ALZHEIMER DISEASE

and
OTHER DEMENTIAS
 Dementia

• The diagnosis of dementia requires “the

development of multiple cognitive deficits that
are sufficiently severe to cause impairment in
occupational or social functioning”.

• The cognitive deficits must involve memory and

other cognitive domains, must represent a
decline from premorbid function, and cannot be
attributed to delirium.
 Causes of Dementia
• Degenerative
– Alzheimer Disease
– Frontotemporal dementias
• Pick disease
– Parkinson Disease and Lewy Body Dementia
– Huntington Disease
• Vascular Diseases
• Infectious Diseases
– Prion-related diseases
– HIV type 1 associated dementia complex
• Inherited Metabolic Diseases
 ALZHEIMER DISEASE
• Clinical Syndrome
– Progressive course, terminating in complete
incapacity and death in 4 to 16 years
– Usual initial presenting complaint: memory
impairment for newly acquired information
– Later, impaired language, abstract reasoning,
executive functions; delusions, other psychotic
behavior; major depression; agitation,
hallucinations (visual or auditory)
 ALZHEIMER DISEASE
• Clinical Syndrome
– Neurologic exam (except for mental status) is
usually normal
– Extrapyramidal features (rigidity, bradykinesia,
shuffling gait, postural change) common in later
stages
– Motor and sensory functions spared
 DIAGNOSIS: Criteria by NINCDS – ADRDA (National Institute of
Neurological and Communicative Disorders and Stroke, and the
Alzheimer Disease and Related Disorders Association) in 1984

• 1. History of progressive deterioration in cognitive ability in the

absence of other known neurologic or medical problems

• 2. Psychological testing, brain imaging and other criteria establish 3

levels of diagnostic certainty

• 3. The designation of “definite” AD is reserved for autopsy-confirmed

disease

• 4. If there is no associated illness, the condition is called “probable”

AD

• 5. “Possible” refers to those who meet the criteria for dementia but
have other illness that may contribute, such as hypothyroidism or CVD
• 90% sensitivity for the diagnosis of probable or possible AD
• 60% specificity
• There are no specific changes in routine laboratory exam
• CSF: normal (there may be slight increase in protein)
• EEG: generalized slowing
• Neuropsychological testing can detect minimal or subtle
cognitive impairment early in the disease, can document
global impairment, or can follow the course of the disease
• CT/MRI: dilatation of the lateral ventricles, widening
of cortical sulci, particularly in frontal and temporal
regions

• PET/SPECT/functional MRI: hypometabolism in the

temporal and parietal areas (moderate to severe
symptoms)
 Epidemiology
• Prevalence
– Before 65 years: less than 1%
– Age 65: 5-10%
– Age 85 and older: 30-40%
• Incidence: less than 1% before age 65; 6% per year for
age 85 and older
• Average duration of symptoms till death: 10 years
(4-16 years)
• Disease duration tends to be longer for women than men
• Rates are slightly higher among women
 Genetic Basis
• Autosomal dominant – may begin as early as 3rd decade of
life
• Mutations in 3 genes
– 1. amyloid precursor protein (APP) gene in chromosome 21
– 2. presenilin 1 (PS1) on chromosome 14
– 3. presenilin 2 (PS2) on chromosome 1
• Є4 polymorphism of the apolipoprotein E (APOE) gene on
chromosome 19 – associated with the more typical sporadic and
familial forms of AD, usually beginning after age 65
 Risk Factors most consistently
associated
with Alzheimer Disease
Risk factor/ Direction Presumed
antecedent mechanism
1. Head injury Risk increased Amyloid precursor
protein in the brain

2. Parental age Risk increased Advanced

physiologic aging

3. Depression Risk increased Neurotransmitter

alteration
 Risk Factors most consistently
associated
with Alzheimer Disease
Risk factor/ Direction Presumed
antecedent mechanism
4. Education Risk decreased “cognitive reserve”

5. Anti- Risk decreased Prevents

inflammatories complement
(NSAIDs) activation
6. Estrogen Risk decreased Trophic; AS-APP
metabolism

7. Smoking Risk increased unknown

 Pathology
• Characterized by atrophy of the cerebral cortex
• Diffuse atrophy, but more severe in the frontal, parietal and
temporal lobes
• Microscopic changes: loss of neurons and neuropil in the cortex;
sometimes secondary demyelination in the white matter
• Most characteristic histopathologic markers:
– senile plaques – core of extracellular amyloid surrounded by enlarged
axonal endings.
– neurofibrillary tangles – fibrillary intracytoplasmic structures within the
neurons, containing paired helical filaments, tau protein
• Biochemical changes: 50-90% reduction of the activity of choline
acetylcholinesterase in the cerebral cortex and hippocampus
 CORRELATING CT SCAN FINDINGS WITH
GROSS AUTOPSY FINDINGS

