bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal hyperactivity measured with task fMRI in individuals at risk for Alzheimer’s disease
Authors: Maass Anne 
Published: December 2023

AbstractBackgroundNeuronal dysfunction occurs early in the course of Alzheimer’s disease (AD) and the hippocampus is one of the earliest regions affected by AD. Animal models have linked higher neural excitability to the early accumulation of AD proteins. In humans, blood oxygen level dependent (BOLD) fMRI can be used as an indirect measure of changes of in neuronal activity. Over the last two decades, many studies have assessed hippocampal fMRI activity during different tasks to assess changes in activity with aging or early cognitive impairment. Is there evidence for increased fMRI activity in the hippocampus in subjects at risk for development of AD and how are these fMRI BOLD changes related to markers of Amyloid‐beta or tau tangles?MethodIn this talk, we will review and discuss findings on hippocampal fMRI activity in cognitively normal older adults or subjects with MCI, focusing on task fMRI.ResultEarly task‐based fMRI studies have often reported increased task activation in the hippocampus in older adults relative to young adults and in patients with MCI compared to cognitively normal controls using different fMRI task paradigms. Increased hippocampal activity has been often seen during mnemonic discrimination or when stimuli are repeated, with a failure of repetition‐related suppression. Notably, also other medial temporal lobe and posterior midline regions have shown task‐related “hyperactivation”. Several studies that also included AD biomarkers have linked increased task activation to abnormal levels of Aβ in cognitively normal elderly and MCI. More recently, with the advent of tau‐specific PET tracers, increased task activation in the hippocampus has been associated with temporal lobe tau. It is debated whether increased fMRI BOLD activation reflects aberrant neuronal activity that is driven by or drives abnormal protein accumulation. Notably, also several other factors might contribute to the altered fMRI BOLD signal in hippocampus, including e.g.vascular changes.ConclusionIncreased fMRI task activity in the hippocampus has been observed in the presence of early cognitive deficits and has been related to early AD pathology. While this increased task fMRI BOLD signal is most widely interpreted as increased neuronal activity, the underlying mechanism needs to be further elucidated.
Associations between depressive symptoms, glial fibrillary acid protein, and cognitive decline in a population‐based study
Authors: Desai Pankaja , Krueger Kristin R , de Leon Carlos Mendes , Wilson Robert S. , Evans Denis A , Rajan Kumar B 
Published: December 2023

AbstractBackgroundDepressive symptoms are a known risk factor for dementia, and higher concentrations of glial fibrillary acid protein (GFAP) is associated with a faster rate of cognitive decline. However, it is unknown whether the two risk factors increase the risk of cognitive decline additively.MethodThis investigation is based on 1,169 participants from the Chicago Health and Aging Project (CHAP), a population‐based cohort study, who completed at least two cognitive performance assessments with baseline serum GFAP measurement. Depressive symptoms were determined utilizing a modified version of the Center for Epidemiologic Studies‐Depression Scale. A composite global cognitive function score was calculated using cognitive performance testing. Linear mixed effects regression models were conducted to examine the association of depressive symptoms and GFAP concentrations on baseline global cognitive function and the annual rate of cognitive decline. Regression models also adjusted for age, race, sex, education, chronic medical conditions, and their interactions with time.ResultOur study sample consisted of 60% African American participants and 63% female participants and had an average age of 77 (SD = 6.0) years. In our sample, 21% had few depressive symptoms (0‐2), and the remaining 79% had more depressive symptoms (3‐10). We found a statistically significant interaction between depressive symptoms and GFAP (β = ‐111 (SE = .039), p = .005) on global cognitive function. Stratified analysis showed that the associations between the log of GFAP and global cognitive function were statistically significant for participants with few (0‐2) depressive symptoms (β = ‐.223 (SE = .087), p = .010) and more (3‐10) depressive symptoms (β = ‐.781 (SE = .198), p = .000). Statistically significant associations were also observed between the log of GFAP and global cognitive decline for participants with few (β = ‐.069 (SE = .017), p = .000) and more (β = ‐.100 (SE = .040), p = .012) depressive symptoms.ConclusionOur findings show additive effects of depressive symptoms in the association between the log of GFAP with baseline global cognitive function and rate of cognitive decline. Prevention and treatment of depression in old age can significantly impact the risk of progressive cognitive decline, especially among individuals with higher concentrations of GFAP.
EXCEL ‐ EXercise for Cognitive hEaLth: A pilot 12‐week online home‐based physical activity program for middle‐aged and older adults with cognitive and mental health concerns.
Authors: Ellis Kathryn A , Curran Eleanor , Moorhead Rebecca Anne , Cox Kay L , Southam Jennifer Amanda , Westphal Alissa , Lai Rhoda , Rego Thomas W H , Rego Thomas W H , Palmer Victoria J , Anstey Kaarin J. , Coulson Brett , Lautenschlager Nicola T , Moss Francine 
Published: December 2023

