Behavioral Neurology and Psychiatry

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Dementias

1. Definition: cognitive impairment that does not achieve the criteria for dementia because the degree of impairment does not significantly affect the patient’s activities of daily living

2. Subtypes

a. amnestic MCI/age-related memory loss: an objective impairment of memory function in comparison with the normal range for the patient’s age, which does not involve significant impairment of other cognitive functions or impair the patient’s activities of daily living

i.    15% of cases/year develop into Alzheimer’s disease, which is ~ 10 times the incidence of non-MCI patients; the incidence of progression to Alzheimer’s disease is increased in MCI patients who express the apolipoprotein E (APOE) ε4 allele

(1) small hippocampal and/or entorhinal cortex volumes on a MRI scan may also predict progression of MCI to Alzheimer’s disease, although the rate of volume loss is not helpful

c. MCI with impairment in multiple domains

3. Treatment: none yet established

B. Definition of Dementia

1. In general, impairment of at least two of five functional domains (memory, language, visuospatial, emotion, executive) that affects the patient’s activities of daily living

a. dementia is usually suspected in patients who have a mini-mental status exam (MMSE) score < 24, but performance is dependent upon the patient’s age and education background; therefore, use the MMSE only for screening, not for establishing the diagnosis

i.    MMSE < 24 often does not identify non-Alzheimer’s dementias

Figure 7–1 Epidemiology of major dementing disorders. (A) <65 years old; (B) >65 years old. (AD, Alzheimer’s dementia; Lewy, Lewy body dementia)

c. endocrine disorders: hypo- and hyperthyroidism, hyperparathyroidism, adrenal failure or Cushing’s syndrome

d. toxin-induced: heavy metal exposure, drugs, alcohol

e. vitamin deficiency, particularly B1/thiamine or B12

f. medication use, particularly benzodiazepines, opioids, and anticholinergic agents

g. chronic brain infections (e.g., HIV, syphilis) or inflammatory conditions

h. intracranial mass lesions or hydrocephalus

i. normal pressure hydrocephalus

a. neurons in the nucleus basalis of Meynert, locus coeruleus, and raphe are also reduced in number early in the disease

b. hippocampal atrophy is predominant in the CA1 area (unlike Lewy body dementia, which affects CA2–3)

c. the cortex and hippocampus lose choline acetyltransferase > nicotinic and muscarinic acetylcholine receptors well into the course of the disease, therefore these are not the primary defects; also exhibit reduced acetylcholine release and decreased choline reuptake (necessary for acetylcholine synthesis), which may relate to a decreased trophic responsiveness to nerve growth factor

Figure 7–2 Neurofibrillary tangles (arrowhead) and neuritic plaque (arrow) in Alzheimer’s disease. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003:123, Fig. 121. Reprinted by permission.)

i.    neurofibrillary tangle: intraneuronal inclusions of hyperphosphorylated tau protein (a microtubule-associated protein) and ubiquitin (which binds and marks other proteins for degradation)

(1) neurofibrillary tangles are associated with an early age of disease onset and a more severe disease course

(2) neurofibrillary tangles may not occupy the whole neuron, and may only fill a dendrite {neuropil thread}

ii.   plaques: all are extracellular

Figure 7–3 The Hirano body (arrow). (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:94, Fig. 222. Reprinted by permission.)

(2) ghost plaque: develop only after cell death when extracellular proteases degrade the neurofibrillary tangle, leaving only the dense amyloid core

(3) diffuse plaque: similar histological appearance to senile plaques; composed of amorphous nonfibrillar β-amyloid or finely fibrillar β-amyloid deposits

(a) the APOE ε4 allele is present in 50% of sporadic AD cases; no clear association with the ε4 allele and the severity of the disease

(b) APOE ε4 binds β-amyloid, creating an insoluble complex that may form plaques

(c) APOE ε3 allele may stabilize tau protein thereby preventing neurofibrillary tangle formation, but only the rare APOE ε2 allele is known to be protective against AD

(3) family history of AD without clear inheritance pattern

(4) low level of education

(5) female gender

(6) history of severe head trauma

(7) stroke and vascular risk factors

(8) small head size

(9) Down’s syndrome

b. familial/early-onset AD (5% of cases): patients are generally < 65 years old at onset, and exhibit a more rapid progression of symptoms than do sporadic AD patients; although the disease course is still insidious

Figure 7–4 Key enzymes of Alzheimer’s disease. (APP, amyloid precursor protein)

