Question

human brain deases Alzimer dease about 7 powerpoint slide

Answer 1

slide 1

INTRODUCTION

Alzheimer’s disease is the most common cause of dementia worldwide, with the prevalence continuing to grow in part because of the aging world population.

This neurodegenerative disease process is characterized classically by two hallmark pathologies: β-amyloid plaque deposition and neurofibrillary tangles of hyperphosphorylated tau.

Diagnosis is based upon clinical presentation fulfilling several criteria as well as fluid and imaging biomarkers.The definitive diagnosis of AD requires post-mortem evaluation of brain tissue, though cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers combined with several relatively new clinical criteria can aid diagnosis in living patients

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Aetiology

majority of AD occurs on an apparently sporadic basis, mutations in three genes – amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) – cause a rare (<0.5%) familial form of AD (fAD).

Typical’ late onset AD is likely to be driven by a complex interplay between genetic and environmental factors. It is now thought that ~70% of AD risk is attributable to genetic factors.

The APOE gene, which has three variants, ε2, ε3 and ε4, is the single biggest risk for sporadic AD: compared to non‐ε4 carriers, ε4 heterozygotes have an odds ratio (OR) for AD of ~3, rising to ~12 in homozygotes

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Pathology

The cardinal features of Alzheimer pathology are amyloid plaques and neurofibrillary tangles (NFTs)

In addition, neuropil threads, dystrophic neurites, associated astrogliosis and microglial activation are seen, and cerebral amyloid angiopathy frequently coexists .

Amyloid plaques are extracellular accumulations principally composed of abnormally folded Aβ with 40 or 42 amino acids (Aβ40 and Aβ42), two by‐products of APP metabolism. Aβ42 is more abundant than Aβ40 within plaques due to its higher rate of fibrillization and insolubility.

Neurofibrillary tangles are primarily composed of paired helical filaments consisting of hyperphosphorylated tau. Tau pathology typically begins in the allocortex of the medial temporal lobe (entorhinal cortex and hippocampus) before spreading to the associative isocortex.

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The amyloid hypothesis, the prevalent theory of AD pathogenesis, suggests that accumulation of pathological forms of Aβ produced by sequential cleavage of the APP by the β‐ and γ‐secretase enzymes in the brain is the primary pathological process, driven through an imbalance between Aβ production and Aβ clearance. The formation of NFTs and subsequent neuronal dysfunction and neurodegeneration, perhaps mediated via inflammation, are thought to be downstream processes.

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DIAGNOSIS

The development of non-invasive diagnostic imaging recently resulted in a test which increases the diagnostic accuracy in AD. After injection of a radiolabeled tracer agent, patients undergo a specialized PET scan that detects the deposition of amyloid-β (Aβ) peptides into plaques in the living brain. In 2012, clinicians were able to accurately diagnose the disease (later autopsy proven) using this method with up to 96% sensitivity and 100% specificity.

The more-invasive but less-costly evaluation involves examination of CSF for Aβ42, hyperphosphorylated tau peptide (p-tau), and total tau protein content. This method has slightly less diagnostic accuracy (85–90%), carries the risks and inconveniences involved with a lumbar puncture procedure, and often takes weeks to obtain results because of the dearth of laboratory facilities which perform the fluid analysis.

Less-invasive serum assays designed to detect the quantity of circulating proteins implicated in AD are currently in development and show promise. In 2017, one test discriminated among normal cognition, MCI, and dementia due to AD in a small number of patients with sensitivities and specificities of 84% and 88%, respectively.

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TREATMENT

Acetyl‐cholinesterase inhibitors (AChEIs) (donepezil, galantamine and rivastigmine) are the mainstay of symptomatic treatment, increasing acetylcholine availability by inhibiting its breakdown in the synapse.

AChEIs have proven beneficial effects in mild to severe AD, with most evidence at the mild to moderate stage

Memantine, a low affinity N‐methyl‐d‐aspartate receptor antagonist, aims to reduce l‐glutamate excitatory neurotoxicity without interfering with its physiological actions. Side effects include constipation and headache. Memantine has been shown to have a small but clinically appreciable benefit on cognition and functional decline in patients with moderate to severe AD, with some evidence that it reduces the likelihood of patients developing agitation.

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FUTURE PROSPECT

Research into future treatments of AD involve targeting of the etiologic pathologies: neurofibrillary tangles (composed of p-tau) and senile plaques (Aβ),

Reearchers found in 2013 that this abnormal amyloid plaque induces the phosphorylation of tau protein, which then spreads almost infectiously via microtubule transport to neighboring neurons, leading to neuronal death. One class of medications developed using this evidence is the monoclonal antibodies (passive immunotherapy). This type of treatment involves injection of an antibody that targets abnormal Aβ and facilitates its removal from the brain.

For disease prevention, it will be necessary to identify accurately which individuals are at risk. The development of new disease‐specific biomarkers using PET, CSF and, in due course, blood has already provided important insights into the pathways leading to the development of AD. Application of these technologies to ever larger cohorts, particularly when combined with genetic data, will improve our ability to detect individuals at risk of developing AD.