Differential Diagnosis in Neurology

Topic 16. Dementia

16.2. Alzheimer's Disease and Dementia with Lewy Bodies

  • General characteristics:
    • Epidemiology:
      • Approximately 4 million Americans affected
      • Prevalence doubles every five years after the age of 60
      • 20% of patients 75–85 years of age are affected
      • 40% of people over the age of 85 are affected
      • Number of people 85 or older will double prior to the year 2020
    • Genetic factors associated with Alzheimer's disease:
      • Familial form 5–10% of patients
      • Mutations causing early onset AD:
        • Chromosome 21:
          • Encodes 695–770 aa precursor protein
          • Gene has 19 exons
          • Exon 16/17 codes AB (amyloid beta)
          • Amyloid beta (39–43 aa long misfolded protein )
            • Pathologic amyloid fibril
        • Specific mutations:
          • Exon 17 (3 mutations); codon 717
          • Most common is APP 717 (Val 717 I Leu)
          • Val/phe 717; Val 717 Gly
          • Double mutation of exon 16 at codon 670 to 671
        • Early onset ALZ:
          • Mutations flank amyloid beta sequence
          • Mutations within the sequence cause hemorrhage
        • Mutation causes increased production of amyloid
        • Altered APP processing
        • Clinical features of the 717 codon mutations:
          • 717 Val/Glycine:
            • Myoclonus
            • HCVD
            • Heart disease
          • 717 Val/ILe:
            • Klüver–Bucy like syndrome (without hyper metamorphopsia or hypersexuality)
            • NPH
            • Auditory hallucinations
            • Pyromania

Presenilin

Presenilin I

  • Chromosome 14
  • S182 gene:
    • Missense mutation
    • Encodes a 467 aa protein
    • 100 mutations all but one identified are missense
    • Missense mutations – Codon 141 (N 141 I); M239 V
    • Mutation in the sixth hydrophilic loop
    • Amyloid B 42 (43) long AB formed
    • Presenilin protein is located within:
      • Nerve cells
      • Golgi apparatus
      • Endoplasmic reticularum
  • Clinical features:
    • Age at onset (35–55 years)
    • Progressive aphasia
    • Myoclonus
    • Generalized seizures
    • Penetrance complete by age 60
    • Extrapyramidal signs
    • Range of onset varies within families
    • Duration of the disease is short (5.8–6.8 years)
    • Pathology:
      • Neurofibrillary tangles
      • AB plaques
      • Amyloid angiopathy-consist of:
        • AB fibril
        • Highly dense osmophilic particles

Presenilin II

  • Chromosome I
  • Gene PS 2 gene:
    • Seven transmembrane domain
    • Encodes 448 aa protein
    • 67% homology to PS I
    • 12 exons; 2 non-coding
    • Missense mutation

Volga Germans

  • General considerations:
    • Chromosome 1
  • Clinical features of PSN II mutations:
    • Age of onset 54.9 ± 8 years
    • Variation at age of onset: 40–75 years
    • Two patients > 80 years of age with no clinical signs
    • Penetrance usually > 95%
    • Duration of illness 7.6 years
  • Pathology:
    • Aβ plaques
    • Congophilic angiopathy
  • Increased production of amyloid-beta throughout the brain

Genetic Risk Factors for Late Onset AD

  • General characteristics:
    • ApoE4 gene:
      • Proximal long arm of chromosome 19
      • Risk factor for late onset AD
      • Apo E important for:
        • Lipid transport
        • Metabolism
        • Targeting and clearance of amyloid β-peptide
        • "Wear and tear" repair
      • Apo E allele frequency:
        • E2/E2 – 1%
        • E3/E3 – 60%
        • E4/E4 – 3%
        • E2/E3 – 12%
        • E2/E4 – 2%
        • E3/E4 – 20%
      • E4 allele:
        • Noted in 40% of patients with late onset ALZ
        • If a patient is homozygous for the E4 allele he has a 90% chance of ALZ by age 80
        • The E4 allele bestows an earlier onset of sporadic ALZ
        • The E4 allele is found in the normal frequency in early onset familial AD
        • 50% of ALZ disease does not have the E4 allele
      • Pathology of ApoE:
        • ApoE associated with:
          • Senile plaques (found within plaques)
          • Amyloid angiopathy
          • Neurofibrillary tangles
        • Binds to amyloid-beta fibrils:
          • Greater Aβ aggregation

LDL-Receptor Related Protein

  • Chromosome 12
  • Mediates the molecular effects of ApoE4
  • HLA-A2 gene:
    • Chromosome 6
    • Alleles may regulate the inflammatory response to AD pathology
  • Bleomycin hydrolase:
    • Chromosome 17
    • Involved in APP processing

