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Cognitive Loss 

Cognitive Loss
Cognitive Loss

Andrea C. Adams

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This chapter discusses dementia, memory loss, and other cognitive dysfunction. Dementia is diagnosed when cognitive or behavioral symptoms interfere with the ability to function at work or at usual activities. This represents a decline from previous levels and is not explained by delirium or major psychiatric disorder. The criteria for dementia include a minimum of 2 of the following cognitive or behavioral impairments: 1) impaired ability to acquire and remember new information, 2) impaired reasoning and handling of complex tasks, 3) impaired visuospatial abilities, 4) impaired language functions, and 5) changes in personality, behavior, or comportment.

The most common cause of dementia is Alzheimer disease (AD) (Box 8.1). Diagnostic criteria and guidelines for AD focus on 3 stages: preclinical, mild cognitive impairment, and dementia due to AD. Accurate diagnosis is important because reversible causes of dementia must be excluded and because of the treatment options available. Early diagnosis is advantageous not only for treatment but also for allowing the patient to be more involved in making important decisions (eg, living arrangements and financial affairs) before the disease progresses to the point when this is not possible. Family members can be educated about the disease process, and proactive measures can be taken with regard to financial affairs, legal matters, driving, living arrangements, and safety. The inherited nature of some dementing illnesses makes the correct diagnosis of dementia important to family members.

Abbreviations: CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; HIV, human immunodeficiency virus.

Adapted from Adams AC. Neurology in primary care. Philadelphia (PA): FA Davis; ©2000. p. 137. Used with permission of Mayo Foundation for Medical Education and Research.

The incidence and prevalence of dementia increase with age, with the prevalence doubling every 5 years. One percent of persons 65 years old have dementia, compared with 50% of those older than 90 years. As the population ages, prompt recognition and intervention will become increasingly important. Failure to diagnose dementia correctly has been attributed to lack of attention to cognitive functioning in routine medical examinations and to misperceptions about the normal aging process.

Diagnostic Approach

Fifty percent to 75% of patients with dementia have AD. When a patient complains of cognitive impairment, the initial focus is to determine whether the symptoms suggest dementia, delirium, or depression. The characteristic feature of a patient with delirium or an acute confusional state is inattention and an impaired and fluctuating level of consciousness. This is uncommon in an outpatient setting.


The history of a patient with memory loss or cognitive dysfunction is critical. However, the patient may not be able to provide sufficient information, and a corroborative history is needed from family or friends, or both. It is more meaningful when a relative complains that the patient has impaired memory than when the patient complains of memory difficulty. Studies have shown that when a family member complains that the patient’s memory is impaired, the likely diagnosis is dementia; however, when the patient complains of memory difficulty, it is likely depression, not dementia.

The history should document the temporal profile of the symptoms, including the onset, duration, and progression. A gradual onset and slow insidious progression of symptoms characterize degenerative dementias such as AD. Information about any changes in the patient’s activities, and when these changes occurred and why, may help to clarify the onset of symptoms (eg, the patient’s spouse starts managing the checkbook because the patient has been forgetting or making errors). Inquiry about instrumental activities of daily living is useful. These include questions about money management, meal preparation, shopping, traveling, housework, using the telephone, and taking medications. In a hospital setting, a patient with an unrecognized mild dementia may appear to have an acute onset of dementia. A change in familiar surroundings, medications, anesthesia, and a greater risk for an acute confusional state in demented patients are all factors for the “sudden” onset of dementia.

Vascular, traumatic, and toxic causes of dementia can have an acute onset. The onset of multi-infarct dementia can be sudden, with a stepwise deterioration in the patient’s mental status. The progression of symptoms is important. Viral and prion diseases (eg, Creutzfeldt-Jakob disease) are rapidly progressive illnesses that occur over several months. Is the problem one of memory loss or memory lapse? Transient symptoms may suggest partial seizure activity, transient global amnesia, or complicated migraine.

It is common for patients and family members to attribute memory and cognitive decline to normal aging. The distinction between mild dementia and normal cognitive aging can be difficult to make. Complicating this is the marked increase in the incidence of dementia with advancing age. Cognitive functions that decline with age include sustained attention, mental flexibility or the ability to multitask, response speed, and visual memory recall. Preserved function includes immediate attention, vocabulary, temporal orientation, and certain visuospatial skills. A healthy 90-year-old person is able to live independently.

Any history of personality changes is significant. Depression can complicate the diagnosis of dementia. Depression is frequently associated with degenerative dementias, and severe depression can mimic dementia. On mental status examination, patients with depression show diminished attention, memory impairment, apathy, and social withdrawal. Historical points that may lead to the diagnosis of depression include a previous history or family history of depression, sleep difficulty, and vegetative signs of depression. The onset of symptoms may follow a major event such as the death of a spouse. Cognitive testing in depression demonstrates impaired attention and performance variability. Patients frequently respond to questions with “I don’t know.” Some features that distinguish between dementia and depression are listed in Table 8.1.

Table 8.1. Comparison of the Features of Depression and Dementia



Patient complains of memory problem

Patient minimizes memory problem

Relatives concerned about depression

Relatives concerned about memory problem

Vegetative symptoms, anxiety

No or few symptoms of depression

Subacute onset of cognitive symptoms; symptoms follow traumatic event

Insidious onset of cognitive symptoms

History of depression is common

History of depression is less common

Orientation intact

Orientation impaired

Concentration impaired

Recent memory impaired

Variable results on mental status testing

Consistent results on mental status testing

Poor effort on testing

Good effort on testing

Aphasia and apraxia absent

Aphasia and apraxia present

Adapted from Adams AC. Neurology in primary care. Philadelphia (PA): FA Davis; ©2000. p. 139. Used with permission of Mayo Foundation for Medical Education and Research.

In addition to depression, prominent changes in personality early in the course of a dementing illness may suggest a frontal lobe process, for example, a tumor or frontotemporal dementia. Any change in behavior needs to be interpreted with respect to the patient’s previous personality, occupation, and standing in the community. Previous psychiatric illness, such as bipolar affective disorder or schizophrenia, is relevant.

