and basic pathology of Alzheimer disease. Acta Neuropathologica, 118, 5–36.Find this resource:

    Fujino, Y., et al. (2005). Increased frequency of argyrophilic grain disease in Alzheimer disease with 4R tau-specific immunohistochemistry. Journal of Neuropathology and Experimental Neurology, 64, 209–14.Find this resource:

    Giasson, B.I., et al. (2002). Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron, 34, 521–33.Find this resource:

    Giasson, B.I., et al. (2003). Initiation and synergistic fibrillization of tau and alpha-synuclein. Science, 300, 636–40.Find this resource:

    Glenner, G.G. and Wong, C.W. (1984). Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochemistry and Biophysical Research Communications, 122, 1131–5.Find this resource:

    Goedert, M. (2001). Alpha-synuclein and neurodegenerative diseases. Nature Review Neuroscience, 2, 492–501.Find this resource:

    Goedert, M., et al. (2012). Frontotemporal dementia: implications for understanding Alzheimer disease. Cold Spring Harbor Perspectives in Medicine, 2, a006254.Find this resource:

    Gold, G., et al. (2007). Identification of Alzheimer and vascular lesion thresholds for mixed dementia. Brain, 130, 2830–6.Find this resource:

    Gomez-Isla, T., et al. (1996). Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. Journal of Neuroscience, 16, 4491–500.Find this resource:

    Gorelick, P.B., et al. (2011). Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 42, 2672–713.Find this resource:

    Gotz, J., et al. (2010). Dissecting toxicity of tau and beta-amyloid. Neurodegenerative Diseases, 7, 10–12.Find this resource:

    Greenberg, S.M. (1998). Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment. Neurology, 51, 690–4.Find this resource:

    Greenberg, S.M., et al. (2009). Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurology, 8, 165–74.Find this resource:

    Grinberg, L.T. and Thal, D.R. (2010). Vascular pathology in the aged human brain. Acta Neuropathologica, 119, 277–90.Find this resource:

    Halliday, G.M., et al. (2003). Identifying severely atrophic cortical subregions in Alzheimer’s disease. Neurobiology of Aging, 24, 797–806.Find this resource:

    Halliday, G.M., Song Y.J., and, Harding, A.J. (2011). Striatal beta-amyloid in dementia with Lewy bodies but not Parkinson’s disease. Journal of Neural Transmission, 118, 713–19.Find this resource:

    Halliday, G.M., et al. (2011). Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathologica, 122, 187–204.Find this resource:

    Halliday, G.M., et al. (2012). Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects. Acta Neuropathologica, 124, 373–82.Find this resource:

    Hardy, J. (2003). The relationship between amyloid and tau. Journal of Molecular Neuroscience, 20, 203–6.Find this resource:

    Hardy, J.A. and Higgins, G.A. (1992). Alzheimer’s disease: the amyloid cascade hypothesis. Science, 256, 184–5.Find this resource:

    Hardy, J. and Selkoe, D.J. (2002). The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science, 297, 353–6.Find this resource:

    Hedreen, J.C. and Roos, R.A.C. (2011). Huntington’s disease. In: Dickson, D.W., and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Holton, J.L., Lees, A.J., and Revesz, T. (2011). Multiple system atrophy. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Huntington’s Disease Collaborative Research Group. (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell, 72, 971–83.Find this resource:

    Hyman, B.T. (1998). New neuropathological criteria for Alzheimer disease. Archives of Neurology, 55, 1174–6.Find this resource:

    Hyman, B.T., et al. (2012). National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s and Dementia, 8, 1–13.Find this resource:

    Ince, P. (2011). Dementia with Lewy bodies and Parkinson’s disease dementia. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Ittner, L.M. and Gotz, J. (2010). Amyloid-beta and tau—a toxic pas de deux in Alzheimer’s disease. Nature Review Neuroscience, 12, 65–72.Find this resource:

    Jankovic, J. (2008). Parkinson’s disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery and Psychiatry, 79, 368–76.Find this resource:

    Jellinger, K.A. (2002). Alzheimer disease and cerebrovascular pathology: an update. Journal of Neural Transmission, 109, 813–36.Find this resource:

    Jellinger, K.A. (2007a). The enigma of mixed dementia. Alzheimer’s and Dementia: Journal of the Alzheimer’s Association, 3, 40–53.Find this resource:

    Jellinger, K.A. (2007b). The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathologica, 113, 349–88.Find this resource:

    Jellinger, K.A. (2008). The pathology of ‘vascular dementia’: a critical update. Journal of Alzheimer’s Disease, 14, 107–23.Find this resource:

    Jellinger, K.A. (2010). Basic mechanisms of neurodegeneration: a critical update. Journal of Cell Molecular Medicine, 14, 457–87.Find this resource:

    Jellinger, K.A. (2011a). Interaction between alpha-synuclein and tau in Parkinson’s disease comment on Wills et al.: elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson’s disease brains with and without dementia. Experimental Neurology 225, 210–18. Experimental Neurology, 227, 13–18.Find this resource:

    Jellinger, K.A. (2011b). Parkinson’s disease. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular patholgy of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

    Jellinger, K.A. (2011d). Criteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp? In: Braissant, O., et al. (eds) Recent Researches in Modern Medicine. Proceedings of the WSEAS International Conference, 23–25 Feb, Cambridge. WSEAS Press.Find this resource:

      Jellinger, K.A. (2012a). Interaction between pathogenic proteins in neurodegenerative disorders. Journal of Cellular Molecular Medicine, 16 (6), 1168–83.Find this resource:

      Jellinger, K.A. (2012b). Neuropathology of sporadic Parkinson’s disease: evaluation and changes of concepts. Movement Disorders, 27 (1), 8–30.Find this resource:

      Jellinger, K.A. (2012c). The role of α‎-synuclein in neurodegeneration—an update. Translational Neuroscience, 3, 75–122.Find this resource:

      Jellinger, K.A. (2012d). Neuropathological subtypes of Alzheimer’s disease (Correspondence). Acta Neuropathologica, 123, 153–4.Find this resource:

      Jellinger, K.A. (2013). Challenges in the neuropathological diagnosis of dementias. International Journal of Neuropathology, 1, 8–52.Find this resource:

        Jellinger, K.A. and Attems, J. (2003). Incidence of cerebrovascular lesions in Alzheimer’s disease: a postmortem study. Acta Neuropathologica, 105, 14–7.Find this resource:

        Jellinger, K.A. and Attems, J. (2005). Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease. Journal of Neurological Science, 229–230, 37–41.Find this resource:

        Jellinger, K.A. and Attems, J. (2006). Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies? Acta Neuropathologica, 112, 253–60.Find this resource:

        Jellinger, K.A. and Attems, J. (2007a). Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathologica, 113, 107–17.Find this resource:

        Jellinger, K.A. and Attems, J. (2007b). Neuropathological evaluation of mixed dementia. Journal of the Neurological Sciences, 257, 80–7.Find this resource:

        Jellinger, K.A. and Attems, J. (2008). Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathologica, 115, 427–36.Find this resource:

        Jellinger, K.A. and Attems, J. (2010a). Prevalence and pathology of vascular dementia in the oldest-old. Journal of Alzheimer’s Disease, 1283–1298.Find this resource:

        Jellinger, K.A. and Attems, J. (2010b). Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathologica, 119, 421–33.Find this resource:

        Jellinger, K.A. and Attems, J. (2012). Neuropathology and general autopsy findings in nondemented aged subjects. Clinical Neuropathology, 31, 87–98.Find this resource:

        Jellinger, K.A. and Lantos, P.L. (2010). Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update. Acta Neuropathologica, 119, 657–67.Find this resource:

        Josephs, K.A., et al. (2008). Beta-amyloid burden is not associated with rates of brain atrophy. Annals of Neurology, 63, 204–12.Find this resource:

        Josephs, K.A., et al. (2011). Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathologica, 122, 137–53.Find this resource:

        Kalaria, R.N., et al. (2004). Towards defining the neuropathological substrates of vascular dementia. Journal of Neurological Science, 226, 75–80.Find this resource:

        Karbowski, M. and Neutzner, A. (2012). Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathologica, 123 (2), 157–71.Find this resource:

        Kouri, N., et al. (2011). Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nature Reviews Neurology, 7, 263–72.Find this resource:

        Kovacs, G.G., et al. (2008). Mixed brain pathologies in dementia: the BrainNet Europe Consortium experience. Dementia and Geriatric Cognitive Disorders, 26, 343–50.Find this resource:

        Launer, L.J., et al. (2008). AD brain pathology: vascular origins? Results from the HAAS autopsy study. Neurobioloy of Aging, 29, 1587–90.Find this resource:

        Lee, J.H., et al. (2000). Small concomitant vascular lesions do not influence rates of cognitive decline in patients with Alzheimer disease. Archives of Neurology, 57, 1474–9.Find this resource:

        Leverenz, J.B., et al. (2008). Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient. Brain Pathology, 18, 220–4.Find this resource:

        Lipton, A.M., White, C.L., 3rd, and Bigio, E.H. (2004). Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathologica (Berlin), 108, 379–85.Find this resource:

        Mackenzie, I.R., et al. (2009). Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathologica, 117, 15–8.Find this resource:

        Mackenzie, I.R., et al. (2010). Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathologica, 119, 1–4.Find this resource:

        Mackenzie, I.R., et al. (2011). A harmonized classification system for FTLD-TDP pathology. Acta Neuropathologica, 122, 111–13.Find this resource:

        Mandelkow, E.M. and Mandelkow, E. (2012). Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harbor Perspectives in Medicine, 2, a006247.Find this resource:

        Masters, C.L. and Beyreuther, K. (2011). Amyloid-β‎ production. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

        Matthews, F.E., et al. (2009). Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Medicine, 6, e1000180.Find this resource:

        McKeith, I.G., et al. (2005). Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology, 65, 1863–72.Find this resource:

        Mirra, S.S., et al. (1991). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology, 41, 479–86.Find this resource:

        Mirra, S.S., Hart, M.N., and Terry, R.D. (1993). Making the diagnosis of Alzheimer’s disease. A primer for practicing pathologists. Archives of Pathology and Laboratory Medicine, 117, 132–44.Find this resource:

        Montine, T.J., et al. (2012). National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathologica, 123, 1–11.Find this resource:

        Munoz, G.D., Morris, H.R., and Rossor, M. (2011). Pick’s disease. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

        Murray, M.E., et al. (2011). Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurology, 10, 785–96.Find this resource:

        Nagy, Z., et al. (1997). The effects of additional pathology on the cognitive deficit in Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 56, 165–70.Find this resource:

        Naslund, J., et al. (1994). Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging. Proceedings of the National Academy of Science USA, 91, 8378–82.Find this resource:

        Nath, U., et al. (2001). The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK. Brain, 124, 1438–49.Find this resource:

        Nelson, P.T., et al. (2007). Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles ‘do count’ when staging disease severity. Journal of Neuropathology and Experimental Neurology, 66, 1136–46.Find this resource:

        Nelson, P.T., et al. (2011). Hippocampal sclerosis in advanced age: clinical and pathological features. Brain, 134, 1506–18.Find this resource:

        Nelson, P.T., et al. (2012). Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. Journal of Neuropathology and Experimental Neurology, 71, 362–81.Find this resource:

        Neumann, M. and Mackenzie, I.R.A. (2011). Frontotemporal lobar degeneration with FUS immunoreactive inclusions. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

        Neumann, M., et al. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science, 314, 130–3.Find this resource:

        O’Brien, J.T., et al. (2003). Vascular cognitive impairment. Lancet Neurology, 2, 89–98.Find this resource:

        Oddo, S., et al. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron, 39, 409–21.Find this resource:

        Olichney, J.M., et al. (1995). Cerebral infarction in Alzheimer’s disease is associated with severe amyloid angiopathy and hypertension. Archives of Neurology, 52, 702–8.Find this resource:

        Parchi, P., et al. (2011). Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathologica, 121, 91–112.Find this resource:

        Parchi, P., et al. (2012). Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathologica, 124, 517–29.Find this resource:

        Parkkinen, L., Pirttila, T., and Alafuzoff, I. (2008). Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathologica, 115, 399–407.Find this resource:

        Perry, G., et al. (1998). Apoptosis and Alzheimer’s disease. Science, 282, 1268–9.Find this resource:

        Petrovitch, H., et al. (2005). AD lesions and infarcts in demented and non-demented Japanese-American men. Annals of Neurology, 57, 98–103.Find this resource:

        Pezzini, A., et al. (2009). Cerebral amyloid angiopathy: a common cause of cerebral hemorrhage. Current Medicinal Chemistry, 16, 2498–513.Find this resource:

        Pfeifer, L.A., et al. (2002). Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study. Neurology, 58, 1629–34.Find this resource:

        Rauramaa, T., et al. (2011). TAR-DNA binding protein-43 and alterations in the hippocampus. Journal of Neural Transmission, 118, 683–9.Find this resource:

        Robinson, J.L., et al. (2011). Neocortical and hippocampal amyloid-beta and tau measures associate with dementia in the oldest-old. Brain, 134, 3705–12.Find this resource:

        Rohrer, J.D., et al. (2011a). The clinical and neuroanatomical phenotype of FUS associated frontotemporal lobar degeneration. Journal of Neurology, Neurosurgery and Psychiatry, 82, 1405–7.Find this resource:

        Rohrer, J.D., et al. (2011b). Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain, 134, 2565–81.Find this resource:

        Saito, Y. (2002). Severe involvement of ambient gyrus in dementia with grains. Journal of Neuropathology and Experimental Neurology, 61, 789–96.Find this resource:

        Santa-Maria, I., et al. (2012). The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathologica, 124, 693–704.Find this resource:

        Sayre, L.M., Smith, M.A., and Perry, G. (2001). Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Current Medicinal Chemistry, 8, 721–738.Find this resource:

        Schmidt, R., et al. (2011). Heterogeneity in age-related white matter changes. Acta Neuropathologica, 122, 171–85.Find this resource:

        Schneider, J.A., et al. (2004). Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology, 62, 1148–55.Find this resource:

        Schneider, J.A., et al. (2007a). Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology, 69, 2197–204.Find this resource:

        Schneider, J.A., et al. (2007b). Subcortical infarcts, Alzheimer’s disease pathology, and memory function in older persons. Annals of Neurology, 62, 59–66.Find this resource:

        Seltman, R.E. and Matthews, B.R. (2012). Frontotemporal lobar degeneration: epidemiology, pathology, diagnosis and management. CNS Drugs, 26, 841–70.Find this resource:

        Shoulson, I. and Young, A.B. (2011). Milestones in Huntington disease. Movement Disorders, 26, 1127–33.Find this resource:

        Spillantini, M.G. (2011). Introduction to α‎-sunucleinopathies. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

        Steele, J.C., Richardson, J.C., and Olszewski, J. (1964). Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Archives of Neurology, 10, 333–59.Find this resource:

        Strozyk, D., et al. (2010). Contribution of vascular pathology to the clinical expression of dementia. Neurobiology of Aging, 31, 1710–20.Find this resource:

        Terry, R.D., et al. (1991). Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Annals of Neurology, 30, 572–80.Find this resource:

        Thal, D.R., et al. (2002a). Two types of sporadic cerebral amyloid angiopathy. Journal of Neuropathological and Experimental Neurology, 61, 282–93.Find this resource:

        Thal, D.R., et al. (2002b). Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology, 58, 1791–800.Find this resource:

        Thal, D.R., et al. (2003). Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. Journal of Neuropathology and Experimental Neurology, 62, 1287–1301.Find this resource:

        Thal, D.R., et al. (2010). Capillary cerebral amyloid angiopathy identifies a distinct APOE epsilon4-associated subtype of sporadic Alzheimer’s disease. Acta Neuropathologica, 120, 169–83.Find this resource:

        Thal, D.R., et al. (2011). Stages of granulovacuolar degeneration: their relation to Alzheimer’s disease and chronic stress response. Acta Neuropathologica, 122, 577–89.Find this resource:

        Tolnay, M. and Braak, H. (2011). Argyrophilic grain disease. In: Dickson, D.W. and Weller, R.O. (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Chichester: Wiley-Blackwell.Find this resource:

        Tomonaga, M. (1981). Cerebral amyloid angiopathy in the elderly. Journal of the American Geriatrics Society, 29, 151–7.Find this resource:

        Troncoso, J.C., et al. (2008). Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Annals of Neurology, 64, 168–76.Find this resource:

        Uchikado, H., et al. (2006). Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. Journal of Neuropathology and Experimental Neurology, 65, 685–97.Find this resource:

        Vernooij, M.W., et al. (2008). Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology, 70, 1208–14.Find this resource:

        Vinters, H.V. (1987). Cerebral amyloid angiopathy. A critical review. Stroke, 18, 311–24.Find this resource:

        Vinters, H.V. and Gilbert, J.J. (1983). Cerebral amyloid angiopathy: incidence and complications in the aging brain. II. The distribution of amyloid vascular changes. Stroke, 14, 924–8.Find this resource:

        Vonsattel, J.P., et al. (1991). Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Annals of Neurology, 30, 637–49.Find this resource:

        Waxman, E.A. and Giasson, B.I. (2009). Molecular mechanisms of alpha-synuclein neurodegeneration. Biochimica Biophysica Acta, 1792, 616–24.Find this resource:

        Weller, R.O., et al. (2009). Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathologica, 117, 1–14.Find this resource:

        Will, R.G., et al. (1996). A new variant of Creutzfeldt-Jakob disease in the UK. Lancet, 347, 921–5.Find this resource:

        Wills, J., et al. (2010). Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson’s disease brains with and without dementia. Experimental Neurology, 225, 210–8.Find this resource:

        Wyllie, A.H. (1997). Apoptosis: an overview. British Medical Bulletin, 53, 451–465.Find this resource:

        Yamada, T., McGeer, P.L., and McGeer, E.G. (1992). Appearance of paired nucleated, tau-positive glia in patients with progressive supranuclear palsy brain tissue. Neuroscience Letters, 135, 99–102.Find this resource:

        Younkin, S.G. (1995). Evidence that A beta 42 is the real culprit in Alzheimer’s disease. Annals of Neurology, 37, 287–8.Find this resource:

        Zekry, D., et al. (2003). The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy. Neurobiology of Aging, 24, 213–9.Find this resource:

        Zhukareva, V., et al. (2002). Sporadic Pick’s disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter. Annals of Neurology, 51, 730–9.Find this resource: