bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Usual Gait Speed in Persons with Mild‐Moderate Alzheimer’s Dementia
Authors: Salisbury Dereck , Yu Fang
Published: December 2022

Background

Gait speed, the time needed to walk a specified distance at normal pace, is a strong predictor of adverse outcomes. Usual gait speed ≥1.0 meters/second (m/s) is associated with better survival in community‐dwelling older adults. The purpose of this cross‐sectional study was to 1) evaluate usual gait speed and their predictors in community‐dwelling older adults with mild‐to‐moderate Alzheimer’s dementia (AD) participating in a pilot study investigating the effects of aerobic exercise on cognitive function.

Method

Usual gait speed was calculated from the 4‐meter walk test (4mWT) (part of the short physical performance battery test [SPPB] according to published guidelines. Potential predictors were selected based on the literature and included: demographics (age, sex, cognition [Mini‐Mental State Examination (MMSE) score], body mass index [BMI], balance (balance score from SPPB), aerobic fitness (peak oxygen consumption [VO2peak] from cycling‐based cardiopulmonary exercise test and walking distance from shuttle walk test [SWT]), and muscle strength/power (repeated chair rise test [RCR] of the SPPB). Data were analyzed using descriptive statistics (means/SD) and multiple linear regression.

Result

The sample (n = 90) averaged 76.9±6.6 years old, 44% female, 21.71±6.6 MMSE, and 24.6±11.2 BMI. Usual gait speed was 0.96±0.24 m/s, with 61% having a usual gait speed ≥1.0 m/s. Regression analysis showed that aerobic fitness (SWT distance) and muscular strength/power (RCR) were significant predictors of usual gait speed. Specifically, 45% of the variability in usual gait speed was accounted for by aerobic fitness (SWT distance) and muscle strength/power (RCR) (R2 = 0.449; SEE = 0.175; p≤0.001). In the subset with usual gait speed <1.0 m/s (n = 45), seventy‐three percent of the variability in usual gait speed was accounted for by aerobic fitness (SWT distance and VO2peak) and muscle strength (RCR) (R2 = 0.728; SEE = 0.07; p≤0.001).

Conclusion

Our findings suggest that aerobic fitness and muscular strength/power are significant determinants of usual gait speed in community‐dwelling older adults with mild‐to‐moderate AD and particularly in persons usual gait speed <1.0 m/s. Exercise interventions that have the capacity to enhance aerobic fitness and muscular strength/power will be important in preventing adverse outcomes associated with reduced usual gait speed in persons with AD.
TREM2 Variants in Parkinson’s Disease: Results from the Parkinson’s Progression Markers Initiative (PPMI) Study
Authors: Nudelman Kelly N. H. , Brumm Michael C. , Marek Kenneth , Foroud Tatiana M. ,   for the Parkinson's Progression Markers Initiative (PPMI) Study
Published: December 2022

Background

While TREM2 coding variants are known risk factors for Alzheimer’s disease, their contribution to Parkinson’s disease (PD) risk is less clear. We hypothesized that rare coding variants in TREM2 are associated with increased risk for Parkinson’s disease (PD), and that carriers of TREM2 coding variants represent a subtype of PD cases with different clinical characteristics and disease trajectory.

Method

TREM2 coding variants were obtained from the whole genome sequencing data available on LONI (https://ida.loni.usc.edu/) using VCFtools and annotated using Annovar for all individuals enrolled in the Parkinson’s Progression Markers Initiative (PPMI, N=1736), a longitudinal study of biomarkers of PD onset and progression. Of the 12 coding variants obtained, 8 variants that had reported or predicted pathogenic function were further analyzed. Fischer’s Exact 2‐sided tests were used to investigate enrichment of all variant carriers, as well as enrichment of specific variants with >20 carriers in the cohort, in sporadic (non‐genetic) PD (sPD) cases compared to controls. Enriched variants were tested for association with PD‐related measures including the MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS) total score, Montreal Cognitive Assessment (MoCA) score, Geriatric Depression Scale (GDS)‐15 score, and the University of Pennsylvania Smell Identification Test (UPSIT) score.

