bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the Locus Coeruleus in depression in Alzheimer’s disease
Authors: Sedgwick Katie Sarah , Dwyer Dominic , Good Mark A , Saito Takashi
Published: December 2022

Background

Depression, one of many common neuropsychiatric symptoms (NPS) seen in Alzheimer’s disease (AD), frequently predisposes the onset of cognitive deficits. NPS are often reported to cause the most suffering in patients and their loved ones so understanding their cause could lead to treatments that afford a better quality of life. The Locus coeruleus (LC) has strong links to depression and, being one of the first areas to show AD pathology, could be integral to understanding this NPS‐AD link. Alongside a natural LC neuron loss with age, AD causes its neurodegeneration reducing the LC’s neuroprotective capabilities and control of inflammatory pathways. Examination of the LC, inflammation and depressive phenotype could offer insights into future treatments.

Method

Behavioural testing was done using a novel, knock‐in mouse model, AppNL‐G‐F
, to assess depressive phenotype at an early and old time point. This included tests for anxiety (open field, elevated plus maze), social deficits (social preference test) and anhedonia (lick cluster analysis) all common NPS symptoms. Brains extracted from these animals were used to stain for LC neurons, plaques and microglia as well as assess astrocytes and inflammatory markers using western blotting technique.

Result

An anxiolytic phenotype was prominent but no social deficits or anhedonia suggesting a lack of depressive phenotype. There was also no loss of LC neurons with age or genotype. Western blotting revealed a large increase in astrocytes within the AppNL‐G‐F
but no differences in inflammatory markers.

Conclusion

Overall, without the loss of LC neurons, it is difficult to draw firm conclusions on its role in NPS onset. Hence, the AppNL‐G‐F
mice are insufficient at modelling affective deficits seen in human AD due to the lack of neurodegeneration of the LC. It may be concluded that, as this is a model of amyloid beta pathology, that plaques and inflammation play a minimal role in NPS without LC loss. Future testing could lesion the LC to better understand its role.
Retromer‐dependent mechanisms of tau dysregulation in Down syndrome
Authors: Curtis Mary Elizabeth , Smith Tiffany , Yu Daohai , Pratico Domenico
Published: December 2022

Background

Deficiencies in the retromer complex are reported in brains of Down syndrome subjects, and retromer protein levels inversely correlate with amyloidosis. The complex is also proposed to influence tau levels, however, the relationship between tau neuropathology and retromer deficiency in Down syndrome remains unclear. In the current study, we examine the relationship between pathological tau and retromer deficiency and explore potential mechanisms involved.

Methods

Post‐mortem brain tissues from Down syndrome and control subjects were evaluated for retromer proteins, pathological tau and proteins relevant to its post‐translational modification. To explore potential mechanisms of retromer‐dependent effects on tau, neuro‐2A cells overexpressing human tau were treated with the pharmacological chaperone, TPT‐172, with or without the CDK5 inhibitor, roscovitine.

Results

Phosphorylated epitopes and insoluble forms tau were elevated in brain tissues of subjects with Down syndrome and inversely correlated with retromer proteins and the activity of cathepsin D. In vitro pharmacological stabilization of the retromer complex with TPT‐172 resulted in decreased levels of phosphorylated tau and the CDK5 activating protein, p25. The effect on tau phosphorylation was neutralized by incubation with the CDK5 inhibitor, roscovitine. Furthermore, CDK5‐p25 immunoprecipitated from cells treated with TPT‐172 caused significantly less histone phosphorylation, indicating that the treatment reduced CDK5 activity.

Conclusion

We conclude that in Down syndrome deficiency of retromer proteins is involved in the development of tau neuropathology. We propose that retromer dysfunction contributes to the development of tau pathology by decreasing the degradative lysosomal pathway and by increasing phosphorylation via CDK5. Because pharmacological stabilization of the retromer complex decreases tau phosphorylation, we propose this could represent a novel therapy against tau pathology in Down syndrome.
Efficacy and safety of pimavanserin in patients with Alzheimer’s dementia psychosis in the HARMONY phase 3, randomized discontinuation study: a post hoc subgroup analysis
Authors: Cummings Jeffrey , Devanand Davangere P , Ballard Clive G , Tariot Pierre N. , Hendrix Suzanne B. , Dickson Samuel P. , Li Caiyan , Abler Victor , Pathak Sanjeev , Stankovic Srdjan
Published: December 2022

Background

Pimavanserin was investigated for the treatment of dementia‐related psychosis (DRP) in HARMONY (NCT03325556), a phase 3 randomized discontinuation study. As the study met the primary endpoint (one‐sided P = 0.0023), we evaluated the consistency of the efficacy for reducing the risk of relapse in the largest dementia patient subgroup (ie, Alzheimer’s dementia psychosis [ADP] patients) treated with pimavanserin 34mg.

Method

Enrolled DRP patients (N = 392) entered the 12‐week open‐label (OL) period and received pimavanserin 34mg daily. During weeks 1‐4, dose could be adjusted to 20mg at investigator discretion. Patients meeting prespecified response criteria at weeks 8 and 12 were randomized to continue pimavanserin or receive placebo for up to 26 weeks in the double‐blind (DB) period. The primary endpoint was time from randomization to adjudicated relapse. Efficacy analyses included patients at the interim analysis (IA); safety analyses included all dosed patients.

Result

Of 260 ADP patients, 243 stayed on pimavanserin 34mg throughout the OL period; 17 patients received pimavanserin 20mg beyond OL week 4. At baseline, mean age in the pimavanserin 34mg group was 75.7 years; mean MMSE score was 16.0. Twenty‐nine patients were terminated with sponsor termination of the study; of the remaining 214 patients, 130 (60.7%) met response criteria at weeks 8 and 12 and were randomized. At the IA, 116 ADP patients were randomized to pimavanserin 34mg (N = 57) or placebo (N = 59). Hazard ratio for psychosis relapse risk with pimavanserin 34mg versus placebo was 0.466 (95% CI: 0.179, 1.214); 6/57 (10.5%) pimavanserin‐treated and 14/59 (23.7%) placebo‐treated patients met relapse criteria. Treatment‐emergent adverse events incidence rates were: OL, 29.6% (72/243); DB‐pimavanserin 34mg, 39.7% (25/63); DB‐placebo, 34.3% (23/67). Pimavanserin did not have a negative effect on Mini‐Mental State Examination or Extrapyramidal Symptom Rating Scale‐Abbreviated score change from baseline versus placebo in the DB period.

Conclusion

In a study that met its primary endpoint, a post‐hoc subgroup analysis in ADP, although not statistically significant, demonstrated a clinically meaningful reduction in the risk of relapse was observed in patients treated with pimavanserin 34mg versus placebo. Pimavanserin was not associated with an adverse impact on cognition or motor function.
Neuropathological Validation of the Alzheimer’s Questionnaire
Authors: Mohebpour Ida , Malek‐Ahmadi Michael H. , Virden Thomas , Breitmeyer Angela , Sue Lucia I , Serrano Geidy E , Sabbagh Marwan N. , Beach Thomas G
Published: December 2022

Background

The Alzheimer’s Questionnaire (AQ) is a brief, informant‐based screening tool that has demonstrated good diagnostic accuracy in identifying clinical Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). The AQ has been further validated by its correlations with established informant‐ and performance‐based cognitive assessments as well as with standard neuropsychological tests. Recent evidence has also demonstrated that the AQ correlates well with PET‐based measures of amyloid plaque. The aim of this study is to validate the AQ with the hallmark neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology of AD.

Method

Data from 205 prospectively‐followed autopsy cases classified as AD (n=90), aMCI (n=42), or cognitively unimpaired (CU, n=73) were used in this analysis. The average age at death was 87.07±7.84 years with the average interval between the last clinical assessment and death of 16.48±14.32 months. Semi‐quantitative measures of NP and NFT pathology from five brain regions were used to assess total plaque and total tangle loads which were then correlated with the AQ, Clinical Dementia Rating Sum of Boxes (CDR‐SOB), and the Mini‐Mental State Exam (MMSE). Spearman correlations were used in the primary analyses and were followed up with robust regression models that adjusted for age at death, sex, education, and APOE ε4 carrier status.

Result

The AQ correlated significantly with NP load (r=0.37, p<0.001) and NFT load (r=0.57, p<0.001). These associations remained significant after covariate adjustment (NP: β=0.28, 95% CI: (0.21, 0.34), p<0.001; NFT: β=0.22, 95% CI: (0.17, 0.28), p<0.001). The MMSE and CDR‐SOB showed similar correlations with NP load (r=‐0.37, r=0.35, respectively) and NFT load (r=‐0.58, r=0.55, respectively).

Conclusion

These findings extend previous clinical and neuroimaging findings of the AQ showing that it correlates well with the hallmark NP and NFT pathology of AD and provide additional confidence to clinicians who use the AQ to screen for AD‐related cognitive impairment.
Cognitive impairment is associated with increased central arterial stiffness in an animal model of chronic kidney disease.
Authors: Grigorova Yulia N , Fox Shanaya , Long Jeffrey M , Santos Carla Rocha Dos , McDevitt Ross A , Zernetkina Valentina , Haghkar Mahdi , Wei Wen , Morrell Christopher H , Juhasz Ondrej , Sodhi Komal , Rapp Peter R. , Lakatta Edward G , Fedorova Olga V
Published: December 2022

Background

The prevalence of cognitive impairment (CI) and dementia in end‐stage chronic kidney disease (CKD) has been estimated at 30‐60%. Cardiovascular diseases (CVD) including increased central arterial stiffness (CAS) accompany CKD development and contribute to CI. Elevated pulse wave velocity (PWV) is associated with higher mortality in CVD and CKD independently of blood pressure (BP). Marinobufagenin (MBG) is a pro‐fibrotic factor, which increases in CKD and contributes to CAS. The aim of this study was to determine whether CKD potentiates CI development via CAS and cardiovascular remodeling in a rat model of CKD.

Method

Four months old male Sprague‐Dawley rats were fed with 0.25% adenine (n=19; CKD group) diet to induce CKD or regular diet (n=16; CTRL group) for 8 weeks. Body weight (BW), BP, heart rate (HR), aortic PWV (aPWV), and behavioral tests were conducted at the end of the study. The level of anxiety was tested in an open field test (OFT). Morris water maze (MWM) was used to test spatial memory. Blood was collected for measurements of plasma sodium, potassium, blood urea nitrogen (BUN), hematocrit and MBG. The data were analyzed using two‐tailed unpaired t‐test and linear regression.

