Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are Lewy body-(LB) related neurodegenerative dementias affecting cognition, behaviour, movement and autonomic function. In terms of molecular pathology, they are both synucleinopathies, characterized by accumulation of misfolded α-synuclein protein in the form of Lewy bodies and Lewy neurites.
DLB and PDD have overlapping clinical, neurochemical, and pathological findings; when the clinical picture is fully developed they are practically indistinguishable.1,2 The main difference is the temporal sequence of symptoms; motor symptoms precede dementia in PDD whereas it coincides with or follows dementia in DLB. They are believed to represent two entities on the same disease spectrum, with pathological and imaging evidence suggesting that there is more concomitant amyloid pathology in DLB.2,3,4,5 Consensus guidelines proposed an arbitrary cut-off with regard to chronology of symptoms to distinguish these two disorders. Patients who develop dementia after one year following the onset of parkinsonian symptoms should be diagnosed as PDD, whereas those who develop dementia and parkinsonism concomitantly or within one year of each other should be diagnosed as DLB.4 This one year rule is perhaps more appropriately used for research purposes: in practice, patients who are diagnosed with PD first and subsequently develop dementia should be given the diagnosis of PDD, whereas those who develop dementia first followed by parkinsonism should be designated as DLB.
Dementia with Lewy bodies
Whilst historically other terms including diffuse Lewy body disease, Lewy body dementia, the Lewy body variant of Alzheimer’s disease, senile dementia of Lewy body type, and dementia associated with cortical Lewy bodies have been used, the term DLB was proposed at a consensus meeting in 19966 and is now widely used. This consortium also described the consensus guidelines for DLB followed by two revisions.7,8
DLB is the second most common cause of neurodegenerative dementias after Alzheimer’s disease (AD), accounting for 15–30 per cent of all dementia cases in autopsy series.9,10,11,12 In a systematic review, prevalence rates were found to vary widely between < 1–5 per cent of the general population, and < 1–30.5 per cent of dementia patients.13 A study in the United States of America revealed an incidence rate of 3.2 per cent among all incident dementia cases and 0.1 per cent in the general population;14 in a Finnish community study, in patients with dementia over 75 years the prevalence rates was 21.9 per cent.15 Lower prevalence rates have been reported in Asian countries16
The mean age of onset is between 60 and 80 years,8 with onset before the age of 60 being rare. Mean survival time (range 2–20 years) and rate of cognitive decline are similar to that seen in AD, although some patients may show rapid progression to death within 1–2 years.17 DLB has been associated with neuroleptic sensitivity which can be fatal, leading to a two to threefold increase in mortality,18 and it can be classified as mild (reversible side-effects such as drowsiness) or severe (worsening parkinsonism, irreversible cognitive decline, delirium, and features of neuroleptic malignant syndrome). Compared to AD, patients with DLB were found to have a greater risk of hospital admissions commonly due to fall-related injuries and bronchopneumonia.19
DLB is more frequent among those with a positive family history of dementia compared to those without.20,21 The syndrome and its core features tend to aggregate in families.22 The first chromosomal locus for DLB was mapped at 2q35–q36 in an autopsy-confirmed Belgian family across three generations with different phenotypes including dementia and/or parkinsonism.23 Molecular genetic analysis did not reveal a simple pathogenic or gene dosage mutation that cosegregated with DLB in this pedigree.24 The findings on apolipoprotein ε (APOE) polymorphisms in DLB are inconclusive. In some studies, an increased APOE4 allele frequency was reported, whereas others found no such difference.25,26,27 Duplications or triplications of α-synuclein gene are known to cause familial forms of PD, PDD, or DLB. Gene multiplications may lead to a gene dose-dependent increase in the expression of α-synuclein, severity of the disease, and a decrease in the age of onset.28,29 Glucoserebrosidase (GBA) mutations have also been associated with pathologically ‘pure’ Lewy body disorders, characterized by more extensive, cortical Lewy body pathology.30 Presence of GBA mutations has been reported in 6.8 per cent of cases with a pathological diagnosis of diffuse Lewy body disease.31
Clinical features of DLB
The central clinical feature is progressive cognitive decline that interferes with normal social and occupational function.8 The cognitive profile is characterized by particularly severe deficits in executive, visuospatial functions and attention.32,33 Prominent memory impairments may be absent in the early stages but usually appear as the disease progresses. Patients with concurrent Alzheimer-type pathology may show prominent memory deficits already in the early stages.
