bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of vitamin B12 on cognitive function in elderly patients
Authors: Kimura Atsushi Michael , Kinnno Ryuta , Tsuji Mayumi , Ono Kenjiro
Published: December 2021

Background

Establishing preventive and therapeutic methods for Alzheimer's disease (AD) is an urgent issue. Because Vitamin B12(VB12) has a neuroprotective effect on the central nervous system, it has begun to receive attention. Recently, we found that VB12 can suppress β‐amyloid toxicity in vitro. Besides, it has been reported that VB12 might be useful for keeping memory in Mild Cognitive Impairment (MCI). To clarify the effects of VB12 in AD and MCI patients, we examined the effects of the VB12 on cognitive function and regional cerebral blood flow (rCBF).

Method

We examined 46 participants who consulted to our memory clinic. They were divided into three groups: Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy controls (HC) based on the National Institute on Aging‐Alzheimer’s Association (NIA‐AA) diagnostic criteria. We used Wechsler Memory Scale‐Revised(WMS‐R) to assess the cognitive function and evaluate what kind of function is degraded. Three‐dimensional stereotactic surface projection(3D‐SSP)was used to quantify the rCBF of hippocampus, thalamus, and callosomarginal regions, which had a well‐established connection with AD. Multiple regression analysis was conducted to examine the correlations among serum VB12, WMS‐R, and rCBF in each group.

Result

Regarding the correlations between VB12 and memory function, we found that the VB12 was significantly correlated with the WMS‐R scores of visual paired association I/II in the MCI group and the verbal paired associates I in the AD group (all, p<0.05). Besides, there were significant correlations between VB12 and WMS‐R scores of the visual reproduction I, logical memory I, and visual memory span in the HC group (all, p<0.05). Regarding the correlations between VB12 and rCBF, VB12 concentration was significantly correlated with the rCBF of the left hippocampal in the MCI group (all, p<0.05). Neither AD nor HC groups showed significant correlations between rCBF and VB12. Finally, the rCBF of the left hippocampus was positively correlated with visual paired association I/II(all, p<0.05).

Conclusion

These results suggested that VB12 affects memory function and rCBF, especially in the MCI. Considering the relationship between WMS‐R and rCBF, VB12 may affect the progression of dementia. The early intervention with VB12 can be more effective in AD treatment strategies.
Modeling the pathological cascade of Alzheimer’s disease and related dementia markers: The MEMENTO cohort
Authors: Lespinasse Jérémie , Chêne Geneviève , Mangin Jean‐Francois , Chupin Marie , Habert Marie‐Odile , Dufouil Carole , Proust‐Lima Cécile ,   MEMENTO Cohort Study Group
Published: December 2021

Background

Alzheimer’s disease and related dementia (ADRD) are characterized by a progressive alteration of clinical (Cognitive and Physical functions) and subclinical (Neuroimaging, blood and CSF markers) features. Understanding the sequence and timing of these alterations is of primary importance to understand the natural history of ADRD and ultimately change its course. Pathological processes underlying ADRD evolve over years prior to dementia diagnostic on a time scale that is still hypothetical before any diagnosis is made. The objective of this work was to describe the sequence of markers changes in the Memento cohort by realigning the individual marker trajectories according to a latent disease time to overcome this issue.

Method

Memento cohort is a French nationwide clinic‐based study which aims at better understanding the natural history of ADRD. Participants with mild cognitive impairment or subjective cognitive complaint were enrolled and followed‐up intensively for a maximum of 5 years. In an analytical sample of 2186 participants, we considered repeated measures of 12 ADRD markers including cognitive performances (memory, verbal fluency, executive function), neuroimaging measures (hippocampal volume, cortical thicknesses, white matter hyperintensities, glucose metabolism of region of interest of FDG‐PET), and CSF (Aβ42, p‐tau, t‐tau). We defined the latent disease time by an individual shift of the observed time, and simultaneously analyzed the ADRD marker trajectories according to this latent disease time using a multivariate mixed model adjusted on potential confounders.

Result

After individual realignment of the trajectories according to the latent disease time, the temporal sequence of alterations suggested that neurodegeneration preceded cognitive decline. However, such sequence largely depended on education and ApoE4 status as illustrated in the figure. Cognitive decline appeared to be delayed among participants with high level of education, whereas changes in Aβ42 and tau proteins levels in CSF seemed to appear prior to neurodegeneration and cognitive decline mainly among ApoE ε4 carriers.

Conclusion

Using longitudinal multidimensional data from a large cohort, we were able to stage participants along the pathological progression of ADRD. Our results show a large heterogeneity in temporal order markers changes which could suggest the existence of several subtypes of ADRD.
Plasma biomarkers distinguish clinical diagnostic groups in memory clinic patients
Authors: Gerards Michelle , Schild Ann‐Katrin , Meiberth Dix U. , Rostamzadeh Ayda , Vehreschild Jörg Janne , Wingen‐Heimann Sebastian , Adami Pamela V. Martino , Onur Oezguer A. , Ramirez Alfredo , Karikari Thomas K. , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Maier Franziska , Jessen Frank
Published: December 2021

Background

Plasma biomarkers as a new approach in Alzheimer’s screening and diagnostics are time‐ and cost‐saving. Blood sampling is easier, less risky, and less invasive than other well‐established diagnostic tools, such as cerebrospinal fluid biomarkers (CSF), and is well tolerated by patients. The goal of this study was to test whether and to what extent plasma biomarkers are suitable for the differentiation between the clinical diagnostic groups dementia of Alzheimer’s type (DAT), mild cognitive impairment (MCI) and subjective cognitive decline (SCD) in a routine care memory clinic.

Method

We examined plasma samples of 144 memory clinic patients. Plasma biomarkers were measured through ultrasensitive Single molecule array (Simoa) immunoassay technology. The concentrations of amyloid‐beta42 (Aß42), amyloid‐beta40 (Aß40), phospho‐Tau181 (pTau181), total‐Tau (tTau) and neurofilament‐light (NF‐L) were determined. Statistical analysis, including receiver operating characteristics (ROC) analyses, were performed. Possible cut‐off values are discussed.

Result

Through Aß40 a weak differentiation between SCD and DAT (AUC=0.64) and through Aß42/Aß40 a weak differentiation between SCD and MCI (AUC=0.64), SCD and MCI+DAT (AUC=0.66) and SCD and DAT (AUC=0.67) was possible. PTau181 was able to distinguish between diagnostic groups and showed a weak differentiation between MCI and DAT (AUC=0.69), a strong differentiation between SCD and MCI+DAT (AUC=0.78) and SCD and MCI (AUC=0.72) and an excellent differentiation between SCD and DAT (AUC=0.85). NF‐L weakly distinguished between SCD and MCI+DAT (AUC=0.70) and MCI and DAT (AUC=0.72), but strongly distinguished between SCD and DAT (AUC=0.81). At a cut‐off point of 10.2pg/ml pTau181 showed a sensitivity of 89% and a specificity of 73% to distinguish between SCD and DAT.

Conclusion

Plasma Aß40, Aß42/Aß40, pTau181 and NF‐L analyzed with the Simoa technology proved to be promising future diagnostic and screening tools in a routine memory clinic setting outside of specific research studies. While amyloid markers showed only moderate discrimination between the groups, pTau181 and NF‐L clearly distinguished between SCD and the more progressed stages of MCI and DAT. These findings agree with the current model of amyloid build‐up already before significant clinical symptoms, and pTau and neurodegeneration correlating with symptomatic progression. In our data, pTau181 provided the best discrimination between the diagnostic groups.
Sex differences in neuropsychiatric symptoms in Alzheimer’s disease dementia: A meta‐analysis
Authors: Eikelboom Willem S. , Pan Michel , Ossenkoppele Rik , Coesmans Michiel , Gatchel Jennifer R , Ismail Zahinoor , Lanctôt Krista L. , Fischer Corinne E. , Mortby Moyra E , van den Berg Esther , Papma Janne M.
Published: December 2021

Background

Although the majority of individuals with Alzheimer’s disease (AD) dementia exhibit neuropsychiatric symptoms (NPS), there is substantial heterogeneity in NPS manifestation. Sex is increasingly recognized as an important factor in explaining clinical variability within AD; yet, prior studies on sex differences in NPS have reported mixed findings. Therefore, we aimed to review the existing literature on sex differences in NPS in AD dementia using a meta‐analytic approach.

Method

Effect sizes were extracted from 54 studies (N=19,730; N=12,092 females [61.3%], N=7,638 males [38.7%]). Random‐effects models were used to investigate sex differences in both NPS prevalence and severity for all studies combined, NPS total scores, and for specific NPS separately. Furthermore, meta‐regression analyses were conducted to examine the effects of study characteristics and demographic and clinical variables.

Result

The majority of the included studies were of fair quality and we found no indications of publication bias. When combining all studies, female sex was associated with overall greater NPS severity (k=17, g=0.07[0.01–0.14], p<0.05), while no sex‐related differences were observed for NPS prevalence (k=41, OR =1.07[0.89–1.28], p=0.46). Meta‐regression analyses showed that younger age (QM
=6.44, p<0.05) and longer disease duration (QM
=4.27, p<0.05) were associated with more prevalent NPS for females with AD dementia. Regarding specific NPS, female sex was associated with more prevalent psychotic symptoms (k=4, OR=1.62[1.12–2.33], p<0.01), aberrant motor behaviors (AMB; k=5, OR=1.61[1.15–2.25], p<0.01), depressive symptoms (k=18, OR=1.56 [1.22–1.99], p<0.001), and delusions (k=11, OR=1.56 1.27–1.92], p<0.001). In addition, female sex was related to more severe depressive symptoms (k=10, g =0.20[0.08–0.29], p<0.001), disinhibition (k=6, g=0.16[0.03–0.28], p<0.05), and AMB (k=6, g=0.14[0.01–0.27], p<0.05).

Conclusion

Female sex was associated with more severe overall and specific NPS in AD dementia and a higher prevalence of specific NPS. These associations are generally not affected by study setting, measurement type, age, education, disease duration, MMSE score, and APOE status. These findings support the existing literature on sex differences in the clinical manifestation of AD, which could reflect sex‐related differences in neurobiological and psychosocial factors. Determining sex differences in NPS may guide personalized assessment and tailored treatment.
Unravelling drivers of age‐ and beta‐amyloid‐related neurodegeneration in medial temporal lobe atrophy in cognitively normal older adults
Authors: Wuestefeld Anika , Berron David , van Westen Danielle , Stomrud Erik , Mattsson‐Carlgren Niklas , Strandberg Olof , Smith Ruben , Palmqvist Sebastian , Glenn Trevor , Hansson Oskar , Wisse Laura
Published: December 2021

Background

The medial temporal lobe (MTL) is affected in aging and dementia. Aging, small vessel disease, β‐amyloid, tau pathology, and inflammation are hypothesized to play a role in neurodegeneration, but their interplay is still unclear. We investigate potential MTL atrophy mediators of (1) Aβ‐related effects in cognitively normal older adults and (2) aging effects in a β‐amyloid negative (A‐) subgroup.

Method

401 adults (41‐91 years) from the Swedish BioFINDER‐2 study were included ([mean±SD] 65.5±11.7 years; A‐ n=274, 62.7±11.8 years). Using the Automated Segmentation for Hippocampal Subfields for T1‐ and T2‐weighted MRI, hippocampal subfield volumes (dentate gyrus (DG), subiculum (Sub), cornu ammonis (CA) 1) and thickness of entorhinal cortex (ERC), Brodmann areas (BA) 35/36, and parahippocampal cortex (PHC) were obtained. [18F]RO948‐ and [18F]Flutemetamol‐PET standard uptake value ratios were calculated for mean MTL tau (excluding hippocampus; partial volume corrected (PVC)) and global Aβ (with and without PVC). White matter lesions (WML; log‐transformed) to estimate small vessel disease and cerebrospinal fluid (CSF) Glial fibrillary acidic protein (GFAP) to estimate neuroinflammation were analyzed. Both global Aβ‐PET and CSF Aβ‐42/40 ratio determined amyloid‐β status.

Result

All predictors were negatively associated with Sub volume and BA35/PHC thickness in the whole sample, with roughly similar results for the A‐ subgroup (Table 1, Fig. 1). PVC global Aβ‐PET showed similar results. Mediation analyses therefore focus on these three regions. In the whole sample, MTL tau‐PET and GFAP fully mediated the associations between global Aβ‐PET and Sub/BA35/PHC (Fig. 2). When including age in the model only MTL tau‐PET, not GFAP, remained a significant mediator for Sub.

In the A‐ group, MTL tau‐PET partially mediated the age‐Sub/BA35 associations. These mediations survived adjusting for Aβ, except for BA35 (p=.054). Global WML partially mediated the age‐PHC association (Fig. 3). No other predictors were significant mediators.

Conclusion

As expected, global Aβ‐PET‐associated neurodegeneration is mediated by MTL tau pathology, but, interestingly, also potentially by inflammation.

MTL tau pathology and small vessel disease seemingly drive age effects on the MTL, but in different MTL regions. The mediating effect of MTL tau is supportive of a role for Primary Age‐Related Tauopathy in age‐related neurodegeneration.
Neurocognitive effects of acupuncture in dementia: A brief literature review
Authors: Nicanord Ernst J , Raji Mukaila
Published: December 2021

Background

Dementia, including Alzheimer’s disease, is one of the biggest global public health challenges that stretches through generations. Given the limitations of current pharmacologic interventions, acupuncture has been proposed as a potential alternative to dementia therapy. We review the literature to find studies that illustrate the effects of acupuncture on mild cognitive impairment (MCI), post stroke cognitive impairment (PSCI), Vascular dementia (VD), and Alzheimer’s disease (AD).

Method

Five databases, including PubMed, Cochrane database, Google Scholar, CINAHL, and Trip database were searched for Keywords: acupuncture OR acupuncture treatment OR acupuncture therapy and mild cognitive impairment OR dementia OR vascular dementia OR poststroke dementia. Articles’ titles and abstracts were reviewed and selected according to their relevance for this review. Most of the selected papers were systematic reviews (SR) and meta‐analysis dated to 2020 publication. Only randomized controlled trials (RCTs) that are not included in the selected systematic reviews are selected for this review.

Result

Of the selected articles, two studies found acupuncture could offer an alternative to conventional treatment of MCI. Three studies showed some cognitive benefits including, improving functional communication and language function in PSCI. One study found that acupuncture might stimulate neurogenesis after a stroke. One RCT revealed acupuncture with routine care may improve cognitive status and activities of daily living (ADLs) but has limited effects on quality of life in those with VD. Four studied showed mixed results of acupuncture in AD. No major adverse reactions from acupuncture were reported.

Conclusion

Acupuncture may improve cognitive function in those with MCI and PSCI. For VD and AD, the evidence is still lacking. More well‐structured, large scale double blinded RCTs are needed with more focus on the different stages of AD.
Alzheimer’s disease prevention: Within reach by 2025
Authors: Vitali Francesca , Branigan Gregory L , Brinton Roberta Diaz
Published: December 2021

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects memory and cognition. Symptoms and onset of AD occur up to 20 years after potential alterations in biology, allowing for a tremendous potential to intervene in disease progression to change the AD course. In 2015, the National Plan to Address Alzheimer Disease as part of the National Alzheimer’s Project Act was signed into law which proposed to effectively prevent AD by 2025 sparking new interested in the clinical and research field to achieve these goals.

Method

We used a novel combination of text‐mining and natural language processing strategies to identify (i) AD risk factors, (ii) therapeutics that can target risk factor pathways and (iii) studies supporting therapeutics in the currently published PubMed database. To classify the literature relevant to AD preventive strategies, we developed a relevance score based on STRING score for protein‐protein interactions and a confidence score on Bayesian inference. This led to generation of a ranked list of candidate therapeutics to reduce AD risk.

Result

Based on our strategy, 364 AD risk factors were identified mining 9,625 publications. Next, using drug databases, 694 FDA‐approved drugs were selected based on drug indications with a given risk factor. The computation of ranking scores enabled exclusion of publications that did not meet inclusion criteria and rank 45 drugs associated with reduced risk. Within this list, 22 therapeutics had at least one clinical study supporting AD risk reduction. The top 20 therapeutics included drugs within the categories of lipid‐lowering, anti‐inflammatory, anxiety/psychiatric, and metabolic‐related therapeutics.