(3) presenilin 2 (PS2, chromosome 1)

(4) 2 macroglobulin (chromosome 12)

3. Epidemiology

a. age distribution: prevalence at 60 years of age = 3%; prevalence at 90 years of age = 50%

b. prevalence as a cause of dementia is likely underestimated because

i.    Lewy body dementia has a high coincidence with AD

ii.   ~ 50% of vascular dementia cases have elements of AD histology on postmortem examination

4. Symptoms: course of impairment is typically memory loss before involvement of any other cognitive functions or behavioral impairment

a. memory loss: early and severe impairment of short-term memory > long-term or immediate memory

i.    episodic memory is most severely affected

ii.   procedural memory is well-preserved, although mild apraxia can be detected early in the disease

b. language impairment: initial language abnormality is anomia (due to lateral temporal dysfunction, not memory impairment) that progresses to a transcortical sensory aphasia

c. behavioral impairment: more common late in the disease

i.    agitation and aggressive behaviors (70%), but rarely sexual disinhibition (10%)

ii.   depression (50%), which is proportionate to cell loss in locus coeruleus

iii.  simple delusions (30%) that are often paranoid in nature

iv.   hallucinations (20%)

d. visuospatial impairment: manifests primarily as difficulty with navigation

i.    myoclonus occurs in 10% of AD cases, which can be confused with prion diseases

ii.   pyramidal signs (increased reflexes, Babinski reflexes, hypertonus) are unlikely to be due to AD, as the primary motor and sensory cortices are not involved in the disease process until very late

5. Diagnostic testing: none are well-established or necessary for diagnosis

a. genetic markers: the low incidence of familial AD makes them impractical as screening tools

b. cerebrospinal fluid protein markers: protein markers correlated with pathologically determined AD include

i.    increased tau protein and hyperphosphorylated tau protein levels

ii.   combined increases in β-amyloid protein and tau protein levels

c. EEG: loss of alpha activity and increased theta and delta frequencies in 80% of AD cases with > 4-year disease duration; useful for differentiating against the frontotemporal lobar degeneration disorders in which EEG is relatively normal

d. neuroimaging

i.    SPECT scans demonstrate hypoperfusion in the temporal and parietal lobes

ii.   PET scans demonstrate hypometabolism in the temporal and parietal lobes

Figure 7–5 Coronal T1 MRI from a patient with Alzheimer’s disease. Note the pronounced hippocampal atrophy (arrows). (From Nestor P, Hodges J. Non-Alzheimer’s dementias. Semin Neurol 2000, 20:443, Fig. 1b. Reprinted by permission.)

(2) tacrine also improves cognitive performance but it has a high rate of side effects (particularly hepatotoxicity) and requires q.i.d. dosing, therefore it is rarely used

ii.   memantine: acts as an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist; improves patient’s functional abilities and reduces caregiver burden in patients with moderate or severe dementia

iii.  no evidence for use of vitamin E, NSAIDs, or estrogens

c. treatment of behavioral impairment

i.    depression: SSRIs or trazodone, which have minimal anticholinergic side effects

ii.   agitation: behavioral modification; buspirone; atypical antipsychotics (olanzapine, quetiapine, risperidone, clozapine)

(1) avoid benzodiazepines because they worsen cognitive function

iii.  insomnia: improve sleep hygiene, avoid daytime naps; trazodone

Abbreviations: CSF, cerebrospinal fluid; EEG, electroencephalogram.

7. Prognosis

a. nursing home placement occurs on average 3 years after diagnosis

4. Diagnostic testing

a. the size and exact number of infarcts are not as predictive of dementia as is cortical atrophy

b. isolated lacunar infarcts occur in 20% of the general population, but are associated with worse cognitive performance and an increased risk of dementia

c. periventricular white matter T2 hyperintensities on an MRI scan {leukoaraiosis} is not specific for vascular dementia or any dementia, but is associated with worse performance on cognitive tests

5. Treatment: as per stroke prevention, with particular attention to the reduction of hypertension (reduces incidence of dementia by 50%) and reduction of elevated homocysteine levels; acetylcholinesterase inhibitors; memantine

6. Prognosis: 30% 5-year survival, which is worse than other types of dementia or nondemented stroke; however, cognitive deterioration progresses more slowly than in AD