AbstractBackgroundPhysical inactivity significantly increases dementia risk (DR). For middle‐aged and older adults with co‐occurring cognitive concerns/impairment and mental health symptoms, DR increases further. Clinical trials indicate lower adherence to PA interventions for dementia risk reduction in such high risk‐group, and interventions tailored to support unique behaviour change needs are required. In EXCEL Phase 1 we developed a model to understand Physical Activity (PA) behavior change needs in this population and identify tailoring requirements to enhance engagement (see Curran et al. AAIC‐23, submitted). Here we report findings of our trial of a pragmatic online intervention to support middle‐aged and older adults with Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI) and mild‐moderate symptoms of depression, anxiety or stress to adopt and maintain PA.MethodAn online individual 12‐week home‐based PA intervention. Participants aged 45‐80 years, experiencing both cognitive (SCD or MCI) and mild‐moderate mental health symptoms (measured by the Depression Anxiety and Stress Scale ‐ DASS‐21) were prescribed individually tailored PA programs combining aerobic and strength PA; plus balance training as indicated, with fortnightly online coaching from researchers. Acceptability, feasibility, safety, and effectiveness (including pre‐post change in PA and mental health scores) were measured.Result55 participants were enrolled (46 females/9 males; mean age = 62.2 years). Retention was high (95%) and the intervention was well received; 98% finding it useful, 100% stating they would recommend to others. The intervention was safe, utilizing a system of email alerts/queries to the study medical team (44 alerts), PA team (35 queries/requests), individual exercise specialist (3 zoom sessions) and case conferences. Mental health improved across all DASS‐21 dimensions. Community Healthy Activities Model Program for Seniors (CHAMPS) scores improved post‐intervention, with higher frequency of all moderate/high intensity exercise (from 8.1 to 12.4 times/week), more strength training frequency (0.8 to 2.5 times/week) and longer time spent strength training (25 to 65 mins/week). Balance activity (older adults only) frequency increased from 0.5 ‐ 4 times/week.ConclusionThis home‐based online intervention, using the Capability, Opportunity, and Motivation model of behavior change, successfully helped an at‐risk cohort adopt and maintain PA in line with Australian PA guidelines.
County‐level cumulative effect of ambient PM2.5 exposure on the Alzheimer’s disease mortality rate in the west coast regions of the United States
Authors: Ni Andrew , Chang Hannah , Tang Lu 
Published: December 2023

AbstractBackgroundSeveral studies have investigated the relationship between long‐term exposure to fine particulate matter (PM2.5) and the risk of Alzheimer’s disease (AD), yet studies on the cumulative effect of PM2.5 exposure are limited. This study assesses the association between the county‐level cumulative PM2.5 exposure at a level above 35 ug/m3, the safe threshold recommended by the World Health Organization (WHO), on Alzheimer’s mortality in the west coast population of the United States.MethodAnnual county‐level Alzheimer’s disease mortality rates from 2010 to 2019 were obtained from the Centers for Disease Control and Prevention WONDER database, and the cumulative county‐level PM2.5 exposure greater than 35 ug/m3 were derived from publicly accessible data at the Environmental Protection Agency (EPA). Analysis focused on 76 counties for about 48 million people in the states of Washington, Oregon, and California of the US.Analysis was conducted using a Bayesian spatiotemporal linear mixed effects model with the Markov Chain Monte Carlo Simulations. For each county, the log transformed county‐level annual AD mortality rates were regressed against the total number of days with concentration levels of PM2.5 over 35 ug/m3 in the year and its past t years, where t = 1, 2, …, 10 (Figure 1 for t = 10). Each of the 10 regression models was adjusted for thirteen potentially confounding variables including the rate of poverty, percent rural land area, median household income, percent unemployed, percent uninsured, percent obesity, percent smokers, percent excessive drinking, percent African American, percent Asian, percent Hispanic, percent ages under 18, and percent ages 65 and older.ResultResults showed that in periods of three calendar years or longer, having a higher number of days of PM2.5 exceeding the safe level is associated with a higher rate of AD mortality (Figure 2). The results also showed an increasing trend between AD mortality and years of cumulative PM2.5 exposure.ConclusionCumulative PM2.5 exposure at a level above the WHO recommended safe threshold is associated with AD mortality rate in three west coast states of the US.
Associations of Cardiovascular Risk Factors and Cerebrovascular Pathologies in the Elderly: A Systematic Review
Authors: Wong Joey , Rajmohan Ravi , Corrada María M. M. , Kawas Claudia H. 
Published: December 2023