Result

Animals in the CKD group had higher levels of plasma creatinine and BUN, which indicate the development of CKD, higher plasma sodium, potassium, and MBG, and higher aPWV, lower hemoglobin, hematocrit, BW, HR, enlarged hearts, aortae, and kidneys, vs. CTRL group (Table 1). BP was similar in both groups. .Rats in CKD group spent less time in the center of open field compared to their CTRL counterparts, indicating increased anxiety‐like behavior (Figure 1 A, B). Although there was no difference in performance in MWM between the groups, there was a positive correlation between aortic weight and ability to find a hidden platform in the CKD group (Figure 1C).

Conclusion

We demonstrated that CKD development in young Sprague‐Dawley rats was accompanied by increased CAS, estimated as aPWV, which developed in blood pressure‐independent manner. Higher PWV was associated with a higher level of anxiety, and aortic tissue remodeling was associated with spatial memory in CKD model.

Supported by NIH/NIA IRP
A Europe‐wide randomized controlled trial of hearing and vision rehabilitation in dementia: Results from the SENSE‐Cog trial
Authors: Leroi Iracema , Camacho Elizabeth , Chaghil‐Boissier Nathalie , Charalambous Anna Pavlina , Conelly JP , Constantinidou Fofi , David Renaud , Elliott Rachel , Frison Eric , Hann Mark , Holden Alison , Kennelly Sean , Lawlor Brian , Longobardi Julie , Politis Antonis , Kontogianni Evangelia , Rao Vinay Sudhindra , Reeves David , Termote Monique , Thodi Chryssoula , Worthington Mark , Yeung Wai
Published: December 2022

Background

Hearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia‐related outcomes. Intervening to optimize sensory function improve these outcomes. The SENSE‐cog Trial evaluated whether a home‐based multi‐part ‘sensory support’ intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their care partners.

Methods

This was a pan‐European, multi‐centre, observer blind, randomized controlled trial (RCT), of PwD with hearing and/or vision impairment and their companions. We compared ‘care as usual’ (CAU) to a multi‐part complex intervention of hearing and vision rehabilitation (SSI) tailored to each participant dyad. The SSI included: assessment and correction of hearing and/or vision impairments; home‐based, therapist‐delivered sensory support (i.e., adherence with devices; improving the sensory environment, communication training, and signposting to other support agencies). Outcomes were collected at baseline, intervention end (18 weeks) and post‐intervention (36 weeks – the primary endpoint) and included: quality of life, sensory and cognitive functional ability, relationship satisfaction, neuropsychiatric symptoms, and mental well‐being. Health resource utilization was measured to estimate cost‐effectiveness of the intervention.

Results

Across 7 European centers (UK, France, Cyprus, Greece), 252 participants with dementia (median age 80 years, 53% female, 59% hearing impairment only, 4% visual impairment only and 37% both impairments) were randomized from May 2018 to May 2021 to receive either CAU or SSI (10 visits over 18 weeks). Mitigating strategies to adapt study procedures to the COVID‐19 pandemic were implemented. Over 75% of participants completed the primary outcome, the DEM‐QoL scale, at 36 weeks. An initial feasibility study yielded positive results for this outcome revealing an average improvement in the DEM‐QoL of 4.9 points (> minimum important clinical change).

Conclusions

Hearing and vision support in PwD is a potentially important and cost‐effective means of improving the lived experience of dementia, representing a critical step in the diagnostic and care pathway. Main RCT results will be available in May 2022.

Trial registration: ISRCTN17056211
BCI‐838, an orally active mGluR2/3 antagonist pro‐drug, mimics the beneficial effects of physical exercise on neurogenesis, behavior and exercise‐related molecular pathways in an Alzheimer’s disease mouse model
Authors: Bicak Mesude , Perez‐Garcia Georgina E. , Buros Jacqueline , Haure‐Mirande Jean‐Vianney , Perez Gissel E. , Otero‐Pagan Alena , Gama‐Sosa Miguel E. , DeGasperi Rita E. , Sano Mary , Gage Fred H. , Barlow Carrolee , Dudley Joel , Glicksberg Benjamin S. , Wang Yanzhuang , Readhead Benjamin , Ehrlich Michelle E. , Elder Gregory A. , Gandy Sam
Published: December 2022

Background

Modulation of physical exercise (PE) represents an intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD). One mechanism proposed to underlie beneficial effects of PE involves the apparent stimulation of adult hippocampal neurogenesis (AHNG). BCI‐838 is a pro‐drug whose metabolite BCI‐632 is one of the most active proneurogenic agents known and is an antagonist at group II metabotropic receptors (mGluR2/3). The drug stimulates AHNG while enhancing learning behavior and exerting anxiolytic and antidepressant properties. We previously demonstrated that the administration of BCI‐838 to a mouse model of cerebral and cerebrovascular accumulation of oligomeric AbE22Q (APPE693Q = “Dutch”) reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Thy1.1‐Dutch APP mice (Kim et al., Mol Psych 2014). Herein, we sought to determine whether BCI‐838 might substitute for PE, and/or whether treatment with a BCI‐838+PE combination might demonstrate synergistic effects in a mouse model of amyloidosis (APPKM670/671NL/PSEN1Δexon9 = APP/PS1).