A core feature of DLB is fluctuation in cognitive performance, occurring in 50 per cent to 75 per cent of patients.8 Fluctuation is defined as pronounced variations in attention and alertness, varying from hour-to-hour to day-to-day, and seemingly occurs regardless of the severity of cognitive impairment.34 There is often no consistent fluctuation pattern even within the same patient. Fluctuations in cognition are reported to be associated with cholinergic deficits34 and can be assessed with neuropsychological evaluations, for example using computerized tests such as choice reaction time (which reveals momentary fluctuations in the performance during the testing period) or with fluctuation rating scales to capture fluctuations within a day or across days.35,36
Visual hallucinations are the most common psychiatric symptom, and are seen in at least two-thirds of patients.8 They are usually present early in the disease courses, are often recurrent, and consist of well-formed, detailed, mute images.37 Patients may have preserved insight into their hallucinations both during and after they occur. Auditory, olfactory, and tactile hallucinations are less common and they usually occur together with concomitant visual hallucinations. Visual illusions may also occur. Delusions are less prevalent,38 but the phantom boarder phenomenon (the conviction that there are strangers living in the patient’s home) and a broader feeling of ‘presence’ are common; delusions of persecution, theft, and infidelity may also occur. Psychotic symptoms have been associated with differential perfusion changes on single photon emission computed tomography (SPECT) imaging, with visual hallucinations observed with dysfunction of the parietal and ventral occipital cortices, misidentifications with dysfunction of the limbic-paralimbic structures, and delusions with dysfunction of the frontal cortices.39 Depression and anxiety may appear years before the onset of dementia, with up to 34 per cent of DLB patients experiencing a major depressive episode as a presenting symptom of DLB.20
Motor, autonomic, and other associated features
Presence of spontaneous parkinsonism is another core feature of DLB, occurring in 70–100 per cent of cases,8 but it is not universally present: in a clinicopathological study, absence of parkinsonism was the most common reason for failure to diagnose DLB.41 Parkinsonism varies in severity, with symptoms including rigidity and bradykinesia, shuffling gait, stooped posture, and masked faces. Conversely, resting tremor is uncommon. Postural instability can already be prominent in the early stages. More than 50 per cent of patients have severe sensitivity to neuroleptics,18 which is not dose-related and may present with as rapid and irreversible worsening of parkinsonism, cognitive decline, drowsiness, or occasionally with a neuroleptic malignant syndrome-like presentation with profound autonomic instability (see Box 36.1).
Other associated features include a range of sleep disturbances. Rapid eye movement (REM) sleep behaviour disorder is characterized by loss of normal skeletal muscle atonia during REM sleep and vivid dreams with simple or complex motor behaviour.42 It is present in nearly 70 per cent of DLB patients and may occur many years before the onset of dementia or parkinsonism.42 As the disease progresses, it may become less frequent or less symptomatic.43 It has been suggested that inclusion of REM sleep behaviour disorder (RBD) as a core clinical feature improves the diagnostic accuracy of autopsy-confirmed DLB patients.44 Disturbed sleep–wake cycle and excessive daytime sleepiness are also common features.
LB pathology and neuronal loss in the autonomic nervous system,8 giving rise to a range of autonomic abnormalities such as orthostatic hypotension, impotence, urinary incontinence, and constipation are may be seen in DLB.45 Urinary incontinence is the most frequent autonomic symptom, followed by constipation.8
Repeated falls, syncope, and transient loss of consciousness may occur and constitute supporting features for diagnosis. Unprovoked falls may be related to postural instability or autonomic dysfunction. Transient and otherwise unexplained lapses of consciousness, with or without falls, may represent orthostatic syncope.
Pathological and biochemical correlates
The core pathological hallmarks include Lewy bodies (LBs) in neuronal cytoplasm and Lewy neurites. They can be seen in the brainstem nuclei, amygdala, limbic-paralimbic cortices, basal ganglia and cerebral cortex, medulla and peripheral autonomic nervous system may also be involved.46 Gliosis and neuronal loss are also present in these regions. LBs are usually found in the deeper layers of the neocortex: α-synuclein is the major protein component;47 neurofilaments, ubiquitin, torsin A, and parkin minor constituents.48 Morphologically, LBs are divided into brainstem and cortical types.46 ‘Brainstem-’ type LBs, easily detected by standard histological methods such as haematoxylin–eosin staining, are spherical intraneuronal cytoplasmic inclusions characterized by hyaline eosinophilic core, concentric lamellar band, and a narrow pale halo. Cortical LBs occur in limbic and neocortical regions, mainly in the layer II, III, V, VI of the cortex. They are not readily identifiable with classical histological stainings, and immunohistochemistry with anti-α-synuclein antibodies is required to detect them. DLB Consortium criteria for a pathological diagnosis of DLB proposes a classification system using α-synuclein immunohistochemistry with semiquantitative grading of Lewy-related pathology (mild, moderate, severe, very severe) in brainstem, limbic, and diffuse neocortical areas rather than counting LBs in various brain regions.8
In addition to LB pathology, 75–90 per cent of patients have concomitant amyloid plaques and many meet pathological criteria for Alzheimer’s disease (AD) according to the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD) criteria.49,50,51 Although concomitant amyloid plaques are common, neurofibrillary tangles are rare. Vascular pathology can be found in up to 30 per cent of DLB patients.52 Concomitant AD-type or vascular pathology may have an impact on the clinical presentation,53 with the presence of significant AD pathology being associated with more severe memory impairment compared to cases with purer LB pathology which are associated with more severe executive and visuospatial dysfunction.
