Ans. a. Temporoparietal (Ref: Harrison 19/e p2598, 18/e p3304-3308)Area of the brain most commonly undergoing atrophy in Alzheimer's disease is Temporoparietal.'Pathologically, atrophy is distributed throughout the medial temporal lobes, as well as lateral and medial parietal lobes and lateral frontal cortex.'- Harrison 18th/3305Alzheimer's DiseaseAD can occur in any decade of adulthood, but it is the MC cause of dementia in the elderly.AD most often presents with an insidious onset of memory loss followed by a slowly progressive dementia over several years.Dementia from Alzheimer's disease is the classical prototype of cortical dementias.Alzheimer's dementia is the MC cortical dementiaQ.Predominantly affects the temporoparietal cortex (although frontal lobe is also frequently involved)Pathology:Pathologically, atrophy is distributed throughout the medial temporal lobes, as well as lateral and medial parietal lobes and lateral frontal cortex.Microscopically, there are neuritic plaques and neurofibrillary tangles (INFTs) composed of hyperphosphorylated tau filaments, and accumulation of amyloid in blood vessel walls in cortex and leptomen ingesQ.At autopsy, the earliest and most severe degeneration is found in the medial temporal lobe (entorhinal/perirhinal cortex and hippocampus), lateral temporal cortex, and nucleus basalis of MeynertQ.Characteristic microscopic findings: Neuritic plaques and NFTsQ.Neurofibrillary tangles are intracellular accumulations that may appear extracellularly after degeneration of neuron (neuronal death)Q.A histopathological diagnosis of Alzheimer's disease is made in cases of progressive dementia when beta-amyloid plaques (Neuritic/Senile plaques) co-occur with Neurofibrillary TanglesQ.Decreased levels of ACH, its synthetic enzyme choline acetyltransferase and nicotinic cholinergic receptors are the primary biochemical abnormality observed in ADQ.Beta-Amyloid Plaques (Extracellular)Neurofibrillary Tangles (Intracellular)* Formed by extracellular accumulation of beta amyloid deposits.* Neuritic or senile beta- amyloid plaques are an early histopathological sign of AD* Amyloid beta-protein accumulated in single neuritic plaques is toxic to surrounding structures and adjacent neurons.* Clinicopathological studies have shown that amyloid burden does not directly correlate with severity or duration of dementia* Formed by intracellular accumulation of hyper phosphorylated microtubule binding protein 'tau'.* NFT's occur in many neurodegenerative diseases and/or a group of diseases called 'taupathies' (Frontotemporal dementia, Pick's disease).* The co-occurrence of beta-amyloid plaques with NFT's suggests a diagnosis of AD.* NFT's are toxic to the neurons and neurons with NFT's eventually die and degenerate leaving a residual 'ghost tangle', in the extracellular space reminding of the pyramidal cell body in which it was initially formed.* Ciinicopathoiogical studies have shown that dementia correlates more strongly with NFT's than with senile plaques (beta- amyloid)Epidemiology:Most important risk factors for AD: Old age and positive family history.Factors associated with increased risk of Alzheimer's disease* Increasing ageQ* Female sexQ* Lower educational attainmentQ* Family history of dementiaQ* Environmental factors (Al, Hg, Viruses and Prions)* Genetic factors: Amyloid Precursor Protein on chromosomes 21Q, adult with trisomy 21 (Down's)QClinical Manifestations:The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and spreading to language and visuospatial deficits.Changes in environment (such as vacations or hospital stays) may be disorienting.Language becomes impaired-first naming, then comprehension, and finally fluency.In some patients, aphasia is an early and prominent feature.Apraxia emerges, and patients have trouble performing learned sequential motor tasks.Visuospatial deficits begin to interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles or copy geometric figures.Approximately 10% of AD patients develop Capgras' syndrome, believing that a caregiver has been replaced by an impostor.Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration.As AD progresses, more distributed but usually posterior-predominant cortical atrophy becomes apparent, along with atrophy of the medial temporal memory structures.Slowly progressive decline in memory and orientation, normal results on laboratory tests, and an MRI or CT scan showing only distributed or posteriorly predominant cortical and hippocampal atrophy is highly suggestive of AD.Treatment:DonepeziI (target dose, 10 mg daily),Rivastigmine (target dose, 6 mg twice daily or 9.5-mg patch daily)Galantamine (target dose 24 mg daily, extended-release)Memantine (target dose, 10 mg twice daily)TacrineDue to hepatotoxicity, tacrine is no longer used.Memantine appears to act by blocking overexcited A-methyl-d-aspartate (NMDA) glutamate receptors.