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Lecture 19

Neuropathology of Neurodegenerative Diseases I: The Dementias

What is the most common form of Alzheimer's Disease? Sporadic late onset AD. Other forms include: Familial late onset AD (uncommon), Familal early onset (rare), AD associated with Down's syndrome, AD associated with other degenerative disease.
Important genes associated with Alzheimer's Disease (1) Amyloid precursor protein gene (2) ApoE gene (3) Presenilin-1 and Presenilin-2
Morphologic features of Alzheimer's disease (1) Neurofibrillary tangles (2) Neuritic plaques (3) Amyloid angiopathy (4) Granulovacuolar degeneration (5) Hirano bodies (6) Marinesco bodies
(T or F) Amyloid precursor protein is not a product of normal astrocytes and neurons. False. Amyloid precursor protein (APP) is normally present in most cell types and secreted by astrocytes and neurons. Alzheimer's disease is associated with altered expression and/or post-translational processing of APP.
Histologic stains for neuritic plaques (NP) used for diagnosis of Alzheimer's disease Bielschowsky silver stain and beta-4 amyloid immunohistochemistry stains
Histologic stains for neurofibrillary tangels (NFT) used for diagnosis of Alzheimer's disease Bielschowsky silver stain and tau immunohistochemistry stains
Components of CERAD criteria for Alzheimer's disease diagnosis (1)Clinical history and age of patient at death (2) Plaque score (3) Assessment of co-existent pathology
Gross pathologic features of the Alzheimer's disease brain (1) cerebral atrophy (2) ex vacuo hydrocephalus
Braak and Braak Criteria Topgraphic staging of neuritic plaques, neurofibrillary tangles, and neuropil threads. Used for neuropathologic diagnosis of Alzheimer's disease
Components of NIA and Reagan Institute Criteria (1) CERAD criteria (2) Braak & Braak score
A neurodegenerative disease with clinical manifestations of progressive cognitive decline with persistent memory impairment, fluctuating cognition, visual hallucinations, and Parkinsonism motor features. Dementia with Lewy Bodies
Pathologic features of Dementia with Lewy Bodies (1) Cerebral atrophy (2) Pallow of substantia nigra & locus ceruleus (3) Lewy bodies
What lobes are found to be atrophied in Dementia with Lewy Bodies? (1) Frontal (2) Temporal (3) Parietal lobes
What is the major protein component of Lewy bodies? Alpha-synuclein
Neurochemical pathology of Dementia with Lewy Bodies (1) Dopaminergic deficit in cortical and subcortical areas related to neuronal loss in Substania nigra (21) Severe cortical cholinergic deficit, possibly more pronounced than Alzheimer's diseae
Frontal release signs (1) Palmar grasping (2) Palmomental reflex (3) Rooting reflex (4) Sucking reflex (5) Snout reflex (6) Glabellar reflex
Clinical features of Frontotemporal Dementias (1)Deterioration in personality and social function (2) Progressive memory loss (3) Affective disorders (4) Decline in speech output, sterotypy of speech, mutism (5) Frontal release signs (6) Atrophy of fronal and temporal lobes on imaging
Gross pathology features of Pick's disease (1)Fronto-temporal atrophy (2) "blade-like" or "knife-edge" gyri (3) Basal ganglia atrophy (+/-)
Histopathologic features of Pick's disease (1) Pick's bodies (2) Spongiform cortical degeneration (3) neuronal dropout (4) Spongiosis cortex (5) Swollen cortical neurons
Histologic stains for Pick's bodies (1)Silver stain (2)Tau immunohistochemical stain (3) Ubiquitin immunohistochemical stain
Anatomical distribution of Pick's bodies (1)Hippocampus (pyramidal neurons and dentate gyrus) (2) Cortical layers II & III
Function of Tau protein Tau proteins are mictotubule associated proteins are a family of six isoforms. Tau proteins bind to microtubules and promotes microtubule assembly.
Where are the binding domains located on the Tau proteins? The binding domains are located on the carboxy-terminal of the protein. The different Tau protein isoforms differ by the number of microtubule-binding repeats.
Role of Tau protein in neurodegenerative diseases Tau filaments are a result of hyperphophorylated Tau proteins which cause them to self assemble into tangles and filaments.
Two sporadic forms of Prion disease (1) Creutzfeldt-Jakob disease (2) Fatal insomnia (SFI)
Dominantly inherited forms of Prion disease (1) Familial Creutzfeldt-Jakob disease (2) Gerstmann-Straussler-Scheinker Syndrome (GSS) (3) Familial Fatal Insomnia (FFI)
Acquired forms of Prion disease (1) Kuru (2) Iatrogenic Creutzfeldt-Jakob disease (3) New variant Creutzfeldt-Jakob disease
Pathogenesis of Prion disease Prion protein (PrP) accumulates in cells and outside cells int he form of amyloid forming abnormal PrP. The abnormal PrPs are conformationally different and resistant to proteases. The abnormal PrP further converts normal PrP into abnormal forms.
