Differential Diagnosis in Neurology

16.5. Hereditary Dementias

• AD (three genes):
  • Presenilin 1 on chromosome 14
  • Presenilin II on chromosome 1
  • Amyloid precursor protein chromosome 21
  • Trisomy 21
• Creutzfeldt-Jacob disease (chromosome 20)
• Gerstmann Straüssler Schindler disease (chromosome 20)
• Huntington's disease (chromosome 4)
• Parkinson ALS dementia complex of Guam (X-linked)
• Adult onset metachromatic leukodystrophy
• Frontotemporal dementia chromosome 17:
  • DDPAC
  • PPND
  • ITDP-17
  • HDDD
  • Pick's complex
• Wilson's disease chromosome 17
• Multiple system atrophy:
  • Olivopontocerebellar atrophy
  • SCA-3 (Machado Joseph)
  • DRPLA
• Alzheimer's disease brain calcification with dementia
• Diffuse NF tangles with calcification:
  • Codon val 717 gly mutation
  • Chromosome 21
• Familial subcortical gliosis
• Variant Creutzfeldt–Jakob disease
• Hallervorden Spatz
• FTD chromosome 9 and 13

Alzheimer's Disease Variants

• AD with spastic paraparesis
• Lewy body variant of AD
• ALZ with rapid decline
  • Seizures
  • Myoclonus
• AD with cortical blindness

Genetic Mutations Associated with Alzheimer's Disease

• Chromosome 1 presenile II (early onset)
• Chromosome 14 presenile I (early onset)
• Chromosome 21 linked:
  • APP: codon mutations:
    • 717
    • 670
    • 691
    • Val 71716
    • Val 717 phe
  • APP:
    • 693, 692; CAA with hemorrhage
• Chromosome 19:
  • ApoE e4

Dementias in Association with Basal Ganglia Degeneration

• Huntington's disease
• Wilson's disease
• Hallervorden Spatz disease
• FTDP-17
• PPND
• DDPAC
• Striatonigral degeneration (SND)
• CBGD
• FPSCG (familial progressive subcortical gliosis)
• Parkinson's disease (Chromosome 4; 6; others)
• PSP (progressive supranuclear palsy)
• Picks disease

Dementia in Association with Inherited Cerebellar Degeneration (Cholestanalosis)

• General characteristics:
  • AR
  • Disorder of bile acid synthesis
  • Mitochondrial enzyme 27-steroid hydrolase (CYP27) deficit
  • Cholestanol increases with age
• Clinical features:
  • Premature bilateral cataracts
  • Intractable diarrhea
  • Tendon xanthomas (Achilles)
  • 50% with cerebellar signs
  • Premature atherosclerosis
  • Thickening of the interatrial septum
• MRI evaluation:
  • Bilateral symmetrical increase of signal on T2 weighted images in white matter:
    • Cerebellum
    • Periventricular areas
    • Basal ganglia
    • Dentate nuclei
    • Brainstem nuclei
    • Cerebellar and cerebral atrophy

Dentatorubral Pallidoluysian Atrophy

• General characteristics:
  • AD; chromosome12 q B37 gene (CAG expansion)
  • Atropin 1 is the gene product
• Clinical manifestations:
  • Onset of age 5 to 55
  • Myoclonus
  • Epilepsy
  • Cerebellar ataxia
  • Choreoathetosis
  • Dementia
  • Some patients have long course with late dementia
• MRI evaluation:
  • Cortical, brainstem and cerebellar atrophy
  • Atrophy of globus pallidus and dentate nuclei
• Pathology:
  • Neuronal intranuclear inclusions intracytoplasmic inclusions only in dentate nucleus