Result

TREM2 variant carriers (total N=77) were enriched in PD cases compared to controls (p=0.002). Within variant analysis showed enrichment of p.R62H carriers (p=0.027), but not p.R47H carriers (p=0.667) in sPD. While there was no significant difference in MDS‐UPDRS (p=0.763) or MoCA (p=0.815) at baseline between p.R62H sPD carriers and non‐carriers, p.R62H carriers were more likely to have a MoCA score <21 at a subsequent visit [HR (95% CI) = 2.78 (1.19‐6.49)], though this effect was not significant in an age‐adjusted model [HR (95% CI) = 2.28 (0.97‐5.34]. Compared to non‐carriers, p.R62H carriers showed a trend for more depressive symptoms (p=0.078) and had worse anosmia (p=0.002).

Conclusion

TREM2 rare coding variants are more common in PD, suggesting that TREM2 may contribute to the genetic etiology of this disease. Interestingly, p.R47H, a risk factor for Alzheimer’s disease, does not appear to contribute to sPD risk, whereas p.R62H may be a novel risk factor for PD.
CSF Alzheimer’s biomarkers in clinical practice
Authors: Agüero Pablo , Querejeta Agustín , Sainz María José , Téllez Raquel , Gómez‐Tortosa Estrella
Published: December 2022

Background

CSF biomarkers are well validated and a useful tool for the diagnosis of Alzheimer’s disease (AD). However, in some cases results are not consistent. In this study we examine to which extent CSF biomarkers support diagnosis in clinical practice.

Method

Analysis of 141 consecutive CSF samples of patients referred to our memory clinic with suspected cognitive decline, using the Lumipulse G600II chemiluminescent immunoassay (Fujirebio, Spain) to determine Ab‐42/Ab‐40 ratio (A+ if <0.068), total Tau (N+ if >410 pg/ml), and phospho‐Tau (T+ if >59 pg/ml).

Clinical diagnosis was classified into three categories: AD, degenerative non‐AD, and non degenerative, considering current clinical criteria at last visit.

Based on biomarkers, we separated the groups as follows: negative for AD (A‐T‐N‐ and A‐T‐N+), positive for AD (A+T+N+ and A+T+N‐), cases with amyloidosis A+ but T‐ (A+T‐N+; A+T‐N‐), and cases without amyloidosis A‐ but T+ (A‐T+N+).

Result

50,5% of the patients had a positive AD result that correlated in a majority of cases with a clinical amnestic AD phenotype or other highly related phenotypes (logopenic aphasia and posterior cortical atrophy). The exceptions were 5 cases meeting diagnostic criteria for non‐fluent/agrammatic aphasia or corticobasal syndrome.

37% had a negative AD result which correlated with a clinical diagnosis of non‐AD neurodegeneration (25 cases) or non degenerative (27 cases).

Therefore, in 87% of the cases CSF biomarkers supported a clinical diagnosis.

On the other hand, 18 cases (13%) had some inconsistencies within biomarkers: 7 with A‐ and 11 with A+ results. As regards clinical diagnosis, all A‐T+N+ and many of the patients with A+ biomarkers (8/11) had been considered AD phenotypes. In two of the cases with A+T‐N‐, an AD diagnosis was later confirmed, respectively, by a positive PET‐amyloid study and full positive CSF biomarkers analyzed two years later.

No differences were found in family history, age of onset, or age at lumbar puncture between the groups of AD positive biomarkers and just amyloidosis A+.

Conclusion

CSF biomarkers were clearly supportive of the clinical diagnosis in a majority of the cases of our cohort. However, in 13% of the cases, most of them with an AD type phenotype, biomarkers were unclear.
Diffusion MRI alterations coincide with memory deficits in a novel hAβKI mouse model of Alzheimer’s Disease
Authors: Jullienne Amandine , Noarbe Brenda P , Keiser Ashley , Trinh Michelle V , Pad Rojina , Kramár Enikö , Dong Tri , Beardwood Joy , Al‐Shammari Ameer , Wood Marcelo A , Obenaus Andre
Published: December 2022

Background

The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse. These mice exhibit age‐dependent cognitive and synaptic impairments. Preclinical neuroimaging was performed, specifically diffusion MRI (dMRI) to investigate brain‐wide structural alterations in conjunction with connectomic analyses across the hAβKI mouse lifespan.

Method

hAβKI and WT mice were compared at 4, 12, and 18 months (mo) of age. Two cohorts were generated for: 1) behavior and long‐term potentiation (LTP), and 2) high resolution diffusion tensor imaging at 9.4T (30 directions b=3000 mm2/sec) to assess regional white and gray matter changes. Regional tissue features based on the AMBMC atlas were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps.

Result

Significant impairments in hippocampal LTP were observed in male hAβKI mice at 4mo of age relative to WT but not at 12 or 18mo. In contrast, in female hAβKI mice, LTP impairments were observed only at 12 and 18mo relative to WT. dMRI heatmaps of MD highlighted regional differences between sexes across time and genotype, with MD progressively decreasing with time. Male hAβKI mice had progressive changes within the brain with advancing age whereas the largest changes in females was at 12mo of age. AxD in 18mo male hAβKI mice was increased in 4 of 7 white matter regions but not in female hAβKI mice compared to WT.

Conclusion

In summary, using the newly developed hAβKI mouse model of AD, we identified progressive altered regional dMRI tissue metrics. The hippocampal CA1 region appeared to be particularly vulnerable, findings consistent with observed impairments in LTP and behavior. MRI of new mouse models is a powerful tool to investigate tissue level modifications to brain structure and function to inform human disease.
Costs of dementia in Europe: a systematic literature review and meta‐analysis
Authors: Jönsson Linus , Frisell Oskar , Wimo Anders
Published: December 2022

Background

Reliable data on costs of dementia care is critically important for estimating the value of novel therapies, technologies and methods in dementia care. The costs of dementia have been described in an increasing number of studies, however many are limited by small, selected samples and incomplete scope of cost categories included. Comparison of results has been challenged by considerable methodological heterogeneity, however increasing standardization of how resource utilization is measured and valued is increasing opportunities for systematic compilation of results. In this study we summarize available evidence on the costs of dementia in Europe through meta‐analysis on individual cost items.

Method

We conducted a systematic literature review to identify studies that collect and report costs of care in individuals with dementia. Costs were assessed in seven categories covering direct medical care (inpatient care, outpatient care, drugs), direct non‐medical care (institutional care, home care) and informal care (caregiver time loss, caregiver work loss). Data on study methodology, patient populations, care setting and disease severity was abstracted and harmonized across studies, and costs were converted to 2021 EUR.

Result

115 studies were included in the final review and meta‐analysis, reporting data for 631,281 patients from 17 countries. Annual total costs vary between regions within Europe, from approximately €6,000 EUR in Eastern Europe to €50,000 in Northern Europe, but consistently increase with disease severity and for institutionalized patients. Costs are dominated by informal care and non‐medical direct costs, while the balance of these two vary between regions. About half of the studies used a standardized scale for collecting resource utilization and cost data, the most common of which was the Resource Use in Dementia (RUD) instrument.

Conclusion

In this study we construct the most comprehensive database to date of costs of dementia in relation to disease severity and care setting. Meta‐analytical estimates of care costs are possible but require categorization of resource use items and cross‐mapping of different measures of disease severity.
Older adults with underidentified dementia exhibit a fragile clinical and neuropsychiatric profile
Authors: Formoso Carolina Rodrigues , Borelli Wyllians Vendramini , Castilhos Raphael Machado , Chaves Marcia L Fagundes
Published: December 2022

Background

Worldwide prevalence of dementia in older adults ranges from 5‐7%, with higher rates observed in Latin America (8.5%). However, underdiagnosis remains frequent. Our aim is to identify the profile of individuals with probable dementia that were underidentified using an epidemiological cohort.