The medical history may suggest the cause of dementia. A history of vascular disease and vascular risk factors are consistent with multi-infarct dementia. A history of thyroidectomy suggests hypothyroidism, and a history of gastrectomy suggests vitamin B12 deficiency. Historical information about head trauma, exposure to toxins, systemic illness, risk factors for human immunodeficiency virus (HIV) infection, alcohol intake, and smoking habits is important. Information also needs to be obtained about what medications the patient is taking, because medications frequently impair cognitive function. Some of the agents that can cause cognitive adverse effects are β‎-blockers, antidepressants, psychotropic drugs, anticonvulsants, histamine2-receptor blockers, and dopamine blockers.

The family history is important. Inherited AD is rare, but genetic factors are likely to play a role in all forms of the disease. Other inherited degenerative dementias include Huntington disease, frontotemporal dementia, Parkinson disease, and prion disease. A positive family history for dementia is a major risk factor for dementia.

Neurologic Examination

When examining a patient who has memory loss, look carefully for neurologic signs. Evidence of any focal neurologic deficit may indicate previous stroke. Abnormal gait is usually seen in Parkinson disease, normal-pressure hydrocephalus, and vascular dementias. If there is evidence of peripheral neuropathy, investigate whether the patient abuses alcohol or has vitamin B12 deficiency, hypothyroidism, or an infectious or inflammatory condition (Box 8.1).

Mental Status Examination

The mental status examination is crucial in the evaluation of memory loss and cognitive impairment. A mild cognitive deficit may not be noticed during superficial conversation or when the history is being taken for an unrelated problem. Major deficits in the history or non sequiturs are reasons to perform a more thorough cognitive evaluation. The mental status examination should determine whether dementia is present. Also, it should establish a baseline status that can be followed at subsequent evaluations. Comprehensive neuropsychometric testing should be performed if the results of mental status screening are equivocal.

Before testing mental status, it is important to be aware of the patient’s mood and motivation. Depression has a marked effect on mental status functioning. Poor motivation also affects performance on tests of cognition. Areas of cognitive function that should be tested are attention, recent and remote memory, language, praxis, visuospatial relationships, judgment, and calculations.

The short screening tests for cognitive impairment such as the Mini-Mental State Examination (MMSE) and the Kokmen, or Short Test of Mental Status (Figure 8.1), are useful, despite the criticism that they are time consuming and insensitive to mild dementia. However, these standardized tests are in widespread use, and the normal values for age and education are known. The results must be interpreted in the context of the patient’s age and education. A score of 23 or less on the MMSE or a score of 29 or less on the Kokmen (Short Test of Mental Status) suggests cognitive impairment. These tests are screening tests only. False-positive results can be obtained if the patient has depression and false-negative results if the patient has high intelligence and mild dementia. Mental status screening tests are valuable for longitudinal screening and should help in making decisions about additional testing.

Figure 8.1. Short Test of Mental Status, or the Kokmen. A, Test; B, Instructions.

Figure 8.1. Short Test of Mental Status, or the Kokmen. A, Test; B, Instructions.

Figure 8.1.
Short Test of Mental Status, or the Kokmen. A, Test; B, Instructions.

(Adapted from Kokmen E, Naessens JM, Offord KP. A short test of mental status: description and preliminary results. Mayo Clin Proc. 1987 Apr;62[4]‌:281–8. Used with permission of Mayo Foundation for Medical Education and Research.)

Understanding cortical anatomy and organization is helpful in interpreting the mental status examination and in understanding abnormalities in patients with cognitive and behavioral disorders (Figure 8.2). The frontal lobe of the brain is involved in executive functions, including attention, planning, evaluating, making decisions, executing motor acts, avoiding distraction, and social skills. The posterior portion of the cerebral hemisphere is receptive, with involvement in sensation, perception, recognition, knowledge, and naming. The right and left hemispheres are distinct. The left hemisphere of the brain can be considered the symbolic hemisphere, with the functions of language and calculation. The right hemisphere is considered holistic and emotional, with the function of visuospatial orientation. The parietal lobe can be considered the “where” portion (eg, spatial relationships) of the cerebral hemisphere and the temporal lobe, the “what” portion (eg, naming objects) (Figure 8.3).

Figure 8.2. Cortical Anatomy. A, Lateral aspect of the left hemisphere of the brain. B, Medial aspect of the right hemisphere. C, Ventral aspect of the brain (with brainstem detached at midbrain). A1 indicates primary auditory cortex; M1, primary motor cortex; PMC, premotor cortex; S1, primary somatosensory cortex; SMA, supplementary motor cortex; V1, primary visual cortex.

Figure 8.2. Cortical Anatomy. A, Lateral aspect of the left hemisphere of the brain. B, Medial aspect of the right hemisphere. C, Ventral aspect of the brain (with brainstem detached at midbrain). A1 indicates primary auditory cortex; M1, primary motor cortex; PMC, premotor cortex; S1, primary somatosensory cortex; SMA, supplementary motor cortex; V1, primary visual cortex.

Figure 8.2.
Cortical Anatomy. A, Lateral aspect of the left hemisphere of the brain. B, Medial aspect of the right hemisphere. C, Ventral aspect of the brain (with brainstem detached at midbrain). A1 indicates primary auditory cortex; M1, primary motor cortex; PMC, premotor cortex; S1, primary somatosensory cortex; SMA, supplementary motor cortex; V1, primary visual cortex.

The first component of the mental status examination that is tested is attention. Inattention can degrade all other cognitive function. Disruption in attention is the defining feature of an acute confusional state. Attention can be tested in several ways, including the use of digit span, as in the Kokmen, or spelling “world” backwards as on the MMSE. Problems with attention may indicate diffuse brain dysfunction, as in a toxic encephalopathy, or frontal lobe dysfunction, as in frontotemporal dementia. Tests of language, including reading and writing, evaluate left hemisphere function. Calculations, right-left orientation, and finger recognition (“show me your left index finger”) test left parietal lobe function or the symbolic “where” aspect of the brain. Visuospatial orientation (the function of the right parietal lobe) can be tested by asking the patient to draw a cube or clock as in the Kokmen. Testing memory and the localization of memory is more complicated. Working memory (eg, remembering a telephone number for a short time) is a function primarily of the frontal lobes. The ability to learn, store, and retrieve information (ie, declarative memory) involves the medial temporal lobes and limbic structures. On both the MMSE and the Kokmen, recall is used to test declarative memory. Remote memories are represented widely throughout the cerebral hemispheres (association cortex) and are the memories most resistant to pathologic change. The functional areas of the cerebral cortex are shown in Figure 8.4.