Olivopontocerebellar Atrophy

• General characteristics:
  • AD/AR
  • Several variants
• Clinical features:
  • Cerebellar ataxia predominates
  • Autonomic dysfunction
  • Parkinsonism
  • Cranial nerve involvement (Fick–Winkler variant)
  • Inspiratory stridor
  • Dorsal column involvement (Menzel variant)
• Pathology:
  • Atrophy of the cerebellar cortex and vermis, pons, and inferior olives; Purkinje cell loss
  • Glial cytoplasmic inclusions in the dentate nucleus
  • Neuronal intranuclear inclusions
• MRI:
  • Vermian atrophy
  • Cruciate atrophy of the pons (atrophy of pontine nuclei and fibers of the middle cerebellar peduncle)
  • Cerebral atrophy (30%)
  • Evidence of atrophy does not correlate with either the duration of illness or the severity of cerebellar ataxia

Machado Joseph Disease (MJD)

• General characteristics:
  • AD; chromosome 14; MJD 1 gene
• Clinical features:
  • Varying age at onset; adult onset most frequent
  • Pronounced phenotypic heterogeneity
  • Core clinical features:
    • Gait ataxia
    • External ophthalmoplegia
    • Nystagmus
    • Bulging eyes
• Unusual clinical features:
  • Dementia
  • Generalized muscle and joint pain
  • Amyotrophy
  • Young onset parkinsonism
  • Peripheral neuropathy
    • Those patients with fewer CAG repeats
    • Axonal sensory and motor neuropathy
  • Restless leg syndrome

Other Cerebellar Diseases with Dementia

• Friedreich's Ataxia
• Late onset hexoaminidases A deficiency
• Marinesco Sjögren Disease

Thalamic Dementia

• Clinical features:
  • Progressive intellectual deterioration
  • Personality change
  • Bizarre behavior
• Pathology:
  • Thalamic degeneration associated with:
    • Cortex, brainstem, basal ganglia, cerebellum and white matter pathology
    • Dorsomedial nucleus most severely affected
    • Pathology in ventroanterior and centromedian nuclei, anterior thalamic nuclei
  • White matter gliosis
  • Cortical neuronal loss (linear spongy type)
  • Bilateral thalamic disease

Dementia in Familial Cerebral Amyloid Angiopathies (CAA)

• General characteristics:
  • Causes of dementia:
    • Recurrent local ischemia
    • Recurrent hemorrhage with white matter damage
    • BA4 protein deposited; or unidentified protein deposited
• Differential diagnosis of cerebral amyloid angiopathies:
  • Alzheimer's disease
  • Hereditary cerebral hemorrhage with amyloidosis (Icelandic type)
  • Hereditary cerebral hemorrhage with amyloidosis (Dutch type)
  • Familial cerebral amyloid angiopathy with non-neuritic plaque formation
  • Familial amyloid angiopathy with deafness and ocular hemorrhage (Danish type)
• Alzheimer's disease:
  • Dementia
• Pathology:
  • Normal or abnormal variant of BA4 and BAPP
  • Cerebral and cerebellar leptomeningeal deposits
  • Cortical arterioles are affected
  • Widespread neuronal loss, diffuse and neuritic plaque; widespread neurofibrillary tangles

Hereditary Cerebral Hemorrhage with Amyloidosis-Icelandic Type (HCHWA-1)

• Clinical features:
  • Recurrent cerebral hemorrhage with stroke
  • Some patients develop dementia secondary to the strokes
• Pathology:
  • Amyloid deposited in walls of arteries and arterioles:
    • Leptomeninges
    • Cerebral cortex
    • Deep grey and white matter
    • Brainstem
    • Cerebellum
  • Repeated hemorrhages in the these areas
  • No parenchymal amyloid plaques or neurofibrillary tangles

Crystallin C Deposited in Vascular Amyloid

• General characteristics:
  • Abnormal form of cysteine proteinase inhibitor crystalline c
  • Cysteine C gene mutation:
    • Chromosome 20
    • Glutamine 68 isoleucine mutation

Hereditary Cerebral Hemorrhage with Amyloidosis (Dutch Type)