AbstractBackgroundCerebrovascular pathologies are common in the elderly and are associated with dementia. Cardiovascular risk factors are thought to contribute to their development, but this evidence mainly comes from imaging studies or autopsy studies in younger individuals. We performed a systematic review to investigate associations of cardiovascular risk factors with cerebrovascular pathologies in the oldest‐old (age >80) vs. the younger‐old (ages 65‐80).MethodsFigure 1 describes how studies were identified. Cardiovascular risk factors were hypertension (HTN), hyperlipidemia (HLD), and diabetes (DM). Cerebrovascular pathologies were arteriolosclerosis, atherosclerosis, CAA, and MVLs. PubMed, Scopus, and Web of Science databases were searched for articles in English that investigated associations between self‐reported cardiovascular risk factors and presence of cerebrovascular pathologies on autopsy with a mean age >65 years, which reported odds ratios (OR), or information to calculate OR, for the individual associations of cardiovascular risk factors and cerebrovascular pathologies. Initial searching involved all combinations of cardiovascular MeSH terms by cerebrovascular pathology MeSH terms (n = 1038). JW and RR screened titles and abstracts to identify potential studies (n = 45), which reduced to 10 after applying the restrictions above. We used meta‐analytic methods to estimate OR when multiple studies reported on the same associations.ResultsWe reviewed 10 studies (Table 1) from 6 unique cohorts (n = 1,815, ages 65‐80 and n = 7,995, age >80). HTN was positively associated with cerebrovascular pathologies for all the instances except arteriolosclerosis‐oldest‐old [OR = 1.20, n = 2,089], (arteriolosclerosis‐younger‐old [OR = 1.30 n = 1,599], atherosclerosis‐oldest‐old [OR = 1.29, n = 2,620], CAA‐oldest‐old [OR = 1.23, n = 2,198], and MVLs‐oldest‐old [OR = 1.54, n = 1,710]) (Figure 2). HLD was associated with arteriolosclerosis in the younger‐old ([OR = 1.27 n = 922]), but not the oldest‐old ([OR = 0.98, n = 1,255]), and not associated with CAA in the oldest‐old ([OR = 1.13, n = 3,508]). DM was not associated in any situation in which it was investigated (Figure 2).ConclusionsCardiovascular risk factors were more associated with cerebrovascular pathologies in the younger‐old than oldest‐old. HTN was consistently associated with cerebrovascular pathologies in both age groups while DM was consistently not associated. Cardiovascular risk factors were understudied in the younger‐old. These findings highlight the importance of further clinicopathologic studies to clarify age‐dependent associations of cardiovascular risk factors and cerebrovascular pathologies.
White matter hyperintensities in behavioral variant frontotemporal dementia and semantic variant of primary progressive aphasia
Authors: Hadad Rafi , Cobigo Yann , Javandel Shireen , Wolf Amy , Milicic Andjelika , Allen Isabel Elaine , Valcour Victor 
Published: December 2023

