bluuebunny/crossref_metadata_2025 huggingface dataset:
Lifestyle Empowerment for Alzheimer’s Prevention (LEAP! Rx) week 12 outcomes
Authors: Watts Amber , Van Sciver Angela R , Baker Jordan , Clutton Jonathan , Finley Katrina , Vacek James , Mahnken Jonathan D , Burns Jeffrey M.
Published: December 2023

Background

Clinicians have few tools to incorporate physical activity into clinical care to capitalize on the benefits of exercise for Alzheimer’s prevention. Barriers limit older adults from initiating and maintaining exercise recommendations. We tested the efficacy of an exercise and healthy lifestyle program, LEAP! Rx, in physician‐referred patients vs. self‐referred patients (typical referral method). Physician referrals occurred via electronic prescription embedded in the electronic health record. The program included 12 weeks of regular supervised exercise at a network of YMCAs, followed by 40 weeks of intermittent supervised exercise. Participants were offered monthly Alzheimer’s prevention classes (diet, cognitive engagement, stress reduction).

Method

An RCT tested efficacy of LEAP! Rx for gains in cardiorespiratory fitness and reduced disease markers. Participants (age 65+) were randomized to the Intervention Group (n = 110) or a Control Group (n = 110). 54% were referred by physicians, 46% were self‐referred. During the pandemic, exercise coaching was moved online. We analyzed increases in cardiorespiratory fitness (VO2max) and changes in insulin resistance, body composition, and lipids between baseline and week 12.

Result

Analyses are based on 179 participants’ data at week 12. The intervention group increased 3.6% in cardiorespiratory fitness (VO2max ml/kg/min) vs. 1.0% in Controls (non‐significant trend, t = 1.66, p = .098). The intervention group reduced fat mass by 2.0% vs. 0.7% in Controls (non‐significant trend, t = 0.163, p = .105). Self‐referred participants increased 4.7% in VO2max (p = .007) vs. 2.0% in physician‐referred (p = 0.20). Both referral groups had reductions in fat mass (p<.05). Adherence was lower in physician‐referred (fewer aerobic goals met (p = .038), more weeks of pandemic‐related gym closures (p<.001)). Physician‐referred had more participants identifying as Black and Latino/a (22%) vs. self‐referred (8%).

Conclusion

Although outcomes improved across 12 weeks, we found no significant differences between intervention and control groups. A potential explanation is differences between physician‐referred and self‐referred groups. Our unique physician referral method resulted in a more racially/ethnically diverse sample. However, the physician‐referred group had fewer VO2 gains, likely due to greater pandemic‐related adherence disruption. When week 52 is complete, we will investigate feasibility and acceptability of the referring physicians’ role and analysis of actigraphy data to clarify mechanisms of differential benefits.
Dementia prevalence in Southern Switzerland across community‐dwelling and institutionalised older adults – the SwissDEM study
Authors: Pacifico Deborah , Annoni Anna Maria , Fiordelli Maddalena , Frei Anja , Graf Gwendolyn , Puhan Milo , Albanese Emiliano
Published: December 2023

Background

Epidemiological evidence on dementia prevalence is outdated and still limited, and recent estimates (including those from the Institute for Health Metrics and Evaluation, IHME) may be an underestimation. Moreover, the recent WHO blueprint exercise confirmed that the quality of data we have is poor and based on weak and non‐standardized or even flawed methods. Dementia prevalence in nursing homes (NH) is likely high but evidence is scarce. We aimed to explore dementia and compare dementia prevalence in Southern Switzerland in community and in NH settings, using standardized and previously validated procedures and assessments.

Method

We conducted a cross‐sectional study among a random sample of community dweller older adults and a convenience sample of NH residents in the Canton of Ticino. Participants were dyads formed by an older adult (≥65 years old) and an informant. We collected socio‐demographic data and assessed cognitive function using the electronic version of the 10/66 short Dementia Diagnostic Schedule, which comprises the Community Screening Instrument for Dementia (CSI‐D), the CERAD animal verbal fluency and ten‐word list learning tasks, and the EURO‐Depression scale (EURO‐D). We performed descriptives, t‐tests, and chi‐square tests.

Result

We recruited 462 participants between June 2021 and August 2022. Participants living in the community (N = 300) had a mean age of 76.11 (SD = 6.46), and those living in NH (N = 162) of 87.62 (SD = 6.44). The prevalence of dementia was 6.3% (CI: 3.56‐9.11) in the community, and 75% (CI: 68.6‐82.02) in NH. Overall, dementia caseness was positively associated with age (p‐value <0.001), being a woman (p‐value < 0.001), and lower educational level (p‐value <0.001). However, these associations were not significant in the NH subsample (all p‐values >0.05). Among community‐dwelling older adults, dementia caseness was associated with age (p‐value <0.001), but not with gender, and education (all p‐values >0.05).

Conclusion

Our study shows the marked differences in dementia prevalence between community and NH settings, expanding recent models from the IHME. It is crucial to include institutionalised older adults when measuring dementia prevalence in populations, particularly in high‐income countries, and where people with dementia are more likely to and can live in NH.
CareMENS : a new model of care for elderly at risk of dementia, applied in 7 swiss memory clinics
Authors: Guevara Andrea Brioschi Brioschi , Leidi‐Maimone Benedetta , Bugnon Sophie , Fumasoli Margaux , Hausmann Alessa , Mélanie Bieler , Demonet Jean‐François , Allali Gilles , Rouaud Olivier
Published: December 2023

Background

Fourty percent of modifying factors explain cognitive decline in elderly, such as a lack of social and physical activities (Livingston 2020). Speech, physical and neuropsychological therapies have shown efficiency, although stopping them can have an impact on quality of life (Leidi, 2020). Therefore, usual models of care need to evolve to build bridges between therapies and community activities. The aim of CareMENS ( = Care, MEmory and NeuroScience), a new model, is to provide a continuity in patients’ care after the therapies, by assisting them to find a leisure activity in their community in order to stay active and socially involved (Annexe).

Setting

Seven Memory clinics in the french speaking part of Switzerland.

Main outcome measures

Quality of life (WHOQOL), cognition (MoCA), severity of symptoms (CDR), autonomy in daily life activities (DAD‐6), anxiety and depression (HAD), satisfaction (self‐assessed questionnaire).

Method

To meet the needs of patients at risk of dementia and according to their symptomatology, they undergo speech, physical or neuropsychological therapy within a Memory clinic. Then, a care manager organize with the patient a leisure activity in the community to perpetuate the therapies’ benefice and to stay socially involved. Paired‐sample t‐tests were conducted between 2 measures: before therapy and after 3 months of leisure activity.

Result

Among 150 patients that started a therapy within CareMENS (Neuropsychology: n = 94, speech:n = 26, physical: n = 30), 100 completed their therapy, 61 already integrated a community activity and 31 ended the follow‐up. Results are reported for 25 patients. In a mean follow‐up time of 366 days, autonomy remained stable (p = 0.14), whereas global cognition decreased significantly (p = 0.01). Among anxious people, level of anxiety decreased significantly (p = 0.02). Global QOL was stable in patients (p = 0.15) and caregivers (p = 0.46), while the QOL’s dimension of “social participation” improved strongly and significantly in patients (p = 0.0001). Satisfaction to the care manager’s interventions and to the therapies were very encouraging (83.5%).

Conclusion

CareMENS is a new model of care that give a high satisfaction to patients and caregivers, improves the social dimension of quality of life and integrate patients in the society through community activities, that are enjoyable therefore sustainable.
CSF levels of the synaptic marker Cyclase‐associated protein CAP2 in Alzheimer disease across clinical stages
Authors: Padovani Alessandro , DiLuca Monica , Marcello Elena , Pilotto Andrea , Borroni Barbara
Published: December 2023

Background

Synaptic dysfunction represent a key event in cognitive decline in Alzheimer disease. There is evidence that Cyclase‐associated protein 2 (CAP2) is involved in synaptic plasticity in AD models but its role in clinical setting has never extensively assessed. Aim of this study was to evaluate CAP2 levels in cerebrospinal fluids of AD and other neurodegenerative diseases and their relationship with amyloid and tau related biomarkers.

Method

one‐hundred ten AD patients (prodromal AD n = 70; mild to moderate AD n = 40), 20 Lewy Body Dementia (LBD), 20 frontotemporal dementia (FTD) and 40 healthy controls (HC) were investigated and clinically assessed following a standardized neurological and cognitive behavioral assessment. All subjects underwent CSF analyses for h‐tau, p‐tau and Aß42 (Lumipulse) while CAP2 levels were assessed by using standard ELISA. Between‐groups differences and correlations between CSF biomarkers were evaluated using non‐parametric comparisons and partial correlation analyses adjusted for the effect of age, sex and disease duration.

Result

AD patients across severity stages showed higher CAP2 levels compared to controls and non‐AD patients (p = 0.001). CAP2 levels did not correlate with disease severity and were independent of APOE genotype. In AD patients, CAP2 levels showed a positive correlation with t‐tau and p‐tau (p<0.001).

Conclusion

CSF levels of CAP2 were significantly increased in AD patients and correlated with t‐tau and p‐tau independently of amyloid pathology. Altogether, these findings support the hypothesis that AD is specifically associated with synaptic dysfunction since early stages and that amyloid‐related synaptic changes parallels tau‐related axonal degeneration.
Roles of CCNY in the amyloid pathology of Alzheimer’s disease
Authors: Kim Hark Kyun , Park Jeonghye , Park Mikyoung , Jo Dong‐Gyu
Published: December 2023

Background

Alzheimer’s disease (AD), the most common form of dementia, has three major pathological features; Aβ plaque, tau tangles, and neuroinflammation. Many studies have focused on developing treatments for AD; however, many clinical trials have failed. It recently has been discussed that depletion of Cyclin Y(CCNY) ameliorates impaired memory function by inhibiting memory plasticity by AMPA receptor. However, very little is known about the molecular mechanisms between CCNY and AD progression. Also, it remains controversial whether CCNY accelerates amyloid pathology or halts it.

Method

We crossed CCNY KO mice with 5xFAD, making 4 groups for the project; WT, CCNY KO, 5xFAD, 5xFAD;CCNY KO. Behavioural tests were conducted at the age of 10 months with Morris Water Maze(MWM) and Elevated Plus Maze(EPM). Brain tissue was collected using perfusion and then analyzed with ELISA, Immunohistochemistry (IHC), Thio‐flavin S(Thio‐S) staining, and RNA sequencing.

Result

In MWM and EPM tests, 5xFAD;CCNY−/− mice showed worse cognition level compared to 5xFAD mice. Analysis of Aβ1‐42 using ELISA illustrated the increased level of Aβ1‐42 in both cortex and hippocampus of 5xFAD;CCNY−/− mice. Aβ plaque level resulted from IHC sustainably upregulated in 5xFAD;CCNY−/− mice. Deficiency of CCNY described bigger size of senile plaques through Thio‐S staining in 5xFAD mice in contrast with 5xFAD mice. Activation of microglia was upregulated in 5xFAD;CCNY−/− mice confirmed via IHC.

Conclusion

In this research, we investigated the role of CCNY in Aβ processing and neuroinflammation. This study demonstrates the association between CCNY and AD, illustrating CCNY as a regulator in the pathogenesis of Aβ plaque and as a candidate for AD therapy.
Effects of a contact‐free behavioral activation program using a digital device
Authors: Jung Jae Yeon , Park Sangmi , Kim Tae Hui
Published: December 2023

Background

According to the literature, untreated depression among older adults is related to a higher likelihood of dementia (Saczynski et al., 2010). Behavioral Activation (BA) was developed as one of the effective interventions for decreasing depression. BA helps to understand and moderate daily behavior and emotions, which helps reduce depression. This study aimed to examine the effect of BA intervention using a digital device in older adults with depression. A digital device was used in this study to provide BA intervention stably in the face of a COVID‐19 pandemic.

Method

A total of 60 older adults with depression participated in this study. Older adults in the intervention group (n = 30) used a tablet PC to participate in the daily one‐on‐one BA program from April to June 2022. Older adults in the control group (n = 30) used the companion robot (Hyodol). The Geriatric Depression Scale (GDS) and UCLA Loneliness Scale (UCLA) were applied to the pre‐test and post‐test. Chi‐squared test and Mann‐Whitney U test were conducted to test homogeneity between the two groups. Mann‐Whitney U test and a Wilcoxon signed rank test were conducted to compare the effect between two groups and changes within group. SPSS 26.0 was used for all analyses.

Result

Two groups were homogeneous in socio‐demographics. In the intervention group, the mean scores of the GDS and UCLA pre‐test were 9.7 (SD = 3.33) and 52.23 (SD = 5.40), respectively. In the control group, the pre‐test mean scores for GDS and UCLA were 10.63 (SD = 3.41) and 52.20 (SD = 6.26), respectively. The decreases in depression and loneliness in the intervention were statistically significant (depression: Z = ‐1.959, p < 0.01; loneliness: Z = ‐2.690, p < 0.01). The decrease in depression in the control group was statistically significant (Z = 2.824, p<0.01), but the decrease in loneliness was not statistically significant (Z = ‐1.494, p = 0.135) (table 1).

Conclusion

The results support that BA program using digital device was effective in decreasing depression of older adults with depression. BA intervention using digital device can be considered as approaches for older adults with depression to prevent dementia.
Pharmacological inhibition of sFRP1 stimulates the non‐amyloidogenic pathway of amyloid precursor protein proteolytic processing
Authors: Lu Wenyan , Macyczko Jesse R , Martens Yuka A , Bu Guojun , Kanekiyo Takahisa , Li Yonghe
Published: December 2023

Background

The accumulation of the amyloid‐β (Aβ) aggregates in the brain is a key pathological event in the development of Alzheimer’s disease (AD). The α‐secretase ADAM10 is responsible for cleavage of the amyloid precursor protein (APP) through a non‐amyloidogenic pathway, thereby preventing the generation of pathogenic Aβ in the brain. Secreted frizzled related protein‐1 (sFRP1), an endogenous antagonist of Wnt signaling, has recently been identified as a key negative modulator of ADAM10. Importantly, proteomic studies reveal that unregulated sFRP1 is one of the top Aβ‐correlated proteins in the human AD brains.

Methods

We determined the therapeutic potential of specific sFRP1 WAY316606 in the N2a/APP695swe cells and patient‐specific iPSC‐derived cerebral organoids.

Results

We herein demonstrated that treatment of sFRP1 inhibitor WAY316606 resulted in augmentation of ADAM10 activity, upregulation of soluble APP‐α (sAPPα) production, and inhibition of Aβ generation in the N2a/APP695swe cells. Moreover, WAY316606 significantly enhanced ADAM10 activity, decreased Aβ production and inhibited tau phosphorylation in human AD patient‐specific iPSC‐derived cerebral organoids.

Conclusion

Our findings indicate that sFRP1 is a promising therapeutic target for AD.
Understanding the role of the mitochondrial AD risk gene LACTB in myeloid cells.
Authors: Molina Carmen Romero , See Wen Yi , Liu Yiyuan , Marcora Edoardo , Goate Alison
Published: December 2023

Background

Although powerful evidence points out the importance of myeloid cells in Alzheimer’s Disease (AD), the relevance of immunometabolism requires further exploration. Our analysis integrating AD genetics and myeloid cell genomics reported that lower LACTB expression is protective for AD, and proteomics studies have confirmed it (Wingo et al., 2021). LACTB is a mitochondrial serin protein that may influence mitochondrial morphology and bioenergetics. LACTB levels are associated with succinyl‐carnitine levels (Ghazalpour et al., 2014, Suhre et al., 2011), a metabolite that has been linked to AD risk (unpublished). LACTB has also been nominated as a tumor‐related and an obesity gene, but its function is not well defined.

Methods

THP1 cells were treated for 6 days with small‐interfering RNA to reduce LACTB expression. iPS cells were CRISPR‐edited to obtain LACTB knock‐out (KO) lines and differentiated into microglial cells (iMGLs). Functional experiments were performed. Collected samples were outsourced for RNAseq, metabolomic and lipidomic analysis.

Results

we characterized, for the first time, the role of LACTB in myeloid cells. We observed that LACTB expression is increased upon differentiation (in iMGLs compared to iPSC, and in THP1 macrophages compared to monocytes) and LPS stimulation. The downregulation of LACTB in THP1 led to an increase in succinyl‐carnitine (predicted to be protective for AD), and in histone succinylation, which may modify the cell epigenetics. Transcriptomics revealed an increase in the oxidative phosphorylation, which was validated by Seahorse experiments, and in the immune response to interferon and virus. In addition, LACTB knock‐down polarized THP1 macrophages towards a DAM‐like state. Lipidomics reported significant changes in specific lipid classes and a decrease in chain saturation. These experiments will be repeated in iMGLs.

Conclusion

LACTB may play a role in cell differentiation and response to stimulus in myeloid cells by modifying mitochondrial respiration and lipid metabolism. As future directions, iMGLs will be xenotransplanted in WT and 5xFAD mice to study LACTB role in vivo. Unlike other AD risk genes, LACTB encodes an enzyme, reduced expression is protective, and succinyl‐carnitine can be used as a biomarker, which highlights it as a promising AD therapeutic target.
Plasma GFAP accuracy and its association with brain pathology
Authors: Lorenzo Elizabeth Lucia Valeriano , Sanchez‐Juan Pascual , Rabano Alberto , Gonzales Alicia Ruiz , Burgueño‐García Iván , del Ser Teodoro
Published: December 2023

Background

Glial fibrillary acidic protein (GFAP) is a biomarker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of many neurological and neurodegenerative conditions, including AD. Recent studies have shown that its determination in blood could be especially helpful in AD diagnosis. However, the neuropathological validation of GFAP as a biomarker of AD is still scarce, and only communications to scientific meetings have shown data with pathological validation.

Method

In our study, we aim to evaluate the effectiveness of plasma GFAP in detecting AD neuropathologically defined compared to cognitively unimpaired individuals and the correlation between GFAP levels and AD pathological lesions, estimated by their ADNC score, and other co‐pathologies. Plasma GFAP from cognitively unimpaired controls (n = 118) from the Vallecas cohort and sequential samples of definite AD cases (n = 101) from the Reina Sofia Centre were quantified by the SIMOA platform. On average, the neuropathological assessment was performed on AD patients 139 days after the last plasma collection.

Result

Plasma GFAP concentrations were significantly increased in AD cases compared to controls, which allowed high discriminative power (area under the curve for plasma GFAP, 0.88‐0.96). Moreover, longitudinal increases in plasma GFAP levels of AD cases were significantly associated with post‐mortem brain pathology. The individuals who evidenced a higher ADNC stage at the post‐mortem experienced in life a significant increase in the rate of change of plasma GFAP across time, adjusted by age, extraction time of GFAP plasma, and estimated age of disease onset.

Conclusion

For the first time, we correlated plasma GFAP levels with post‐mortem brain pathology with exceptionally low time intervals. This study confirms with autopsy data that plasma GFAP is a sensitive biomarker for detecting and tracking AD pathological changes.
Preventing cognitive decline using portable, non‐invasive sleep enhancement.
Authors: Züst Marc Alain
Published: December 2023

Background

Recently, disturbed slow wave sleep (SWS) has been identified as an early, modifiable risk factor for dementia. SWS is crucial for memory and metabolic clearance functions, and lack of SWS causes these important functions to suffer, which in turn worsens cognitive decline. A vicious cycle forms between cognitive decline and loss of SWS. Improving SWS could be a way to break this cycle by providing the much‐needed opportunity for the brain to recuperate and ameliorate cognitive decline. We aim to enhance slow wave activity in older adults using phase‐locked auditory stimulation (PLAS). Our laboratory‐based results show that the magnitude of the physiological response to PLAS predicts improvement of memory functions and metabolic clearance. However, larger, long‐term studies in an ecologically valid setting are needed to assess the efficacy of PLAS for the improvement of sleep, memory, and metabolic clearance with the goal of preventing cognitive decline. Laboratory‐based studies quickly become economically and logistically unfeasible to achieve this goal.

Method

We propose a blinded, sham‐controlled cross‐over study utilizing home‐use devices to study the effect of PLAS on memory functions in 60 older adults with MCI or SCD. Participants will undergo verum‐ and sham‐PLAS in the comfort of their own home across a 12‐week study period. Cognitive performance will be assessed using engaging “serious games”, and blood will be sampled before‐ and after each experimental period to test levels of dementia‐related biomarkers (amyloid beta, pTau181 and 217, GFAP and NfL) and their response to PLAS.

Result

We expect PLAS to enhance sleep, which will lead to down‐stream effects on memory performance and metabolic clearance. Using a novel approach allowing brain‐age estimation from sleep‐electrophysiology, we hypothesize to see a “rejuvenating” effect of PLAS, restoring an electrophysiological profile typically seen in younger brains.

Conclusion

This study could pave the way for PLAS‐capable home‐use devices as an affordable, non‐invasive tool to combat cognitive decline, and could lead to novel preventative applications for memory clinics, relieving their clinical burden and improving public health.
Reminiscence therapy and dementia care in the Pacific island of Guam
Authors: Twaddle Iain K. B. , Gutierrez Nikolas Jude
Published: December 2023

Background

Persons living with dementia often find it easier to remember experiences from long ago—including memories from their youth and early adulthood—than to recall recent events, such as what they did that week or even earlier that day. As a result, trying to navigate the present can be stressful and overwhelming, while reminiscing about the past can be a comforting experience. Connecting with valued memories from the past often helps persons living with dementia maintain their identity, preserve their sense of self, and enhance their overall quality of life. Reminiscence therapy was developed as a way to achieve these benefits by engaging older adults in the exploration of cherished memories to improve cognitive functioning and psychological well‐being. In recent years, reminiscence therapy has become an effective and popular approach to providing therapeutic support for persons living with dementia.

Method

Training in reminiscence therapy was provided to family and professional caregivers in the Pacific island of Guam through a weekly online support group. Training sessions were designed to help caregivers learn to use reminiscence therapy with persons with dementia in culturally sensitive ways reflecting the oral storytelling traditions of Pacific island cultures. Session topics addressed: (1) the benefits of reminiscence for persons with dementia, from maintaining memory health to building confidence and self‐esteem; (2) guidance from local writers and historians on how to talk with older adults about their life histories, including questions to ask and ways to evoke favorite memories; (3) the use of historical photos from Guam as conversation starters for older adults with memory loss; and (4) sharing stories about growing up in Guam in the 1930s, '40s, ‘50s, and ‘60s, along with readings from memoirs based on this period.

Result

Participants reported highly positive experiences with implementing reminiscence therapy with persons with dementia in their care. The techniques helped persons with dementia to relive beautiful memories and to share these memories with their families.

Conclusion

Program outcomes indicate that online training in reminiscence therapy is an effective way to teach caregivers skills to promote memory health and psychological well‐being for persons living with dementia.
Exploring barriers and facilitators for effective implementation of a physical activity project for people with dementia based on the consolidated framework for implementation research (CFIR)
Authors: Cardona Maria Isabel , Monsees Jessica , Schmachtenberg Tim , Thyrian Jochen René
Published: December 2023

Background

Although recent studies show that physical activity (PA) may be beneficial for persons with dementia (PwD) [1], their participation in PA is still low compared to healthy older adults [2]. Therefore, there is a need for a further increase in comprehension regarding both barriers and facilitating factors leading to PA promotion in PwD. The main objective of this research was to assess barriers and facilitators during the implementation of a German project designed to promote PA among PwD using the Consolidated Framework for Implementation Research (CFIR) as an evaluation framework.

Method

Semi‐structured interviews were conducted with project leaders and sports trainers participating in the project “Sport bewegt Menschen mit Demenz” (Sport moves people with dementia). This project consisted in implementing PA initiatives for PwD including sport clubs from four German sports associations. In addition, the CFIR guided data collection and analysis.

Results

In total, twenty‐one participants were part of the study. The most frequent barriers identified were lack of funding and involvement of persons with dementia. The most reported facilitators were engaged sports trainers/project leaders and positive implementation climate within sports clubs. Future fields of action should be focused on developing networks for improved communication between involved actors; assuring financial opportunities from local, regional, or national institutions; designing enjoyable and secure strategies that encourage PA participation among persons with dementia; spreading education opportunities for sports trainers to develop skills that will guarantee that sports clubs promote the inclusion of people with dementia in PA initiatives.

Conclusion

The CFIR framework has the potential to support and facilitate implementation of long‐term PA projects for PwD by making it possible to address factors affecting their success.

References

1. Nuzum, H., et al., Potential Benefits of Physical Activity in MCI and Dementia. Behav Neurol, 2020. 2020: p. 7807856.

2. Hartman, Y.A.W., et al., Dementia Patients Are More Sedentary and Less Physically Active than Age‐ and Sex‐Matched Cognitively Healthy Older Adults. Dement Geriatr Cogn Disord, 2018. 46(1‐2): p. 81‐89.
Amyloid‐Beta and Cerebrovascular Disease Pathology Influence White Matter Microstructure and Executive Function in a Community‐Based Pre‐Dementia Asian Cohort
Authors: Vipin Ashwati , Soo See Ann , Kumar Dilip , Sandhu Gurveen Kaur , Zailan Fatin Zahra , Leow Yi Jin , Kandiah Nagaendran
Published: December 2023

Background

White matter(WM) fibres have been shown to be vulnerable to amyloid‐beta and cerebrovascular disease(CVD) (Vipin et al.,2019; Croall et al.,2017; Salthouse et al.,2011). Indeed, fractional anisotropy(FA) of corpus callosum genu has been shown to capture variability in systemic vascular health and CVD (Vemuri et al., 2018). WM alterations are also associated with memory and executive function decline(Salthouse 2011). Additionally, the CAIDE risk score estimates future dementia risk based on vascular, demographic and genetic risk factors(Kivipelto et al.,2006). However, given the high CVD load among Asians, the combined influence of such risk factors and amyloid‐beta on WM microstructure and cognition in an Asian cohort needs further exploration. Thus, we examined WM FA between low, medium and high CVD‐amyloid pathology and association with cognition in a pre‐dementia Asian cohort. We hypothesized that derogatory WM FA reduction would be greatest in the high CVD‐amyloid group and relate to worse cognition.

Method

In a community cohort of 78 pre‐dementia subjects having undergone diffusion tensor imaging (mean age:55.37 years; mean education:14.72 years), neuropsychological assessments, CAIDE derivation (CVD risk) and oligomeric amyloid‐beta from the Dementia Research Centre (Singapore), we identified low CVD‐amyloid pathology (A‐C‐,n = 24), intermediate CVD‐amyloid (A±C±,n = 46) pathology and high CVD‐amyloid (A+C+,n = 8). TRActs Constrained by UnderLying Anatomy, FreeSurfer, was used to reconstruct major white matter tracts and fibre‐based FA, a measure of white matter tract overall health, was derived.

Result

Increasing CVD‐amyloid pathology related to worsening white matter microstructure with A+C+ subjects showing lowest FA in the corpus callosum genu compared to the A‐C‐ group (Fig. 1). Furthermore, higher FA in the corpus callosum splenium related to better executive function/ working memory performance (indexed using the digit span backwards test) in the A‐C‐ group (Fig. 2). In the A±C± group, presence of either amyloid or CVD pathology related to reduced executive function performance.

Conclusion

In this community cohort of pre‐dementia older adults, we illustrate associations between presence of amyloid and CVD pathology and WM microstructure and cognitive disruption, especially in fibre tracts related to vascular disease and cognitive resilience. Early interventions targeting amyloid and vascular risk factors could encourage neuroplasticity, providing a window for recovery in cognitive performance.
Interactive associations between sleep properties and regional brain structure by race in midlife women
Authors: Paget‐Blanc Alexandra , Thurston Rebecca C , Schroeder Rachel A , Aizenstein Howard J , Derby Carol A. , Wu Minje , Chang Yuefang , Maki Pauline M
Published: December 2023

Background

Poor sleep is a modifiable factor associated with increased risk of Alzheimer’s disease (AD). In cognitively normal adults, poor sleep is associated with AD‐like patterns of brain atrophy. Females experience greater age‐related deterioration in sleep quality than males, particularly around midlife, and these changes are more pronounced in racial/ethnic minority women than White women. Nevertheless, the association of sleep quality with brain health in midlife women, and race differences in this association is poorly understood. Here we examined the interactive associations of sleep and race on regional brain volume.

Method

Participants were cognitively normal women from the MsBrain cohort (n = 182; 59.16±4.23 years old; 99.0% postmenopausal; 88.5% White). Brain imaging was performed at the MR Research Center of the University of Pittsburgh on a 3T Siemens Tim Trio MR scanner. Freesurfer was used to segment and evaluate cortical thickness. Participants completed 72‐hour wrist actigraphy monitoring, which generated four sleep parameters: total sleep time (TST), wake after sleep onset (WASO), sleep fragmentation (SF) and sleep efficiency. The associations between sleep regional brain volume, and modification of these associations by race were evaluated using multiple linear regression adjusted for age, education, and presence of APOE 4 allele.

Result

TST was inversely associated with cortical volume in the bilateral inferior parietal lobules (L: p<0.001; R: p<.01), superior parietal lobules (L: p<0.01; R: p<.05), precuneus (L:p<0.01; R: <.05), the left caudal anterior cingulate cortex (p<.05), and right parahippocampal cortex (p<.05). There was a significant interaction of SF and WASO and race on brain volume such that among Black women but not White women, higher SF and WASO were each associated with lower volume in bilateral orbitofrontal cortex (p<.05) and left cuneus (p<.01).

Conclusion

In midlife women, longer sleep time and poorer sleep continuity may influence brain structure even in the absence of dementia. Results suggest that differences in the impact of sleep on brain health be explored further to understand race disparities in AD.. Understanding factors contributing to sleep degradation at midlife, particularly in Black women, may be a critical step to address gender and race disparities in AD.
STRUCTURAL BRAIN CHANGES IN LATE ONSET DEPRESSION
Authors: Ribeiz Salma Rose Imanari , Duran Fabio L.S. , da Costa Daniele Lima , Alves Tania Correa de Toledo Ferraz , Filho Geraldo Busatto
Published: December 2023

Background

Structural brain changes in grey matter in late‐life depression (LLD) remains an intriguing area of research. Furthermore, late‐onset depression (LOD) has been frequently associated with general medical comorbidities, cognitive deficits and structural abnormalities of the brain. This magnetic resonance imaging (MRI) study compares the grey matter volume of elderly people with and without major depression (DSM‐IV‐TR criteria), as well LOD, early onset depression (EOD) and controls.

Method

The sample consisted of elders with and without depression from community. Brain MRI scans were processed using statistical parametric mapping and voxel‐based morphometry.

Result

Sixty three elders with depression and 24 controls were enrolled. Demographic characteristics were analyzed and sex showed a statistically significant difference (p = 0.001) between the groups, with males representing 17.5% of the patient sample and 54.2% of the control sample. Furthermore, MMSE and CAMCOG showed a statistically significant difference between groups (p<0.0001 for both tests), with the control group performing better. Although we excluded cases of patients with below‐expected performance according to the neuropsychological assessment, it is likely that this cognitive impairment presented by the patient group is secondary to major depressive disorder. We did not find a significant volumetric difference between depressed and control group (CG). We used the age of onset of depression as another way of classifying the patient sample and compared it with the control group regarding key demographic and clinical characteristics. Gender was statistically significant different between groups, however there were only 2 male subjects in the EOD group, making it not possible to control the analysis by gender. Compared to the CG (n = 24), the LOD group (n = 32) showed a statistically significant volumetric reduction with correction for multiple comparisons in the right thalamus (464 voxels; peak xyz coordinates = 14 ‐10 16; Z = 4, 62; p‐FWEcorr = 0.052) when using the whole brain for multiple comparisons.

Conclusion

Our findings support the use of regional brain atrophy as a tool to better understand LOD.
The Association Between Street Network Accessibility and Cognitive Impairment
Authors: Zied Eman , Wu Yu‐Tzu , Matthews Fiona E
Published: December 2023

Background

Access to different amenities has been hypothesised to reduce the risk of cognitive impairment in older adults. Literature in urban planning shows that a well‐connected street network enables access to amenities, however, the role of street network accessibility has not been studied extensively in relation to cognitive function. The aim of this study is to investigate the cross‐sectional relationship between street network accessibility and cognitive impairment in older people in England, UK.

Method

The baseline data from the Cognitive Function and Ageing Study (CFAS) II (2008‐2011), a cohort study of people aged 65+ across three areas in England, was used (N = 7485) excluding 144 housebound participants. Cognitive impairment was defined by the Mini Mental State Exam (MMSE) score: mild‐severe (MMSE<26) and moderate‐severe (MMSE<21). Using Geographical Information System (GIS) data, proximity to a main road was represented by betweenness centrality (shortest routes corresponding to high potential of through movement) of the street network, using normalised angular choice (NACH ‐ range of 0‐1.5, with 0.9+ meaning a main road). Mean NACH was calculated within 300m walk of participants’ postcode centroid and categorised into tertiles (low = NACH<0.8, medium = NACH 0.8‐0.9, high = NACH>0.9). Logistic regression was used to investigate the relationship between proximity to a main road, the risk of mild‐severe and moderate‐severe cognitive impairment adjusting for age, sex, education, and area deprivation.

Result

The prevalence was 24% for mild‐severe cognitive impairment and 7.3% for moderate‐severe cognitive impairment. Compared to those living at low proximity from a main road, those who lived at medium (OR 0.817 95% CI [0.716, 0.932]) and high proximity (OR 0.756 95% CI [0.662, 0.863]) had lower risk of mild‐severe cognitive impairment. The adjusted associations remained similar (OR 0.771 95% CI [0.671, 0.886] for medium proximity, OR 0.755 95% CI [0.656, 0.869] for high proximity). Proximity to a main road was not associated with moderate‐severe cognitive impairment.

Conclusion

The results suggest evidence for the role of proximity to a main road in reducing the risk of mild‐severe cognitive impairment in non‐housebound individuals, but not moderate‐severe cognitive impairment. More research is needed on other aspects of street network accessibility.
Characterizing PRN Use of Psychotropic Medications for Acute Agitation in Canadian LTC Residents With Dementia Before and During COVID‐19
Authors: Wang Janet Hui Jue , Kusumo Raphael , Kiss Alex , Tennen Gayla Beth , Marotta Giovanni , Viaje Shirley , Lanctôt Krista L.
Published: December 2023

Background

Agitation is a prevalent and disabling neuropsychiatric symptom of dementia that comprises a constellation of behaviours involving excessive motor activity, physical aggression, and verbal aggression. Pro re nata (PRN) injections of antipsychotics and benzodiazepines can be administered for severe acute agitation, but best practices surrounding their use remain poorly characterized. The aim of this study was to compare the frequency of use of injectable PRN haloperidol, olanzapine, and lorazepam for acute agitation in Canadian long‐term care (LTC) residents with dementia before and during the COVID‐19 pandemic.

Methods

A retrospective chart review was conducted for patients from two Canadian LTC facilities who had orders for PRN haloperidol, olanzapine, or lorazepam between January 1, 2018–May 1, 2019 (i.e. pre‐COVID‐19) and January 1, 2020–May 1, 2021 (i.e. COVID‐19). We reviewed electronic medical records to document PRN administrations of these psychotropic medications and collect data on age, sex, dementia diagnosis, days of observation, care type, medical history, and concomitant medications. Descriptive statistics and multivariate logistic and Poisson regression models were used to analyze the data.

Results

Of the 250 residents with dementia included, 45 of 103 (44%) people in the pre‐COVID‐19 period and 85 of 147 (58%) people in the COVID‐19 period with standing orders for injectable PRN haloperidol, olanzapine, or lorazepam received ≥1 injections of their prescribed medication. Haloperidol was the most frequently used agent (74% pre‐COVID‐19 and 81% during COVID‐19) and excessive motor activity (85% and 80%) was the most common indication for use in both time periods. Residents in the COVID‐19 period were two times more likely to receive PRN injections compared with those in the pre‐COVID‐19 period (OR = 1.96; 95% CI = 1.15‐3.34; p = 0.01). Count of injections per patient was not significantly different between the two time periods (IRR = 1.35; 95% CI = 0.78‐2.33; p = 0.3).