• Clinical features:
  • Acute cerebral hemorrhage between 45–60 years
  • 2/3 die; remainder develop deficits and dementia
  • Rarely dementia is a presenting features of the disease
• Pathology:
  • Hemorrhage and infarcts in the temporal and occipital lobes
  • Amyloid deposited in arteries and arterioles:
    • Leptomeninges
    • Cerebrum and cerebellum
    • Cerebral cortex:
      • Diffuse BA 4 amyloid plaques
      • Little neuritic pathology
      • Vascular deposits contain BA 4 protein and BAPP

Point Mutation of the BAPP Gene at Codon 618

• Clinical features:
  • Symptoms develop in the fifth decade
  • Progressive dementia
  • Spastic paralysis
  • Ataxia
  • Memory impairment is rare
  • Stroke like episodes are uncommon
• Neuropathology:
  • Atrophy of cerebral and cerebellar hemispheres
  • Cystic infarcts of deep white matter
  • Arteries demonstrate:
    • Fibrotic thickening and obstruction
    • Fragmentation of the elastic lamina
    • Periarteriolar microhemorrhages
    • Periarteriolar microhemorrhages
  • Ischemic necrosis is found in the:
    • Cerebral cortex and white matter
    • Thalamus
    • Cerebellum
  • Non-neuritic amyloid plaques occur in the:
    • Cerebral and cerebellar cortex
  • Neurofibrillary tangle are demonstrated in the:
    • Hippocampus
    • Amygdala
  • Vascular and neurodegenerative changes cause the dementia

Familial Amyloid Angiopathy with Deafness and Ocular Hemorrhage (Danish Type)

• Clinical features:
  • Cataracts early life
  • Deafness at age 30
  • Fifth and sixth decade patients have:
    • Ataxia
    • Dementia
    • Death in 10 years
    • Rare ocular hemorrhage
    • Rare stroke like episodes
• Pathology:
  • Amyloid angiopathy found in:
    • Cerebrum
    • Retina
    • Choroid plexus
    • Neuritic plaques and neurofibrillary tangles present in the hippocampus

Gerstmann–Straüssler Schenker Syndrome

• Clinical features:
  • Dementia
  • Ataxia
• Pathology:
  • PrP in parenchymal plaques
  • BA4 protein in blood vessels
  • Involvement of small arteries and arterioles of the:
    • Cerebral cortex
    • Leptomeninges of the cerebral and cerebellar cortex
  • Primarily non-neuritic plaques
  • Some patients have neurofibrillary tangles

Amyotrophic Lateral Sclerosis (Parkinsonism, Dementia, Complex of Guam)

• General characteristics:
  • Cycad containing foods:
    • Chamoro people of Guam
    • Putative neurotoxin
    • B-N-methylamino-L-alanine (BMAA)
    • Similar disease is found in the Kii peninsula of Japan and New Guinea
• Clinical features:
  • Motor neuron disease
  • Parkinsonism with severe dementia
  • 30% of patients present with dementia
• Pathology:
  • Cerebral atrophy
  • Pallor of the substantia nigra (patients with parkinsonism)
  • ALS patients (loss of anterior horn cells)
  • Abundant neurofibrillary tangles
  • Anatomical areas affected:
    • Hippocampus
    • Amygdala
    • Enterorhinal cortex
    • Periaqueductal grey
    • Substantia nigra
    • Nucleus basalis of Meynert

Overlapping Features of the Primary Dementias

• General characteristics:
  • 30% of ALZ patients have Parkinsonian symptoms
  • 30% of PD patients have dementia
  • Approximately 30% of ALZ patients have Lewy bodies as well as AD pathology
  • 60% of PD patients have ALZ pathology
• If extrapyramidal signs precede the dementia by 12 months or longer:
  • Probable PD with dementia
• If dementia precedes the parkinsonism features probably diffuse Lewy Body disease
• Possible spectrum:
  • ALZ at one end pure PD at the other
• Those demented patients that hallucinate have Lewy body pathology (in general):
  • Alzheimer's disease
  • Diffuse Lewy body disease
  • Parkinson's disease
• Tauopathies include:
  • Pick complex
  • Corticobasal ganglionic degeneration
  • Post encephalologic PD
  • Multiple head trauma (boxers)
  • Progressive supranuclear palsy