Method

3‐month‐old APP/PS1 mice were treated with either BCI‐838, PE (running wheels), or a combination of BCI‐838+PE for 1 month. We performed learning behavior tests (novel object recognition and Barnes maze), biochemical, and transcriptomic analyses on the hippocampal dentate gyrus (DG) of APP/PS1 mice. We performed gene set enrichment analysis, drug repurposing, and chemogenomic enrichment analyses to reveal molecular pathways of interest and investigated compounds with transcriptomically similar profiles as well as drug targets and side effects.

Result

We report that: (i) BCI‐838, PE, or BCI‐838+PE combination enhanced AHNG, (ii) BCI‐838 alone or associated with PE led to improvement in both spatial and recognition learning behaviors, (iii) BCI‐838 treatment increased mRNA levels of BDNF, metabotropic glutamate receptors, and PIK3C2A of the PI3K‐MTOR pathway, and decreased EIF5A of ketamine‐modulating mTOR activity in the hippocampal DG. qPCR results validated the statistical significance of the association between BCI‐838 treatment and increased levels of BDNF.

Conclusion

Our study points to BCI‐838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHNG, learning behavior, and anxiety in the APP/PS1 mouse model.
Investigating the protective contribution of PLCG2 P522R variant in microglia‐mediated immune pathways in Alzheimer’s Disease
Authors: Liang Xinyan
Published: December 2022

Background

As the main innate immune cell in central nervous system (CNS), microglia plays an indispensable roles in neuroinflammation and neurodegenerative diseases, such as Alzheimer’s Disease (AD). Large scale population studies have identified an AD‐associated rare coding variant in the Phospholipase C Gamma 2 (PLCG2) locus (rs72824905, P522R, P=5.38x10‐10, odds ratio = 0.68), which potentially offers protection against AD. This variant is associated with lower Aβ1‐42 and pTau181 levels in patients, as well as delays cognitive decline in mild cognitive impairment (MCI) progression. It has been reported that PLCG2 highly expresses in microglia in CNS and mainly involved in immune response, therefore, PLCG2 P522R variant may be a central player in the microglial‐mediated immune pathways during AD pathogenesis.

Method

We generated a PLCG2522R/R knock‐in mouse model carrying this human variant with CRISPR‐mediated gene editing. To explore the protective nature of PLCG2 P522R variant, we generated PLCG2522R/R; 5XFAD mouse model by crossing PLCG2522R/R knock‐in model with the 5XFAD mice, and accessed major AD phenotypes including Aβ load and microgliosis in vivo.

Result

Our data showed that PLCG2522R/R;5XFAD mice exhibited attenuated AD pathologies compared with PLCG2522P/P;5XFAD mice, including less burden of Aβ in cortical and hippocampal regions, and less Aβ‐associated microglia clustering around Aβ plaques at early stage of AD.

Conclusion

PLCG2 P522R variant can protect against AD pathology in PLCG2522R/R;5XFAD mice, which may likely link to its hypermorphic effect in immune pathways, so that PLCG2522R/R microglia potentially have improved phagocytotic function and restrict Aβ accumulation in brain. We believe that investigating the protective role of PLCG2 P522R mutation may help us better understand the neuroinflammation aspect of AD pathogenesis, and provide new strategies to developing clinical therapy in the future.
Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias
Authors: Gordon Elizabeth , Bocchetta Martina , Nicholas Jennifer M , Cash David M , Rohrer Jonathan D.
Published: December 2022

Background

Frontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.

Method

Longitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.

Result

Relatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.

Conclusion

This work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.
The longitudinal relationship between fatigue, mobility, and cognitive function in older adults with chronic stroke: secondary analysis of a randomized controlled trial
Authors: Liu‐Ambrose Teresa , Noseworthy Matt W
Published: December 2022

Background

Fatigue is a common consequence of stroke. Cross‐sectional evidence suggests post‐stroke fatigue is negatively associated with both mobility and cognitive function. We aim to understand the longitudinal relationship between fatigue, mobility, and cognitive function in community‐dwelling adults with chronic stroke (defined as having a stroke = or > 12 months prior to study).

Methods

A secondary analysis of data from a 6‐month randomized controlled trial with 120 adults with chronic stroke who were randomized to group‐based, supervised: 1) exercise training; 2) complex social and mental activities; and 2) stretch and balance exercises with general education sessions. We constructed linear regression models to assess the contribution of changes in fatigue to changes in usual gait speed (over 4 meters) and to changes in cognitive function. Cognitive function was measured by the Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog) Plus. Higher ADAS‐Cog Plus scores indicate greater cognitive impairment. Fatigue was assessed using: 1) Fatigue Severity Scale; and 2) Visual Analogue Scale. The Fatigue Severity Scale measures fatigue severity and its impact on daily activities global fatigue The Visual Analogue Scale asks individuals to rate their global fatigue. Higher Fatigue Severity Scale and Visual Analogue Scale scores indicate greater severity and degree of fatigue, respectively. In the regression models, we controlled for experimental group, age, and biological sex.

Results

Reduced severity of fatigue over the 6 months was associated with improved gait speed (p = 0.02). Reduced global fatigue was associated with improved cognitive function (p = 0.04). Specifically, a reduction of 25 points on the Fatigue Severity Scale was associated with an increase of 0.1 m/s in gait speed (R‐square = 5%). For the Visual Analogue Scale, a reduction of 3.3 points in global fatigue was associated with a reduction of 1 point (i.e., improvement) in the ADAS‐Cog Plus (R‐square = 4%).