Conclusion

Outcomes of our novel bioinformatic strategy supports therapeutic targeting of biological mechanisms and pathways underlying AD risk factors. Based on our analyses, we propose that early interventions that target pathways associated with increased risk of AD has the potential to achieve the goal of effectively preventing AD by 2025.
The impact of the first wave of the COVID‐19 pandemic on health service use by persons with dementia in Ontario, Canada: A population‐based time series analysis
Authors: Bronskill Susan E , Maclagan Laura C , Wang Xuesong , Guan Jun , Harris Daniel A , Austin Peter C , Maxwell Colleen J , Jaakkimainen Liisa , Iaboni Andrea , Marras Connie , Vedel Isabelle , Sourial Nadia , Godard‐Sebillotte Claire , Swartz Richard H
Published: December 2021

Background

Little has been quantified, at a population‐level, about the magnitude of heath service disruption to persons living with dementia in community settings during the COVID‐19 pandemic. Sustained access to health care services is particularly important for persons with dementia and other neurodegenerative diseases as they are vulnerable to decline.

Method

Health administrative data from Ontario, Canada were used to examine patterns of health service use among all persons with Alzheimer disease and related dementias (dementia) who were alive and living in the community. This cohort was compared to persons with Parkinson’s disease (PD) as well as all older adults (age 65+ years) without neurodegenerative diseases. Rates of all‐cause hospital admissions, emergency department visits, primary care and specialist physician visits and home care visits were analyzed for all individuals alive and eligible for provincial health insurance at the start of each weekly period from March 1, 2020 to September 20, 2020 (pandemic period) and from March 3, 2019 to September 22, 2019 (pre‐pandemic period). Rates of health service use during specific weeks in the pandemic period (i.e., lowest week, last available week) were compared to corresponding weeks in the pre‐pandemic period within each cohort using percent changes.

Results

On March 1, 2020, 128,696 persons with dementia, 30,099 with PD and 2,460,358 older adults were eligible for provincial health services. Across cohorts and services, dramatic declines in use of health services were observed at the lowest week: hospitalization (‐38.7% dementia, ‐72.3% PD, ‐44.2% older adults); emergency department (‐54.9% dementia, ‐57.7% PD, ‐53.6% older adults); home care (‐14.8% dementia, ‐19.4% PD, ‐7.4% older adults). Health services varied in how quickly they rebounded to pre‐pandemic levels within cohorts; notably, by the end of the study period, emergency department visits had increased to a level higher than corresponding 2019 weekly rates (24.2% dementia, 15.2% PD, 7.4% older adults).

Conclusions

The first wave of the COVID‐19 pandemic meaningfully and immediately disrupted use of health care services for persons living with dementia and PD and may have resulted in long‐term consequences that should be monitored.
Perivascular space volumes relate to arterial stiffness and cognition
Authors: Bown Corey W. , Khan Omair A. , Liu Dandan , Remedios Samuel , Pechman Kimberly R. , Schrag Matthew , Davis L. Taylor , Terry James G. , Nair Sangeeta , Carr J. Jeffrey , Gifford Katherine A. , Landman Bennett A. , Hohman Timothy J. , Jefferson Angela L.
Published: December 2021

Background

Enlarged perivascular spaces (PVS) are a marker of small vessel disease (SVD). PVS in the basal ganglia are associated with hypertensive damage to arteries and arterioles; however, prior work relating arterial stiffness to changes in PVS have been inconclusive. Additionally, clinical consequences of PVS are poorly understood, possibly due to reliance on manual rating systems that lack precision. This study used an automated process to measure basal ganglia PVS count and volume and cross‐sectionally assess their associations with central arterial stiffness and cognition.

Method

Vanderbilt Memory and Aging Project participants free of clinical stroke and dementia (n=327, 73±7 years, 41% female) completed T1‐weighted brain MRI to measure PVS burden, neuropsychological assessment, and cardiac MR to quantify pulse wave velocity (PWV) in the thoracic aorta, a marker of central arterial stiffness. PVS volume and count were quantified using an automated approach. Basal ganglia volume and count measures were log‐transformed. Linear regression models related PWV separately to PVS volume and count adjusting for demographic and health variables, apolipoprotein E‐e4 status, and intracranial volume. Models were repeated separately relating PVS volume and count to neuropsychological performance with identical covariates.

Result

Higher PWV related to greater basal ganglia PVS volume (b=7.0e‐5, p=0.04) and count (b=0.02, p=0.03). When excluding outliers, PVS volume results were attenuated (p=0.17) but count results persisted (p=0.03). Higher PVS volume was associated with worse sequencing (b=1560, p=0.002), digit symbol (b=‐979, p=0.003), executive function (b=‐82.3, p<0.001), and visuospatial performances (b=‐193, p=0.02). Cognitive results were comparable for models using PVS count as the predictor.

Conclusion

Central arterial stiffness is associated with greater PVS burden in the basal ganglia. Findings support the hypothesis that increased aortic stiffness and resulting changes in hemodynamics essential for maintaining perfusion pressure may result in PVS damage. Greater PVS burden is associated with worse cognitive performance, primarily on tests of executive function and information processing, aligning with our prior findings relying on a manual PVS rating system. PVS may account for damage to frontal subcortical networks which integrate the basal ganglia and play an important role in executive function and information processing. Funding: F31‐AG066358, T32‐AG058524, Alzheimer’s Association IIRG‐08‐88733, R01‐AG034962, R01‐AG056534, K24‐AG046373, P20‐AG068082
Biomarker driven enrichment strategies for tau pathology in AD clinical trials
Authors: Leuzy Antoine , Smith Ruben , Cullen Nicholas , Strandberg Olof , Janelidze Shorena , Ohlsson Tomas , Jögi Jonas , Borroni Edilio , Klein Gregory , Dage Jeffrey L , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Stomrud Erik , Hansson Oskar
Published: December 2021

Background

Tau‐PET has great potential in Alzheimer’s disease (AD) clinical trials as pre‐trial inclusion biomarker and as trial endpoint. However, it is unclear which Tau‐PET ROI is optimal for tracking treatment response in relevant trial populations, and how best to enrich trials if using Tau‐PET as an endpoint. We aimed to determine the sample required to achieve 80% power to observe a reduction in Tau‐PET increase when using different combinations of A/T/N biomarkers as trial inclusion measures. Tau‐PET outcome variables were selected based on ROIs that showed greatest increases using longitudinal data.

