bluuebunny/crossref_metadata_2025 huggingface dataset:
Hippocampal hyperactivity measured with task fMRI in individuals at risk for Alzheimer’s disease
Authors: Maass Anne
Published: December 2023

Background

Neuronal 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?

Method

In 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.

Result

Early 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.

Conclusion

Increased 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

Background

Depressive 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.

Method

This 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.

Result

Our 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.

Conclusion

Our 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

Background

Physical 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.

Method

An 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.

Result

55 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.

Conclusion

This 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

Background

Several 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.

Method

Annual 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.

Result

Results 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.

Conclusion

Cumulative 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

Background

Cerebrovascular 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).

Methods

Figure 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.

Results

We 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).

Conclusions

Cardiovascular 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

Background

White 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.

Methods

In 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.

Results

After 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).

Conclusion

Individuals 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

Background

The 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.

Method

We 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.

Result

CSF 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).

Conclusion

Coupling 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

Background

Post‐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.

Method

The 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.

Conclusion

This 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

Background

Neuropsychiatric 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.

Method

Participants 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.

Result

After 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).

Conclusion

These 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.
Long noncoding RNA MALAT1; A novel and potential therapeutic target for Alzheimer’s disease
Authors: Khan Mohammad Moshahid , Tripathi Manish , Xiao Jianfeng
Published: December 2023

Background

Alzheimer disease (AD) is the most common form of dementia, characterized pathologically by amyloid plaques and neurofibrillary tangles. Despite considerable advances in the knowledge of AD pathogenesis, we know little about preventing or delaying the ongoing neurodegenerative process, indicating that there remain critical gaps in our understanding of disease mechanisms and opportunities for new treatment approaches. Long noncoding RNAs (lncRNAs) are larger than 200 nucleotides, structurally resemble mRNAs but do not encode proteins. LncRNAs participate in regulation of several physiological and pathophysiological processes by modulating gene expression and have been documented in several neurodegenerative diseases. Among them, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is a highly abundant and evolutionary conserved lncRNA and regulates a subset of genes involved in synaptic plasticity, cognitive function and memory.

Method

To test the hypothesis that lncRNA MALAT1 plays an important role in AD pathology, we quantified expression levels of lncRNA MALAT1 in the brains of age‐matched AD patients and cognitively normal controls (Non‐AD) by QRT‐PCR and RNAScope in situ hybridization assays, respectively. We further examined the lncRNA MALAT1 expressions and AD‐related neuropathology in the brains of 5XFAD transgenic mouse model of AD and their WT littermates using dual RNAScope/Immunofluorescence technique.

Result

We observed reduced expressions of lncRNA MALAT1 in the hippocampus of AD brains compared to the non‐AD control brains. Next, we found marked reduced expression of lncRNA MALAT1 in the brain of 5xFAD mice compared to non‐transgenic mice. Interestingly, decreased expression levels of lncRNA MALAT1 are correlated with AD‐related neuropathology and memory deficits in 5xFAD mice.

Conclusion

These findings provided compelling evidence that AD is associated with altered expression of lncRNA MALAT1 which may influence several pathways related to neural damage and memory deficits in AD. Because expression patterns, interacting proteins, pathways, and biological functions of lncRNA MALAT1 are remain largely unexplored in AD, understanding how lncRNA MALAT1 regulates AD‐related neuropathology may allow development of effective therapies for this incurable disease.
Physiotherapist And Physiotherapy Student Knowledge, Confidence, Attitudes, And Beliefs About Providing Care For People With Dementia: A Mixed‐Methods Systematic Review
Authors: Quick Stephen M , Snowdon David A , Lawler Katherine , Soh Sze_Ee , McGinley Jennifer L , Callisaya Michele L
Published: December 2023

Background

Clinical care for people with dementia as a primary diagnosis, or as a co‐morbidity, can be complex. Physiotherapists play a key role in the care of people living with dementia in multiple settings. The aim of this systematic review was to understand the attitudes, beliefs, knowledge and confidence of physiotherapists and physiotherapy students when working with people living with dementia.

Methods

This was a mixed‐methods systematic review that included qualitative and quantitative studies. Participants were physiotherapists working in any clinical specialty (e.g. gerontology, orthopaedic, neurological), and physiotherapy students who had completed at least 5 weeks of clinical placement. The phenomena of interest were attitudes, beliefs, knowledge and confidence when working with people with dementia in any setting. Eleven databases were searched. Data synthesis followed a convergent integrated approach according to Joanna Briggs Institute methodology for mixed methods systematic reviews.

Results

Fifteen studies were included (9 quantitative and 6 qualitative studies). Seven key themes evolved. Five related to the belief that (1) working with people with dementia is complex and challenging; (2) opportunities for education in dementia care are lacking; (3) working with people with dementia is a specialized area of practice; (4) there are unsupportive systems for working with people with dementia; and (5) people with dementia deserve rehabilitation, but their potential to improve is less certain. One theme related to knowledge (lack of knowledge in some areas of dementia care), and one theme related to confidence (lack of confidence in working with people with dementia).