Biochemically DLB is associated with severe dopaminergic and cholinergic deficiency,54 the latter typically being more prominent in DLB than in AD.55 In DLB there is loss of cholinergic neurons in the nucleus basalis of Meynert56 and reductions in markers of cholinergic activity (choline acetyltransferase levels) in temporal and parietal cortex. Reduction of choline acetyltransferase activity in the temporal lobe is correlated with the degree of the cognitive impairment.57 Cholinergic deficits are greater in the temporal cortices of patients with visual hallucinations as compared to those without.58 Muscarinic M1 postsynaptic receptor binding in the temporal lobe may be increased in patients with delusional thinking.59
Dopaminergic deficit is the other prominent neurochemical feature. Reduction in postsynaptic D2 receptor density in striatum is greater in DLB than in PD or healthy controls, which may contribute to the weak response to dopaminergic drugs or neuroleptic sensitivity.60 LB pathology also occurs in the dorsal raphe nucleus, leading to marked reduction of serotonin levels in the basal ganglia and cerebral cortices. Deficits in serotoninergic and noradrenergic systems may contribute to cognitive and behavioural symptoms.61
In structural magnetic resonance imaging (MRI), hippocampus and medial temporal lobes are relatively well-preserved compared with AD patients,62 although mild hippocampal atrophy (10–20 per cent) can be seen compared to controls.63 The utility of MRI in differential diagnosis is, however, limited. Atrophy in other cortical and subcortical structures has also been reported, including striatum, substantia innominata, hypothalamus, and dorsal midbrain.64 In longitudinal MRI studies, the rate of cerebral atrophy was found to be 1.4 per cent per year, three times more than that seen in controls, but less than that seen in AD.65
In one MR spectroscopy (MRS) study, no changes were found in the grey matter N-acetyl aspartate/Creatinine (NAA/Cr) ratio—considered to be a marker of neuronal integrity—in DLB patients compared to healthy controls.66 In another study of proton MRS focusing on posterior cingulate gyri and inferior precunei, NAA/Cr levels were reduced in all dementia groups (AD, vascular dementia, frontotemporal dementia (FTD)) except for DLB, suggesting relative preservation of posterior cingulate cortex neuronal integrity in DLB.67 In a diffusion tensor imaging (DTI) study, changes (increased diffusion (D) and decreased fractional anisotropy (FA) values) in corpus callosum and pericallosal areas were found in DLB patients compared to normal controls.68 White matter was also affected in the frontal, parietal, and occipital areas with less involvement of the temporal lobe. Areas of reduced FA in DLB versus controls were also observed primarily in parietooccipital white matter tracts where the changes were more diffuse in AD; compared to AD, DLB was also associated with reduced FA in pons and left thalamus.69 Resting state functional MRI (fMRI) studies suggest increased functional connectivity between the right posterior cingulate and other brain areas.70,71 These imaging studies would suggest relatively preserved neuronal integrity, diffuse white matter tract breakdown and disrupted connectivity in DLB patients.
SPECT and positron emission tomography (PET) studies have demonstrated decreased glucose metabolism and perfusion deficits in parietal and occipital cortices.72,73 Occipital hypometabolism is, however, not always present and FDG-PET changes may be similar to that seen in AD (Fig. 36.1). Reduced uptake of18 F-fluorodopa in the striatum may distinguish DLB from AD with high sensitivity and specificity.74 123I-β-CIT SPECT demonstrates reduced dopamine transporter binding in the caudate and posterior putamen in DLB compared to AD patients.75,76 SPECT using 123I-metaiodobenzylguanidine (MIBG), a marker of post-ganglionic cardiac sympathetic innervation, shows reduced cardiac MIBG uptake in DLB and PD patients as opposed to normal findings in AD.77 Using Pittsburgh compound B (PiB), an in vivo marker of β-amyloid burden, as predicted by pathological studies, 80 per cent of DLB cases were found to have increased amyloid load.78,79,80
Electro-encephalography (EEG) may show slowing of background activity in DLB patients in early stages, and epoch- by-epoch analysis may demonstrate fluctuations. Frontal intermittent delta activity and transient temporal slow waves are other changes which can occur more commonly in DLB than in AD.81,82
Currently, there are no blood or cerebrospinal fluid (CSF) markers that can be reliably used for diagnosis, to follow disease progression, or as an outcome measure for therapeutic interventions. CSF α-synuclein has been studied as a potential biomarker for DLB but results have been controversial.83,84 Several studies reported lower amyloid β40–42 levels in DLB compared to controls and PDD cases,85,86 CSF amyloid β38 was suggested as a diagnostic biomarker for DLB;87 Aβ42:Aβ38 ratio discriminated AD from with a sensitivity of 78 per cent and a specificity of 67 per cent.
Diagnosis of DLB
The central feature required for the diagnosis of DLB is progressive cognitive decline that interferes with the social and occupational functionality of the patient (Table 36.1).8 Core features include fluctuation in cognition with pronounced variation in attention and alertness, recurrent and persistent visual hallucinations, and spontaneous (i.e. not drug-induced) parkinsonism. Consensus guidelines recommend that two of the core clinical features have to be present for a diagnosis of probable and one for a diagnosis of possible DLB.4 Suggestive and supportive features may increase diagnostic accuracy; they are more frequent than in other dementing diseases but their specifity is low. Suggestive features include REM sleep behaviour disorder, severe neuroleptic sensitivity, and decreased dopamine transporter binding in striatum. Possible DLB can be diagnosed if one or more suggestive features are present in a patient with dementia even in the absence of any core features. Supportive features include repeated falls and syncope, transient or unexplained loss of consciousness, severe autonomic dysfunction, systematized delusions, hallucinations in other modalities (i.e. auditory and tactile), depression, relative preservation of medial temporal lobe on computed tomography (CT) or MRI scan, decreased tracer uptake on SPECT or PET imaging in occipital regions, abnormal 123I-MIBG scintigraphy, prominent slow waves on EEG with transient sharp waves in temporal lobe.
Table 36.1 Revised criteria for the clinical diagnosis of dementia with Lewy bodies
Reproduced from Neurology. 65(12), McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium, pp. 1863–72, Copyright (2005), with permission from Wolters Kluwer Health, Inc.
The diagnosis of DLB is principally based on clinical features and exclusion of other diagnoses. A history of stroke, focal neurological signs, and the presence of significant comorbid physical illness and other brain disorders reduce the certainty of diagnosis.
