Understanding Neurodegenerative Diseases

Neurodegenerative Diseases

• Characterized by progressive neuronal loss involving specific neuronal circuits and brain regions
• Associated with accumulation of abnormal protein aggregates, typically in the form of cellular inclusions
• Clinical phenotype reflects the patterns of brain involvement more than the type of inclusions

Pick's Disease

• Microscopically: swelling neurons (Pick cells) with cytoplasmic, round to oval, filamentous inclusions (Pick bodies)
• Weakly basophilic but stain strongly with silver methods and contain 3R tau

Parkinson's Disease (PD)

• A neurodegenerative disease marked by a prominent hypokinetic movement disorder
• Caused by loss of dopaminergic neurons from the substantia nigra
• Presumptive diagnosis based on the presence of the central triad of parkinsonism—tremor, rigidity, and bradykinesia—in the absence of a toxic or other known underlying etiology
• Macroscopically: pallor of the substantia nigra
• Microscopically: Lewy bodies and areas of neuronal loss with gliosis

Dementia with Lewy Bodies

• Dementia developed at least one year prior to the onset of parkinsonism
• Microscopically: cortical Lewy bodies similar to classical Lewy bodies but seen in the cortex

Huntington's Disease (HD)

• An autosomal dominant disease characterized by progressive movement disorders and dementia
• Caused by degeneration of striatal neurons
• Mutation in gene coding for huntingtin protein on chromosome 4: 36–86 CAG repeats
• Clinical manifestation: chorea, psychiatric and cognitive symptoms, and cachexia
• Macroscopic: variable cerebral atrophy, depending on the stage of disease, with atrophy of striatum (caudate nucleus and putamen)
• Microscopic: neuronal loss and gliosis in striatum, with globus pallidus, substantia nigra, cerebral neocortex, entorhinal cortex, and hypothalamus also involved

Alzheimer's Disease (AD)

• The most common cause of dementia in older adults
• Typically becomes symptomatic after 50 years of age, with incidence increasing with age
• Causes alterations in tau phosphorylation, along with oxidative injury to neurons
• Basis for cognitive impairment: presence of a large burden of plaques and tangles, with biochemical markers including loss of choline acetyltransferase and amyloid burden
• Macroscopic: cortical atrophy most pronounced in the frontal, temporal, and parietal lobes, with secondary ventricular enlargement
• Microscopic: neuritic (senile) plaques and neurofibrillary tangles, with progressive neuronal loss and reactive gliosis

Frontotemporal Lobar Degenerations (FTLDs)

• One of the more common causes of early onset dementia, occurring at the same frequency as Alzheimer disease in those under the age of 65 years
• Distinguished from AD by the fact that alterations in personality, behavior, and language (aphasias) precede memory loss
• FTLD is associated with cellular inclusions of specific proteins
• Macroscopically: atrophy of frontal and temporal lobes to variable extent and severity
• Microscopically: neuronal loss, gliosis, and the presence of tau-containing neurofibrillary tangles
• Pick disease: a subtype of FTLD-tau, characterized by severe circumscribed asymmetric “knife-edge” atrophy of frontal and temporal lobes with conspicuous sparing of the posterior two thirds of the superior temporal gyrus and only rare involvement of either the parietal or occipital lobe