CT scan showing atrophy of the brain

with widening of the cerebral sulci and Horizontal section of the brain of a
dilatation of the ventricles patient with Alzheimer disease
 Treatment
• Currently the only US FDA-approved treatment –
anticholinesterases
• MOA: decrease the hydrolysis of Ach by inhibiting the
cholinesterase resulting in stimulation of the cholinergic
receptors
• Tacrine (use limited by hepatotoxicity), donepezil (Aricept),
rivastigmine (Exelon), galantamine (Reminyl)
• Other drugs: alpha tocopherol and selegiline delay later stages;
psychotropic drugs for agitation, delusions, psychosis and
depression in AD
 FRONTOTEMPORAL DEMENTIAS –
Pick Disease
• progressive form of dementia characterized by
personality change, speech disturbance,
inattentiveness, sometimes extrapyramidal signs
• rare, in contrast to AD; some familial
• atrophy of frontal and temporal poles
• inclusion bodies: Pick bodies – round intraneuronal
inclusions containing tau protein
• Tau proteins are the major structural components
of Pick bodies (tau is microtubule-associated
protein found in axons)
• Other degenerative diseases associated with
dementia and specific tau mutations
– familial frontotemporal dementia and parkinsonism
– progressive supranuclear palsy
– familial progressive subcortical gliosis
– corticobasal ganglionic degeneration
– familial multisystem tauopathy with presenile dementia
 PARKINSON DISEASE and
LEWY BODY DEMENTIA

• Parkinson Disease
• As many as 40% with PD can develop dementia
• Risk of dementia with PD is 4x that of other
people of same age
• Dementia associated with PD – 3rd most
common form of dementia overall
• Three distinct neuropathological changes:
– senile plaques and neurofibrillary tangles
– Lewy bodies
– primary nigral degeneration
• Lewy Body Dementia (diffuse Lewy Body disease or
DLBD)
– Cognitive decline, visual hallucinations, parkinsonism,
repeated falls, sensitivity to neuroleptics (like haloperidol)
– Fluctuating cognitive function; episodic confusion, delusions,
hallucinations may differ from AD

• A “Lewy body variant” of Alzheimer Disease

characterized by greater degree of impairment in
attention, verbal fluency, visuospatial function than
typically seen in AD
 CEREBROVASCULAR DISEASES
and DEMENTIA
• Dementia in association with stroke – 2nd most
frequent cause of dementia overall
• 15-20% with acute ischemic stroke over age 60
have dementia at the time of the stroke
• Risk factors: advancing age, diabetes, history of
prior stroke, size and location of stroke
• Hypertension – associated with both AD and
dementia after stroke
• CT/MRI – evidence of leukoaraiosis
 CEREBROVASCULAR DISEASES
and DEMENTIA
• Mechanisms:
– critically located single infarcts
– multiple large infarcts
– extensive small vessel disease
– hemorrhagic stroke
– CORTICAL SYNDROME – repeated atherothrombotic or
cardioembolic strokes, focal sensorimotor signs, aphasia,
abrupt onset of cognitive failure.
 CEREBROVASCULAR DISEASES
and DEMENTIA
– SUBCORTICAL SYNDROME (deep white matter
lesions) – pseudobulbar signs, pyramidal signs, depression,
emotional lability, “frontal” behavior, mildly impaired
memory, disorientation, poor response to novelty, restricted
interests, dfficulty passing from one idea to another,
inattention, perseveration
– CADASIL – cerebral autosomal dominant inherited
arteriopathy with subcortical infarcts and
leukoencephalopathy
 INFECTIOUS DISEASES

• PRION-RELATED DISEASES
– rare
– Creutzfeldt-Jakob disease (CJD) – most common prion
disease
– 50-70 years old
– Spongy degeneration, neuronal loss, astrocyte proliferation
– Progressive dementia, myoclonus, pyramidal signs,
cerebellar or extrapyramidal signs
– EEG: periodic sharp waves
– Subacute – decline in weeks or months; most die within 1
year of onset
 INFECTIOUS DISEASES
• HIV TYPE 1-ASSOCIATED DEMENTIA COMPLEX
– AIDS Dementia Complex (ADC)
– Other terms: HIV encephalitis, HIV encephalopathy
– Frequent sequela of AIDS
– Severe dementia, behavioral changes; motor disorder,
myelopathy and peripheral neuropathy in 25%
– SYMPTOMS:
• Early – apathy, social withdrawal, slow thinking, poor
concentration, forgetfulness; psychiatric symptoms are
psychosis, depression and mania
 INFECTIOUS DISEASES
• Motor signs – slow movements, leg weakness, gait ataxia
• Advanced stage – akinetic mutism; immobile; global cognitive
impairment, urinary incontinence
– Diagnosis – clinical features and laboratory tests
– Frontotemporal atrophy, multinucleated giant cells, microglial
nodules, perivascular infiltrates
– Treatment:
• Zidovudine (AZT), selegiline, nimodipine – mixed results
(some improved; some no effect)
– Predictors of dementia: CD4+ count <100 cell/uL, anemia, or
AIDS-defining infection or neoplasm (19% to 25% risk in 2
years)
 INHERITED METABOLIC DISEASES

• Rarely cause dementia in adults

• Important because some are potentially treatable

• Young onset of dementia or involvement of other

areas in the nervous system (cerebellar, visual,
peripheral nerves, muscle) and body (skin,
skeletal, visceral organs)
 INHERITED METABOLIC DISEASES
• Abnormal metal metabolism
– 1. Wilson disease
– 2. Hallervorden-Spatz disease
– 3. Fahr syndrome
• Disorder of lipid metabolism
– 1. Cerebrotendinous xanthomatosis
– 2. Kufs disease
– 3. Membranous lipodystrophy
• Mitochondrial disorders
– 1. MELAS
– 2. MERRF
 INHERITED METABOLIC DISEASES
• Lysosomal disorders
– 1. metachromatic leukodystrophy
– 2. Sanfilippo disease
– 3. Gaucher disease
– 4. Niemann-Pick disease
– 5. Fabry disease
– 6. Krabbe disease
• Disorders of carbohydrate metabolism
– 1. Lafora disease
– 2. Adult polyglucosan body disease