Figure 8.4. Functional Areas of the Cerebral Cortex.

Figure 8.4. Functional Areas of the Cerebral Cortex.

(Adapted from Adams AC. Neurology in primary care. Philadelphia [PA]: FA Davis; ©2000. p. 142. Used with permission of Mayo Foundation for Medical Education and Research.)

The evaluation of mental status depends on the patient’s use of language. Memory complaints may actually represent aphasia or a language problem. Pay attention to the patient’s speech during the interview. Fluency of speech is usually normal if the patient uses sentences with 7 or more words. Phonemic (“the sky is glue”) or paraphasic (“the sky is cheese”) errors indicate a language problem. The MMSE assesses language by having the patient name objects, repeat a phrase, and read and write a sentence. To test for comprehension, ask the patient to perform a 3-stage command, for example, “Look up, raise your hand, and point to the door.” A test that can be used for a more thorough evaluation of languages is shown in Figure 8.5.

Figure 8.5. Language Screen Examination.

Figure 8.5. Language Screen Examination.

Figure 8.5.
Language Screen Examination.

(C, Courtesy of Bradley F. Boeve, MD, and Joseph R. Duffy, PhD. Used with permission of Mayo Foundation for Medical Education and Research. E, Adapted from Goodglass H, Kaplan E, Barresi B. Boston diagnostic aphasia examination. 3rd ed. Philadelphia [PA]: Lippincott Williams & Wilkins; ©2001. Used with permission in print version only. Remove from legend for e-version.)

Further neuropsychologic testing may be indicated if the results of the initial evaluation are borderline or suggestive of dementia. Neuropsychologic tests are helpful in identifying dementia in highly intelligent persons who may have normal results on mental status screening evaluations. In addition, these tests may be needed for patients with limited educational background or for people with intellectual disabilities, because of the limitations of mental status screening tests. Neuropsychologic tests are recommended for distinguishing between dementia and depression, for determining competency for legal purposes, and for determining disability. As with screening tests, a baseline study with follow-up evaluation may be necessary to make the diagnosis of dementia.

Laboratory Investigation

The laboratory work-up in the evaluation of dementia is dictated by the findings of the history and physical examination. Laboratory tests are performed to exclude metabolic and structural causes of dementia that may be amenable to specific treatment. The routine tests recommended by the American Academy of Neurology include a complete blood count; serum level of electrolytes (including calcium), glucose, blood urea nitrogen, creatinine, vitamin B12, free thyroid index, and thyroid-stimulating hormone; and liver function tests. For the initial evaluation of patients with dementia, structural neuroimaging with either noncontrast computed tomography (CT) or magnetic resonance imaging (MRI) is appropriate. Optional studies include the syphilis serologic test, erythrocyte sedimentation rate, serum folate level, HIV test, chest radiography, urinalysis, 24-hour urine collection for heavy metals, toxicology screen, neuropsychologic testing, cerebrospinal fluid (CSF) analysis, electroencephalography (EEG), positron emission tomography (PET), and single-photon emission computed tomography (SPECT).

CSF analysis is recommended in the evaluation of dementia if a central nervous system infection, metastatic cancer, or central nervous system vasculitis is a possibility. Consider CSF analysis if there are atypical features such as the onset of symptoms before age 55 years or rapid progression of symptoms. The CSF 14-3-3 protein assay is useful for confirming the diagnosis of Creutzfeldt-Jakob disease. Be aware that acute neurologic conditions such as stroke, viral encephalitis, and paraneoplastic disorders can give false-positive results on this immunoassay. Before performing a lumbar puncture for CSF analysis, review the indications and contraindications for the procedure (see Chapter 2).

CSF levels of amyloid-β‎ 1-42 and phosphorylated tau may become useful biomarkers in the future. AD is associated with a decrease in CSF amyloid-β‎ 1-42 thought to be related to the accumulation of it in the brain. Phosphorylated tau is thought to be a biomarker for neuronal injury and degeneration.

Removal of CSF is therapeutic for patients who have normal-pressure hydrocephalus. The clinical features of normal-pressure hydrocephalus include dementia, gait disturbance, and incontinence. Brain imaging studies show ventricular enlargement out of proportion to cortical atrophy. Ventricular shunting may be reasonable to consider if the patient’s gait improves after CSF has been removed (see “Normal Pressure Hydrocephalus” later in this chapter).

EEG may have some value in investigating possible dementia. Patients who have cognitive impairment and seizures should have EEG. This test may be valuable in distinguishing between delirium and dementia or in evaluating any patient who has a fluctuating level of consciousness. EEG may also be helpful in distinguishing between dementia and depression. If a patient has depression, one would expect the EEG to be normal, compared with a slow pattern likely to be seen if the patient has dementia. The EEG of a patient who has a rapid decline in cognitive function over a 3-month period or less and early neurologic findings may suggest prion disease. Creutzfeldt-Jakob disease often shows characteristic sharp waves on EEG (Figure 8.6).

Figure 8.6. Electroencephalogram of a 48-Year-Old-Patient With Creutzfeldt-Jakob Disease Showing Generalized Triphasic Waves.

Figure 8.6. Electroencephalogram of a 48-Year-Old-Patient With Creutzfeldt-Jakob Disease Showing Generalized Triphasic Waves.

(Adapted from Westmoreland BF. Clinical EEG manual. [cited 2015 Dec 16]. Available from: Used with permission of Mayo Foundation for Medical Education and Research.)

Neuroimaging is reasonable at least once in the evaluation of patients with dementia. CT can detect all the potentially treatable causes of dementia, including tumor, subdural hematoma, hydrocephalus, and stroke. MRI is more sensitive for detecting vascular and demyelinating disease, and it often shows nonspecific white matter changes. The term used to describe periventricular white matter abnormalities is leukoaraiosis (Figure 8.7). It is observed commonly in MRI scans of elderly patients and is thought to reflect vascular brain injury. Leukoaraiosis, or white matter hyperintensities, is also seen in multiple sclerosis, in certain infections, and after cardiac arrest. Leukoaraiosis is recognized as a risk factor for dementia. On CT, leukoaraiosis appears as areas of low attenuation in the periventricular region.