Discussion/Conclusion

Physiotherapists and physiotherapy students have low levels of knowledge and confidence in areas including cognition, communication and management of behavioural symptoms. Given that higher levels of knowledge and confidence may be associated with more positive attitudes and beliefs, dementia education needs of physiotherapists at all levels needs to be addressed.
Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Zhang Shengwei , Evia Arnold M , Schneider Julie A , Arfanakis Konstantinos
Published: December 2023

Background

Brain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.

Method

Participants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B).

Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p<0.05, after family‐wise error rate (FWER) correction for multiple testing.

Result

Arteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.

Conclusion

The current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.
Synergistic role of white matter changes and CSF biomarkers in amnestic and non‐amnestic AD phenotypes
Authors: Fernandez Paulo Eduardo Lahoz , Liger Ivy , Curti Nayara Christina de Lima , Bond Marisa Macedo Kuenzer , Falcão Mariana Braga , Bertolucci Paulo Henrique Ferreira
Published: December 2023

Background

Alzheimer’s disease (AD) is pathologically diagnosed based on abnormal amyloid and tau pathology but is also related to additional pathologic processes. (1) The cognitive symptoms are not directly associated with AD pathology but are the consequence of a complex mechanism, showing discordance between clinical symptoms and CSF biomarkers. (2) Previous evidence suggests a range from the synergistic role of white matter signal abnormality (WMSA) and CSF biomarkers on AD to no relationship between the two. (1) We aimed to analyze the CSF biomarker profiles, and brain MRI changes in AD patients with different phenotypes.

Method

CSF was collected by lumbar puncture from 40 individuals with AD. We analyzed CSF levels (Aβ‐42, Aβ‐40, t‐tau, p‐tau, tau / Aβ‐42, and Aβ‐42/40) in two different samples. The clinical characteristics included: AD phenotype (amnestic or non‐amnestic), age, gender, education, and age‐onset. We used the brain MRI scales: MTA (mesial temporal lobe atrophy), and Fazekas, for white matter signal abnormality (WMSA), considering pathological changes (≥ 2).

Result

Preliminary results in 16 patients showed that most of the patients with CSF typical AD pattern presented an amnestic phenotype, revealing WMSA changes. The patients with no CSF changes showed little or no WMSA changes in both clinical presentations. The amnestic phenotype showed more MTA changes in patients with typical AD CSF pattern, and no difference was found between the phenotypes in patients with no CSF changes.

Conclusion

It can be a positive relation between cerebrovascular diseases, WMSA changes, and CSF pathological changes in AD, regardless of the phenotype, supporting that Aβ pathology may lead to secondary vascular damage including white matter lesions.

References: 1. Lindemer ER, Greve DN, Fischl B, Salat DH, Gomez‐Isla T. White matter abnormalities and cognition in patients with conflicting diagnoses and CSF profiles. Neurology. 2018 Apr 24;90(17):e1461‐9.

2. Alexopoulos P, Roesler J, Thierjung N, Werle L, Buck D, Yakushev I, et al. Mapping CSF biomarker profiles onto NIA‐AA guidelines for Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 2016 Oct;266(7):587‐97.
Cognitive function in older adults with hearing loss; outcomes for treated versus untreated groups at 3‐year follow‐up.
Authors: Sarant Julia Z , Harris David , Maruff Paul , Schembri Adrian , Lemke Ulrike , Launer Stefan , Phillips Jocelyn , Nixon Grace , Canagasabey Manasi , Anderson Charlotte , Davine Ella
Published: December 2023

Background

Hearing loss has been identified as the largest potentially modifiable risk factor for dementia and affects 50% adults aged 50‐64 years, and 70% aged 70 years and older. The quality of evidence the effect of hearing aid use on cognition in older adults is currently poor due to methodological limitations. Few studies have objectively studied these outcomes beyond 6‐12 months. This prospective longitudinal observational cohort study investigated the effects of hearing aid use on cognitive performance in older adults over 3 years.

Method

183 first‐time hearing aid users aged 60 years and older with mild to severe hearing loss were assessed using gold standard measures before hearing aid fitting, with subsets of this group re‐assessed after 18 and 36 months as they reached these timepoints. Outcomes for the treatment group were compared with those of participants of a large longitudinal cohort study of community‐living older adults (AIBL) using the same measures. Objective assessment measures included cognitive function, hearing loss, hearing aid use, genetic phenotyping, and speech perception. Subjective measures included hearing disability, mood, quality of life, social isolation, and loneliness.

