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

Background: Regional cerebral hypoperfusion is characteristic of Alzheimer’s disease (AD). Previous studies report conflicting findings in cognitively normal individuals at high risk of AD. Understanding early preclinical perfusion alterations may improve understanding of AD pathogenesis and lead to new biomarkers and treatment targets. Methods: 3T arterial spin labelling MRI scans from 162 participants in the PREVENT-Dementia cohort were analysed (cognitively normal participants aged 40–59, stratified by future dementia risk). Cerebral perfusion was compared vertex-wise according to APOE ε4 status and family history (FH). Correlations between individual perfusion, age and cognitive scores (COGNITO battery) were explored. Results: Regional hyperperfusion was found in APOE ε4+group (left cingulate and lateral frontal and parietal regions p<0.01, threshold-free cluster enhancement, TFCE) and in FH +group (left temporal and parietal regions p<0.01, TFCE). Perfusion did not correlate with cognitive test scores. Conclusions: Regional cerebral hyperperfusion in individuals at increased risk of AD in mid-life may be a very early marker of functional brain change related to AD. Increased perfusion may reflect a functional ‘compensation’ mechanism, offsetting the effects of early neural damage or may itself be risk factor for accelerating spread of degenerative pathology

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study.

BACKGROUND: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD. METHODS: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen. RESULTS: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory. CONCLUSION: Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score's potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk.Research grants from the UK Alzheimer's Society, the US Alzheimer’s Association and philanthropic donations. This work was funded by a grant for the PREVENT-Dementia programme from the UK Alzheimer’s Society (grant numbers 178 and 264), and the PREVENT-Dementia study is also supported by the US Alzheimer’s Association (grant number TriBEKa-17–519007) and philanthropic donations. AL is supported by the Lee Kuan Yew Fitzwilliam PhD Scholarship and the Tan Kah Kee Postgraduate Scholarship. JDS is a Wellcome clinical PhD fellow funded on grant 203914/Z/16/Z to the Universities of Manchester, Leeds, Newcastle and Sheffield. EM is supported by Alzheimer’s Society Junior Research Fellowship (RG 9611). LS is supported by the Cambridge NIHR Biomedical Research Centre (BRC) and Alzheimer’s Research UK (ARUK-SRF2017B-1). HSM is supported by an NIHR Senior Investigator award. JOB and HSM receive infrastructural support from the Cambridge NIHR Biomedical Research Centre (BRC). This research was supported by the NIHR Cambridge BRC (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care

7T MRI for neurodegenerative dementias in vivo: a systematic review of the literature.

The spatial resolution of 7T MRI approaches the scale of pathologies of interest in degenerative brain diseases, such as amyloid plaques and changes in cortical layers and subcortical nuclei. It may reveal new information about neurodegenerative dementias, although challenges may include increased artefact production and more adverse effects. We performed a systematic review of papers investigating Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and Huntington's disease (HD) in vivo using 7T MRI. Of 19 studies identified, 15 investigated AD (the majority of which examined hippocampal subfield changes), and 4 investigated HD. Ultrahigh resolution revealed changes not visible using lower field strengths, such as hippocampal subfield atrophy in mild cognitive impairment. Increased sensitivity to susceptibility-enhanced iron imaging, facilitating amyloid and microbleed examination; for example, higher microbleed prevalence was found in AD than previously recognised. Theoretical difficulties regarding image acquisition and scan tolerance were not reported as problematic. Study limitations included small subject groups, a lack of studies investigating LBD and FTD and an absence of longitudinal data. In vivo 7T MRI may illuminate disease processes and reveal new biomarkers and therapeutic targets. Evidence from AD and HD studies suggest that other neurodegenerative dementias would also benefit from imaging at ultrahigh resolution.The authors acknowledge the support of the Cambridge NIHR Biomedical Research Centre

Translating research into practice: outcomes from the Healthy Living after Cancer partnership project

Healthy Living after Cancer (HLaC) was a national dissemination and implementation study of an evidence-based lifestyle intervention for cancer survivors. The program was imbedded into existing telephone cancer information and support services delivered by Australian state-based Cancer Councils (CC). We report here the reach, effectiveness, adoption, implementation, and maintenance of the program.In this phase IV study (single-group, pre-post design) participants - survivors of any type of cancer, following treatment with curative intent - received up to 12 nurse/allied health professional-led telephone health coaching calls over 6\ua0months. Intervention delivery was grounded in motivational interviewing, with emphasis on evidence-based behaviour change strategies. Using the RE-AIM evaluation framework, primary outcomes were reach, indicators of program adoption, implementation, costs and maintenance. Secondary (effectiveness) outcomes were participant-reported anthropometric, behavioural and psychosocial variables including: weight; physical activity; dietary intake; quality-of-life; treatment side-effects; distress; and fear of cancer recurrence and participant satisfaction. Changes were evaluated using linear mixed models, including terms for timepoint (0/6 months), strata (Cancer Council), and timepoint x strata.Four of 5 CCs approached participated in the study. In total, 1183 cancer survivors were referred (mostly via calls to the Cancer Council telephone information service). Of these, 90.4% were eligible and 88.7% (n = 791) of those eligible consented to participate. Retention rate was 63.4%. Participants were mostly female (88%), aged 57 years and were overweight (BMI = 28.8 ± 6.5 kg/m2). Improvements in all participant-reported outcomes (standardised effect sizes of 0.1 to 0.6) were observed (p