Clinical Features of Classic Alzheimer's Disease

Stages of Illness

  • Amnesic stage (approximately two years):
    • Disorders of memory:
      • Episodic
      • Semantic
    • Language dysfunction – mild
  • Dementia (approximately two years):
    • Loss of cognitive function
    • Difficulties with activities of daily living
    • Plateaus of function alternating with precipitous decline
  • Vegetative state (many years):
    • Inability to perform activities of daily living
    • Difficulties with communication

The Cognitive Defects in Alzheimer's Disease

  • Attention:
    • Definition:
      • The ability to select specific information to process
      • Limitation of selective attention:
        • Divided attention:
          • Inability to process multiple sources of information as efficiently as one source
    • Focused attention:
      • Difficulty in blocking irrelevant information
    • AD patients:
      • Difficulty in dividing attention
      • Better at focusing their attention
      • Difficulty in disengaging from an attended stimulus
    • Alertness in AD patients:
      • Phasic changes:
        • The time to process an expected input
      • Tonic changes:
        • Slow decline in performance during a long and repetitive task
    • Language deficits:
      • Failure of semantic speech (the production and comprehension of meaning of words):
        • Inability to find the appropriate word
        • Comprehension of complex sentences
        • Inability to search semantic categories
        • Poor production of a semantic association to a given stimulus
        • Minimal difficulty with syntax; speech is grammatically correct
    • Memory:
      • Severe disruption of memory
      • Deficiencies in encoding new information
      • Memory for distant events (remote memory):
        • Less disrupted
        • Demonstrate a temporal gradient (recall distant information better than more recent information)
      • Implicit memory relatively preserved in some studies but deficient in others

Neuropsychiatric Aspects of Alzheimer's Disease

  • Behavioral changes in Alzheimer's disease:
    • Psychosis
    • Agitation
    • Depression
    • Anxiety
    • Personality change
    • Neurovegetative changes
  • Distribution of behavioral changes in ALZ disease
    • Apathy – 72%
    • Agitation – 60%
    • Delusion – 22%
    • Hallucinations – 10%
    • Anxiety – 48%
  • Neuropsychological detection of preclinical Alzheimer's disease:
    • Deficits on confrontation naming abilities
    • Decreased abstract reasoning
    • Decreased memory (encoding)
    • Delayed recall (list learning task a good psychometric measure for differentiating early AD from normal aging)

Alzheimer's Disease Variants

  • Alzheimer's disease with extrapyramidal features:
    • Faster rate of decline
    • Earlier neuropsychiatric manifestations
  • Subgroup of AD patients with visual complaints:
    • Present with Balint's syndrome
    • Complex visual complaints
    • Decreased occipital cortex and visual association area metabolism by PET
  • Variant of AD with spastic paraparesis:
    • Deletion of exon 9 of presenilin I
    • Clinical features:
      • Finnish kindred
      • Spastic paraparesis
      • Onset (40–60 years of age; mean 50.9 years)
      • Memory impairment
      • Decreased hand coordination
      • Dysarthria
    • Pathology:
      • "Cotton wool" plaques
      • Immunoreactive for beta amyloid
      • No congophilic cores
    • MRI:
      • Temporal and hippocampal formation atrophy
    • PET:
      • Bilateral temporoparietal hypometabolism

British Dementia

  • General characteristics:
    • Chromosome 13
    • Familial presenile dementia with spastic paraparesis or cerebral familial amyloid angiopathy
  • Clinical features:
    • Progressive tetraparesis
    • Cerebellar dysfunction
    • Onset in 5th decade
  • Pathology:
    • Severe cerebral amyloid angiopathy
    • Neurofibrillary tangles
    • Non-neuritic amyloid plaques

Presenilin 1 – 1 Gene Mutations

  • General characteristics:
    • Chromosome 14
  • Clinical features:
    • E280 A mutation:
      • Headache
    • Mutation in 46V:
      • Prominent myoclonus
    • Ser169Pro codon mutation:
      • Myoclonic seizures

Risk Factors for AD

  • Genetic:
    • Mutations causing early onset AD:
      • Amyloid precursor protein gene:
        • Chromosome 1
        • APP gene mutations
      • Presenilin:
        • Presenilin 1 (PS 1) gene mutations on chromosome 14
        • Presenilin 2 (PS2) gene mutation; chromosome 1
    • Genetic risks for late onset Alzheimer's disease:
      • Apo E4 gene (chromosome 19)
      • LDL receptor related protein (chromosome 12)
      • HLA A2 gene (chromosome 6)
      • Bleomycin hydrolase (chromosome 17)
  • Age is the major risk factor
  • Geographic distribution:
    • Similar incidence world wide
  • Women more affected than men
  • Prevalence putatively related to education background
  • Weak associations:
    • Head injury (repeated)
    • Parental age at birth
    • Never married individuals
  • E4 allele:
    • No change in progression rate (some studies show increased progression)
    • Decreased frequency with age
    • Increased ischemic heart disease
    • Earlier death
    • E2 allele protective
  • Age associated cognitive decline:
    • Brain atrophy:
      • Normal control 0.4% per year
      • ALZ disease 2.4% per year
    • Deficits associated in only one of six cognitive areas (memory)
    • Greater than six month duration
    • One standard deviation below values for age matched controls
    • ApoE4: no relation with cognitive decline of aging
  • MCI (minimal cognitive impairment)