Both nonpharmacological and pharmacological interventions can be used in management. Recognition and amelioration of sensory impairments such as impaired vision or hearing, environmental optimization such as improving lighting, may reduce hallucinations, delusions, and falls. Education of caregivers is important: behavioural symptoms may be relieved or reduced by an appropriate approach to patients, and can reduce use of antipsychotics.
Consideration should be given to discontinuation of drugs with anticholinergic effects such as tricyclic antidepressants, anticholinergics or antispasmodics as they may impair cognition, exacerbate psychotic symptoms, and cause orthostatic hypotension.38 Levodopa is the drug of choice to treat motor symptoms and should be started at low doses and increased slowly to the minimum required dose. Response to levodopa can be limited, partly due to primary unresponsiveness and partly due to the predominance of symptoms (such as postural instability) known to be unresponsive to levodopa.88,89 Potential side-effects of levodopa include visual hallucinations, delusions, orthostatic hypotension, and nausea.
Orthostatic hypotension can be treated with hydration, increased salt intake, avoiding prolonged bed rest, thigh-high compression stockings, efforts to stand up slowly, and minimizing or discontinuing medication that contributes to orthostasis. In refractory cases fludrocortisone and midodrine can be considered. Constipation may benefit from exercise, increased dietary fibre, increased water intake, and laxatives. REM sleep behaviour disorder can be treated with low dose clonazepam (0.25–1.0 mg) at bedtime; however, this can worsen the symptoms of obstructive sleep apnoea or may cause daytime sleepiness and unsteadiness.42 Melatonin may also be used at a dose of 3–12 mg, either as monotherapy or in conjunction with clonazepam.90 Modafinil and methylphenidate can be considered to treat excessive daytime sleepiness although there is no direct evidence for its use in DLB. Serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) can be used to treat depressive symptoms.
Although being often the most troubling neuropsychiatric feature, visual hallucinations may not require drug treatment if they are not frightening. Neuroleptics should be used with great caution to treat psychotic features as some patients may show severe neuroleptic sensitivity which is not predictable.18 In addition, antipsychotics may increase the risk of cerebrovascular events and death in elderly patients with dementia.91 As reductions in cholinergic activity correlate with hallucinations, cholinesterase inhibitors may be considered for management of mild hallucinations and delusions before using neuroleptics,92,93 and are often very effective (see following). Classical neuroleptics such as haloperidol are contraindicated, risperidone and olanzapine can also worsen parkinsonism, and so when required quetiapine and clozapine are the neuroleptics which can be considered. Initial doses should be low and the dose should be titrated slowly while monitoring for adverse effects. Neuroleptics can cause orthostatic hypotension and blood pressure should be monitored.
As patients with DLB have severe cholinergic deficits, cholinesterase inhibitors rivastigmine and donepezil were tested in randomized, placebo-controlled trials. In the study with rivastigmine (6–12 mg/day) there were no statistically significant differences from placebo on mean mini-mental state examination (MMSE) score, clinician-assessed global change from baseline and mean neuropsychiatric inventory (NPI, 10 items) score. More than twice as many patients on rivastigmine (63.4 per cent) than on placebo (30.0 per cent) showed at least a 30 per cent improvement from baseline in their NPI-4 scores (P ≤ 0.001), with psychotic features resolving almost completely in over half of the treated patients. Apathy, anxiety, delusions, and hallucinations showed most response. There was also a significant improvement in a computerized test of attention. Nausea, vomiting, anorexia and somnolence were the most common side-effects. Worsening of parkinsonism was not reported, except for emergent tremor in four rivastigmine-treated patients.92 In the study with donepezil,93 patients given 5 mg or 10 mg donepezil showed greater improvement in the majority of the cognitive and behavioural scales, including the MMSE and NPI; 10 mg was also associated with improved global function and reduced caregiver burden. Patients taking donepezil were less apathetic, less anxious, had less cognitive fluctuation, and fewer delusions and hallucinations compared to placebo patients. Adverse effects (AEs) were usually mild to moderate.
Some changes in glutamatergic activity have been reported in patients with DLB94 and the uncompetitive N-methyl-D-aspartate antagonist memantine was tested in two randomized controlled studies with inconsistent results.95,96 In the larger study with 121 PDD and 78 DLB patients,96 those treated with memantine had greater improvements in clinicans global impression of change score compared to placebo; improvements were predominantly in the DLB group. Likewise, behavioural symptoms as assessed with NPI total score significantly improved in the DLB group only. Cognitive tests, activities of daily living, or caregiver burden scores did not show significant improvements in either patient group. Adverse events in the two treatment groups were similar except for slightly more sedation in the memantine group. In another, smaller randomized trial of memantine including both patients with DLB or PDD, significantly improved mean global impression of change score was observed in the total population; the difference was, however, driven by a larger efficacy in the PDD group.95 NPI scores showed a statistically significant improvement under memantine in the DLB group, but not in the PDD population. No statistically significant differences were observed for individual cognitive tests, activities of daily living, or caregiver burden scores.
Based on the available evidence, cholinesterase inhibitors such as rivastigmine and donepezil should be considered in patients with a diagnosis with DLB, taking into account potential benefits and risks. The data on benefits of memantine are less clear, perhaps being considered in patients with prominent behavioural symptoms.
Parkinson’s disease dementia
Although considered primarily a motor disorder, non-motor symptoms may accompany Parkinson’s disease (PD) from early stages and be present even before the manifestation of motor symptoms. Due to advances in treatment and increased life expectancy, cognitive impairment and dementia in PD have become increasingly more recognized.