Methods

We included 179 cognitively unimpaired (CU) individuals (39% Aβ‐positive) and 103 MCI (62% Aβ‐positive) with longitudinal Tau‐PET ([18F]RO948;baseline and after ∼18‐months [mean 18.81±4.02]) from BioFINDER‐2. Annual change in Tau‐PET SUVR was calculated across event‐based modelling (EBM) (Figure 1) ROIs. For the power analysis, linear models were fit with the best ROI identified in the first step as outcome and different combinations of A (Amyloid‐PET), T (CSF/plasma P‐tau217, baseline Tau‐PET in outcome ROI), and N (CSF/plasma NfL, hippocampal volume) biomarkers as predictors. Model fit was assessed using change in AIC relative to no enrichment (i.e. all subjects).

Results

In CU, annual Tau‐PET increase was highest in EBM stage‐I (1.26%,95%CI [0.82‐1.70%]) (Figure 2); in MCI, the greatest change was seen in EBM stage‐II (1.89%, 95%CI[1.22‐2.56%]). Using these ROIs as outcome variables (assuming selection of top 50% of individuals), regression models showed that plasma P‐tau217 provided the best model fit in CU (44% fewer participants,∆AIC=‐5,P<0.01), followed by CSF P‐tau217 (‐32%, ∆AIC=‐3,P<0.05). In MCI, Amyloid‐PET provided the best model fit (‐71%,∆AIC=‐8, P<0.01), followed by plasma P‐tau217 (‐69%,∆AIC=‐6,P<0.01) and CSF P‐tau217 (‐71%,∆AIC=‐6,P<0.01). When combining biomarkers (Figure 3), plasma P‐tau217, CSF P‐tau217 and Amyloid‐PET proved the best model in CU (‐74%,∆AIC=‐3,P<0.0001). In MCI, Amyloid‐PET with EBM‐II baseline Tau‐PET and plasma P‐tau217 proved the best model (‐92%,∆AIC=‐3,P<0.0001). Combining plasma P‐tau217 with Amyloid‐PET (CU) or baseline Tau‐PET (MCI) provided similar results, however (69%,∆AIC=‐4,P<0.0001; 87%,∆AIC=‐6,P<0.0001, respectively).

Conclusion

Plasma P‐tau217 combined with either Amyloid‐PET (preclinical AD) and baseline Tau‐PET (prodromal AD) may prove optimal and feasible enrichment strategies for trials with Tau‐PET as endpoint.
Sexually dimorphic association of circulating leptin levels with early amyloid‐beta pathology assessed by amyloid PET
Authors: Ishii Makoto , Iadecola Costantino , Sanjay Apoorva Bharthur , Apostolova Liana G.
Published: December 2021

Background

Weight loss can precede the cognitive decline in Alzheimer’s Disease (AD), suggesting that mechanisms regulating body weight such as the adipocyte hormone leptin are an early target of AD pathology (Cell Metabolism 22:761,2015). In mouse models, we previously found that amyloid‐beta pathology can cause hypothalamic dysfunction that was associated with low body adiposity and low plasma leptin levels prior to significant memory impairment (J Neuroscience 34:9096,2014). In this study, we sought to determine if circulating leptin levels are associated with brain amyloid‐beta pathology, assessed by amyloid PET, in individuals with normal cognition or mild cognitive impairment (MCI).

Method

This cross‐sectional study involved community dwelling volunteers originally recruited for the Imaging and Genetic Biomarkers for AD (ImaGene) study. All subjects were age ≥ 50 years, normal cognition or MCI as defined by Clinical Dementia Rating (CDR) score of 0 or 0.5 respectively, and underwent PET scan using the amyloid‐beta tracer 18F‐flutemetamol. Subjects were classified as positive for amyloid‐beta pathology if standard uptake value ratios (SUVr) ≥ 1.27. Serum leptin levels were measured by enzyme linked immunosorbent assay and log transformed. Multiple linear regression analysis was used to examine correlations between serum leptin levels and amyloid PET SUVr.

Result

In men, body mass index (BMI) and serum leptin levels were significantly lower in amyloid PET positive subjects (n = 12) compared to control subjects (n = 8). Furthermore, BMI and serum leptin levels were significantly associated with amyloid PET SUVr (BMI: age‐adjusted β coefficient = ‐0.53, p = 0.018; leptin: age‐adjusted β coefficient = ‐0.69, p = 0.002). However, in women, BMI and serum leptin levels were not significantly different between control and amyloid PET positive subjects and were not associated with amyloid PET SUVr (12 control and 5 amyloid PET positive subjects, all p > 0.05).

Conclusion

These studies raise the possibility that, in men, amyloid‐beta pathology causes alterations in leptin signaling and metabolic dysfunction early in AD. Studies in larger cohorts will be needed to confirm these observations and to help determine their clinical utility as well as the underlying mechanisms of the sex differences.
Baseline plasma total tau predicts longitudinal cognitive and functional decline in aging adults
Authors: Bolton Corey J. , Khan Omair A. , Liu Dandan , Moore Elizabeth E. , Pechman Kimberly R. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Gifford Katherine A. , Jefferson Angela L.
Published: December 2021

Background

Plasma total‐tau (t‐tau) is an emerging biomarker of neurodegeneration and cognitive decline; however, findings are mixed regarding what specific cognitive domains are affected and it is unknown whether plasma t‐tau predicts early functional changes in aging adults at risk for dementia. This study examined baseline plasma t‐tau in relation to longitudinal cognitive and functional trajectories among community‐dwelling older adults.