Conclusions

Given the prevalence and consequence of fatigue on function in chronic stroke, future work is needed to identify effective interventions.
Tasks and activities of an effective collaborative Dementia Care Management program in German Primary Care
Authors: Mühlichen Franka , Michalowsky Bernhard , Raedke Anika , Platen Moritz , Mohr Wiebke , Thyrian Jochen René , Hoffmann Wolfgang
Published: December 2022

Background

Recent studies have demonstrated the efficiency of collaborative dementia care, which aim to improve post‐diagnostic support. However, tasks carried out of such models are currently unknown, hindering its implementation.

Objectives

To describe the tasks of an efficient collaborative dementia care management and analyze the association of these tasks with patients’ characteristics.

Methods

The analysis was based on 183 persons screened positive for dementia (PwD), who received dementia care management conducted by nurses with a dementia‐specific qualification. A standardized computer‐assisted assessment, patients’ and caregivers’ unmet needs were identified, based on these, pre‐specified algorithms generated an individual list of intervention tasks for each PwD. Tasks performed to meet unmet needs were documented and categorized and descriptively analyzed. We used multivariate regression models to identify socio‐demographic and clinical factors that are associated with a specific subgroup of tasks or a higher number of tasks.

Results

On average 22.7 tasks were carried out per dyad (PwD and caregiver). 38%, 19% and 13% of tasks could be categorized to cooperation with other healthcare providers, medical and nursing care, and social and legal support, respectively. A lower mental and physical health‐related quality of life, age of PwD, lower education, higher deficits in daily living activities, higher depressive symptoms, and a higher number of drugs taken of the PwD, as well as female sex of the caregiver were associated with a significantly higher number of tasks carried out.

Conclusions

Socio‐demographic and clinical characteristics and the subjective perception of health determine the intensity of intervention needed to address unmet needs of PwDs. A variability of the intensity of collaborative care should be considered in the development of future intervention studies and in the implementation into routine care.
Memorability of Word‐Pairs: Developing a Method for Generation of Calibrated Stimulus Sets for Repeat, Remote, Automated Testing
Authors: Kaula Alexander J , Cormack Francesca K
Published: December 2022

Background

Verbal‐Paired Associates (VPA) is widely used measure of memory. However, the memorability characteristics of the word‐pairs are not well‐understood, and the task currently suffers from ceiling effects (Uttl et al. 2002). Here we describe a data driven process for word‐pair selection, yielding precise estimates of memorability at the item and list level. This allows tuning of task difficulty to participant characteristics, and the development of many well‐calibrated parallel forms for longitudinal automated testing.

Method

For model development we recruited a total of 185 participants aged 18–40 years without psychiatric diagnoses, chronic medication, or historical head injury using the Prolific online testing platform. We used Cambridge Cognition’s NeuroVocalix software to automatically deliver and score Learning and Recall phases of VPA.

In a series of experiments, we explored the contributions of item‐level, pair‐level, list‐level, and study‐level properties to the probability of subsequent recall. At the item‐level, we considered word‐concreteness and word‐frequency. To capture the semantic relatedness of word‐pairs, we trained the GloVe neural network model (Pennington et al, 2014) to predict the co‐occurrence of words from a corpus of transcribed English. This yields high‐dimensional vectors, from which we could calculate the semantic cosine distance between items in a word‐pair. At the list‐level we considered order effects (primacy and recency), and at the study level we considered practice effects.

Data from these experiments was combined in a linear mixed effects logistic regression model to yield predicted memorability estimates for new sets of word‐pairs. These test sets were then deployed with a cohort of 43 older adults (aged 55 years and upwards) to evaluate this prediction.

Result

Modelling showed significant contributions of item‐level, pair‐level, list‐level, and study‐level factors to probability of recall. When applied to the new set of words and tested with our older cohort, we found that this model‐derived measure was a robust predictor of recall (r = .931, p < 10−6).

Conclusion

We have a robust method of predicting, for a given word‐pair, what the likelihood of recall will be. This enables the generation of sets of word‐pairs with well‐understood memorability characteristics, for use in automated, repeat, remote assessment.
Innate immune cGAS/STING in HFD‐induced obesity, prediabetes, and cognitive impairment
Authors: Elzinga Sarah E , Henn Rosemary E , Mendelson Faye E , Hayes John , Feldman Eva L
Published: December 2022

Background

Increasing in parallel with the worldwide aging population are rates of cognitive impairment and dementia, including Alzheimer’s Disease and Alzheimer’s Disease Related‐Dementia. Understanding underlying mechanisms that promote cognitive impairment with aging is therefore critical. One factor that significantly increases the risk of cognitive impairment and is reaching pandemic levels is obesity and prediabetes/diabetes. Common mechanisms that could underly the relationship between obesity and prediabetes/diabetes with cognitive impairment are changes in immune system function, particularly microglial dependent changes. Specifically, the innate immune cGAS/STING pathway is implicated in both cognitive impairment and obesity and prediabetes/diabetes.

Method

1 yr old BL6 male mice were fed 60% HFD (high fat diet) or 10% SD (standard diet) for 13 weeks. Body weight and glucose tolerance were used to determine metabolic phenotype. Cognition was measured using social recognition and fear conditioning. Hippocampal inflammatory gene expression was determined using Nanostring nCounter and cGAS/STING specific protein expression using western blotting. Additionally, we induced a prediabetic phenotype in a human microglial cell line by treating microglia for 24 hr with either palmitate alone or a combination of insulin and palmitate. Cells were then assessed for cGAS/STING protein expression using western blotting.