Subtle cognitive deficits may be detected even in the early stages of PD if appropriate neuropsychological tests are administered. In the majority of patients, however, overt cognitive impairment becomes manifest in the late stages of the disease, especially in old age. In a community-based study, 36 per cent of newly diagnosed patients were found to have cognitive impairment at the time of diagnosis, while 57 per cent of this cohort developed cognitive deficits within 3.5 (+/–0.7) years; the incidence of dementia was estimated to be 38.7 per 1000 person-years of observation.97 In another study, 24 per cent of 115 newly diagnosed PD patients displayed impaired performance on at least three neuropsychological tests and were classified as cognitively impaired.98 A pooled analysis comprising 1346 non-demented PD patients from 8 centres showed that 25.8 per cent of patients had fulfilled criteria for mild cognitive impairment (MCI).99
Both the prevalence and incidence of dementia are increased in PD. In a systematic review, the point prevalence of dementia was 24–31 per cent. The prevalence of PDD in the general population aged 65 years and over was calculated to be 0.3–0.5 per cent, and 3–4 per cent of all dementias were estimated to be due to PDD.100
The incidence of dementia in PD was reported to be 1.7–5.9 times higher compared to controls.101,102 In the Sydney cohort, 48 per cent of surviving patients with PD had developed dementia 15 years after the diagnosis103 and the cumulative incidence had risen to 83 per cent 20 years after the diagnosis.104 In a study in Norway, the 8-year cumulative prevalence of dementia was 78.2 per cent (26 per cent of cases being demented at baseline).105 In a door-to-door survey, 15 per cent of PD patients developed dementia compared to 4.9 per cent of the control group.101
The most established risk factors for PDD include age and disease severity. Old age at disease onset or at the time of evaluation are significant risk factors. In one study, older patients (mean age 79 years) with more severe disease had a 12-fold increased dementia risk compared to younger patients with mild disease;106 severe motor disability, long disease duration, atypical neurological features such as early autonomic impairment, symmetrical disease presentation, and unsatisfactory response to dopaminergic treatment were additional risk factors.
Low cognitive scores at baseline, early development of confusion or hallucinations on dopaminergic medication, axial involvement including speech impairment and postural imbalance and excessive daytime sleepiness may also be associated with increased risk of dementia in PD. REM sleep behaviour disorder (RBD) is frequently seen in PD: in one study, PD patients with RBD had a sixfold higher occurrence of dementia than those without.107 Dementia is associated with postural instability and gait disorder phenotype, and tremor-dominant patients have lower risk of developing dementia. Poor verbal fluency, poor performance on verbal memory tests, and subtle impairment in executive functions at baseline were significantly associated with incident dementia.108 In one cohort, impairment in cognitive tests relying on frontal executive functions were associated with a lower risk of dementia whereas impairment in those tests assessing more posterior cortical functions was associated with a higher risk.97 White matter hyperintensities were associated with cognitive decline in PD patients.109 Smoking has been associated with a two- to fourfold higher risk for dementia in PD,110 but no significant association with head injury or diabetes mellitus has been reported with incident dementia.111
Siblings of PDD patients have been reported to have a threefold increased risk of history of AD.112 The data concerning the association of apolipoprotein ε4 (APOE4), a genetic risk factor for AD, with PDD have been inconsistent; along with APOE4, APOE2 has also been suggested to be associated with PDD.113
There is some evidence that variations in the tau (MAPT) gene seem to be a genetic risk factor, the H1/H1 haplotype being associated with a greater rate of cognitive decline and dementia in PD,114,115 but not for other neurodegenerative diseases such as DLB and AD.116
A significantly higher frequency of heterozygote mutations in the glucocerebrosidase gene (GBA) has been reported in PD and DLB. Up to half of PD patients heterozygous for GBA mutations developed cognitive impairment later in their disease in one series,117 and compared to PD patients without mutations PD patients with GBA mutations were found to be at higher risk of dementia with an odds ratio of 5.8.118
Altered expression of, or missense mutations in the α-synuclein gene have been linked to familial PD, sometimes associated with dementia. There is, however, a more robust relationship with cognitive decline and α-synuclein duplication, and even more so with the triplication of the α-synuclein gene.29,119
Mutations in parkin, PINK1, and DJ-1 genes cause autosomal recessive PD. Dementia rates seem to be lower in patients with PINK1 and DJ-1 mutations, with the rate in parkin mutation carriers may be more similar to sporadic PD. G2019S LRRK2 mutations, a cause of autosomal-dominant PD, may be associated with cognitive impairment,120 but overall the frequency of dementia in monogenic forms of PD may be lower than in sporadic PD. This observation may in part relate to the relatively younger age of these patients, especially in the case of recessive mutations.121
Clinical features of PDD
In typical cases, the profile of dementia can be best described as a dysexecutive syndrome with prominent impairment of attention, executive, and visuospatial functions, moderately impaired episodic memory, and associated neuropsychiatric symptoms including apathy and psychosis (Table 36.2).
Table 36.2 Clinical features of dementia associated with PD
I Core features
II Associated clinical features
Cognitive impairments seen in non-demented PD patients (which is designated as PD-MCI) have in general similar profile to those found in patients with dementia, with quantitative rather than qualitative differences. The most common deficits are in executive functions, visuospatial functions, memory, and attention. The profile of cognitive deficits in PD-MCI is variable, the most frequent subtype being single-domain non-amnestic MCI, the most frequent single deficit being episodic memory impairment.99
Impairment of attentional functions and working memory is an early and prominent feature in PDD. Attentional fluctuations occur in a similar way to patients with DLB. PDD patients tend to be more apathetic compared to AD patients, and impaired attention is an important determinant of ability to undertake activities of daily living in PDD.122
Impairment in executive functions is one of the early and prominent cognitive features of PDD. Using the Mattis Dementia Rating Scale which is sensitive to executive function, PDD patients were found to have lower initiation, perseverance, and construction, but higher memory subscores compared to patients with AD.123 Insight is usually relatively preserved in PDD, in contrast to many patients with AD.
