Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer’s and concomitant cerebrovascular burdens

Chun, Mun-Suk; Kim, Soo-Jong; Park, Yu Hyun; Yun, Jihwan; Lockhart, Samuel N.; Weiner, Michael W.; Carli, Charles De; Moon, Seung Hwan; Choi, Jae Yong; Nam, Kyung Rok; Byun, Byung-Hyun; Lim, Sang-Moo; Kim, Jun Pyo; Choe, Yeong Sim; Kim, Young Ju; Na, Duk L.; Kim, Hee Jin; Seo, Sang Won

doi:10.1136/jnnp-2023-331603

Cited by 4 publications

(4 citation statements)

References 35 publications

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Section: Regional Distribution Of Cerebrovascular Reactivity Impairme...mentioning

confidence: 84%

“…We argue that the observed cerebrovascular dysfunction in FTD represents an early dysregulated pathophysiology, interacting with regional neurodegenerative changes, as postulated in AD [61–63]. Potential causes for the CVR decreases include pH dysregulation and impaired modulation of nitric oxide, which may diminish endothelium-dependent dilator responses and the dynamic range of the BOLD signal [16, 64, 65]. Alterations in the neurovascular unit, including dysfunctional vascular endothelium, hypercontractile vascular smooth muscle cells [62], depleted pericytes [5], and activated microglia [6] have been documented in familial FTD.…”

Section: Discussionmentioning

confidence: 99%

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Cerebrovascular reactivity impairment in genetic frontotemporal dementia

Kancheva,

Bouzigues,

Russell

et al. 2024

Preprint

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INTRODUCTION: Cerebrovascular reactivity (CVR) is an indicator of cerebrovascular health and its signature in hereditary frontotemporal dementia (FTD) remains unknown. We investigated CVR in genetic FTD and its relationship to cognition. METHODS: CVR differences were assessed between 284 pre-symptomatic and 124 symptomatic mutation carriers, and 265 non-carriers, using resting-state fluctuation amplitudes (RSFA) on component-based and voxel-level RSFA maps. Associations and interactions between RSFA, age, genetic status, and cognition were examined using generalised linear models. RESULTS: Compared to non-carriers, mutation carriers exhibited greater RSFA reductions, predominantly in frontal cortex. These reductions increased with age. The RSFA in these regions correlated with cognitive function in symptomatic and, to a lesser extent, pre-symptomatic individuals, independent of disease stage. DISCUSSION: CVR impairment in genetic FTD predominantly affects frontal cortical areas, and its preservation may yield cognitive benefits for at-risk individuals. Cerebrovascular health may be a potential target for biomarker identification and disease-modifying efforts.

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Section: Regional Distribution Of Cerebrovascular Reactivity Impairme...mentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Cerebrovascular reactivity impairment in genetic frontotemporal dementia

Kancheva,

Bouzigues,

Russell

et al. 2024

Preprint

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“…Cerebrovascular pathology often accompanies typical neuropathology of AD 39 , 40 . Even in the presence of cerebrovascular pathology in AD, plasma P-tau181 and P-tau217 can discriminate AD from other age-related dementias and healthy controls 41 .…”

Section: Discussionmentioning

confidence: 99%

Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease

SS,

AM,

et al. 2023

MRAJ

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Background: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer’s disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals. Aims: To evaluate the relationship of medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, and head injury, with cognitive impairment and blood-based biomarkers of AD, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort. Methods: Three-hundred individuals, aged 65 and older, were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four groups based on absence (Asym) or presence (Sym) of cognitive impairment and low (NEG) or high (POS) P-tau 217 or P-tau 181 levels, determined previously in the same cohort: (Asym/NEG, Asym/POS, Sym/NEG, Sym/POS). We examined differences in individual characteristics across the four groups. We performed post-hoc analysis examining the differences across biomarker and cognitive status. Results: P-tau 217 or P-tau 181 positive individuals had lower BMI than P-tau negative participants, regardless of symptom status. Symptomatic and asymptomatic participants did not differ in terms of BMI. BMI was not a mediator of the effect of P-tau 217 or P-tau 181 on dementia. Frequencies of other risk factors did not differ between the four groups of individuals. Conclusions: Participants with higher levels of P-tau 217 or P-tau 181 consistent with AD had lower BMI regardless of whether the individual was symptomatic. These findings suggest that weight loss may change with AD biomarker levels before onset of cognitive decline. They do not support BMI as a confounding variable. Further longitudinal studies could explore the relationship of risk factors with clinical diagnoses and biomarkers.

