Neuropath - Neurodegenerative Diseases

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Neurofibrillary tangles

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Neurofibrillary changes are due to the cytoplasmic, intracellular accumulation of paired helical filaments whose formation is mainly secondary to the hyperphosphorylation of tau. Tau is a microtubule-associated protein that promotes tubulin assembly and stabilizes microtubules.

Neurofibrillary tangles consist of tortuous, argyrophilic (stain with silver dyes), tau positive fibrils found in the neuropil (neuropil threads), , in the halo of neuritic plaques (dystrophic neurites), in the cytoplasm of pyradmial neurons (flame shaped neurofibrillary tangles) or oval neurons (globose tangles) and in the cytoplasm of oligodendrocytes or astrocytes (glial cytoplasmic tangles). Tau labeled glial cytoplasmic inclusions are observed in certain forms of familial frontotemporal dementia associated with parkinsonism due to a mutation involving the tau gene on chromosome 17.

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Neuritic plaques

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Extracellular pathologic changes. Develop in the cerebral cortex, amygdala, hippocampal formation and in the striatum especially in the nucleus accumbens. THey may occur in the thalamus particularly within the dorsomedian and anterior nuclei; and in the cerebellar cortex.

Composed of a centrally located Congo red positive amyloid core (b-amyloid). THis core is srrounded by a halo of distorted neurites containing argyrophilic, paired helical filaments. Microglial cells and macrophages can be seen within the plaques. Reactive astrocytes tend to be at the periphery of the plaques and in the parenchyma surrounding the plaques.

Front 3

Hirano bodies

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Ovoid, or rod-shaped, eosinophilic, amorphous structures found adjacent to or within the cytoplasm of hippocampal pyramidal neurons, especially in CA-1.

Front 4

Granulovacuolar degeneration (GVD)

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Consists of the presence of one or more cytoplasmic granules surrounded by an optically empty rim, or vacuole. THese changes most frequently involve the pyramidal neurons of the Sommer sector (CA1) and subiculum of the hippocampus. They may be seen in the cortical and subcortical neurons. Common in AD (though it can be seen in normal patients)

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Alzheimer disease

Main areas affected

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Prefrontal, parietal, and temporal regions.
Amygdaloid nucleus, hippocampal formation, and the anterior part of the thalamus.

Motor and visual are relatively spared

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Alzheimer disease

Pathological changes

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A decrease of neuronal density the severity of which varies according to region
Neurofibrillary tangles of Alzheimer (predominately in layer III and V of the neocortex)
Neuritic plaques (predominately in layers II and III)
Cerebral amyloid angiopathy (CAA)

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Alzheimer disease

Linked genes

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Chromosome 21 (amyloid precursor protein)
Chromosome 14 (presenilin-1)
Chromosone 1 (presenilin-2)

These mutations are associated with early onset of symptoms (<65 years)

Chromosome 19 (apolipoprotein E is an important genetic factor for familial and sporadic AD. Carriers of the variant e4 gene have an increased risk of developing AD.

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Alzheimer disease

Amyloid-beta peptide

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Deposition of amyloid-beta peptide contributes to the etiology of AD. A-beta is generated from amyloid-beta precursor protein (APP by beta- and gamma--secretases. Both secretases are transmembrane proteases: beta-site APP cleaving enzyme 1, the main neuronal beta-secretase

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Hallmarks of Pick disease

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- Diffuse atrophy with regional, circumscribed accentuation of the atrophy
- The presence of
- Neurons containing Pick bodies
- Ballooned neurons
- Status spongiosus

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Pick bodies

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Round, or oval, well-outlined, argyrophilic, tau positive, ubiquitin positive, synuclein, negative, cytoplasmic bodies measuirng 10-15 um across. They are found in cortical pyramidal neurons and in the hippocampal formation; and in the amygdala, and occasionally within the striatum and brainstem. Pick bodies are found in about 30-50% of brains from demented patients with discrete, circumscribed atrophy

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Diseases with ballooned neurons (Pick cells)

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Pick disease
Primary progressive aphasia
Corticobasal degeneration
Chromosome 17-linked dementia
Alzheimer disease
Progressive supranuclear palsy
Creutzfeldt-Jakob disease

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Diffuse Lewy Body Disease (DLBD)

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Lewy body containing neurons occur in the same areas as those involved in PD, but are additionally present within the cerebral cortex

Main symptoms are parkinsonism and dementia

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Parkinsonism symptoms

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Resting tremr
Bradykinesia
Rigidity
Postural instability (gait disturbance)

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Alzheimer disease Lewy body variant

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Diagnosis made postmortem when the brain of a demented patient shows the changes of Alzheimer disease together with those of diffuse Lewy body disease. WIdespread presence of the Lewy body-containing neurons with neuronal loss, dense neuritic plaques and neurofibrillary tangles of AD.

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Status spongiosus

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Irregular cavitation of the neuropil in the presence of a dense glial meshwork.

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Alzheimer's disease

Associated inclusions

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Inclusion:
Senile plaque (Composition: Beta-amyloid, apoE)
Neurofibrillary tangles (Compositions: Tau, ubiquitin)
Hirano bodies (Compositions: Actin, actin-binding proteins)

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Lewy body diseases

Associated inclusions

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Inclusion:
Lewy body

Composition:
Alpha-synuclein, neurofilament, ubiquitin

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Pick's disease

Associated inclusions

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Inclusion: Pick body

Composition: Tau, ubiquitin

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Chromosome 17-linked dementia

Associated inclusions

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Inclusion:
Neurofibrillary tangles (Composition: Tau)
Glial tangles (Composition: Tau)

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Huntington's disease

Associated inclusions

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Inclusion: Intranuclear inclusions
Composition: Huntingtin, ubiquitin