Working memory, explicit visual and verbal memory, and implicit memory such as procedural learning can all be impaired in PDD. The relative severity of memory impairment as compared to general level of cognitive dysfunction, and the profile of impairment usually differ from that seen in AD. In typical cases, the memory impairment is characterized by a deficit in free recall with relatively preserved recognition. Memory scores in patients with PDD were found to correlate with performance in executive function tests, suggesting that impairment of memory in PDD may partly be due to difficulties in developing search strategies, although this view has been recently challenged.124 Memory impairment resembling that seen in typical AD can also be seen in a subpopulation of PDD patients.125
Another early cognitive deficit in PDD is impairment in visuospatial functions. Impairment, especially in visuoperceptual abilities, is typically more severe than patients with typical, amnestic AD.126 Visuospatial abilities such as object assembly are often more impaired in PDD, whereas visuospatial memory tasks are worse in AD. Deficits in visuospatial functions may be more evident in more complex tasks, which require planning, sequencing of response, or generation of strategies, suggesting that these deficits may be, at least partly, due to problems in sequential organization of behaviour (i.e. executive dysfunction).
Core language functions are largely preserved in PDD. Where present, deficits usually consist of word finding difficulties, pauses in spontaneous speech, or relate to difficulties understanding complex sentences.
Several structured scales, some specifically developed for PD, can be used for screening cognitive impairment. The Montreal Cognitive Assessment (MoCA), with a high test–re-test and inter-rater reliability, can be used as a screening instrument, with a cut off score of 21/30 yielded a sensitivity of 90 per cent in PDD patients compared to non-demented PD patients.127 Both the MoCA and cognitive screening instruments specifically developed for PD including Mini Mental Parkinson and the Parkinson neuropsychometric dementia assessment (PANDA) may be more sensitive than the MMSE to detect cognitive impairment in PD.128,129 More elaborate cognitive scales for in depth assessment include the general cognitive scales such as Mattis Dementia Rating Scale and the Cambridge Cognition–Revised (CAMCOG–R), as well as PD-specific scales such as SCales for Outcomes of PArkinson’s disease-cognition (SCOPA-Cog) and PD Cognitive Rating Scale (PD-CRS).130
A wide range of neuropsychiatric symptoms are seen in PDD, the most common are hallucinations, apathy, depression, anxiety, and insomnia. At least one neuropsychiatric symptom is present in more than 90 per cent of the patients.131 Hallucinations and delusions may result de novo following treatment with dopaminergic agents, but do so more frequently in patients with pre-existing dementia. When minor forms such as feeling of presence are included, hallucinations occur in 70 per cent of patients with PDD, as compared to 25 per cent of those with AD.132 Visual hallucinations are similar to those seen in in DLB, with well-formed figures of humans or animals, often with preserved insight. Delusional misidentification syndromes (the house not being their real home, individuals being replaced by a double, i.e. the impostor or Capgras syndrome) are found in 17 per cent of PDD patients.133 Apathy is common in the earlier stages while delusions increase with more severe motor and cognitive dysfunction. Depression is more common in PDD than in AD.
Motor, autonomic, and other associated features
In PDD motor symptoms are typically symmetrical with predominance of bradykinesia, rigidity, and postural instability. In a cross-sectional study, postural-instability gait difficulty (PIGD) subtype was over-represented with 88 per cent in patients with PDD in contrast to 38 per cent in non-demented patients.134 A transition from tremor dominant to PIGD-type is associated with higher risk of dementia.135 PD patients with falls are more likely to have lower MMSE scores and also are more likely to have dementia. L-dopa-responsiveness may diminish as cognitive impairment emerges; potential underlying mechanisms may include the development of α-synuclein pathology in striatum and loss of striatal dopamine D2 and D3 receptors, or predominance of non-dopaminergic axial features, such as postural instability.
Autonomic disturbances include constipation, urinary incontinence, orthostatic and postprandial hypotension, and can result in syncope and falls, excessive sweating, reduced heart rate variability predisposing to ventricular arrhythmias, and sexual dysfunction. In a comparative study, cardiovascular autonomic dysfunction was more frequent in patients with PDD as compared to those with DLB, vascular dementia, and AD, PDD, due to both impairment of parasympathetic and sympathetic function.136
REM sleep behaviour disorder (RBD) is common in PDD. Presence of RBD in non-demented patients with PD is also associated with cognitive deficits, specifically on measures of episodic verbal memory, executive function, and visuospatial and visuoperceptual processing.137 RBD can be an early indicator of incipient dementia and may predate the onset of dementia by many decades. Excessive daytime sleepiness (EDS) and poor sleep quality are also common in patients with PDD (see Box 36.2).