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“…Therefore, in this study, we aim to investigate (1) the association of CSVD and Aβ with glymphatic markers focused on AD continuum participants from cognitively normal to dementia and (2) whether glymphatic markers mediate the relationship between CSVD/Aβ and cognitive performance. CSVD was defined using WMH, a widely recognized and frequently utilized imaging marker for CSVD in the context of AD [ 31 , 32 ]. We speculate that both WMH and Aβ are independently associated with glymphatic impairment and could damage cognitive performance via glymphatic dysfunction.…”

Section: Introductionmentioning

confidence: 99%

The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer’s disease continuum participants

Hong,

Luo

et al. 2024

Alz Res Therapy

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Background Glymphatic dysfunction is a crucial pathway for dementia. Alzheimer’s disease (AD) pathologies co-existing with cerebral small vessel disease (CSVD) is the most common pathogenesis for dementia. We hypothesize that AD pathologies and CSVD could be associated with glymphatic dysfunction, contributing to cognitive impairment. Method Participants completed with amyloid PET, diffusion tensor imaging (DTI), and T2 fluid-attenuated inversion-recovery (FLAIR) sequences were included from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). White matter hyperintensities (WMH), the most common CSVD marker, was evaluated from T2FLAIR images and represented the burden of CSVD. Amyloid PET was used to assess Aβ aggregation in the brain. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, the burden of enlarged perivascular spaces (PVS), and choroid plexus volume to reflect glymphatic function. The relationships between WMH burden/Aβ aggregation and these glymphatic markers as well as the correlations between glymphatic markers and cognitive function were investigated. Furthermore, we conducted mediation analyses to explore the potential mediating effects of glymphatic markers in the relationship between WMH burden/Aβ aggregation and cognition. Results One hundred and thirty-three participants along the AD continuum were included, consisting of 40 CN − , 48 CN + , 26 MCI + , and 19 AD + participants. Our findings revealed that there were negative associations between whole-brain Aβ aggregation (r = − 0.249, p = 0.022) and WMH burden (r = − 0.458, p < 0.001) with DTI-ALPS. Additionally, Aβ aggregation (r = 0.223, p = 0.041) and WMH burden (r = 0.294, p = 0.006) were both positively associated with choroid plexus volume. However, we did not observe significant correlations with PVS enlargement severity. DTI-ALPS was positively associated with memory (r = 0.470, FDR-p < 0.001), executive function (r = 0.358, FDR-p = 0.001), visual-spatial (r = 0.223, FDR-p < 0.040), and language (r = 0.419, FDR-p < 0.001). Conversely, choroid plexus volume showed negative correlations with memory (r = − 0.315, FDR-p = 0.007), executive function (r = − 0.321, FDR-p = 0.007), visual-spatial (r = − 0.233, FDR-p = 0.031), and language (r = − 0.261, FDR-p = 0.021). There were no significant correlations between PVS enlargement severity and cognitive performance. In the mediation analysis, we found that DTI-ALPS acted as a mediator in the relationship between WMH burden/Aβ accumulation and memory and language performances. Conclusion Our study provided evidence that both AD pathology (Aβ) and CSVD were associated with glymphatic dysfunction, which is further related to cognitive impairment. These results may provide a theoretical basis for new targets for treating AD.

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Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer’s and concomitant cerebrovascular burdens

Cited by 4 publications

References 35 publications

Cerebrovascular reactivity impairment in genetic frontotemporal dementia

Cerebrovascular reactivity impairment in genetic frontotemporal dementia

Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease

The relationship between amyloid pathology, cerebral small vessel disease, glymphatic dysfunction, and cognition: a study based on Alzheimer’s disease continuum participants

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