Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

Robinson, John; Corrada, María M.; Kovács, Gábor G.; Dominique, Myrna A.; Caswell, Carrie; Xie, Sharon X.; Lee, Virginia M.‐Y.; Kawas, Claudia H.; Trojanowski, John Q.

doi:10.1007/s00401-018-1872-5

Cited by 121 publications

(115 citation statements)

References 47 publications

(88 reference statements)

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“…Although we and others found that infarcts and small vessel disease (a term encompassing hyaline arteriolosclerosis) were related to cognitive impairment in younger and very old participants (2,9,20,21,37,50), it is important to note that we found an attenuation in the association between infarcts and cognitive impairment in very old participants that were not previously described (28,41). Very old participants with infarcts had more than 3 times the odds of cognitive impairment compared to older participants without infarcts; however the association was much stronger in younger participants with infarcts that showed an odds for cognitive impairment of almost 7 times.…”

Section: Prevalence Of Neuropathological Lesions and Their Associatiomentioning

confidence: 66%

“…When we examined the association of neuropathological lesions with cognitive impairment, we found higher odds of impairment with increasing NFT BB stages, chronic infarcts and hyaline arteriolosclerosis in both age groups. Indeed, high NFT BB stages were associated with dementia in several studies with very old participants (15,28,37,46), while neuritic plaque burden has been inconsistently associated with dementia (6,37,38,41,50). Interestingly, several studies pointed to an attenuation of the association between AD neuropathological changes and dementia in the very old (19,21,28,41).…”

Section: Prevalence Of Neuropathological Lesions and Their Associatiomentioning

confidence: 99%

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Neuropathological lesions in the very old: results from a large Brazilian autopsy study

et al. 2019

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Objective To compare neuropathological correlates of cognitive impairment between very old and younger individuals from a Brazilian clinicopathological study. Methods We assessed the frequency of neuropathological lesions and their association with cognitive impairment (Clinical Dementia Rating scale ≥0.5) in the 80 or over age group compared to younger participants, using logistic regression models adjusted for sex, race and education. Results Except for infarcts and siderocalcinosis, all neuropathological lesions were more common in the 80 or over age group (n = 412) compared to 50–79 year olds (n = 677). Very old participants had more than twice the likelihood of having ≥2 neuropathological diagnoses than younger participants (OR = 2.66, 95% CI = 2.03–3.50). Neurofibrillary tangles, infarcts and hyaline arteriolosclerosis were associated with cognitive impairment in the two age groups. Siderocalcinosis was associated with cognitive impairment in the younger participants only, while Lewy body disease was associated with cognitive impairment in the very old only. In addition, we found that the association of infarcts and multiple pathologies with cognitive impairment was attenuated in very old adults (Infarcts: P for interaction = 0.04; and multiple pathologies: P = 0.05). However, the predictive value for the aggregate model with all neuropathological lesions showed similar discrimination in both age groups [Area under Receiver Operating Characteristic curve (AUROC) = 0.778 in younger participants and AUROC = 0.765 in the very old]. Conclusion and relevance Despite a higher frequency of neuropathological findings in the very old group, as found in studies with high‐income populations, we found attenuation of the effect of infarcts rather than neurofibrillary tangles and plaques as reported previously.

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Section: Prevalence Of Neuropathological Lesions and Their Associatiomentioning

confidence: 66%

Section: Prevalence Of Neuropathological Lesions and Their Associatiomentioning

confidence: 99%

Neuropathological lesions in the very old: results from a large Brazilian autopsy study

et al. 2019

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“…adding mathematical models that describe how molecular changes alter population activity -so called cause--and--effect models. We will focus here on the disrupted inhibitory function of interneurons and consecutive hyperexcitability caused by Abeta -while we are aware of various other factors with potential roles for AD aetiology, such as vascular changes (19--21), neuroinflammation (22--25), genetics (26--28), environmental factors (29,30) and concomitant proteinopathies others than Abeta pathology (31,32). Beside Abeta there is a second molecular hallmark associated with the pathogenesis of AD: the phosphorylated Tau 'tubulin--associated unit' protein (8,33,34) which contributes to microtubule stability in the neural cytoskeleton (34).…”

mentioning

confidence: 99%

“…with BAN--2401 (42). A relevant percentage of clinically diagnosed AD patients show additional brain pathologies beside Abeta and Tau in autopsy (32). Even in the cases of neuropathological AD diagnosis (i.e.…”

mentioning

confidence: 99%

Linking molecular pathways and large-scale computational modeling to assess candidate disease mechanisms and pharmacodynamics in Alzheimer’s disease