Pathological and biochemical correlates
PDD is characterized by variable combination of degeneration in subcortical nuclei, cortical AD-type pathology and Lewy body (LB)-type degeneration.2 Combination of LB-type and AD-type pathology was found to be a better predictive of dementia than the severity of the single pathology.138 It is probably the topographical and temporal sequence of neuronal loss rather than the type of protein aggregation which ultimately determine the clinical phenotype. AD-type and LB-pathology do not need to be mutually exclusive as there are interactions between different protein aggregations: α-synuclein can induce phosphorylation and fibrillization of tau; and β-amyloid may promote the aggregation of α-synuclein-exacerbating α-synuclein-induced neuronal dysfunction.139
In contrast to earlier studies with ubiquitin staining, recent studies using the more sensitive α-synuclein immunohistochemistry revealed that dementia best correlates with LB pathology, although some degree of AD-type pathology (more plaques than tangles) usually coexists. The fact that families with α-synuclein gene duplications and triplications develop dementia more often also supports a primary and possibly a ‘dose-dependent’ role of synuclein-based pathology in development of PDD.
Dementia usually develops later in the disease course and may be related to an ascending order of pathological changes.140,141 Some support for this ‘bottom-up’ hypothesis is also provided by other studies:142 PD patients with relatively long disease duration prior to dementia onset had lower levels of cortical cholinergic activity than those with a short disease duration before developing dementia, implying greater loss of ascending cholinergic projections in the former group. A more ‘top-down’ pathological process, with greater burden of cortical pathology in PD patients with a more rapid disease course and short time before dementia onset, has also been described.141,142 Younger patients who developed dementia late in the disease process seem to have a predominance of α-synuclein pathology with little amyloid pathology whereas those with a late age of onset and rapid progression to dementia seem to have mixed α-synuclein and amyloid pathology, typically with both severe neocortical Lewy body disease, and high amyloid burden.141 Approximately 55 per cent of subjects with widespread α-synuclein pathology (Braak PD stages 5–6) lacked clinical signs of dementia or extrapyramidal signs before death:143 it is unclear why these subjects could ‘tolerate’ high levels of synuclein deposition without having symptoms.
Biochemically, degeneration of the subcortical nuclei results in various neurochemical changes including cholinergic, dopaminergic, serotoninergic, and noradrenergic deficits, of which cholinergic loss is most prominent. Loss of cholinergic cells in the nucleus basalis of Meynert (nbM) greater than that observed in AD occurs in patients with PDD. LBs are frequently found in nbM cells. Cholinacetyltransferase activity is markedly decreased in the frontal cortex of PDD and DLB when compared to normal controls and patients with AD. In contrast to AD, PDD is also associated with neuronal loss in the pedunculopontine cholinergic nuclei which project to structures such as thalamus. Using vesicular acetylcholine transporter (123I-iodobenzovesamicol, IBVM) as a marker of cholinergic integrity, SPECT studies demonstrate reductions in parietal and occipital cortices in non-demented PD patients, while demented PD cases have a more extensive decrease in cortical binding.144 Functional imaging studies with PET have shown that that, compared to controls, mean cortical AChE activity was lowest in patients with PDD, followed by patients with PD without dementia and AD patients.145 The degree of cortical cholinergic deficits correlated particularly well with typical cognitive deficits found in PDD, (e.g. impaired performance on tests of attention and executive functions).146
The noradrenergic locus coeruleus shows neuronal loss especially in demented and depressed PD patients.147 Degeneration in serotonergic dorsal raphe nucleus has been reported and may contribute to affective symptoms.148 Neuronal loss was also observed in ventral tegmental areal, which provides dopaminergic input to meso-limbic and prefrontal cortex and medial substantia nigra.149
Correlates in neuroimaging
MRI studies reveal frontal, occipital, and parietal grey matter loss and an increased rate of whole brain atrophy in PDD patients compared with control subjects. Atrophy of grey and white matter is typically less prominent than in DLB patients. A volumetric study revealed a relationship between decrease in caudate volume (but not in hippocampus) and cognitive decline.150 Although there are studies showing atrophy of medial temporal lobe structures such as the hippocampus in PDD, these are not as prominent as in AD. Supratentorial white matter hyperintensities were also found to be independently associated with cognitive decline in PDD patients.109
Reduced fractional anisotrophy (FA) was found in the substantia nigra of non-demented PD patients with DTI. PDD patients showed significant FA reduction in the bilateral posterior cingulate bundles compared with non-demented PD patients;151 both FA and mean diffusivity values in cingulate and corpus callosum showed significant correlations with cognitive parameters.151,152 In a resting state functional MRI study, corticostriatal connectivity was found to be selectively disrupted in PDD patients.153
PET usually shows hypometabolism in parietal and temporal cortex similar to that seen in AD, with hypometabolism in visual areas and frontal lobe also described.154 In PET with N-[11C]-methyl-4-piperidyl acetate (MP4A) and 18F-fluorodopa (FDOPA), which assesses cholinergic innervation of cortex, PDD patients exhibited a severe cholinergic deficit in various cortical regions including frontal and temporoparietal cortices.155 In PET studies with PiB, in PDD mean cortical amyloid load was comparable to controls and non-demented PD patients.156 In another study, 83 per cent of PDD patients had ‘normal’ PiB uptake whereas 85 per cent of DLB patients had significantly increased amyloid load in one or more cortical regions.78
Regional cerebral blood flow (rCBF) SPECT studies have shown frontal hypoperfusion or bilateral temporoparietal deficits in PDD.157 Perfusion deficits in precuneus and inferior lateral parietal regions have also been described. 123I-MIBG is a marker of postganglionic sympathetic cardiac innervation: SPECT studies with this compound demonstrate innervation deficits both in PDD and DLB but not in AD. The integrity of nigro-striatal dopaminergic terminals can be assessed using markers of dopamine transporter, such as 123I-FP-CIT SPECT. Significant reductions were found in 123I-FP-CIT binding in the caudate, anterior, and posterior putamen in subjects with DLB and PDD compared to those with AD and controls.