1. Histology: Selective atrophy of the frontal (particularly orbitofrontal) and/or anterior temporal lobes often involving the hippocampus, amygdala, and/or underlying basal ganglia (particularly the caudate); atrophy tends to spare the sensory cortices (as with AD) but also the parietal lobe (unlike AD)

a. pronounced astrocyte gliosis in cortex and subcortical white matter with loss of cortical layers I–III (versus AD that affects layers V–VI predominantly)

b. loss of acetylcholine receptors > choline acetyltransferase (in comparison with AD)

Figure 7–6 The Pick body (arrow). (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:98, Fig. 233. Reprinted by permission.)

ii.   in cases without Pick bodies or cells, intranuclear ubiquitin inclusions can often be identified

2. Pathophysiology

a. genetics: 20% of cases have a familial pattern that is usually autonomic dominant

i.    tau gene mutations: mutations in the tau gene on chromosome 17 are responsible for 10% of familial frontotemporal lobar degeneration disorders, particularly those that involve parkinsonian features (i.e., the FTDP-17 variant)

b. associated with Parkinson’s disease and amyotrophic lateral sclerosis (ALS)

a. frontotemporal dementia—common symptoms include impersistence of attention, apathy or disinhibition, and irritability; occasionally may also involve

i.    Kluver-Bucy syndrome (usually incomplete): placidity, hypersexuality, hyperorality, and/or increased manual exploration

ii.   perseverative behaviors with stereotypies

iii.  echolalia and perseveration of speech progressing to mutism

b. primary progressive aphasia—caused by disease predominantly in the dominant frontal or temporal lobes

i.    symptoms: aphasia of either a nonfluent or fluent type; progresses to dyslexia, agraphia, and apraxias, suggesting parietal lobe involvement

(1) isolated aphasia is usually present > 2 years before the development of other symptoms

c. semantic dementia—symptoms include reduced verbal fluency and pronounced naming difficulties; usually seen in patients with anterior temporal lobe atrophy

d. progressive prosopagnosia—usually seen in patients with nondominant temporal lobe (i.e., fusiform gyrus) atrophy

4. Diagnostic testing

Figure 7–7 Coronal T1 MRI from a patient with semantic dementia. Note the pronounced atrophy of the left temporal lobe (arrows). (From Nestor P, Hodges J. NonAlzheimer’s dementias. Semin Neurol 2000, 20:443, Fig. 1c. Reprinted by permission.)

b. PET demonstrates hypometabolism and SPECT demonstrates hypoperfusion in the frontal and temporal lobes and often the basal ganglia

5. Treatment: None with proven efficacy; SSRIs for management of behavioral abnormalities irrespective of depression

H. Lewy Body Dementia

1. Histology: degeneration of the temporal and parietal cortices (like AD), but also of the occipital cortex; hippocampal atrophy predominantly affects the CA2–3 regions, unlike AD that predominantly affects CA1

a. exhibit significant loss of acetylcholine but limited loss of neurons in the cholinergic basal forebrain nuclei (i.e., basal nucleus of Meynert), unlike AD

b. exhibits loss of basal ganglia dopamine as in Parkinson’s disease, but also loss of basal ganglia D2 receptors

c. 80% of cases exhibit some Alzheimer’s-like histological abnormalities, particularly neuritic-like plaques that do not contain tau protein

d. inclusion bodies

Figure 7–8 The Lewy body (arrow). Courtesy of Dr. C. Yamada.

ii.   Lewy neurites: intracellular inclusions of ubiquitin and α-synuclein, which are limited to dendrites

2. Pathophysiology: Rare familial disease patterns are weakly associated with cytochrome P450 mutations or α-synuclein mutations

3. Symptoms

a. fluctuating cognitive abilities and level of arousal that may relate to cyclic sleep disturbance

i.    hallucinations may be caused by intrusion of REM sleep while the patient is awake (i.e., as in peduncular hallucinosis)

d. sleep disturbance, particularly REM (rapid eye movements) sleep behavioral disorder (RSBD) that may precede the dementia by decades

i.    conversely, an unspecified dementia occurring in conjunction with RSBD is likely to be Lewy body disease

f. Parkinsonism: symptoms are symmetric and poorly responsive to dopaminergic agonists; tremor is mild and often involves a positional as well as resting component

i.    the parkinsonism must develop no sooner than 1 year before the dementia to be diagnosed as Lewy body disease and not as Parkinson’s disease dementia

4. Diagnostic testing

a. polysomnography may demonstrate RSBD (i.e., the lack of atonia during REM sleep)