Result

The treatment group showed good hearing aid compliance, significant improvement in speech perception (quiet and noise) and decreased self‐reported listening disability despite further significant hearing loss over the 3‐year follow‐up. There was significant improvement in cognitive performance from baseline for the treatment group versus the comparative group for working memory, attention, psychomotor function, and visual learning. Comparatively, AIBL participants showed statistically significant decline across all cognitive functions.

Conclusion

Older adults with untreated hearing loss are expected to decline cognitively at 2‐5 times the rate of adults without hearing loss. Comparatively, cognitive performance in treated participants in this study instead improved after 3 years of hearing aid use, while the comparative group declined. These results suggest that treatment of hearing loss with hearing aids may delay cognitive decline.
Specific Association of Worry and Amyloid‐β Deposition in Cognitive Unimpaired Older Adults
Authors: Lee Soyoung , Siddiqi Shan , Donovan Nancy J
Published: December 2023

Background

Anxiety symptoms are common in cognitively unimpaired (CU) older adults prior to the onset of cognitive impairment. Evidence suggests that anxiety symptoms may be sequelae of amyloid‐beta (Aβ) deposition in early Alzheimer’s disease (AD) and/or anxiety may potentiate the pathophysiologic process. Despite this pivotal role, the specific components of anxiety associated with high brain Aβ in CU older adults are relatively unknown. It was previously reported that Aβ deposition is associated with a global anxiety score measured by State‐Trait Anxiety Inventory‐6 (STAI‐6) but not depression measured by Geriatric Depression Scale (GDS) total scores. Here, we examined the specific associations of individual anxiety symptoms with Aβ.

Method

Older adult participants were screened for the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s study (“A4 study”) and underwent assessments of anxiety (STAI‐6), depression (GDS), cognitive performance (MMSE and Preclinical Alzheimer Cognitive Composite /PACC), subjective cognition (Cognitive Function Instrument/CFI) and cortical Aβ deposition using Florbetapir PET standardized uptake value ratio (SUVR). Linear regression models estimated associations of STAI‐6 items, “calm,” “tense,” “upset,” “relax,” “content,” and “worry,” with Aβ deposition, adjusting for multiple potential confounders.

Result

The sample (n = 4486) were older adults ages 65 ‐ 85 (mean [SD] age, 71.29 [4.67] years, included 2647 women (59%) and 1323 (29.5%) who were classified as Aβ+. STAI‐6 total score ranged from 6 ‐ 24 (Mean 9.9 [3.1]). A significant positive association was found between the anxiety item measuring “worry”, and Aβ, adjusting for age, sex, education, marital status, depression (GDS), objective cognition (MMSE or PACC), and subjective cognition (CFI) [Table 1]. There were other significant (negative) associations between items measuring “calm” and “relax” and Aβ in similar regression models. Only the association of “worry” with Aβ remained significant after further adjustment for global anxiety measured by the total STAI‐6 score.

Conclusion

In a large, well‐characterized sample of CU older adults, worry was significantly and most strongly associated with Aβ, independent of psychosocial factors, subjective and objective cognition and global anxiety. These findings suggest that self‐reported worry may have unique explanatory value in the clinical assessment of CU older adults at high risk of AD and cognitive impairment.
Xanamem shows pro‐cognitive activity with clinically meaningful effect sizes across 3 independent, placebo‐controlled clinical trials
Authors: Hilt Dana , Rolan Paul , Taylor Jack , Miller Tamara , Jaros Mark , Harrison John E , Ritchie Craig W , Woodward Michael
Published: December 2023

Background

Xanamem® is a brain‐penetrant inhibitor of 11‐beta hydroxysteroid dehydrogenase type 1, which converts intracellular cortisone to cortisol and is highly expressed in brain regions such as the hippocampus. Elevated plasma and CSF cortisol is strongly associated with cognitive decline.

Method

Effects of Xanamem on cognition were assessed in 3 independent, placebo‐controlled, double‐blind trials. The XanaHES (n = 42, 20 mg) and XanaMIA (n = 105, 5 & 10 mg) Phase 1b trials used the computerised Cogstate system to assess cognition in normal, older volunteers. The XanADu‐X biomarker extension study (n = 72, 10 mg) explored clinical and cognitive outcomes in subgroups (n = 34 each) of the XanADu Phase 2a AD trial with higher (H) or lower (L) plasma p‐Tau181 in a new prospective analysis. To compare the results across trials, we focus on the cognitive effect sizes measured by the Cohen’s statistic (treatment effect vs. placebo / pooled baseline standard deviation).

Result

Xanamem was safe and well‐tolerated with no treatment‐related SAEs and the predominantly mild AEs were generally equally distributed between Xanamem and placebo. In XanaHES and XanaMIA, a pattern of clinically significant improvements was observed in attention and working memory compared to placebo in the Xanamem groups, with Cohen’s d ranging up to 1.27. Improvements from baseline were observed in both Xanamem and placebo in domains of episodic memory and executive function without a treatment difference. In XanADu, Xanamem demonstrated clinically significant benefit with a Cohen’s d of 0.41 on the CDR‐SB compared to placebo in the H group but not in the L group. In both L and H groups improvements in executive function were seen favouring Xanamem (Cohen’s d = 0.34 and 0.26, respectively) and the MMSE (Cohen’s d = 0.32 and 0.16, respectively). There were no improvements observed on original XanADu primary outcome measures of ADAS‐Cog14 and ADCOMs.

Conclusion

Xanamem displays activity in multiple domains of cognition including attention, working memory, and executive function with clinically meaningful effects in normal subjects and in patients with p‐Tau‐elevated mild AD. These data suggest Xanamem may be both a pro‐cognitive drug and disease‐modifying agent and guide design of future trials.
Prevalence of Cognitive Domain Impairments in Mild Cognitive Impairment Subtypes in the NACC Database
Authors: Lerner Alan J. , Appleby Brian , Elkasaby Mohamed , Leverenz James B , Malone Joseph , Miller‐Scott Lindsay J , Murphy Tamara B , Ogrocki Paula K. , Pillai Jagan A. , Duffy Charles
Published: December 2023

Background

Mild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living. MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD. In this study, we explore frequencies of domain impairment by MCI subtype, and frequency of each combination of (memory ±) all combinations of Language, Attention, Executive and Visuospatial impairment in the NACC database. This is of practical importance for both localization of amyloid or tau deposition as well as relative localization of areas of deficit.

Method

Using the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with sub‐typing. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. 9852 individuals with MCI on baseline UDS visits were analyzed: 45.4% AMD, 33.7% ASD, 12.6% NASD, 8.2% NAMD.

Result

Figure one shows the distribution overall of domain specific impairment by MCI subtype. Except for ASD, Executive function was the most common domain affected, and visuospatial was the least common. NAMD had higher percentages affected for all domains compared to AMD. In Figure 2, all combinations of language, executive, attention and visuospatial are compared. The most frequent combination was Language‐Executive, and the least common combination was Language‐Attention‐Visuospatial. The mean absolute percentage difference between AMD and NAMD was 2.2%. The Spearman’s rho of AMD vs. NAMD was 0.845.

Conclusion

Within an MCI subtype, there is substantial variability in the frequency of individual domains. However, comparison of AMD and NAMD shows striking uniformity in frequency of combinations of individual domains with very correlation. The latter findings suggests that Amnestic and Nonamnestic multidomain subtypes may be closely related in pathophysiology but show greater heterogeneity within a MCI subtype.
Volumetric and cognitive findings in transient global amnesia: results of the FORGOT cohort
Authors: Hernández Micaela A , Chaves Hernan , Allegri Ricardo Francisco , Calandri Ismael Luis
Published: December 2023

Background

Transient global amnesia (TGA) is a sudden onset syndrome of episodic amnesia with unclear pathophysiology. Although expected to last less than 24 hours, different studies described persistent cognitive impairment primarily in memory and executive functions. We aim to analyze the cognitive performance and cortical volume of patients after a TGA as contributing factors to its pathophysiology.

Method

Case‐control study of matched TGA subjects (n = 50) and normal controls (NC) (n = 50). All were studied with brain MRI with volumetric T1 sequences (in TGA subjects performed 1.4 months after the episode (SD±3.4)). Voxel‐based morphometry (VBM), region‐based morphometry (RBM) and surface‐based morphometry (SBM) steps were performed using an extension of the software package SPM12. All subjects were evaluated with a modified UDS3 neuropsychological battery. TGA patients were assesed 3 months after the event to avoid confusors. A deficit in each cognitive domain was diagnosed when individuals scored below ‐1.5 SD for normal values for age, sex and education. Anxiety, depression and cognitive complaints were also assessed. For VBM and RBM, a two‐sample independent t‐test was modeled and estimated with TIV, sex, and age as covariates. For SBM, a two‐sample independent t‐test without covariates was modeled and estimated. We applied the FDR method for multiple comparison corrections and defined a p<.05 threshold for statistical significance.

Result

Among 50 patients with TGA, 54% were female. Mean age was 66 (±9). No significant differences were found in VBM analysis. In the RBM test, we observed reduced volume in the left accumbens nucleus (figure 1) and in SBM, reduced cortical thickness on the right temporal pole and ventromedial visual area 2 (figure 2). No differences were found among cognitive performance between TGA and control patients (table 1).

Conclusion

The absence of abnormalities in cortical volume and cognitive failure beyond three months of the event affirms the transient nature of the episode and dispells the association with a neurodegenerative disease as a predisposing factor. SBM abnormalities in distant regions may suggest a network disruption beyond the hippocampus.