Diagnosis of PDD
Clinical diagnostic criteria for PDD and and practical recommendations for diagnosis have been described by a Movement Disorder Society task force.158,159 Clinical features of PDD are shown in Table 36.2 and diagnostic criteria for probable and possible PDD are given in Table 36.3. Diagnostic criteria for mild cognitive impairment in PD (PD-MCI) have also been recently published by a task force of the Movement Disorder Society.160
Table 36.3 Diagnostic criteria for PDD
Reproduced from Mov Disord. 22(12), Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease, pp. 1689–707, Copyright (2007), with permission from John Wiley and Sons.
Diagnosis of dementia in PD can be confounded by several factors, not least the coexistence of motor and speech dysfunction. When severe motor impairment is present it may be difficult to discern the presence and magnitude of cognitive deficits and to what extent they contribute to functional impairment. Depression, other systemic disorders, or adverse effects of drugs may mimic symptoms of dementia. The mode of onset, speed of progression, the type of behavioural symptoms, pattern of cognitive deficits, and the clinical context in which these symptoms occur are helpful in differentiating dementia from its mimickers such as acute confusion or pseudo-dementia. Once a dementia syndrome with parkinsonism is established, differential diagnosis include DLB, AD associated with drug-induced parkinsonism, other degenerative diseases such as progressive supranuclear palsy, corticobasal syndrome or FTDP-17, cerebrovascular disease, hydrocephalus, intoxications, metabolic, endocrine, systemic disorders, or infections. A detailed history specifically inquiring the features known to be associated with PDD, a comprehensive neuropsychological assessment, neurological and systemic examination, a review of current medication, and use of appropriate auxiliary investigations are helpful in differential diagnosis.
Management of patients with PDD
Non-pharmacological measures include education of the family about disease symptoms and appropriate care (which can reduce behavioural symptoms and unnecessary use of psychopharmacological medication), providing and promoting sufficient mental and physical activities. Before initiating pharmacological treatment conditions including systemic diseases, depression and adverse events of medication should be considered and managed appropriately. In particular, treatments with anticholinergics, tricyclic antidepressants, and benzodiazepines should be minimized and ideally discontinued where possible. The need for pharmacological intervention should be determined based on symptom frequency, severity, and burden.
Based on the prominent cholinergic deficits associated with PDD, cholinesterase inhibitors (ChE-Is) have been investigated in PDD patients. There have been two large randomized placebo-controlled trials, one with rivastigmine and the other with donepezil. In the rivastigmine trial, both cognitive and general status scales showed significant improvements compared to placebo; there were also benefits in the behavioural, attentional, and executive function test scores.161 Except for slightly more patients having worsening of tremor there were no significant effects on motor symptoms as compared to placebo; the beneficial effects seemed to last for at least six months:162 a subanalysis revealed consistent benefits on all aspects of attention.163 In the large placebo-controlled trial, donepezil 10 mg was also associated with beneficial effects in cognitive and overall scales, with no significant differences on ADLs or behavioural scores. In a smaller randomized placebo-controlled trial in non-demented PD patients, galantamine did not show any significant benefits on cognitive function tests.164 In a Cochrane meta-analysis, cholinesterase inhibitors in PDD were concluded to be associated with a positive impact on global assessment, cognitive function, behavioural disturbance, and activities of daily living rating scales.165 Based on the two large randomized controlled trials and the results of meta-analysis, treatment with cholinesterase inhibitors such as rivastigmine or donepezil should be considered in patients with PDD, taking into account expected benefits and risks.
Memantine, a partial NMDA receptor antagonist used in the treatment of AD, was tested in patients with DLB or PDD in two randomized controlled trials. In one, there was a significant difference in favor of memantine only in the global outcome scale, where patients with PDD had more benefits as compared to those with DLB.95 In the larger study the global outcome scale and behavioural scores were significantly better with memantine in the DLB group, whereas there were no significant differences in the PDD population.166 These results suggest that memantine may have mild beneficial effects in patients with Lewy body-related dementias, possibly more so in the DLB population, in global status and for behavioural symptoms.
Patients with mild psychotic symptoms such as hallucinations should be first treated with ChE-I before considering neuroleptics as ChE-I may improve these symptoms.161 Nevertheless, neuroleptic treatment may become necessary in patients with severe psychosis or agitation. Classical neuroleptics are contraindicated as they worsen motor function and may result in life-threatening neuroleptic hypersensitivity. In a systematic review of atypical neuroleptics for the treatment of psychosis in PD, clozapine was concluded to be the only drug with proven efficacy and acceptable tolerability, although in practice this is not straightforward as regular blood monitoring for leucopenia is required.167 Other atypical neuroleptics such as olanzapine and risperidone can worsen motor function. The efficacy of quetiapine is not well demonstrated although it may be considered under monitoring for side-effects.
Tricyclic antidepressants such as amitriptyline and nortriptiline may be effective in PD depression but should not be used in patients with PDD, due to their anticholinergic effects. Selective serotonin reuptake inhibitors such as paroxetine, or mixed serotonin and noradrenalin reuptake inhibitors such as venlafaxine, have been shown to be effective in PD depression.168 Sedating antidepressants such as trazodone can be considered to treat sleep disturbances. Melatonin or very low doses of clonazepam may be used to treat RBD; daytime somnolence, however, should be monitored. EDS may be treated with modafinil, although there are no studies in PDD patients.169
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