Result

HFD feeding resulted in increased weights and impaired glucose tolerance along with cognitive deficits. Hippocampal gene expression profiles showed changes in several genes, such as cGAS, STAT2, and IL‐6 and there were changes in hippocampal cGAS/STING proteins in HFD mice. In microglia, prediabetic conditions increased expression of multiple cGAS/STING proteins, along with the immunosenescence marker p21.

Conclusion

Changes in inflammatory profiles indicate that HFD dysregulates hippocampal inflammatory gene expression and cGAS/STING protein expression in obese prediabetic mice with cognitive impairment. Microglial cGAS/STING changes indicate that this cell type is particularly sensitive to prediabetic conditions and may promote premature immunosenescence. While more data are needed to fully understand cGAS/STING mediated microglial mechanisms of cognitive decline in obesity and prediabetes, these data support the hypothesis that inflammatory mechanisms are an important contributor and that the cGAS/STING pathway represents a potential target for future research.
Characterization of CDR® plus NACC FTLD at Phenoconversion from Asymptomatic to Mild Behavioral and/or Cognitive Impairment in Familial Frontotemporal Lobar Degeneration: Data from the ALLFTD Consortium
Authors: Miyagawa Toji , Brushaber Danielle , Syrjanen Jeremy A. , Kremers Walter K. , Fields Julie A. , Forsberg Leah K. , Heuer Hilary W. , Huey Edward D. , Knopman David S. , Kornak John , Boxer Adam L. , Rosen Howard J. , Boeve Bradley F. , Consortium ALLFTD
Published: December 2022

Background

The three most common genes responsible for the familial Frontotemporal Lobar Degeneration (f‐FTLD) are MAPT, GRN, and C9orf72, with the C9orf72 mutation being the most common cause of f‐FTLD. The ALLFTD Consortium targets to characterize f‐FTLD, including its preclinical stage, to prepare for clinical trials in FTLD. We sought to investigate the initial symptoms and clinical picture of f‐FTLD and compare them among the common pathogenic genes using longitudinal CDR® plus NACC FTLD.

Method

We longitudinally assessed the CDR® plus NACC FTLD among 292 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD caused by MAPT (n = 99), GRN (n = 67), or C9orf72 (n = 126) mutations, and described the detailed profiles of the CDR® plus NACC FTLD in the participants who developed Mild Behavioral and/or Cognitive Impairment (MBCI).

Result

Forty‐one participants (17 MAPT, 11 GRN, 13 C9orf72) developed MBCI during follow‐up visits . Age at the diagnosis of MBCI was 52.3±13.0 years (GRN 63.2±11.8, MAPT 43.5±8.6, C9orf72 54.7±10.7). Frequencies of abnormal rating on the eight CDR® plus NACC FTLD domains at the time of MBCI diagnosis were: “Memory” 44% (MAPT 47%, GRN 55%, C9orf72 31%); “Orientation” 7% (MAPT 6%, GRN 9%, C9orf72 8%); “Judgment and Problem Solving” 39% (MAPT 41%, GRN 55%, C9orf72 23%); “Community Affairs” 22% (MAPT 24%, GRN 18%, C9orf72 23%); “Home and Hobbies” 22% (MAPT 35%, GRN 0%, C9orf72 23%); “Personal Care” 0%; “Behavior/Comportment/Personality” 51% (MAPT 59%, GRN 55%, C9orf72 38%); “Language” 29% (MAPT 18%, GRN 55%, C9orf72 23%).

Conclusion

Initial symptoms and clinical picture of f‐FTLD in MBCI stage differ among responsible FTLD genes, which could be useful in detecting very early features of f‐FTLD in pathogenic mutation carriers.
Associations between dual‐decline in cognition and gait speed with risk of dementia – results from the ASPREE trial cohort
Authors: Collyer Taya , Murray Anne , Woods Robyn , Storey Elsdon , Chong Trevor , Ryan Joanne , Orchard Suzanne , Brodtmann Amy , Srikanth Velandai K , Shah Raj C , Callisaya Michele L
Published: December 2022

Background

Dual decline in gait speed and cognition is associated with an increased risk of dementia. However, it is unclear if risks are conferred by decline in domain‐specific cognition and gait. We aimed to examine associations between dual decline in gait speed and cognition (global cognition, memory, processing speed and verbal fluency) with risk of dementia.

Methods

Prospective cohort study. Participants were from the ASPREE (ASPirin in Reducing Events in the Elderly) study, a double‐blind, randomized, placebo‐controlled trial of low dose aspirin in older adults (≥70 years; ≥65 if US minority). Of 19,114 randomized participants, 16,855 (88%) had longitudinal gait and cognitive data. Gait speed was measured at 0, 2, 4, 6 years and close‐out. Cognitive measures included Modified Mini‐Mental State examination (3MS, global cognition), Hopkins Verbal Learning Test‐Revised (HVLT‐R, memory), Symbol Digit Modalities (SDMT, processing speed) and Controlled Oral Word Association Test (COWAT‐F, verbal fluency), assessed at years 0, 1, 3, 5, and close‐out. Participants were classified into four groups: 1) dual decline in gait and cognition; 2) gait decline only; 3) cognitive decline only and 4) non‐decliners. Cognitive decline was defined as membership of the lowest tertile of annual change. Gait decline was defined as decline in gait speed ≥0.05 m/s per year across the study. Dementia (DSM‐IV criteria) was adjudicated by an expert panel using cognitive tests, functional status and clinical records. Cox proportional hazard models were used to estimate risk of dementia adjusting for covariates with death as competing risk.

