Neurodegenerative Diseases PDF

NEURODEGENERATIVE DISEASES ▪ Neurodegenerative diseases are disorders characterized by the progressive loss of neurons, typically affecting groups of neurons with functional relationships even if they are not immediately adjacent. ▪ Recent genetic and molecular studies have shaped the current classi...

NEURODEGENERATIVE DISEASES ▪ Neurodegenerative diseases are disorders characterized by the progressive loss of neurons, typically affecting groups of neurons with functional relationships even if they are not immediately adjacent. ▪ Recent genetic and molecular studies have shaped the current classification of neurodegenerative diseases, in part from the recognition that there are many shared features. ▪ The pathologic process that is common across most of the neurodegenerative diseases is the accumulation of protein aggregates, which can be used as a morphologic hallmark of the disease. ▪ The protein aggregates are recognized histologically as inclusions. ▪ The basis for aggregation varies from one disease to another. It may be: ▪ Directly related to an intrinsic feature of a mutated protein (e.g., expanded polyglutamine repeats in Huntington disease). ▪ Intrinsic feature of a peptide derived from a larger precursor protein (e.g., Aβ in Alzheimer disease), ▪ An unexplained alteration of a normal cellular protein (e.g., α-synuclein in sporadic Parkinson disease). ALZHEIMER DISEASE (AD) ▪ Alzheimer disease (AD) is the most common cause of dementia in older adults. ▪ Typically over a course of 5 to 10 years, the affected individual becomes profoundly disabled, mute, and immobile. ▪ Patients rarely become symptomatic before 50 years of age and the incidence of the disease increases with age. ▪ While pathologic examination of brain tissue remains necessary for the definitive diagnosis of AD, the combination of clinical assessment and modern radiologic methods allows accurate diagnosis in 80% to 90% of cases as confirmed at autopsy. Molecular Genetics and Pathogenesis of Alzheimer disease ▪ The fundamental abnormality in AD is the accumulation of two proteins (Aβ and tau) in specific brain regions, likely as a result of excessive production and defective removal. ▪ The two pathologic hallmarks of AD, particularly evident in the end stages of the illness, are plaques and tangles. Plaques Tangles aggregated Aβ peptides in the neuropil aggregates of the microtubule binding protein tau ▪ Aβ generation is the critical initiating event for the development of AD. ▪ Point mutations in proteins that are part of the protease complexes that generate Aβ from amyloid precursor protein (APP) also give rise to AD. ▪ In contrast, mutations in the gene for tau do not give rise to AD but rather cause frontotemporal lobar degenerations Role of inflammation in Alzheimer disease ▪ Both small aggregates and larger deposits of Aβ elicit an inflammatory response from microglia and astrocytes. ▪ This response probably assists in the clearance of the aggregated peptide, but may also stimulate the secretion of mediators that cause damage. ▪ It also cause alterations in tau phosphorylation, along with oxidative injury to the neurons Basis for cognitive impairment in Alzheimer disease ▪ The presence of a large burden of plaques and tangles is highly associated with severe cognitive dysfunction. ▪ Biochemical markers that have been correlated with the degree of dementia include: ▪ loss of choline acetyltransferase. ▪ Am yloid burden. Macroscopic findings in Alzheimer disease ▪ Cortical atrophy most pronounced in the frontal, temporal, and parietal lobes. ▪ Secondary ventricular enlargement. ▪ Structures of the medial temporal lobe, including hippocampus, entorhinal cortex and amygdala, are involved early in the course and are usually severely atrophied in the later stages. Microscopic findings in Alzheimer disease ▪ Neuritic (senile) plaques. ▪ Neurofibrillary tangles. ▪ Progressive, eventually severe, neuronal loss and reactive gliosis in the same regions that bear the burden of plaques and tangles