Inheritance pattern of inherited forms of Prion disease Autosomal dominant
(T or F) Majority of Prion disease are acquired. False. 85% of human cases of Prion disease are sporadic. Only rarely human cases are due to transmission.
What form of Prion disease is associated with a point mutation that replaces Leucine for Proline in the Prion protein gene sequence? Gerstmann-Straussler-Scheinker Syndrome (GSS)
What is the genetic susceptibility factor for Prion disease? Codon 129 of the Prion protein has been identified as the susceptibility factor. Codon 129 codes for valine or methionine. Having the same amino acid at codon 129 may facilitate conversion of normal Prion protein into the abnromal form
Neuropathologic features of Prion disease (1) Neuronal loss (2) Astrocytosis (3) Spongiform change (4) Synaptic loss (5) Accumulation of Prion protein
Classic clinical symptoms of Parkinson's Disease (1) Bradykinesia (2) Muscle rigidity (3) Postural instability/abnormalities (4) Resting tremor
Neuropathologic features of Parkinson's disease (1) Selective degeneration of neuromelanin-containing, dopaminergic neurons (2) Variable degrees of neuronal degeneration in other pigmented nuceli (3) Lewy bodies (4) Nueronal dropout (5) Pigment incontinence
What area of the brain are depleted of dopaminergic neurons in Parkinson's disease? (1) Pars compacta of the Substantia Nigra (2) Retrorubral of midbrain (3) Ventrolegmental areas of the midbrain
What precentage of dopaminergic neurons must be depleted for clinically apparent symptoms of Parkinson's diseae? 80-85% of nigral neurons and at least 80% of the striatal dopamine content must be depleted for frank clinical symptoms to appear.
(T or F) Dementia in the setting of Parkinson's disease is secondary to the presence of Lewy bodies. False. Dementia in the setting of chronic Parkinson's disease is secondary to chronic neuronal degeneration.
Subtypes of Multiple System Atrophy (1)Olivopontocerebellar atrophy (2) Shy-Drager syndrome (3) Striatonigral degeneration
Gross pathologic features of Mutliple System Atrophy (1) Atrophy of cerebellum, mimddle cerebellar peduncles, and pons (2) Pallor of Substania Nigra and Locus Coeruleus (3) Atrophy and gray-brown discoloration of putament
A neurodegenerative disease characterized by oligodendroglial inclusions in gray and white matter and neuronal cytoplasmic inclusions present in the pons and putamen. Multiple system atrophy
Gross pathologic features of Progressive Supranuclear Palsy (1) Depigmentation of Substania Nigra and Locus Coeruleus (2) Occasional atropy of midbrain, pons and globus pallidus
Microscopic findings of Progressive Supranuclear Palsy (1) Globose tangles (2) Abnormal Tau accumulatio in neurons and glia (3) Neuronal loss (4) Astrogliosis
Histologic characteristics of Globose Tangles Globose tangles are basophilic, rounded tangles that are identified with silver stain and Tau immunohistochemical stains.
Gross pathologic features of Corticobasal Degneration (1) Asymmetric atrophy of frontal and parietal lobes (2) Pallor of Substania Nigra and Locus Coeruleus
Microscopic findings of Corticobasal Degneration (1) Swollen cortical neurons (2) neuronal loss of the cerebral cortex and Substania nigra (3) microvacuolation of the cortex (4) Tau accumulation in neurons and glia
Trinucleotide repeat and protein product associated with Huntington's Disease CAG and Huntingin
Trinucleotide repeat and protein product associated with Spinocerebellar ataxias CAG and Ataxin1, 2, or 3
Trinucleotide repeat and protein product associated with Friedreich's ataxia GAA and Frataxin
Trinucleotide repeat associated with Dentatorubral-pallidoluysian atrophy (DRPLA) CAG
Inheritance pattern of Hungtington's disease Autosomal dominant
Clinical symptoms of Huntington's disease (1) Chorea (2) Rigidity (3) Congitive decline leading to dementia
Number of CAG repeats resulting in Huntington's disease 37 to 100 or more repeats in the Hungtingin gene results in Huntington's disease.
Concept of anticipation in Huntington's disease The number of repeats inversely correlates to the age of disease onset. Later generations are affected in earlier age and more severly than previous generations.
Hyperkinetic form of Huntington's disease The most common clinical form of Huntington's disease characterized by choreiform movements and early psychiatric disease. The mean duration of the disease is 17 years.
Akinetic rigid form of Huntington's disease Common clinical symtpoms characterized by rigidity and akinesia. This form has rapid disease progression.
Microscopic findings of Hyperkinetic form of Huntington's disease (1) Neuronal loss and reactive astrogliosis in striatium (2) Variable loss of large pyramidal neurons in neocortex and hippocampus (3) Abnormal neurites positive for ubiquitin
Created by: UVAPATH2