Figure 8.7. Magnetic Resonance Image of Leukoaraiosis (arrows) in a Patient With Alzheimer Disease.

Figure 8.7. Magnetic Resonance Image of Leukoaraiosis (arrows) in a Patient With Alzheimer Disease.

The role of MRI in the evaluation of dementia is likely to expand in the future. It has been shown that quantitative measurements of brain structures and size made with MRI have some predictive value in the diagnosis of AD. MRI is superior to CT in demonstrating atrophy. Atrophy of the cerebral cortex, hippocampi, and cerebellum evolves with age. It is important not to overinterpret atrophy seen on MRI scans of patients older than 80 years and not to underinterpret the findings in patients younger than 65. Both coronal and axial images are useful in the evaluation of dementing disorders. Coronal images are better for showing temporal atrophy, and axial images are better for showing focal atrophy of the frontal, parietal, and occipital lobes (Figure 8.8). MRI can also detect microhemorrhages that are seen in amyloid angiopathy.

Figure 8.8. Axial and Coronal Images in Alzheimer Dementia (AD) and Frontotemporal Dementia (FTD). Coronal images show hippocampal and temporal cortical atrophy better than axial images. However, axial images show focal frontal, parietal, and occipital cortical atrophy better than coronal images.

Figure 8.8. Axial and Coronal Images in Alzheimer Dementia (AD) and Frontotemporal Dementia (FTD). Coronal images show hippocampal and temporal cortical atrophy better than axial images. However, axial images show focal frontal, parietal, and occipital cortical atrophy better than coronal images.

PET and SPECT, which measure glucose metabolism and regional blood flow, respectively, may also be used in the evaluation of dementia. In patients with AD, glucose metabolism and cerebral blood flow are decreased in the temporoparietal region compared with those of normal controls. Although cerebral blood flow patterns are not specific for a given disease, they may be useful for distinguishing AD from vascular or frontotemporal dementia. The clinical usefulness of these tests is being established.

PET amyloid imaging is rapidly advancing and may be useful to detect early AD pathology in a living patient. Amyloid imaging is useful for estimating β‎-amyloid neuritic plaque density in the brain (Figure 8.9). Neuroimaging and CSF biomarkers have been incorporated into diagnostic recommendations and are anticipated to become applicable in clinical practice. The indications for optional laboratory tests used in the evaluation of memory loss are summarized in Table 8.2. The laboratory tests for dementia and the rationale for each one are summarized in Table 8.3.

Figure 8.9. Amyloid Positron Emission Tomography Imaging Using Pittsburgh Compound B.

Figure 8.9. Amyloid Positron Emission Tomography Imaging Using Pittsburgh Compound B.

Table 8.2. Indications for Diagnostic Tests in Evaluation of Dementia



Routine dementia screen

  • Complete blood count

  • Electrolytes, including calcium; glucose; BUN; creatinine

  • Liver function tests

  • Thyroid function tests

  • Vitamin B12

  • Head CT or MRI

Clinical suspicion of infection

Syphilis serology

  • CNS infection

  • CNS vasculitis

  • Metastatic cancer

  • Rapidly progressive dementia

  • Early age at symptom onset

Cognitive Loss

CSF analysis

Normal-pressure hydrocephalus

Lumbar puncture

  • Dementia versus delirium

  • Dementia versus depression

  • Seizures

Cognitive Loss


  • Suspicious or borderline mental status screening test results

  • Dementia versus depression

  • Legal competency determination

  • Baseline

Cognitive Loss

Neuropsychologic tests

Abbreviations: BUN, blood urea nitrogen; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalography; MRI, magnetic resonance imaging.

Adapted from Adams AC. Neurology in primary care. Philadelphia (PA): FA Davis; ©2000. p. 144. Used with permission of Mayo Foundation for Medical Education and Research.

Table 8.3. Laboratory Tests for Differential Diagnosis of Dementia


Evaluation for

Complete blood count

Anemia, infection

Electrolytes, including calcium; glucose

Metabolic dysfunction


Endocrine dysfunction

BUN, creatinine

Renal dysfunction

Liver function tests

Liver dysfunction

Thyroid function


Vitamin B12

Vitamin B12 deficiency

Syphilis serology



Vascular disease, mass lesion, hydrocephalus, demyelinating disease, focal and diffuse atrophy

CSF analysis

Chronic meningitis, syphilis, vasculitis, meningeal carcinomatosis


Seizures, Creutzfeldt-Jakob disease, metabolic disturbances

Heavy metal screen

Lead, mercury, arsenic intoxication

Erythrocyte sedimentation rate

Inflammatory disease

Antinuclear antibody

Inflammatory disease

Anti-extractable nuclear antibodies

Inflammatory disease


HIV dementia

Chest radiography

Cardiopulmonary disease, lung tumor


Cardiopulmonary disease


Focal cortical atrophy, frontotemporal dementia

Long-chain fatty acids


Arylsulfatase A

Metachromatic leukodystrophy

Ceruloplasmin, copper level

Wilson disease



Cerebral biopsy

Inflammatory or infectious disease

Paraneoplastic antibodies


Abbreviations: BUN, blood urea nitrogen; CSF, cerebrospinal fluid; CT, computed tomography; ECG, electrocardiography; EEG, electroencephalography; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography.

Adapted from Adams AC. Neurology in primary care. Philadelphia (PA): FA Davis; ©2000. p. 145. Used with permission of Mayo Foundation for Medical Education and Research.

Mild Cognitive Impairment

The term mild cognitive impairment (MCI) is used to define the condition of elderly persons who have impaired memory but not dementia or disability. The concept of MCI was developed with the assumption that there is a cognitive continuum between normal cognitive function and AD. Patients in whom a degenerative dementia develops undergo a transition phase of mild impairment. Among patients with MCI, the rate of progression to AD is high, with estimates of 10% to 15% per year. This point emphasizes the importance of diagnosis and therapeutic intervention at an early stage, namely MCI.