Neuritic plaques ▪ Focal, spherical collections of dilated, tortuous, neuritic processes (dystrophic neurites) often around a central amyloid core. Neurofibrillary tangles ▪ Tau-containing bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. ▪ They are basophilic structures by H&E ▪ Seen more clearly by silver (Bielschowsky) staining (black) ▪ Can be demonstrated by immunohistochemical stain against Tau. Clinical features of Alzheimer disease ▪ Initial symptoms are forgetfulness and other memory disturbances. ▪ With progression of the disease other symptoms emerge, including language deficits, loss of mathematical skills, and loss of learned motor skills. ▪ In the final stages of AD, affected individuals may become incontinent, mute, and unable to walk. FRONTOTEMPORAL LOBAR DEGENERATIONS (FTLDS) ▪ FTLDs are one of the more common causes of early onset dementia and occur at the same frequency as Alzheimer disease in those under the age of 65 years ▪ They are 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. The two most common patterns are: ▪ Tau-containing inclusions (FTLD-tau). ▪ Pick disease ▪ TDP43-containing inclusions (FTLD-TDP). morphology ▪ Macroscopically: ▪ There is atrophy of frontal and temporal lobes to variable extent and severity. ▪ Microscopically : ▪ The atrophic regions of cortex are marked by neuronal loss, gliosis, and the presence of tau-containing neurofibrillary tangles Pick disease ▪ It is a subtype of FTLD-tau. ▪ 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. ▪ Microscopically: ▪ swelling neurons (Pick cells). ▪ cytoplasm ic, round to oval, filam entous inclusions (pick bodies) (weakly basophilic but stain strongly with silver m ethods and contain 3R tau) PARKINSON DISEASE (PD) ▪ Is a neurodegenerative disease marked by a prominent hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra. ▪ The presumptive diagnosis of PD can be 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. Molecular Genetics and Pathogenesis ▪ PD is associated with protein accumulation and aggregation, mitochondrial abnormalities, and neuronal loss in the substantia nigra and elsewhere in the brain Morphology ▪ Macroscopically: ▪ pallor of the substantia nigra ▪ Microscopically: ▪ Lewy bodies ▪ Areas of neuronal loss also typically show gliosis. ▪ Lewy neurites are dystrophic processes that contain aggregated α-synuclein. Dementia with Lewy Bodies ▪ Dementia developed at least one year prior to the onset of parkinsonism. ▪ Microscopically they show cortical lewy bodies that are similar to the classical lewy bodies but seen in the cortex. HUNTINGTON DISEASE (HD) ▪ It is 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 - Normal: 6–35 CAG repeats - Huntington disease: 36–86 CAG repeats Clinical manifestation of HD ▪ Usually starts in fourth–fifth decade, but may manifest earlier. ▪ Chorea (involuntary, jerky, brisk movements, vaguely “dance-like”) ▪ Psychiatric and cognitive symptoms and cachexia. Morphology of HD ▪ Macroscopic: ▪ Variable cerebral atrophy, depending on the stage of disease ▪ A trophy of striatum (caudate nucleus and putam en) ▪ Microscopic ▪ Neuronal loss and gliosis in striatum but globus pallidus, substantia nigra, cerebral neocortex, entorhinal cortex, and hypothalamus also involved ▪ Neuronal nuclear, cytoplasm ic, and neuritic accum ulation of abnorm al huntingtin protein seen in striatum and cerebral cortex IN SUMMARY Neurodegenerative diseases are characterized by progressive neuronal loss involving specific neuronal circuits and brain regions. Most of these diseases are associated with accumulation of abnormal protein aggregates, typically in the form of cellular inclusions. The clinical phenotype reflects the patterns of brain involvement more than the type of inclusions. Among dementias, AD (with plaques of Aβ and tangles of tau) is the most common; and dementia with Lewy bodies (with α-synuclein containing lesions). Among the hypokinetic movement disorders, Parkinson disease is the most common, again with α-synuclein containing inclusions); THANK YOU..