Topographic Markers Drive Proteinopathies to Selection of Target Brain Areas at Onset in Neurodegenerative Dementias

Abbate, Carlo

doi:10.3389/fnagi.2018.00308

Cited by 4 publications

(2 citation statements)

References 39 publications

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“…3 ). Interestingly, the regions targeted by degeneration during early stages in AD, considering LOAD, EOAD, FAD and all the syndromic variants together, seem to be arranged at opposite locations along the same A-P, D-V, and M-L brain axes [ 366 ] ( Fig. 3 ).…”

Section: The Scaling Of Molecular Pathology To the Macroscopic Brainmentioning

confidence: 99%

The Adult Neurogenesis Theory of Alzheimer’s Disease

Abbate

2023

JAD

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Alzheimer’s disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this “reactive” pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission.

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Section: The Scaling Of Molecular Pathology To the Macroscopic Brainmentioning

confidence: 99%

The Adult Neurogenesis Theory of Alzheimer’s Disease

Abbate

2023

JAD

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“…It is unclear why and from which association cortex tau pathology begins; however, a hypothesis that the genetic programs active during neural development in their target brain area is reactivated as a topographic markers system, which drives proteinopathies, including tau, is proposed. 46 In another hypothesis, phenotypic diversity is interpreted as the Turing reaction, in which two interacting pathogenic proteins (tau and Aβ) spread diffusively through neural networks, including hubs of the default mode network, such as the posterior cingulate, temporo-parietal junctions, hippocampus, and medial prefrontal cortex. 47 Hippocampal sparing Alzheimer's disease and clinical diagnosis of pure Alzheimer's disease with atypical presentation…”

Section: Clinical Diversity On a Common Pathological Substrate In Pure Alzheimer's Diseasementioning

confidence: 99%

Clinicopathological heterogeneity of Alzheimer's disease with pure Alzheimer's disease pathology: Cases associated with dementia with Lewy bodies, very early‐onset dementia, and primary progressive aphasia

et al. 2021

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We report four cases depicting the heterogeneity of Alzheimer's disease (AD) associated with pure AD pathology. Case 1 was a 77-year-old man with a false positive diagnosis of dementia with Lewy bodies with reduced dopamine transporter uptake activity of the striatum but no Lewy body pathology. There were tau deposits in the large neurons in the putamen, which may be related to the development of parkinsonism. Case 2 was an AD patient in his early 30s who presented with a psychotic episode and a cognitive decline, and later developed myoclonus and seizures. He demonstrated considerable amyloid-beta deposits in the cerebral cortex, including cotton wool plaques, basal ganglia, and cerebellum. Tau deposits were also abundant in the cerebral neocortex, hippocampus, basal ganglia, and brain stem. Case 3 was a 60-year-old woman who exhibited typical symptoms characteristic of the logopenic variant of primary progressive aphasia (lvPPA). Case 4 was a 68-year-old man who exhibited the semantic variant of primary progressive aphasia (svPPA) plus repetition impairment, a rare case associated with AD pathology. In addition to tau pathology, astrocytic pathology was prominent in the white matter and cortical layers of the left temporoparietal cortices. While the main AD lesion in case 4 was evaluated by tau accumulation and astrogliosis in the left temporal lobe, that in case 3 in was evaluated by the same points in the left parietal lobe. Within the spectrum of lvPPA, case 4 may be regarded as a temporal variant of lvPPA presenting svPPA. The pathology of PPA associated with AD may have broader clinical manifestations than that in previously described cases. Case 4 also showed pathological features characteristic of cerebral amyloid angiopathy throughout the cerebral cortex. The distribution of tau and astrocytic pathologies in the cerebral cortex, basal ganglia, brain stem, and cerebellum may explain the various symptoms of atypical pure AD patients.

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Selective vulnerability in neurodegenerative diseases is not easily reconcilable with clinical diversity and clinical-anatomical convergence

Abbate

2019

Journal of the Neurological Sciences

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Topographic Markers Drive Proteinopathies to Selection of Target Brain Areas at Onset in Neurodegenerative Dementias

Cited by 4 publications

References 39 publications

The Adult Neurogenesis Theory of Alzheimer’s Disease

The Adult Neurogenesis Theory of Alzheimer’s Disease

Clinicopathological heterogeneity of Alzheimer's disease with pure Alzheimer's disease pathology: Cases associated with dementia with Lewy bodies, very early‐onset dementia, and primary progressive aphasia

Selective vulnerability in neurodegenerative diseases is not easily reconcilable with clinical diversity and clinical-anatomical convergence

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