The National Institute on Aging and the Alzheimer’s Association revised the diagnostic criterion for the symptomatic predementia phase of AD (or MCI due to AD). The first criterion for the clinical and cognitive syndrome of MCI includes a concern regarding a change in cognition in comparison to the patient’s previous level. This concern can be from the patient, family member or informant who knows the patient well, or a skilled clinician. The second criterion is impairment in 1 or more cognitive domains including memory, executive function, attention, language, and visuospatial skills. This impairment should be lower than expected for the patient’s age and educational background. The third clinical criterion is preservation of independence in functional abilities. The fourth clinical criterion is that the patient should not be demented and has no evidence of significant impairment in social or occupational functioning. MCI consistent with AD should exclude vascular, traumatic, and medical causes of cognitive decline. Additionally, evidence of longitudinal decline in cognition should be provided.

Subtypes of MCI have been described. Patients with prominent memory impairment have amnestic MCI. Patients with impairment in more than 1 cognitive domain have multiple-domain MCI. Patients who have cognitive impairment in a single domain other than memory have single nonmemory domain MCI. For example, this may include executive function or language. This subtype of MCI may progress to frontotemporal dementia or primary progressive aphasia. Each clinical subtype can have various causes, including vascular, metabolic, traumatic, and degenerative causes.

The use of CSF and neuroimaging biomarkers can facilitate the identification of patients with MCI due to AD. They may also provide prognostic information. At the current time, biomarkers are used for research purposes.

As noted above, the rate of progression of MCI to dementia is high. Poor performance on cued memory tasks may be a clinical indicator of those at higher risk for progression to AD. Hippocampal atrophy has also been reported to be predictive of a more rapid progression to AD. This rate is variable, but 10% to 15% annually is the range reported, as compared with the 1% to 2% annually for normal older adults. This emphasizes the importance of early recognition and treatment. Despite the use of cholinesterase inhibitors in clinical practice, their use in MCI is not indicated.

Alzheimer Disease

AD is the most common form of dementia. The definitive diagnosis is made at autopsy, with the demonstration of neuronal loss, neurofibrillary tangles, neuritic plaques, and amyloid angiopathy. However, autopsy studies have confirmed that the clinical diagnosis of AD has a high rate of accuracy.

The criteria used for the diagnosis of AD were developed by the National Institute on Aging and the Alzheimer’s Association revised from previous criteria found in the Diagnostic and Statistical Manual, Fourth Edition, Text Revision, and those of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (Box 8.2).

Abbreviation: AD, Alzheimer disease.

Adapted from McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3):263-9. Epub 2011 Apr 21. Used with permission.

AD is a complex and heterogeneous disorder, and many genes have been identified with its development. Genes associated with AD include the amyloid β‎-protein precursor on chromosome 21, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1. A genetic risk factor identified with AD is apolipoprotein E-4 (APOE-4). APOE is on chromosome 19, with 3 alleles (2, 3, and 4). APOE*4 is a susceptibility gene; it does not cause the disease but may modulate the age at onset and increase the probability of the disease developing. Apolipoprotein is a plasma protein produced in the brain by astrocytes. It is involved with cholesterol transport and is found in neuritic plaques, neurofibrillary tangles, and vascular amyloid. Apolipoprotein binds strongly to amyloid protein. A patient with dementia who has the APOE*4 genotype is more likely to have AD than any other dementing illness. APOE genotyping has been suggested as a predictive test for AD, but the genotype is not necessary or sufficient for the diagnosis. Currently, APOE*4 testing is not recommended for diagnosing or predicting AD. Testing for amyloid β‎-protein precursor, presenilin 1, and presenilin 2 may be appropriate in families with an autosomal dominant pattern of inheritance of dementia. Appropriate genetic counseling should be part of genetic testing.

When the risk of developing AD is discussed with family members, emphasize that it is an age-related disease. Although the risk of developing the disorder increases with age, patients in whom it develops live a substantial portion of their lives without the disease. The risk of the disease in the population with a negative family history is about 8% per decade starting at age 70 years. In persons with a first-degree family member with the disorder, the risk doubles. The age at onset of dementia is also correlated in families. Despite all this, the chances are greater that first-degree relatives will not develop the disease.

Many risk factors have been identified for AD. Primary risk factors are age, positive family history, and, for persons older than 80 years, female sex. Other primary risk factors include the cerebrovascular risk factors of hypertension, diabetes mellitus, obesity, and hypercholesterolemia. Possible risk factors for AD include head injury, low educational attainment, hyperhomocysteinemia, folate deficiency, hyperinsulinemia, depression, and low thyroid-stimulating hormone levels (but within the normal range). The increased risk associated with head injury is thought to be related to an increase in amyloid deposition, neuronal injury, and synaptic disruption.

Factors that may help prevent or delay the onset of AD are being investigated for potential therapies. Possible protective factors include regular consumption of fish and omega-3 fatty acids, high educational attainment, regular exercise, moderate alcohol consumption, nonsteroidal antiinflammatory medications, folate, and vitamins C, E, B6, and B12 supplementation.

Epidemiologic reports suggested estrogen replacement therapy in postmenopausal women may reduce the occurrence of AD, but randomized, placebo-controlled trials did not show benefit. The Women’s Health Initiative study of estrogen and medroxyprogesterone showed an increased risk of dementia. Currently, estrogen is not recommended for the treatment and prevention of AD.

The diagnosis of AD is understandably devastating to the patient and family. The diagnosis is a “family” diagnosis because of the major effect the disease will have on the patient’s caregiver. The patient and caregiver need to know that the disease is progressive and that cognition and function will decline continuously. Changes in the patient’s behavior and personality are common and part of the dementing process. Although there is no cure for the disease, many of the common symptoms can be treated. The clinician often needs to attend to the caregiver as much as to the patient. In addition to the medical management of the disease, clinicians have an important part in addressing issues of living arrangements, legal matters, and whether the patient should drive a motor vehicle.

The strategy in the treatment of AD is to improve the patient’s quality of life and to maximize function. Several pharmacologic treatments are based on the neurodegenerative mechanisms involved in the disease. For example, the observation of a cholinergic deficit in the cerebral cortex of patients with AD led to the development of the first cholinesterase inhibitor, tacrine. Clinical studies have demonstrated that cholinesterase inhibitors have a modest benefit in treating the clinical symptoms of mild-to-moderate AD. Three cholinesterase inhibitors have been approved by the US Food and Drug Administration for the treatment of mild-to-moderate dementia (Table 8.4). Common adverse effects include nausea, vomiting, and diarrhea. These effects may be reduced by introducing the medication at the lowest dose and gradually increasing it.

Table 8.4. Symptomatic Treatment of Dementia


Nonpharmacologic Therapy

Pharmacologic Therapy, Dose

Adverse Effects

Cognitive impairment

Compensatory strategies: notes, pillbox, calendar, signs

  • Cholinesterase inhibitors

  • Donepezil, 5 mg daily, may increase to 10 mg daily in 4 weeks, 23 mg sustained release

Nausea, diarrhea, insomnia, twice the rate of adverse events with 23 mg

Galantamine, 4 mg twice daily (with food) for 4 weeks, may increase if tolerated every 4 weeks to maximum 32 mg daily

Nausea, diarrhea, insomnia

Rivastigmine, 1.5 mg twice daily (with food), may increase every 2 weeks to maximum 6 mg twice daily; 4.6, 9.5, or 13.3 mg per 24 h transdermal patch

Nausea, diarrhea, insomnia, avoids first-pass hepatic metabolic effect

  • N-methyl- d-aspartate antagonist

  • Memantine, 5 mg once daily; increase dose at minimum 1-week intervals in 5-mg increments to 5 mg twice daily to target dose of 20 mg/day

Dizziness, constipation, headache, hypertension

Agitation, hallucinations, delusions

Redirect patient, reassure patient and caregiver

  • Haloperidol (Haldol), 0.25 mg daily

  • Risperidone (Risperdal), 0.5 mg twice daily

  • Quetiapine (Seroquel), 25 mg twice daily

  • Parkinsonism, tardive dyskinesia, postural hypotension

  • Nausea, insomnia, parkinsonism

  • Hypotension, somnolence


Modify environment, music, reduce demands on patient

  • Sertraline (Zoloft), 50 mg daily

  • Paroxetine (Paxil), 10 mg every morning

  • Nausea, diarrhea, insomnia

  • Somnolence, insomnia


Improve sleep hygiene, eliminate or limit naps, daytime exercise, avoid caffeine and night-lights

Trazodone (Desyrel), 25 mg at bedtime

Oversedation, hypotension

Anxiety, agitation

Reassurance, lessen demands on memory, reduce noise

Lorazepam (Ativan), 0.5 mg 1–2 times daily

Sedation, confusion, falls, dependency

Adapted from Adams AC. Neurology in primary care. Philadelphia (PA): FA Davis; ©2000. p. 148. Used with permission of Mayo Foundation for Medical Education and Research.

Overstimulation of N-methyl-d-aspartate (NMDA) receptors by glutamate has been implicated in dementia and other neurodegenerative disorders. On the basis of this, memantine, an NMDA receptor antagonist, has been used to treat moderate-to-severe AD. Memantine therapy has been associated with a decreased rate in the deterioration of global, cognitive, and functional measures. Behavioral improvement has also been noted, particularly for agitation. Memantine and cholinesterase inhibitors are often used together because of their different mechanisms of action.

Antioxidant agents are being investigated for treating AD. Free radicals, byproducts of oxidative metabolism, damage cell membranes and tissues. According to the oxidative stress hypothesis of neuronal death, antioxidants should prevent cytotoxic injury. Selegiline, a monoamine oxidase inhibitor, may act as an antioxidant and reduce neuronal damage. It also may improve cognitive deficits by increasing levels of catecholamines. Vitamin E (α‎-tocopherol), another antioxidant, is being investigated for preventing or slowing the progression of AD. Despite the theoretical value of these agents, the evidence is not sufficient to make recommendations about treatment.

Epidemiologic studies have suggested that nonsteroidal antiinflammatory drugs, statins, and estrogen may have a preventative effect in AD, but these findings were not confirmed by prospective trials. An herbal remedy extracted from the leaves of the ginkgo tree, Ginkgo biloba, is claimed to be effective in treating memory deficits. Its mechanism of action is not known, but it may be an antioxidant. Although a randomized trial reported the extract had a slight positive effect on dementia, several flaws have been cited in the study, limiting its usefulness. Although ginkgo has platelet-inhibiting effects, bleeding is not a common adverse effect. Reported adverse effects include mild gastrointestinal symptoms, headache, and allergic reactions. The purity and potency of the extract are not known. Currently, no recommendation can be made about ginkgo.

Dementia-related behavioral symptoms are common. Problems include sleep disruption, agitation, depression, hallucinations, and delusions. Before treatment is initiated with a psychoactive drug, the specific behavior needs to be documented and its cause or contributing factors investigated. Some of the causes of abnormal behavior are pain, depression, medication effect, infection, physical limitations, and hospitalization. Intervention may not be needed if safety is not an issue, if the patient is not distressed, or if the living situation is not compromised. Often, nonpharmacologic approaches can be used.

When psychoactive drugs are prescribed, they should be prescribed on a scheduled basis instead of an as-needed basis. One drug should be prescribed and started at a very low dose and the dose slowly increased until the desired therapeutic effect occurs. Monitor the patient’s condition regularly to assess response and adverse effects to the medication. Attempts should be made periodically to discontinue the treatment. Some pharmacologic and nonpharmacologic options for symptomatic treatment of dementia are summarized in Table 8.4.

Dementia With Lewy Bodies

Dementia with Lewy bodies (DLB) is a distinct clinical and neuropathologic dementia syndrome. It is the second most common dementing disorder, accounting for 15% to 25% of all cases of dementia. Lewy bodies are eosinophilic neuronal inclusion bodies; when present in subcortical nuclei, they are a pathologic hallmark of idiopathic Parkinson disease. These inclusion bodies occur in the brainstem and cerebral cortex of patients who have DLB.

Similar to AD, the clinical criteria for the diagnosis of DLB include progressive cognitive decline that interferes with normal social and occupational functions. Memory may not be impaired in the early stages but is involved as the disease progresses. Prominent deficits are apparent on tests of attention and executive and visuospatial ability. The core features of DLB are fluctuating cognition with pronounced variation in attention and alertness, recurrent visual hallucinations that are particularly well formed and detailed, and spontaneous motor features of parkinsonism (ie, bradykinesia, resting tremor, rigidity, and loss of postural reflexes). Suggestive features include rapid eye movement sleep behavior disorder and severe neuroleptic sensitivity. Neuroleptic hypersensitivity is very important in the management of this disease. Other clinical features that support the diagnosis are repeated falls, syncope, delusions, transient loss of consciousness, and hallucinations (auditory, olfactory, or tactile). Although no diagnostic tests are available for DLB, low dopamine transporter uptake in basal ganglia seen with PET or SPECT is a suggestive feature of the disease. Supportive features include relative preservation of medial temporal lobe structures as seen with MRI or CT scans, generalized hypometabolism on SPECT and PET perfusion scans with reduced occipital activity, and prominent slow wave activity on EEG with temporal lobe transient sharp waves. The criteria for the clinical diagnosis of DLB from the third report of the Dementia With Lewy Bodies Consortium are summarized in Box 8.3.

Abbreviation: REM, rapid eye movement.

Adapted from McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, et al; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005 Dec 27;65(12):1863-72. Epub 2005 Oct 19. Erratum in: Neurology. 2005 Dec 27;65(12):1992. Used with permission.

The differential diagnosis of DLB includes AD and Parkinson disease. All 3 disorders occur with higher frequency in older age groups. Both DLB and Parkinson disease show a male predominance. Unlike AD and Parkinson disease, DLB can have an abrupt onset and a fluctuating and rapid progression, a feature that may cause this disease to be confused with delirium. Visual hallucinations and other psychotic symptoms are prominent features of DLB, and although hallucinations occur in AD, they are usually a late feature. The timing of the dementia is used to differentiate DLB from Parkinson disease dementia. DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism. The term Parkinson disease dementia should be used to describe dementia that occurs in the context of well-established (1 year) Parkinson disease. The clinical features of these 3 disorders are summarized in Table 8.5.

Table 8.5. Comparison of the Clinical Features of Dementia With Lewy Bodies, Alzheimer Disease, and Parkinson Disease

Clinical Feature

Dementia With Lewy Bodies

Alzheimer Disease

Parkinson Disease

Initial symptom

Confusional state

Memory impairment

Tremor, bradykinesia, rigidity


Abrupt or insidious




Fluctuating, rapid



Sex distribution

Male > female

Female > male

Male > female

Prominent feature

Visual hallucinations


Tremor, bradykinesia, rigidity

Adapted from Adams AC. Neurology in primary care. Philadelphia (PA): FA Davis; ©2000. p. 149. Used with permission of Mayo Foundation for Medical Education and Research.

The treatment of DLB is the same as that for AD (Table 8.4). Cholinesterase inhibitors are reasonable for symptomatic treatment of the patient’s cognitive impairment and some neuropsychiatric symptoms. The parkinsonism can be treated with carbidopa/levodopa, but care needs to be taken to avoid exacerbating psychiatric symptoms. Because irreversible parkinsonism developed after treatment with neuroleptics, the recommendation was made to avoid these agents. Neuroleptic sensitivity can occur with atypical neuroleptics such as risperidone, olanzapine, clozapine, and quetiapine. They can be given at low dose but may be of limited benefit. The management of orthostatic hypotension (see Boxes 5.1 and 5.2) and sleep disorders (see Tables 9.11–9.13) are discussed in other chapters.

Vascular Cognitive Impairment

Cerebrovascular disease is an important cause of cognitive impairment. Terms used for cognitive impairment associated with cerebrovascular disease have included multi-infarct dementia, vascular dementia, and vascular cognitive impairment (VCI). The American Heart Association and American Stroke Association define VCI as a syndrome with evidence of clinical stroke or subclinical vascular brain injury and cognitive impairment affecting at least 1 cognitive domain. Disorders include multiple infarcts, strategic infarct, small-vessel disease, hypoperfusion, or hemorrhage. In VCI, there is a temporal relation between the clinical characteristics of dementia and cerebrovascular disease. Evidence of cerebrovascular disease can be demonstrated by history (sudden-onset dementia, fluctuating course), clinical examination, and brain imaging (MRI or CT). The temporal relation between a stroke and the onset of dementia is probably the best predictor of VCI.

VCI can occur purely from cerebrovascular disease or be mixed—that is, caused by cerebrovascular disease and degenerative changes like AD. Strokes and AD can occur together. The risk factors for stroke-like hypertension, hypercholesterolemia, or diabetes mellitus are risk factors of VCI and AD. Vascular dementia is a common cause of dementia.

VCI is heterogeneous. Multi-infarct dementia is a common subtype. The dementia results from multiple, bilateral cortical and subcortical infarcts. Multi-infarct dementia occurs more often in men than in women. Hypertension and peripheral vascular disease are often associated with this dementia. The cognitive and neurologic findings vary depending on the location of the infarcts; however, gait disturbances, urinary incontinence, and pseudobulbar palsy are common. Pseudobulbar palsy is a syndrome characterized by emotional incontinence and slow, strained speech.

VCI and dementia can also result from a single infarct in a functionally important cortical or subcortical area. For example, a thalamic infarct can produce disturbances in attention, memory, language, and abstract thinking. An infarct in the left angular gyrus or left frontal lobe can impair memory. Infarcts of the caudate nuclei or right parietal lobe can also impair cognition. If dementia occurs acutely, consider the diagnosis of vascular dementia due to a strategic single infarct.

Another cause of VCI is small-vessel disease. Hypertension and diabetes mellitus are frequently associated with small-vessel cerebrovascular disease. Chronic ischemia due to hypertension and arteriolar sclerosis produces central white matter demyelination, with leukoaraiosis seen on brain imaging studies (Figure 8.7). Diffuse brain ischemia due to cardiac arrest or severe hypotension can also cause VCI.

Chronic subdural hematomas, subarachnoid hemorrhage, and cerebral hemorrhage all can impair cognition. The term hemorrhagic dementia has been used for this subtype of VCI. VCI is treated by reducing cerebrovascular risk factors and preventing additional strokes (see Chapter 11). Cholinesterase inhibitors have not been shown to be helpful but might be reasonable in patients who have evidence of both vascular and degenerative disease. Symptomatic treatment of VCI is the same as that for AD (Table 8.4).