Pathology of AD

  • Extensive neuronal loss:
    • Strategic loss of the cholinergic neurons of the nucleus basalis of Meynert of the substantia innominata is important for the early memory deficit
  • Intraneuronal neurofibrillary tangles (FT's) associated with:
    • Neuritic plaques and dystrophic neurites:
      • Filamentous insoluble inclusions
      • Located in the cell body
      • Extend into the dendrites but not the distal axons
    • NFT tangles:
      • Major component is the hyper phosphorylated microtubule associated protein tau:
        • Tau normally binds to tubulin to stabilize microtubules
        • Hyper phosphorylated to an aggregate cell function
        • Ghost tangles represent insoluble residues in dead neurons
    • Evolution of NFT spread:
      • Earliest area is entorhinal cortex; progression to limbic cortex; last area involved is cortex
      • Tau differential diagnosis:
        • Post encephalitic PD
        • PSP
        • FTD
        • GBGD
        • Repeat head trauma
        • Pick's complex
        • Age
    • The amyloid plaque:
      • Amyloid plaques are extracellular and diffuse initially
      • Later stages they are cored
      • 50–200 mm in diameter (cores)
      • Cored plaques:
        • Surrounded by dystrophic neuritis
        • Reactive glial inflammatory response
        • Plaque core:
          • 70% of proteinaceous material is amyloid beta (derived from enzymatic cleavage of APP)
          • Abnormal organelles
          • Tau protein
          • Apo lipoprotein E (ApoE)
    • Synaptic alternations:
      • Decreased presynaptic terminal density
      • Disconnected neurons
      • Synaptic pruning
    • Cerebral amyloid angiopathy (CAA):
      • A feature of AD
      • Can occur separately
      • Associated with hemorrhagic stroke
        • AD Dutch disease
      • ApoE allele predisposes for angiopathy in contra distinction for ApoE4 that predisposes for AD
    • Granulovacuolar degeneration:
      • Mainly confined to the hippocampus
      • Vacuoles are found in pyramidal cells that contain a single granule:
        • Reactive with anti neurofilament antibodies
    • Plaques and tangles noted in normal aging:
      • Less widely distributed
      • Few numbers; amyloid can be abundant with pathologic aging
    • Distribution of pathology (amyloid plaques):
      • Amygdala
      • Hippocampus:
        • Dentate gyrus (molecular layer)
        • CA 1 and CA 3
        • Subiculum
      • Layers III, V of the entorhinal cortex
      • Layer II is NFT
      • Temporal parietal neocortex > frontal lobe
      • Laminar degeneration posterior cingulated cortex
    • Histological diagnosis of AD requires both neuritic amyloid plaques and NFT's in the neocortex

Dementia with Lewy Bodies (DLB)

  • General characteristics:
    • Alpha synuclein plaques in greater numbers throughout the cortex than expected
  • Clinical features:
    • Initial deficiencies:
      • Deficits of frontal subcortical abilities
      • Decreased visuospatial skills
    • Later:
      • Memory deficits
  • Core components of the syndrome:
    • Fluctuating cognitive function with pronounced variation in attention
    • Recurrent visual hallucinations
      • Formed; detached
    • Parkinsonism:
      • Bradykinesia and rigidity
      • Rare tremor
      • Poor response to L-dopa
    • Associated features:
      • Repeated falls
      • Syncope and transient loss of consciousness
      • Neuroleptic hypersensitivity
      • Delusion (other than visual) often paranoid
      • Urinary incontinence later than cognitive decline
      • REM sleep disorder
      • Depression
  • Pathology:
    • The number of cortical LBs is variably correlated with the severity of the dementia:
      • Temporal lobe Lewy Bodies correlate with visual hallucinations
    • Cortical Lewy Bodies:
      • Lack a clearly definable central core and distinct peripheral corona
      • Inclusions formed from aggregated masses of intermediate neurofilaments
      • Major antigenic components of LBs:
        • Presynaptic protein alpha synuclien
        • NF proteins
        • Ubiquitin (involved in the nonlesional intracellular degradation of cellular products)
      • Cortical Lewy bodies occur:
        • Cingulate gyrus
        • Entorhinal cortex
        • Insular cortex
        • Frontal cortex
        • Amygdala
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