Conclusion

Our results contribute to the mounting evidence that agitation worsened in LTC residents with dementia during the pandemic and add to the limited existing literature on actual use of PRN psychotropic medications for acute agitation. The increased need for PRN rescue medications may be an indirect consequence of COVID‐19 restrictions, particularly the restrictions on socialization.
A longitudinal analysis of the frontotemporal dementia rating scale as a sensitive measure of disease trajectory
Authors: Ferry‐Bolder Eve , Bouzigues Arabella , Foster Phoebe H , Peakman Georgia , Greaves Caroline V , Convery Rhian S , van Swieten John C. , Jiskoot Lize C. , Seelaar Harro , Moreno Fermin , Sanchez‐Valle Raquel , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Carmela , Rowe James B. , Borroni Barbara , Finger Elizabeth , Synofzik Matthis , Galimberti Daniela , Vandenberghe Rik , de Mendonça Alexandre , Butler Christopher , Gerhard Alexander , Ducharme Simon , Ber Isabelle Le , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Levin Johannes , Otto Markus , Sorbi Sandro , Rohrer Jonathan D. , Russell Lucy L. ,   Genetic FTD Initiative (GENFI)
Published: December 2023

Background

Previous research in genetic frontotemporal dementia (FTD) has suggested that the FTD Rating Scale (FRS) may be a more sensitive measure of disease severity than the Clinical Dementia Rating scale plus National Alzheimer’s Coordinating Centre Frontotemporal Lobar Degeneration score (CDR+NACC FTLD). This study aims to assess the potential of longitudinal measurement of the FRS to track disease trajectory, using data from the Genetic FTD Initiative (GENFI).

Method

119 mutation negative controls and 270 mutation carriers (52 MAPT, 107 GRN, 111 C9orf72) from the GENFI cohort completed the FRS at their baseline and follow‐up visits. Participants were grouped by disease severity according to their CDR+NACC FTLD global score at the baseline visit, which generated five mutation groups: asymptomatic (0), prodromal (0.5), mild (1), moderate (2), and severe (3), plus the control group. Annualised FRS change scores were generated for each participant (mean interval between visits = 1.3 years, standard deviation = 0.6). For each of the genetic groups, correlations with annualised change score for the MMSE and the CDR+NACC FTLD SOB were performed.

Result

As disease becomes more severe, the annualised change in FRS was larger, peaking at the moderate stage: asymptomatic 0.6 (8.0), prodromal ‐5.1, (23.2), mild ‐7.2 (24.8), moderate ‐7.8 (11.6), severe ‐1.8 (8.2). The moderate group was significantly different from controls (p = 0.018) and the asymptomatic group (p = 0.030). The annualised change in FRS negatively correlated with the annualised change in CDR+NACC FTLD Sum of Boxes (Rho = ‐0.4, p<0.001) and positively correlated with the annualised change in MMSE (Rho = 0.3, p = 0.001) in GRN MCs but not in MAPT or C9orf72.

Conclusion

The FRS shows promise as a sensitive clinical outcome measure, but only at certain stages of the disease. More sophisticated modelling utilising the wider GENFI cohort will help to establish the real potential for use in clinical settings.
The relationship between telomere length and neuropsychological test performance in a diverse sample of Wisconsin Alzheimer’s Disease Research Center participants
Authors: McLester‐Davis Lauren W. Y. , James Taryn T. , Norton Derek L. , Salazar Hector , Papale Ligia A , Alisch Reid S , Hogan Kirk J. , Jeffers Beckie , Gooding Diane C. , Lewis Jordan P. , Roy Trevor R , Drury Stacy S , Gleason Carey E. , Zuelsdorff Megan
Published: December 2023

Background

Age is the most significant predictor of Alzheimer’s disease and related dementias (ADRD). Biological age, in contrast to chronological age, is modifiable – shaped by environmental and social factors which contribute to the functional declines observed in aging. Accelerated biological aging has been observed in historically underrepresented populations in ADRD research who are at highest risk for developing ADRD. Telomere length (TL) is a marker of biological age and empirically associated with cognitive aging. However, this association has not been investigated in historically underrepresented populations such as American Indians / Alaska Natives (AI/AN). This study reports on the utility of TL to predict cognitive performance in a sample of middle‐aged and older adults from Wisconsin communities historically underrepresented in ADRD research.

Method

The Wisconsin Alzheimer’s Disease Research Center’s (WADRC) Inclusion of Underrepresented Groups Core engages AI/AN, Blacks / African Americans (B/AA), and participants of multi‐race and ethnicity identities through community based participatory research practices. A sample (n = 188) identifying their race as AI/AN or B/AA were included if they provided whole blood and completed the Rey Auditory Verbal Learning Test (RAVLT, Trials 1‐5) and the Trails Making Test (TMT, A and B times) for verbal learning and executive functioning, respectively. DNA was extracted from whole blood and analyzed with monochrome multiplex quantitative polymerase chain reaction for TL. Multivariable linear regression analyses tested relationships between TL and cognitive test performance.

Result

The participants (mean age = 60.88 ±9.06) were majority female, with 79.26% B/AA and 12.77% AI/AN (Table 1). In bivariate analyses, TL significantly correlated with all outcomes: longer telomeres correlated with better verbal learning and executive functioning performance (Figure 1A‐C). In multivariable regression models, TL significantly predicted cognitive performance for all outcomes independent of participant sex, race, age, and cognitive status (Table 2).

Conclusion

These findings suggest that TL is a strong predictor of cognitive performance for historically underrepresented populations, offering potential opportunities for screening of accelerated biological aging and interventions. The community‐led research at the WADRC makes this analysis the first of its kind to include AI/AN participants. Future ADRD research should consider behavioral and socioeconomic interventions shown to modify biological aging.