Regional hyperperfusion in cognitively normal<i>APOE ε4</i>allele carriers in mid-life: analysis of ASL pilot data from the PREVENT-Dementia cohort

McKiernan, Elizabeth; Mak, Elijah; Dounavi, Maria‐Eleni; Wells, Katie; Ritchie, Craig W.; Williams, Guy B.; Su, Li; O’Brien, John

doi:10.1136/jnnp-2020-322924

Cited by 18 publications

(23 citation statements)

References 40 publications

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“…Conflicting results have been reported on CBF changes in CU individuals with elevated risk of AD. While some studies have shown patterns of hyperperfusion in CU APOE ε4 carriers (Wierenga et al, 2014;McKiernan et al, 2020), others have found no CBF changes in CU individuals with Aβ pathology (Binnewijzend et al, 2016). Our findings endorse the latter indicating that ASL-CBF is a marker of the disease severity, not directly related to Aβ deposition.…”

Section: Discussionsupporting

confidence: 60%

Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease

Ahmadi

Pereira

Berron

et al. 2021

Preprint

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Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic dysfunction and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in the temporo-occipito-parietal regions in the Aβ-positive cognitively impaired compared to both the Aβ-positive and Aβ-negative cognitively unimpaired individuals. In participants along the AD spectrum (those with Aβ pathology regardless of their cognitive status), CBF was inversely associated with tau and synaptic dysfunction, but not Aβ in similar cortical regions. Moreover, the disease progression modeling revealed that CBF disruption followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and synaptic degeneration are more closely connected with CBF changes rather than Aβ pathology. This supports the notion that hypoperfusion is not an early event associated with the build-up of Aβ during the preclinical phase of AD.

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Section: Discussionsupporting

confidence: 60%

Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease

Ahmadi

Pereira

Berron

et al. 2021

Preprint

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“…Their association with cognitive performance in APOEe4 carriers was examined using longitudinal data from the PREVENT-Dementia study. Building on previous findings from our group, 37 our hypothesis was that we would observe evidence of hyper-perfusion and reduced CVRi in APOEe4 carriers at baseline. Furthermore, we hypothesised that significant interactions between hemodynamic measures and APOEe4 carriership in predicting cognitive scores would be recorded (positive for CBF and negative for CVRi for APOEe4 carriers), in line with our baseline compensatory perfusion hypothesis.…”

Section: Introductionmentioning

confidence: 70%

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study

Dounavi

Low

McKiernan

et al. 2021

J Cereb Blood Flow Metab

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Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer’s disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40–59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+.

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“…Our group’s previously reported findings from cognitively healthy middle-aged participants have related these three risk factors to a range of structural and functional brain changes, including APOE □4 genotype to loss of volume in the hippocampal molecular layer [17], and to cerebral hyperperfusion [18-19]; FH to volumetric alterations in hippocampal subfields and to disrupted white matter integrity [18, 20]; and, CAIDE to whole brain atrophy [21-23] and to hippocampal volume loss [20, 23]. APOE □4, FH and CAIDE have also been found to impact cognition in mid-life.…”

Section: Introductionmentioning

confidence: 99%

Modifiable lifestyle activities affect cognition in cognitively healthy middle-aged individuals at risk for late-life Alzheimer’s Disease

Heneghan

Deng

Wells

et al. 2022

Preprint

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It is now acknowledged that Alzheimers Disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in midlife. We asked whether modifiable lifestyle activities impact cognition in middle aged individuals who are cognitively healthy, but at risk for late life AD. Participants (40 to 59 years) completed cognitive and clinical assessments at baseline (N = 210) and two years follow up (N = 188). Mid-life activities were measured with the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities, known risk factors for sporadic late onset AD (Apolipoprotein E Ɛ4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score), and their interactions on cognition. More frequent engagement in physically, socially and intellectually stimulating activities was associated with better cognition (verbal, spatial and relational memory), at baseline and follow up. Critically, more frequent engagement in these activities was associated with stronger cognition (verbal and visuospatial functions, and conjunctive short-term memory binding) in individuals with family history of dementia. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the presymptomatic stages of AD. These findings suggest that modifiable lifestyle activities offset cognitive decrements due to AD risk in midlife and support the targeting of modifiable lifestyle activities for the prevention of Alzheimers Disease.

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Regional hyperperfusion in cognitively normalAPOE ε4allele carriers in mid-life: analysis of ASL pilot data from the PREVENT-Dementia cohort

Cited by 18 publications

References 40 publications

Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease

Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study

Modifiable lifestyle activities affect cognition in cognitively healthy middle-aged individuals at risk for late-life Alzheimer’s Disease

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