Results

The mean age of participants was 75.0 (SD4.4) years. Compared with non‐decliners, risk of dementia was highest in the gait+HVLT‐R decliners (HR 24.7; 95% CI 16.3‐37.3), followed by the gait+3MS (HR 22.2; 95% CI 15.0‐32.9), gait+COWAT‐F (HR 4.66 95%; CI 3.5‐6.3) and gait+SDMT (HR 4.3 95% CI 3.2‐5.8) groups. Dual decliners also had higher risk of dementia than those with either gait or cognitive decline alone for 3MS and HVLT‐R.

Conclusion

The combination of decline in gait speed and memory may be the best suited to predict future dementia risk.
A novel episodic memory test optimized for smart phone high‐frequency assessments
Authors: Anwyl‐Irvine Alexander L , Kaula Alexander J , Cashdollar Nathan , Taptiklis Nick , Cormack Francesca K
Published: December 2022

Background

Decline in episodic memory is a strong marker of neurodegenerative diseases, making it an important target for cognitive assessment. We present a new remote, repeatable, and brief assessment of episodic memory and visual short‐term memory (VSTM) for smart phone deployment. We evaluated this task for sensitivity to age and established cognitive measures of memory and attention.

Method

The task consists of a learning phase where participants see a sequence of items, then are asked to replicate the item order and location by dragging and dropping these items on‐screen. A recall phase follows a minimum 12‐hour delay, with replication of the earlier response. Each session takes less than 2 minutes. The first phase supplies metrics of spatial and order precision VSTM, with the second phase characterising long‐term episodic memory.

Experiment 1 (n = 133) compares the task with CANTAB assessments of visuospatial memory. In Experiment 2 (n = 80) the novel task was repeated twice daily for a week, alongside momentary mood ratings, and a more comprehensive battery of CANTAB tasks at baseline.

In Experiment 1, multiple regression and dominance analyses explore the independent and shared variance of measures in explaining age. In Experiment 2, clustering and multivariate autoregressive models outline differences in timeseries relationships between mood and memory, and age.

Result

Experiment 1 revealed that CANTAB measures and novel spatial and order metrics were correlated with age (r = .20 to r = .37, adjusted P = <.05). Multiple regression showed models with CANTAB Paired Associate Learning (PAL) score, and delayed novel spatial metrics were significantly predictive of age (t = ‐4.08, 3.17, p <.005). The dominance analysis revealed novel immediate precision overlapped with existing measures in predicting Age, while delayed precision had more unique variance (4.6% vs 0.62% unique sample variance explained in Age, accounting for PAL).

Experiment 2 characterised variance in individual learning curves over time and differing autoregressive processes associated with age and CANTAB measures.

Conclusion

We present a brief novel episodic memory task that can be deployed remotely, with delayed spatial precision significantly predictive of healthy Ageing. Additionally, we show this test’s suitability as a repeated assessment, compatible with high‐frequency study designs in older populations.
Neuropathology in the LifeAfter90 Study: Update on an Ethnically Diverse Cohort Study of Oldest‐Old
Authors: Dugger Brittany N , Jin Lee‐Way , Vargo Veronica , DeCarli Charles S. , Johal Sharan , Gilsanz Paola , Mungas Dan M. , Kawas Claudia H. , Glymour M. Maria , Corrada Maria M. , Whitmer Rachel A.
Published: December 2022

Background

Neuropathology studies of the oldest‐old have significantly advanced our understanding of the multiple etiologies late in very late life; however, this has been limited to studies of oldest‐old non‐Hispanic white (NHW) decedents. Our goal was to characterize neuropathology in a cohort of diverse oldest‐old decedents.

Method

The Life after 90 study is an ongoing cohort study of members of Kaiser Permanente Northern California, aged 90+ with targeted recruitment of individuals across different racial/ethnic groups with no prior diagnosis of dementia in their medical record. Participants are examined on average every 6 months. Brain donation was available to all interested consenting participants. Neuropathology was assessed using the National Alzheimer’s Coordinating Center Neuropathology form v. 10.

Result

As of January 2022, 216 participants (26% of sample) were enrolled in autopsy (autopsy enrollees: 20% Asian, 15% African American, 17% Latino, 9% Multiracial/Other, and 39% NHW) with 25 deceased and neuropathological evaluations completed. Average age of death was 95 years (range 91‐106), 13 (62.5%) were female, 6 Latino, 14 NHW, 3 Multiracial, 1 Asian, and 1 African American. At final clinical exam, 3 participants had dementia (12%), 8 questionable/mild cognitive impairment (32%), and 14 were cognitively normal (56%). With respect to Alzheimer’s disease (AD) neuropathologic diagnosis, 8 met criteria for intermediate likelihood (32%), 11 low (44%), and 6 did not have AD (24%); none had high AD likelihood. All participants had some level of neurofibrillary tangles (NFTs); median Braak NFT stage was II (range I‐V). Six participants lacked plaques, and highest Thal phase was 4. Eleven participants (44%) had Lewy bodies. Hippocampal sclerosis was seen in 1 participant, whereas TDP‐43 inclusions were detected in 5 (20%). Cerebral amyloid angiopathy was seen in 13 participants (25%). The most common assessed pathologies were age related tau astrogliopathy in 19 participants (76%) and some degree of arteriolosclerosis in 24 participants (96%) although only 4 were considered to have severe arteriolosclerosis.