Stefanovski

Triebkorn

Spiegler

et al. 2019

Preprint

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Introduction. While the prevalence of neurodegenerative diseases associated with dementia such as Alzheimer's disease (AD) increases, our knowledge on the underlying mechanisms, outcome predictors, or therapeutic targets is limited. In this work, we demonstrate how computational multi--scale brain modelling links phenomena of different scales and therefore identifies potential disease mechanisms leading the way to improved diagnostics and treatment. Methods. The Virtual Brain (TVB; thevirtualbrain.org) neuroinformatics platform allows standardized large--scale structural connectivity--based simulations of whole brain dynamics. We provide proof of concept for a novel approach that quantitatively links the effects of altered molecular pathways onto neuronal population dynamics. As a novelty, we connect chemical compounds measured with positron emission tomography (PET) with neural function in TVB addressing the phenomenon of hyperexcitability in AD related to the protein amyloid beta (Abeta). We construct personalized virtual brains based on individual PET derived distributions of Abeta in patients with mild cognitive impairment (MCI, N=8) and Alzheimer's Disease (AD, N=10) and in age--matched healthy controls (HC, N=15) using data from ADNI--3 data base (http://adni.lni.usc.edu). In the personalized virtual brains, individual Abeta burden modulates regional inhibition, leading to disinhibition and hyperexcitation with high Abeta loads. We analyze simulated regional neural activity and electroencephalograms (EEG). Results. Known empirical alterations of EEG in patients with AD compared to HCs were reproduced by simulations. The virtual AD group showed slower frequencies in simulated local field potentials and EEG compared to MCI and HC groups. The heterogeneity of the Abeta load is crucial for the virtual EEG slowing which is absent for control models with homogeneous Abeta distributions. Slowing phenomena primarily affect the network hubs, independent of the spatial distribution of Abeta. Modeling the N--methyl--D--aspartate (NMDA) receptor antagonism of memantine in local population models, reveals potential functional reversibility of the observed large--scale alterations (reflected by EEG slowing) in virtual AD brains. Discussion. We demonstrate how TVB enables the simulation of systems effects caused by pathogenetic molecular candidate mechanisms in human virtual brains.

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“…It is possible that these tauopathies may often be overlooked against the background of severe AD neurofibrillary pathology. Reports from centers that specifically look for argyrophilic grains and aging-related tau astrogliopathy (ARTAG) find AD comorbidity rates up to 40% for both [143][144][145][146][147][148][149][150]. The classical conditions in this group, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease, are much less prevalent, although PSP may be considerably more common than previously realized due to low clinical sensitivity for the diagnosis [143,[151][152][153][154][155][156][157][158].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s Disease Neuropathological Comorbidities Are Common in the Younger-Old

Beach

Malek‐Ahmadi

2020

Preprint

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Clinicopathological studies have demonstrated that Alzheimer's disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the presence and rate of cognitive decline in aging and ADD. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown. We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer's Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer's Association (NIA-AA) intermediate or high AD Neuropathological Change (ADNC) levels, excluding those with known autosomal dominant AD-related mutations. Subjects were divided into age-atdeath categories for analysis: under 60, 60-69, 70-79, 80-89, 90-99 and 100 or over. Confirmatory of earlier reports, ADD histopathology is less severe with advancing age, effectively increasing the relative contribution of comorbidities, most of which rise in prevalence with age. Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where "pure" ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20% in the 70s and beyond. Comorbidity rates for some pathologies, especially LBD, are high even in subjects in their 60s and 70s, at nearly 60%, but for most others, their prevalence increases with age. TDP-43 pathology affects more than 35% of ADD subjects 80 and over while microscopic infarcts reach this rate a decade later. Gross infarcts rise more slowly and affect fewer subjects but still involve 15-20% of ADD after age 80. White matter rarefaction may be underestimated in the NACC database but is present in almost 70% of centenarians with ADD. Effective clinical trials depend on accurate estimates of required subject numbers, which are dependent on observed effect size and clinical response variability. Comorbidities are likely to affect both, leading to lower probability of clinical trial success. Stratifying ADD clinical trial analyses by presence and types of accompanying comorbidities might identify subgroups with higher effect sizes and greater clinical response rates, but accurate in-vivo diagnostic methods for most comorbidities are still lacking. Neuropathological studies are increasingly demonstrating that Alzheimer's disease dementia (ADD) is most often not the sole brain pathology in those that die and are autopsied, but is very likely to be accompanied by comorbid neurodegenerative and cerebrovascular disease. Comorbidities are likely to alter the presence and rate of ...

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Non-Alzheimer’s contributions to dementia and cognitive resilience in The 90+ Study

Cited by 121 publications

References 47 publications

Neuropathological lesions in the very old: results from a large Brazilian autopsy study

Neuropathological lesions in the very old: results from a large Brazilian autopsy study

Linking molecular pathways and large-scale computational modeling to assess candidate disease mechanisms and pharmacodynamics in Alzheimer’s disease

Alzheimer’s Disease Neuropathological Comorbidities Are Common in the Younger-Old

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