AbstractBackgroundWhite matter hyperintensities (WMHs) are imaging abnormalities of white matter noted by hyperintense signals on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). When present among patients with CVRF (hypertension, diabetes, hypercholesteremia and smoking), WMHs are interpreted as cerebral vascular changes. However, WMHs in older individuals can be a feature of late onset leukodystrophies or varied neurodegenerative diseases such as Alzheimer disease (AD), Parkinson’s disease, and Frontotemporal Lobar Degeneration (FTLD). Additionally, WMHs can be present before symptom onset in neurodegenerative disorders and have been linked to the presence of some mutations, including progranulin (GRN). A clearer understanding of the underling etiology of WMHs in bvFTD and svPPA may improve management and treatment considerations.MethodsIn this cross‐sectional study, we included all participants meeting research diagnostic criteria for bvFTD (n = 152) and svPPA (n = 49) from ongoing studies at the UCSF Memory and Aging Center between the dates of September 2008 and December 2021 in comparison to a group of healthy controls enrolled at the same center with similar imaging parameters (n = 152, 1:1 matching for age and sex). All participants underwent a 3T FLAIR MRI and automated quantification of WMHs was performed. Linear regression analyses were performed to determine if WMHs were more frequent in participants with bvFTD or svPPA in comparison to controls and to explore associations with CVRF.ResultsAfter adjusting for age, sex, apolipoprotein E4 (APO‐E 4) status, and intracranial volume (ICV), both groups demonstrated a higher burden compared to controls (bvFTD (p = 0.012, R2 = 0.146) and svPPA (p = 0.008, R2 = 0.329). Modeling cardiovascular risk factors (CVRFs) as none or at least one, we did not find an association between CVRFs and WMH volume in models adjusting for ICV, ApoE4, and age among those with svPPA and bvFTD combined (p = 0.450).ConclusionIndividuals with bvFTD and svPPA appear to face a greater burden of WMHs compared to age‐ and sex‐matched healthy controls. WMHs in bvFTD and svPPA do not appear to be related CVRF.
Reduced coupling between cerebrospinal fluid flow and global brain activity is linked to tau pathology
Authors: Han Feng , Lee JiaQie , Chen Xi , Ziontz Jacob , Landau Susan M. , Baker Suzanne L. , Harrison Theresa M. , Jagust William J. 
Published: December 2023

AbstractBackgroundThe glymphatic system clears brain waste, including β‐amyloid (Aβ) and tau, through cerebrospinal fluid (CSF) movement. CSF inflow is coupled to global brain activity measured by global resting state fMRI (gBOLD). Weaker coupling has been proposed to reflect impaired glymphatic function and found associated with cognitive decline and Aβ accumulation in early Alzheimer’s disease (AD). Few studies have explored the role of glymphatic activity in tau pathology in the human brain, which we investigated by assessing glymphatic function with gBOLD‐CSF coupling.MethodWe identified 121 ADNI‐3 participants (72.4 ± 8.0 years; 65 females; 50 cognitively impaired, including 6 AD dementia and 44 mild cognitive impairment) who underwent both resting‐state fMRI (rsfMRI; TR = 0.607s sessions), tau PET (flortaucipir [FTP]), and amyloid PET (florbetapir or florbetaben). These participants were classified into different sub‐groups based on amyloid deposition (Aβ+: florbetapir > 1.11 SUVR; florbetaben > 1.08 SUVR) or diagnosis (cognitively impaired or unimpaired). CSF signal was extracted at the bottom rsfMRI slice, and gBOLD signal was from gray matter. Correlation analysis between gBOLD‐CSF coupling and tau load was performed on the whole cohort and the sub‐groups, respectively. Predefined regions of interest (ROIs) included Braak ROIs and a meta‐temporal ROI.ResultCSF inflow signal was coupled with global brain fMRI. Each participant’s coupling was quantified by the gBOLD‐CSF cross‐correlation at the negative peak (Fig. 1). We found significant correlations between the coupling metric and tau load in Braak III‐IV, V‐VI, and the meta‐temporal ROI (but not in Braak I [entorhinal cortex]) across all participants and the Aβ+ subgroup. In these regions, participants with weaker gBOLD‐CSF coupling (less negative; presumably impaired glymphatic clearance) have more tau deposition (Fig. 2). Similar patterns were seen in the relatively small (N = 30) Aβ+ impaired subgroup (Fig. 3).ConclusionCoupling between gBOLD and CSF signals, which could be a proxy for glymphatic function, is associated with tau deposition across the neocortex, particularly in Braak V‐VI ROIs. Furthermore, this effect is particularly evident in participants with elevated amyloid or cognitive impairment. These findings suggest that gBOLD‐CSF coupling is important for tau clearance, likely through its association with the glymphatic system.
Forward with dementia: process evaluation of an Australian campaign to improve post‐diagnostic support
Authors: Low Lee‐Fay , Phillipson Lyn , Gresham Meredith D , Jeon Yun‐Hee , Hall Danika , Tan Amy , Wong Nora , Brodaty Henry 
Published: December 2023

