Clinicopathologic Studies in Cognitively Healthy Aging and Alzheimer Disease

Abstract

(1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E epsilon4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque-based neuropathologic criteria for AD are highly accurate.

The citrus flavonoid “Nobiletin” impedes STZ-induced Alzheimer’s disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism

“…Moreover, Nobiletin, as an activator of SIRT1 signaling pathways, deacetylated p-tau, hence preventing tauopathy. Remarkably, our results are in concordance with former studies revealing tau pathology is exceedingly reflective of cognitive decline in AD indicating that Nobiletin may be an efficient therapy targeting phosphorylated tau and preceding to cognitive enhancement (Berg et al 1998 ; Arriagada et al 1992 ). Previous studies have reported a similar response of animal models to Nobiletin as a therapeutic potential for AD and other neurodegenerative disorders, which supports these findings (Nakajima and Ohizumi 2014 ; Qi et al 2019 ; Onozuka et al 2008 ).…”

The citrus flavonoid “Nobiletin” impedes STZ-induced Alzheimer’s disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism

“…Moreover, Nobiletin, as an activator of SIRT1 signaling pathways, deacetylated p-tau, hence preventing tauopathy. Remarkably, our results are in concordance with former studies revealing tau pathology is exceedingly reflective of cognitive decline in AD indicating that Nobiletin may be an efficient therapy targeting phosphorylated tau and preceding to cognitive enhancement (Berg et al 1998 ; Arriagada et al 1992 ). Previous studies have reported a similar response of animal models to Nobiletin as a therapeutic potential for AD and other neurodegenerative disorders, which supports these findings (Nakajima and Ohizumi 2014 ; Qi et al 2019 ; Onozuka et al 2008 ).…”

Neuropathologic Heterogeneity Does Not Impair Florbetapir-Positron Emission Tomography Postmortem Correlates

“…Our results demonstrated that AD cases with LBs had significantly decreased SUVr measures compared to AD cases without LBs; additionally, the only significantly different comparison, out of all possible comparisons, of average cortical SUVr between all AD subgroups, was between the AD/CAA subgroup and the AD/LB subgroup, and again, the AD/LB subgroup had a lower average cortical SUVr. These results are consistent with previous neuropathological reports demonstrating plaque densities may be lower in the cortex of AD subjects with DLB as compared to AD subjects without DLB (14, 38,42, 43). High densities of CAA are likely to be additive to amyloid plaques in affecting cortical SUVr, as a high-resolution postmortem study has demonstrated that another amyloid imaging agent, PiB, binds with high sensitivity to CAA (44).…”

Modeling regional vulnerability to Alzheimer pathology

“…We have also confirmed that regional vulnerability to either NFT or NP can be associated with both cross-sectional and longitudinal cognitive test performance. Similar to previous studies (Neary et al, 1986; Arnold et al, 1991; Arriagada et al, 1992; Berg et al, 1993; Bierer et al, 1995; Nagy et al, 1995; Berg et al, 1998), dNFT was a stronger correlate of cognition than was dNP, and dNP had no significant effect on cognition independently of dNFT (Arnold et al, 1991; Bennett et al, 2004). Conversely, only dNP was significantly related to APOE e4 burden (Kok et al, 2009).…”

The citrus flavonoid “Nobiletin” impedes STZ-induced Alzheimer’s disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism

“…Moreover, Nobiletin, as an activator of SIRT1 signaling pathways, deacetylated p-tau, hence preventing tauopathy. Remarkably, our results are in concordance with former studies revealing tau pathology is exceedingly reflective of cognitive decline in AD indicating that Nobiletin may be an efficient therapy targeting phosphorylated tau and preceding to cognitive enhancement (Berg et al 1998 ; Arriagada et al 1992 ). Previous studies have reported a similar response of animal models to Nobiletin as a therapeutic potential for AD and other neurodegenerative disorders, which supports these findings (Nakajima and Ohizumi 2014 ; Qi et al 2019 ; Onozuka et al 2008 ).…”

Neuropathologic Heterogeneity Does Not Impair Florbetapir-Positron Emission Tomography Postmortem Correlates

“…Our results demonstrated that AD cases with LBs had significantly decreased SUVr measures compared to AD cases without LBs; additionally, the only significantly different comparison, out of all possible comparisons, of average cortical SUVr between all AD subgroups, was between the AD/CAA subgroup and the AD/LB subgroup, and again, the AD/LB subgroup had a lower average cortical SUVr. These results are consistent with previous neuropathological reports demonstrating plaque densities may be lower in the cortex of AD subjects with DLB as compared to AD subjects without DLB (14, 38,42, 43). High densities of CAA are likely to be additive to amyloid plaques in affecting cortical SUVr, as a high-resolution postmortem study has demonstrated that another amyloid imaging agent, PiB, binds with high sensitivity to CAA (44).…”

Modeling regional vulnerability to Alzheimer pathology

“…We have also confirmed that regional vulnerability to either NFT or NP can be associated with both cross-sectional and longitudinal cognitive test performance. Similar to previous studies (Neary et al, 1986; Arnold et al, 1991; Arriagada et al, 1992; Berg et al, 1993; Bierer et al, 1995; Nagy et al, 1995; Berg et al, 1998), dNFT was a stronger correlate of cognition than was dNP, and dNP had no significant effect on cognition independently of dNFT (Arnold et al, 1991; Bennett et al, 2004). Conversely, only dNP was significantly related to APOE e4 burden (Kok et al, 2009).…”

The citrus flavonoid “Nobiletin” impedes STZ-induced Alzheimer’s disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism

“…Moreover, Nobiletin, as an activator of SIRT1 signaling pathways, deacetylated p-tau, hence preventing tauopathy. Remarkably, our results are in concordance with former studies revealing tau pathology is exceedingly reflective of cognitive decline in AD indicating that Nobiletin may be an efficient therapy targeting phosphorylated tau and preceding to cognitive enhancement (Berg et al 1998 ; Arriagada et al 1992 ). Previous studies have reported a similar response of animal models to Nobiletin as a therapeutic potential for AD and other neurodegenerative disorders, which supports these findings (Nakajima and Ohizumi 2014 ; Qi et al 2019 ; Onozuka et al 2008 ).…”

Neuropathologic Heterogeneity Does Not Impair Florbetapir-Positron Emission Tomography Postmortem Correlates

“…Our results demonstrated that AD cases with LBs had significantly decreased SUVr measures compared to AD cases without LBs; additionally, the only significantly different comparison, out of all possible comparisons, of average cortical SUVr between all AD subgroups, was between the AD/CAA subgroup and the AD/LB subgroup, and again, the AD/LB subgroup had a lower average cortical SUVr. These results are consistent with previous neuropathological reports demonstrating plaque densities may be lower in the cortex of AD subjects with DLB as compared to AD subjects without DLB (14, 38,42, 43). High densities of CAA are likely to be additive to amyloid plaques in affecting cortical SUVr, as a high-resolution postmortem study has demonstrated that another amyloid imaging agent, PiB, binds with high sensitivity to CAA (44).…”

Modeling regional vulnerability to Alzheimer pathology

“…We have also confirmed that regional vulnerability to either NFT or NP can be associated with both cross-sectional and longitudinal cognitive test performance. Similar to previous studies (Neary et al, 1986; Arnold et al, 1991; Arriagada et al, 1992; Berg et al, 1993; Bierer et al, 1995; Nagy et al, 1995; Berg et al, 1998), dNFT was a stronger correlate of cognition than was dNP, and dNP had no significant effect on cognition independently of dNFT (Arnold et al, 1991; Bennett et al, 2004). Conversely, only dNP was significantly related to APOE e4 burden (Kok et al, 2009).…”