Method

Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=332, 73±8 years, 40% mild cognitive impairment (MCI)) underwent baseline fasting venous blood draw and serially completed a comprehensive neuropsychological protocol and a 50‐item informant functional abilities questionnaire at study entry, 18‐month, 3‐year, and 5‐year intervals (mean 4.5±1.2 year follow‐up). Plasma t‐tau concentration was measured using single molecule array technology. Linear mixed effects models related baseline t‐tau to cognitive and functional trajectories through interaction with follow‐up time adjusting for baseline age, sex, education, race/ethnicity, apolipoprotein E (APOE) ∑4 status, modified Framingham Stroke Risk Profile, and cognitive diagnosis. Subsequent models assessed t‐tau x cognitive diagnosis and t‐tau x APOE‐∑4 interactions on cognitive and functional trajectories.

Result

A higher baseline concentration of t‐tau was associated with faster decline in processing speed (p<.05). Baseline t‐tau concentration interacted with diagnosis on longitudinal trajectories of processing speed (p‐values<.03). After excluding outliers, higher baseline t‐tau was associated with faster decline in language, processing speed, and functional abilities (p‐values<.05) with t‐tau interacting with diagnosis on each of these measures (p‐values<.05). Baseline t‐tau interacted with APOE‐∑4 status on longitudinal trajectories of language after outlier exclusion (p‐values<.04). Associations linking baseline t‐tau with faster decline were largely driven by participants with MCI (p‐values<.05) and APOE‐∑4 carriers (p‐values<.04).

Conclusion

Among community‐dwelling aging adults free of clinical dementia, higher baseline plasma t‐tau concentration was associated with faster cognitive and functional decline over a mean 4.5‐year follow‐up. Processing speed was consistently implicated, especially in individuals with MCI. T‐tau may reflect non‐specific brain changes involving widely distributed neuronal networks, leading to slowed processing, a common complaint in aging adults. Taken together, results suggest that plasma t‐tau may be a useful biomarker for cognitive and functional decline in at‐risk individuals.
Automated vehicles as a tool to extend the safe driving of people with dementia: Family caregivers’ perspectives
Authors: Haghzare Shabnam , Delfi Ghazaleh , Mohamud Hodan , Stasiulis Elaine , Rapoport Mark , Naglie Gary , Mihailidis Alex , Campos Jennifer L.
Published: December 2021

Background

The progression of dementia often leads to complete driving cessation, which poses major challenges for persons with dementia (PwD) and their caregivers. In response to these challenges, the use of Automated Vehicles (AV) by PwD has been considered as a way of prolonging PwD’s safe driving. AVs can either be used to assist PwD with certain driving tasks, such as steering or braking (Partially Automated Vehicles; PAVs), or by performing all driving tasks (Fully Automated Vehicles; FAVs). There are unique considerations regarding the use of AVs by PwD that are currently not well‐understood. This study examined caregivers’ perspective on the usefulness of AVs in addressing the driving‐related challenges faced by PwD.

Method

Semi‐structured interviews were conducted with 20 primary family caregivers of PwD. Both in the interviews and using a Likert scale questionnaire, participants were asked about their attitude towards PAV and FAV use by themselves and the PwD in their care. Thematic analysis with inductive coding was used to analyse the transcribed interview data.

Result

Caregivers reported significantly more negative attitudes towards PAV/FAV use by the PwD in their care compared to use by themselves (Table 1). The thematic analysis yielded two overarching types of caregiver concerns. (1) unresolved concerns about PwD’s mobility that persist after PAV/FAV use: difficulty navigating tasks at the destination; AVs not providing the same sense of freedom as driving; need for caregivers’ presence in the vehicle; caregivers’ unawareness of PwDs’ driving ability decline until a traffic incident. (2) emerging concerns specific to PAV/FAV use by PwD: PwD’s confusion caused by lack of exposure to AVs; PwD’s possible distress/agitation in AVs; PwD’s possible inability to navigate tasks required by the AV (e.g., response to system failures, negotiating pick‐up/drop‐off locations); PwD’s manual driving skill degradation upon constant use of AVs; AVs enabling PWD to wander to distant locations.

Conclusion

This study helps to identify AV design targets specific to PwD. In addition, study results outline caregivers’ concerns around AV use by PwD that extend beyond PwD’s driving, which highlights the importance of considering a holistic perspective when addressing mobility‐related needs of PwD by introducing AVs.
Measuring synaptic loss in early AD stages: Trajectories of SNAP25 and SYT1 using serial CSF sampling
Authors: Duits Flora H. , Brinkmalm Ann , Scheltens Philip , Blennow Kaj , Zetterberg Henrik , van der Flier Wiesje M. , Teunissen Charlotte E.
Published: December 2021

Background

It is increasingly recognized that synaptic dysfunction plays an important role in Alzheimer pathology, already in an early phase. In this study we investigated the presynaptic biomarkers SNAP25 and SYT1 in early stages of AD. Using serial CSF samples in a cohort of memory clinic patients with detailed clinical follow‐up, we studied prognostic value, the association with cognitive decline and longitudinal trajectories of these biomarkers.