AbstractBackgroundPost‐diagnostic support for dementia is lacking in Australia and internationally. Across five countries, we co‐designed and delivered Forward with Dementia, a campaign to improve the communication of diagnosis and provision of post‐diagnostic support. This is a process evaluation of the Australia campaign which included social media, online advertising, webinars, a website hosting downloadable materials, newsletters and promotion through partner organisations. The campaign ran between September 2021 and June 2023 with a budget of AUD$50,000 and staff time.MethodThe Reach, Effectiveness, Adoption, Implementation, Maintenance (RE‐AIM) Framework with the addition of Appropriateness structured the evaluation. Data collected included a campaign activity log, surveys of health and social care professionals immediately after webinars (n = 81) and 3‐6 months afterwards (n = 45), interviews with eight health and social care professionals and six key stakeholders, and surveys and interviews with people with dementia (n = 24) and carers (n = 47).Result
Reach: 28,460 interactions with campaign activities including engagement through the website, webinars, and social media. Appropriateness: Campaign activities and resources were described to have appropriate content, a hopeful friendly tone, user‐friendly, and trustworthy and be authoritative. >75% of professionals reported webinars were helpful to their work. Adoption: 95% of professionals planned on using the information from webinars, and 93% intended to share the website with patients. Professionals provided examples of how they had changed practice – for instance being more positive, writing a care plan, making referrals, and sharing Forward with Dementia resources. Effectiveness: Professionals described being more confident in managing dementia. Some people with dementia and carers gave examples of how the campaign decreased self‐stigma, increased carer confidence, and led to actions which increased wellbeing. Maintenance: The majority of professionals had made ongoing changes to their post‐diagnostic support practices, some organisations were routinely using Forward with Dementia resources, which are also included in Department of Health and Dementia Australia websites.ConclusionThis relative short and economical campaign had broad reach and appropriate materials that produced sustained changes to post‐diagnostic support provided by health and social care professionals and organisations. Qualitative data suggests improved outcomes for people with dementia and carers.
Neuropsychiatric Symptoms and Alzheimer’s Disease Risk Differences across Racial and Ethnic Groups
Authors: Nguyen Victoria V , Escobar Esteban G , Gillen Daniel L , Sultzer David L 
Published: December 2023

AbstractBackgroundNeuropsychiatric symptoms (NPS) emerging after the age of 50 may be a risk factor or an early clinical expression of AD dementia. Mild Behavioral Impairment (MBI) is a syndrome of new‐onset and persistent NPS in older adults either with or without cognitive impairment. NPS in the context of race and ethnicity have not been studied and the influence of biology or culture on the expression of NPS is unknown.MethodParticipants over the age of 60 ranging from cognitively normal to mild AD (N = 17,491) from the National Alzheimer’s Coordinating Center were categorized for MBI status (yes/no) using Neuropsychiatric Inventory‐Questionnaire (NPI) scores and a published algorithm. MBI prevalence across White non‐Hispanics, White Hispanics, African Americans, and Asians was compared using multivariable logistic regression with adjustment for a priori specified confounding factors including diagnostic group, age, sex, and other relevant factors. Among MBI negative participants at baseline, a Cox proportional hazards model was also fit to estimate the relative risk of progression to MBI across race/ethnicity groups.ResultAfter adjustment, White Hispanics were estimated to have a 2‐fold higher odds of MBI when compared to White non‐Hispanics (OR, 2.03; 95% CI, 1.65‐2.50; p<0.001). In contrast, African Americans were less likely than White non‐Hispanics to have MBI (OR, 0.79; 95% CI, 0.68‐0.92; p<0.003). The odds of MBI were significantly higher among men when compared to women (OR, 1.28; 95% CI, 1.16‐1.41; p<0.001). In the prospective analysis, African Americans were estimated to have 26% lower risk of progressing to MBI when compared to White non‐Hispanics (RR, 0.74; 95% CI, 0.65‐0.84; p<0.001).ConclusionThese findings suggest there are racial/ethnic differences in the prevalence of MBI and the progression to MBI in older adults at risk for or with mild AD dementia. African Americans had a lower likelihood of having MBI and progression to MBI, while White Hispanics had a higher likelihood compared to White non‐Hispanics. Future research is warranted to investigate potential biological features or cultural factors such as the differential expression or perception of NPS in older adults that explain these differences.