Normal-Pressure Hydrocephalus

Normal-pressure hydrocephalus (NPH) is characterized by the triad of dementia, gait disturbance, and urinary incontinence. It is important to recognize this disorder early in its course because it potentially can be treated with shunting (Cognitive Loss Video 8.1A and B). NPH is separated into idiopathic (iNPH) and secondary NPH. Disorders that interfere with CSF absorption, for example, subarachnoid hemorrhage, meningitis, and trauma, are associated with secondary NPH.

Despite normal CSF pressure, as determined with lumbar puncture, NPH causes enlargement of the lateral ventricles and, thus, compression of adjacent structures. The dementia in this condition is thought to be caused by compression of the cerebral cortex, and it is difficult to distinguish from the dementia of AD. The radiographic feature of this disorder is enlarged ventricles disproportionate to cortical atrophy (Figure 8.10).

Figure 8.10. Magnetic Resonance Images of Normal-pressure Hydrocephalus (A) and Alzheimer Disease (B).

Figure 8.10. Magnetic Resonance Images of Normal-pressure Hydrocephalus (A) and Alzheimer Disease (B).

The gait disorder in NPH is characterized by slow short steps, reduced step height, and a widened base (Cognitive Loss Video 8.2). It is often described by the terms magnetic and lower half Parkinson. Magnetic refers to the shuffling nature of the steps. As in Parkinson disease, the patient may have a slow and stiff gait and the tendency to move en bloc. However, the arm swing is normal, unlike the reduced arm swing in Parkinson disease. The incontinence in NPH results from an uninhibited bladder (see Table 4.3).

The earlier the diagnosis of NPH is made, the greater the chance of reducing the symptoms with a shunt. A useful test to determine the potential benefit from shunting is to remove 30 to 50 mL of CSF and see if the clinical symptoms improve. The American Academy of Neurology practice guidelines reported shunting as possibly effective in iNPH with an 83% chance of improvement on timed walk test at 6 months. The serious adverse event risk was 11%. Predictors of success included an elevated Ro (measure of outflow resistance during CSF infusion test), impaired cerebral blood flow reactivity to acetazolamide by SPECT, and a positive response to external lumbar drainage or repeated lumbar punctures.

Frontotemporal Dementia

The term frontotemporal dementia includes focal degenerative dementias of the frontal and temporal lobes. The clinical features include behavioral and language problems. Frontotemporal dementia, previously called Pick disease, has 3 anatomical variants: the frontal variant, temporal variant (also called semantic dementia), and left frontal-predominant variant (also called progressive nonfluent aphasia).

Patients with frontotemporal dementia may become disinhibited and exhibit inappropriate social behavior, which reflects the involvement of orbitofrontal cortex. Other frontal lobe behavioral abnormalities may include apathy, lack of motivation, and little response to stimuli. The predominant clinical feature in the temporal variant of frontotemporal dementia is impaired understanding of word meaning or object identity (agnosia) or both. This reflects pronounced degeneration of the left temporal lobe. A disorder of expressive language is the dominant clinical feature of patients with predominant left frontal lobe degeneration. The features of the 3 subtypes as developed by an international collaborative on frontotemporal dementia are summarized in Table 8.6.

Table 8.6. Frontotemporal Dementia Variants


Core Diagnostic Features

Supportive Diagnostic Features

Speech and Language


Physical Signs



  • Insidious onset and gradual progression

  • Early decline in social interpersonal conduct

  • Early impairment in regulation of personal conduct

  • Early emotional blunting

  • Early loss of insight

  • Altered speech output

  • Aspontaneity and economy of speech

  • Press of speech

  • Stereotype of speech

  • Echolalia

  • Perseveration

  • Mutism

  • Decline in personal hygiene and grooming

  • Mental rigidity and inflexibility

  • Distractibility and impersistence

  • Hyperorality and dietary changes

  • Perseverative and stereotyped behavior

  • Utilization behavior

  • Primitive reflexes

  • Incontinence

  • Akinesia, rigidity, and tremor

  • Low and labile blood pressure

  • Neuropsychology—significant impairment on frontal lobe tests in absence of severe amnesia, or perceptuospatial disorder

  • EEG—normal on conventional EEG despite clinically evident dementia

  • Brain imaging (structural and/or functional)—predominant frontal and/or anterior temporal abnormality

Temporal (semantic dementia)

  • Insidious onset and gradual progression

  • Language disorder characterized by:

  • Progressive, fluent, empty spontaneous speech

  • Loss of word meaning, manifest by impaired naming and comprehension

  • Semantic paraphasias

  • and/or

  • Press of speech

  • Idiosyncratic word usage

  • Absence of phonemic paraphasias

  • Surface dyslexia and dysgraphia

  • Preserved calculation

  • Loss of sympathy and empathy

  • Narrowed preoccupations

  • Parsimony

Absent or late primitive reflexes, akinesia, rigidity, and tremor

  • Neuropsychology—

  • Profound semantic loss, manifest in failure of word comprehension and naming and/or face and object recognition

  • Preserved phonology and syntax, and elementary perceptual processing, spatial skills, and day-to-day memorizing



Speech and Language


Physical Signs


  • Perceptual disorder characterized by:

  • Prosopagnosia (impaired recognition of identity of familiar faces)

  • and/or

  • Associative agnosia (impaired recognition of object identity)

  • Preserved perceptual matching and drawing reproduction

  • Preserved single-word repetition

  • Preserved ability to read aloud and write orthographically regular words from dictation

  • EEG—normal

  • Brain imaging (structural and/or functional)—predominant anterior temporal abnormality (symmetrical or asymmetrical)

Left frontal-predominant (progressive nonfluent aphasia)

  • Insidious onset and gradual progression

  • Nonfluent spontaneous speech with at least 1 of the following: agrammatism, phonemic paraphasias, anomia

  • Stuttering or oral apraxia

  • Impaired repetition

  • Alexia, agraphia

  • Early preservation of word meaning

  • Late mutism

  • Early preservation of social skills

  • Late behavioral changes similar to frontal variant

Late contralateral primitive reflexes, akinesia, rigidity, and tremor

  • Neuropsychology—nonfluent aphasia in the absence of severe amnesia or perceptuospatial disorder

  • EEG—normal or minor asymmetrical slowing

  • Brain imaging (structural and/or functional)—asymmetrical abnormality predominantly affecting dominant (usually left) hemisphere

Abbreviation: EEG, electroencephalography.

Adapted from Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998 Dec;51(6):1546–54. Used with permission.

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