Method

We included 150 subjects with subjective cognitive decline (SCD; 62±7 years), mild cognitive impairment (MCI; 66±8 years) and AD dementia (64±7 years) from the Amsterdam dementia cohort, based on availability of CSF at two time points (median[IQR] 2.1[1.4‐2.7] years) and clinical follow‐up of at least one year. CSF SNAP25 and SYT1 were analyzed using immunoprecipitation mass spectrometry. To assess differences in SNAP25 and SYT1 levels between diagnostic groups at baseline, change in biomarker levels over time and association with cognitive decline we used linear mixed models. We used Cox regression models to assess predictive value of baseline biomarker level for disease progression. Analyses were adjusted for age and gender, Cox models also for ATN biomarker status.

Result

Table 1 shows the results of the linear mixed models. Baseline levels of SNAP25 were higher in AD dementia compared to SCD and MCI, SYT1 levels were similar between groups. Over time SNAP25 increased in SCD subjects (B[SE] 0.24[0.10], p<0.05), SYT1 decreased in AD dementia patients (B[SE] ‐2.6[0.8], p<0.01). In SCD and MCI subjects higher SNAP25 was associated with faster decline in MMSE over time (st.B[SE] ‐0.24[0.12], p<0.01 for SCD; ‐0.39[0.16], p<0.05 for MCI). For SYT1 there was an effect only for SCD subjects (st.B[SE] ‐0.18[0.07], p<0.01). Baseline SNAP25 was a significant predictor for conversion to MCI or AD in non‐demented subjects (HR[95%CI] 4.4 [2.1‐9.1]), even after addition of ATN status (HR[95%CI] 2.8 [1.1‐7.3]; table 2, figure 1).

Conclusion

SNAP25 levels increased over time in SCD subjects, and both SNAP25 and SYT1 were associated with cognitive decline in early stages of AD. High levels of SNAP25 predicted conversion to AD dementia. Hence, they may have potential to be used for disease monitoring or as amyloid‐independent outcome measure in clinical trials.
Effects of fitness and sedentarism on a biomarker of early AD progression
Authors: Carrasco‐Gómez Martín , García‐Colomo Alejandra , Nebreda Alberto , de Frutos Jaisalmer , Salas‐González María Dolores , Lorenzo‐Mora Ana María , Pedrero‐Chamizo Raquel , Sobaler Ana Maria Lopez , Higes Ramón López , Dolado Alberto Marcos , Losada María Luisa Delgado , González‐Gross Marcela , Maestú Fernando
Published: December 2021

Background

Given the lack of an effective treatment for Alzheimer’s Disease (AD), research on factors that might prevent it or delay its symptoms is needed. Physical activity (PA) stands as a means for favourably altering cognitive performance and neuropathologic processes and has been identified as a relevant and easily modifiable lifestyle factor against AD progression. This study thrives to understand the effects of both cardiorespiratory fitness (CRF) and sedentary behaviours (SB) in adult controls through the assessment of magnetoencephalography (MEG).

Method

30 healthy adults (age between 50 and 70 years) participated in the study. The sample underwent a five minutes of eyes‐closed resting MEG recording (NMEG = 24), a cycloergometer incremental exercise test to evaluate CRF through VO2peak (Nstress = 17), and carried an accelerometer for one week to estimate SB (NACC = 26). The alpha peak frequency at posterior brain areas was extracted, and then its partial correlation to VOpeak and the relative sedentary time from the accelerometer data were calculated, respectively, while also controlling for age. Partial correlation between VO2max and relative sedentary time was calculated as well.

Result

Statistical analysis yielded a significant direct correlation between VO2peak and Alpha peak frequency (N=17, rho = 0.504, p‐value = 0.023), while relative sedentary time and Alpha peak frequency showed a significant inverse correlation (N = 20, rho = ‐0.435, p‐value = 0.032). Partial correlation between VO2peak and relative sedentary time was not significant (N = 17, rho = ‐0.404, p‐value = 0.120).

Conclusion

Despite the small cohort, results pinpoint a strong influence of both CRF and SB. Greater CRF, described as higher VO2peak, appears associated with increased alpha frequency in posterior brain regions, a robust biomarker of brain health which is negatively affected in AD. At the same time, higher levels of sedentarism show a strong relation to decreased alpha peak frequency, indicating that low levels of PA might put subjects entering old age at risk.
Statin therapies reduce risk of Alzheimer’s disease and dementia with increased protective therapeutic effect with increasing age
Authors: Torrandell‐Haro Georgina , Branigan Gregory L , Vitali Francesca , Brinton Roberta Diaz
Published: December 2021

Background

A previous peer‐reviewed publication (Torrandell‐Haro et al. 2020, Alzheimer’s & Dementia: TRCI) reported that statin therapy was associated with risk reduction of Alzheimer’s disease. Herein we sought to determine the replication validity of statin therapy on the incidence of Alzheimer’s disease and dementia in a larger dataset with a clinical population of 15 million participants.

Method

This retrospective cohort study used the Mariner claims dataset, which includes prescription and records of 15 million patients from private‐payer and Medicare insurance from across the United States. Patient records surveyed for a diagnosis of Alzheimer’s or dementia starting 1 year after statin exposure. 304,662 participants aged 45 years and older, without prior history of neurodegenerative diseases or brain surgery, were included in the study. In this study, patients with and without exposure to statins were categorized by age groups (60‐65, 70‐75, 80‐85) to determine an association between age and Alzheimer’s outcomes.