Conclusion

This diverse cohort of oldest‐old individuals indicate numerous brain pathologies are present with advanced age, albeit most participants having mild severity and distributions of pathologies providing further evidence of the complex and multifactorial nature of clinic‐pathological correlations.
Ex vivo Expanded Human Regulatory T Cells Modify Neuroinflammation in a Preclinical Model of Alzheimer’s disease
Authors: Faridar Alireza , Vasquez Matthew , Thome Aaron D , Yin Zheng , Xuan Hui , Wang Jing Hong , Thonhoff Jason R , Zhao Weihua , Zhao Hong , Beers David , Wong Stephen T.C. , Masdeu Joseph C. , Appel Stanley
Published: December 2022

Background

Regulatory T cells (Tregs) play a neuroprotective role by suppressing microglia and macrophage‐mediated inflammation and modulating adaptive immune reactions. We previously documented that Treg immunomodulatory mechanisms are compromised in Alzheimer’s disease (AD). Ex vivo expansion of Tregs restores and amplifies their immunosuppressive functions in vitro. A key question is whether adoptive transfer of ex vivo expanded human Treg can suppress neuroinflammation and amyloid pathology in a preclinical mouse model.

Method

An immunodeficient mouse model of AD was generated by backcrossing the 5xFAD onto Rag2 knockout mice (5xFAD‐Rag2KO). Human Tregs were expanded ex vivo for 24 days and administered to 5xFAD‐Rag2KO. Changes in amyloid burden and microglia characteristics were evaluated using ELISA and confocal microscopy. NanoString Mouse AD multiplex gene expression analysis was applied to explore the impact of ex vivo expanded Tregs on the neuroinflammation transcriptome.

Result

Elimination of adaptive immune system in 5xFAD‐Rag2KO mice was associated with upregulation of 95 inflammation genes, amplified number of reactive microglia and increased plaque size. Following peripheral administration, ex vivo expanded human Tregs crossed blood‐brain barrier of 5xFAD‐Rag2KO and reduced amyloid burden and reactive microglia. Interrogation of inflammation gene expression documented down‐regulation of pro‐inflammatory cytokines (IL1A&B, IL6, Tnfa, IFNγ), complement cascade (C1qa, C1qb, C1qc, C4a/b), toll‐like receptors (Tlr3, Tlr4 and Tlr7) and microglial activations markers (CD14, Tyrobp,Trem2).

Conclusion

Ex vivo expanded human Tregs, with amplified immunomodulatory function, suppressed neuroinflammation and alleviated AD pathology in vivo. Our results provide preclinical evidences for Treg cell therapy as a potential treatment strategy in AD.
Convergent and criterion validity of a computer adaptive self‐administered word list memory test and the Mayo Test Drive composite: correlations with traditional measures and group difference by PET imaging biomarker status in persons without dementia.
Authors: Stricker Nikki H. , Twohy Erin L , Albertson Sabrina M. , Christianson Teresa J. , Stricker John L , Machulda Mary M. , Karstens Aimee J , Kremers Walter K. , Hassenstab Jason J. , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Petersen Ronald C.
Published: December 2022

Background

Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform optimized for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). Study aims were to determine 1) convergent validity of MTD through correlations with in‐person neuropsychological measures and 2) criterion validity of MTD by qualitatively comparing the ability of Mayo Test Drive and in‐person administered neuropsychological measures to differentiate biomarker‐defined groups, independent of clinical diagnosis.

Methods

Mayo Clinic Study of Aging participants (N = 282) completed a brief remote cognitive assessment (mean age = 74, SD = 12; 262 CU and 20 MCI per consensus conference diagnosis; see Table 1). A subset of participants had brain amyloid and/or brain tau PET scans available within 3 years; overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n = 31) or not (A‐, n = 57) and for 2) those with biological AD (A+T+, n = 19) or without any AD biomarkers (A‐T‐, n = 47). Primary outcome variables were SLS sum of trials, AVLT sum of trials, SYM Correct Trials response time, Digit Symbol Coding, MTD composite and Mayo‐PACC (AVLT sum of trials, Trails B, animals). Bivariate correlations were performed across all participants. Linear model ANOVAs were used to investigate biomarker subgroup differences; Hedge’s g effect sizes are reported.

Results

Convergent validity was supported through significant correlation (p’s < .001) of SLS and AVLT (r = .63), SYM and Coding (r = ‐.64), and MTD composite with Mayo‐PACC (r = .67); see Table 2. MTD subtests showed expected relationships with age and education (p’s < .05; Table 3). All MTD performances were significantly lower for A+ and A+T+ participants relative to A‐ or A‐T‐ (p’s<.001; Table 4). All MTD outcome measures showed a similar or greater group difference effect size relative to traditional in‐person administered neuropsychological measures for separating A+ vs. A‐ and A+T+ vs. A‐T‐ groups. See Figure 1 and Table 4.

Conclusions

MTD subtests show evidence of convergent validity through strong correlations with traditional in‐person cognitive measures. Preliminary analyses suggest MTD has promise for differentiating PET biomarker groups.