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(AD), one of the most common causes of adult dementia, is as yet not well

understood. AD has been identified as a protein misfolding disease due to the


accumulation of abnormally folded amyloid beta protein in the brains of
Alzheimer's patients.
AD is also considered a tauopathy due to abnormal aggregation of the tau protein,
a microtubule-associated protein expressed in neurons that normally acts to
stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated
proteins, tau is normally regulated by phosphorylation; however, in AD patients,
hyperphosphorylated tau accumulates as paired helical filaments that in turn
aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and
as dystrophic neurites associated with amyloid plaques. Although little is known
about the process of filament assembly, it has recently been shown that a depletion
of a prolyl isomerase protein in theparvulin family accelerates the accumulation of
abnormal tau
Atrophy in AD
The major contributors to atrophy are thought to be dendritic and neuronal losses.
Studies of regional (e.g., hippocampal) MRI volumes have shown these are closely
related to neuronal counts at autopsy
1)The histological validation of post mortem magnetic resonance

imaging-determined hippocampal volume in Alzheimer's


disease.Bobinski M- http://www.ncbi.nlm.nih.gov/pubmed/10670438/
2) Hippocampal volume as an index of Alzheimer
neuropathology: findings from the Nun Study http://www.ncbi.nlm.nih.gov/pubmed/12034782
Individuals with an isolated pathologic diagnosis of AD, hippocampal sclerosis,
frontotemporal degeneration, and neurofibrillary tangle--only degeneration usually
had substantial hippocampal atrophy, while those with changes of typical aging did
not
3) Antemortem MRI findings correlate with hippocampal

neuropathology in typical aging and dementia.


- http://www.ncbi.nlm.nih.gov/pubmed/11889239/
The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe
atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in

autopsy confirmed cases, and to determine pathological correlates of MTA in Alzheimer's


disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI)

4) Medial temporal lobe atrophy on MRI differentiates Alzheimer's

disease from dementia with Lewy bodies and vascular cognitive


impairment: a prospective study with pathological verification of
diagnosis.
- http://www.ncbi.nlm.nih.gov/pubmed/19022858
The unequivocal diagnosis of Alzheimer's disease (AD) rests on histopathological evidence
at brain autopsy or biopsy. The morphology of AD includes cerebral atrophy, deposition of
beta A4 amyloid (A beta) (senile plaques and amyloid angiopathy), neuritic changes
(neuritic plaques, neurofibrillary tangles (NFT) and neuropil threads) with formation of paired
helical filaments (PHF) containing polymerized hyperphosphorylated tau protein triplet,
causing disruption of the neuronal cytoskeleton with loss of synapses and neurons, with
altered cortico-cortical connectivity, leading to disconnection of the cerebral cortex. Defining
criteria for the morphologic diagnosis of AD is difficult due to the phenotypic heterogeneity
of the disease, the absence of specific markers, and overlap of AD morphology with that
observed in non-demented elderly individuals. This gray zone between normal to pathologic
aging and full-fledged AD represents an important diagnostic problem and should be
overcome by better standardized criteria that will allow to minimize interrater and
interlaboratory variability in the diagnosis of AD. Current criteria for the morphologic
diagnosis of AD are based on (semi)quantitative assessment of diffuse and neuritic plaques
(NIA), exclusively neuritic plaques (CERAD), plaques and NFT in neocortex and
hippocampus (Tierney et al., 1988), and staging of hierarchic spreading of neuritic AD
changes (Braak and Braak, 1991);
5)

Neuropathology of Alzheimer's disease: a critical update

- http://www.ncbi.nlm.nih.gov/pubmed/9850917
AD is characterized by an insidious onset and inexorable
progression of atrophy that is first manifest in the medial
temporal lobe. The entorhinal cortex is typically the earliest site of
atrophy, closely followed by the hippocampus, amygdala, and
parahippocampus
6) MRI measures of entorhinal cortex vs hippocampus in

preclinical AD.
http://www.ncbi.nlm.nih.gov/pubmed/11971085/

7) MRI-derived entorhinal and hippocampal atrophy in incipient

and very mild Alzheimer's disease


http://www.ncbi.nlm.nih.gov/pubmed/11705634/

8) Neuropathological stageing of Alzheimer-related changes.


http://www.ncbi.nlm.nih.gov/pubmed/1759558

9) Tracking atrophy progression in familial Alzheimer's disease:

a serial MRI study


http://www.ncbi.nlm.nih.gov/pubmed/16987729/

10) Change in rates of cerebral atrophy over time in early-onset

Alzheimer's disease: longitudinal MRI study.


http://www.ncbi.nlm.nih.gov/pubmed/14550701/

11) MRI and CSF biomarkers in normal, MCI, and AD subjects:

predicting future clinical change.


http://www.ncbi.nlm.nih.gov/pubmed/19636049/

12) MRI of hippocampal volume loss in early Alzheimer's disease

in relation to ApoE genotype and biomarkers.


http://www.ncbi.nlm.nih.gov/pubmed/19251758/

13) An ensemble-of-classifiers based approach for early

diagnosis of Alzheimer's disease: classification using structural


features of brain images
http://www.ncbi.nlm.nih.gov/pubmed/25276224

14) Early diagnosis of Alzheimer's disease: contribution of

structural neuroimaging.
http://www.ncbi.nlm.nih.gov/pubmed/12595205

SEVERAL OTHER A-DEGRADING ENZYMES APART FROM NEPRILYSIN ( ref:

A-degrading enzymes: potential for treatment of Alzheimer


disease)
insulin-degrading enzyme
endothelin-converting enzyme
cathepsin B