Result

Of the 304,662 participants included in the study, 152,331 patients (mean [SD] age, 61.75 [3.4] years) were exposed to statin therapy, and 152,331 patients (59.76 [2.6] years) were not treated with statins. Statin exposure was associated with a lower incidence of Alzheimer’s (relative risk, 0.51; 95%CI, 0.46‐0.57; P < .001) and dementia (relative risk, 0.61; 95%CI, 0.58‐0.61; P < .001). The incidence of Alzheimer’s and dementia was reduced by all statins with variances in individual risk profiles. Increasing age was associated with a greater risk reduction of Alzheimer’s disease in patients with statin exposure compared to non‐statin controls.

Conclusion

Outcomes of these analyses validated previous findings that statin therapy is associated with decreased risk of Alzheimer’s and dementia using a larger database than the previously reported. Further, statin exposure was associated with age‐dependent reduction in risk of Alzheimer’s disease diagnosis.

This work was supported by the National Institute on Aging (grants P01AG026572 [Perimenopause in Brain Aging and Alzheimer's Disease], the Sex Differences in the Molecular Determinants of Alzheimer’s Disease Risk: Prodromal Endophenotype (grant 5R01AG057931‐02), the Women's Alzheimer's Movement and the Center for Innovation in Brain Science to Dr Brinton.
Cardio‐autonomic control during exercise and risk for incident delirium
Authors: Gao Lei , Ulsa Ma Cherrysse , Zheng Xi , Yang Hui‐Wen , Li Peng , Hu Kun
Published: December 2021

Background

Delirium is associated with increased risk for Alzheimer’s disease (AD) and mortality; it is characterized by acute confusion commonly after stressors of illness during hospitalization. Integration between the heart and brain via the autonomic nervous system, or cardio‐autonomic control (CAC) is thought to be potentially protective during such stressors. Related to CAC, heart rate (HR) fluctuations display fractal correlations (similar temporal autocorrelation across different time scales) that reflect a dynamic interplay between sympathetic and vagal outflows, where disruption is thought to contribute to neuronal damage. We hypothesized that fractal correlations in HR fluctuations can serve as a novel physiological biomarker for predicting incident delirium.

Method

We derived fractal correlations (α) using ECG data from 37,978 participants (mean age 57.4) free from delirium and AD within the UK Biobank who underwent a 7‐minute stationary bike stress test between 2009‐2010, and had ≥1 inpatient hospitalization episode through to August 2020. Cox proportional hazards models were used to examine the association between α and incident delirium. We adjusted for demographics, physical activity levels, BMI, smoking, alcohol, cholesterol, diabetes, hypertension, ischemic heart disease, stroke, as well as test‐specific peak exercise load and mean heart rate achieved.

Result

Incident delirium was newly diagnosed in 247 cases (6.5/1,000) during a median follow‐up time of 8.1 years (SD: 2.0, range: 0.2‐10.2) following ECG assessment. α showed a normal distribution with mean of 1.27±0.3 (SD). Negative association between α and incident delirium was observed. The fully adjusted hazard ratio was 1.26 (95% confidence interval: 1.10‐1.45; p=0.001) for each 1‐SD decrease in α. Putting this into context, a subject with a lower α at the 10thpercentile (vs. 90th) showed a 59% increased risk of developing incident delirium, equivalent to the additional risk of being 5‐years older or a current smoker in this cohort.

Conclusion

Fractal correlation of heartbeat fluctuations during an exercise ECG recording was independently associated with incident delirium, and may be a hidden measure of brain‐heart resilience. As this cohort ages, future work will be able to answer the crucial question of whether this is a shared marker of vulnerability between delirium and AD.
Building a training program to diversify the academy and advance Alzheimer’s disease research
Authors: Ingram Lucy A , Ford Marvella E , Johnson Christiana , Ashford‐Carroll Brianna , McCollum Quentin , Chen Hongtu , Friedman Daniela B , Levkoff Sue E
Published: December 2021

Background

Alzheimer’s disease and related dementias (ADRD) are at the forefront of the United States (US) public health agenda, with a disproportionate impact on racial/ethnic minorities. Aging scholars have called for prioritizing ADRD disparities research and addressing the systems that promote research as essential to achieving equity in healthy aging scholarship. In 2018, the National Institute on Aging (NIA)‐funded, Carolina Center on Alzheimer’s Disease and Minority Research (CCADMR) was founded to increase the diversity of the research workforce in population health and ADRD disparities. The CCADMR provides underrepresented minority (URM), junior/mid‐career faculty scientists with opportunities for pilot grant funding, mentorship by senior faculty, and health disparities‐focused training. We share evaluation findings from the training and mentorship components of the Center.

Method

Using a mixed methods approach, we analyzed data from quarterly scientist progress reports, interviews with mentors and scientists, and health disparities seminar evaluations.

Result

Nine scientists have been chosen as pilot project awardees since Center inception. They represent four academic institutions and have implemented disparities‐focused ADRD research ranging from estimating the prevalence of clusters of multi‐morbidity by ADRD type and race, to understanding the determinants of ADRD for African Americans to inform the development of a social robot to engage the community in ADRD‐related activities. Scientists have presented their research at aging and ADRD‐focused conferences, each with manuscripts currently under development. Qualitative interview data (N=9) show that mentors and scientists feel positively about the CCADMR, particularly the mentorship component. Junior scientists have a strong desire to advance their ADRD research, but they face challenges partly due to their institutions’ emphasis on diversity, which typically force them to assume additional responsibilities, leaving limited time for their research. Evaluation data show that nearly 85% of seminar attendees are greatly satisfied with the speakers and content. Since the conversion to virtual seminars due to the COVID‐19 pandemic, over 90% of attendees report being “very satisfied” with speakers and content.

Conclusion

While the evaluation of CCADMR outcomes is ongoing, our experience may be a practical resource for others developing interdisciplinary training programs to increase the pipeline of URM scientists conducting ADRD research.