Method

An epidemiological study named ELSI‐Brazil was evaluated for potential underidentification of dementia. Individuals at or above 60 years of age with probable dementia were selected using semantic fluency test scores (adjusted for age and education) and loss of any basic activity of daily living (Katz scale<6). Groups were divided into reported and unreported diagnosis of dementia (UpD), according to previous history of Alzheimer’s disease. UpD group compounds individuals potentially living with probable dementia without a proper medical evaluation. Individuals were evaluated for self‐reported risk factors, previous medical history, frailty scores, cognitive tests and neuropsychiatric symptoms. A multivariate logistic regression was performed to demonstrate predictors of UpD.

Result

Among 5221 older adults of the ELSI‐Brazil sample, 474 individuals (mean age 73.30±8.65, 67% females) were classified as probable dementia (pD), and 4747 individuals (mean age 69.6±7.42, 59% females) as probable not dementia (pND). Among probable dementia, unreported dementia (UpD) comprehended 459 older adults (96.4%), with significantly more clinical comorbidities, such as hypertension, diabetes, ischemic events (stroke or myocardial infarction), hearing loss and malignancy (p < 0.001). They also presented higher neuropsychiatric symptoms, such as poor quality of sleep, frequent usage of sleep drugs, and depression (p<0.001). Strong predictors of UpD included frailty score (OR: 2.06 [1.58 ‐ 2.68]), poor sleep quality (OR: 1.46 [1.13 ‐ 1.90]), frequent usage of sleep drugs (OR: 1.54 [1.15 ‐ 2.05]), and recent hospitalization (OR: 1.67 [1.20 ‐ 2.30]).

Conclusion

A specific profile of vulnerability was demonstrated in older adults with unidentified probable dementia in this cohort. Frailty, poor sleep quality, frequent usage of sleep drugs, and recent hospitalization were important predictors of UpD. This study provides insights to guide public health policies and target individuals more vulnerable to underidentified dementia.
Integrating music‐based interventions with gamma‐frequency stimulation for Subjective Cognitive Decline and Mild Cognitive Impairment
Authors: Tichko Parker , Kim Ji Chul , Zappi Victor , Large Edward , Loui Psyche
Published: December 2022

Background

Alzheimer’s disease (AD) is characterized by disrupted, synchronous neural activity in the gamma‐band range (30‐100 Hz) and atypical cross‐frequency coupling between gamma and other bands of brain activity1‐3. In non‐human‐animal models, restoring aberrant gamma activity with non‐invasive gamma sensory stimulation remediates multiple pathophysiologies of AD (e.g., amyloid‐beta, tau tangles) and improves cognition4,5. While promising, gamma sensory stimulation may be difficult to use with human patients. We theorize that combining gamma sensory stimulation with natural music may increase the efficacy of gamma interventions for dementia, as music naturally drives gamma brain activity; engages multiple brain networks that are important for learning, memory, and reward processing; and music‐based interventions can reduce distress and agitation in older adults with dementia6.

Method

We developed a non‐invasive, gamma‐ and music‐based intervention for dementia, called SynchronyGamma (SynG). SynG delivers synchronized bursts of gamma‐frequency visual stimulation during natural music listening, cross‐frequency coupled to delta (0.5 – 4 Hz) and theta (4 – 8 Hz) visual rhythms, which adapt in real‐time to musical rhythms. In a preclinical experiment featuring older adults with and without Mild Cognitive Impairment (MCI) and Subjective Cognitive Decline (SCD) (N = 19 experimental group, 3 with MCI/SCD; N = 18 control group, 2 with MCI/SCD), we tested whether a single‐dose of music listening with SynG, relative to a control intervention, drives gamma neural activity; induces cross‐frequency coupling between delta, theta, and gamma brain activity; and improves cognition (e.g., delayed‐match‐to‐sample working‐memory task)

Results

SynG was found to drive scalp‐recorded gamma brain activity (p<0.05), and induce stronger cross‐frequency coupling, relative to the control condition (p<0.05). Additionally, enhanced gamma activity was observed during the working‐memory task that followed the intervention. Finally, SynG participants performed more accurately on a visual working memory task compared to their control counterparts, although this improvement fell short of statistical significance following a single dose (p>0.05).

Conclusion

Together, these findings suggest that combining self‐selected music with delta, theta, and gamma frequency visual stimulation is effective at driving gamma neural activity, inducing cross‐frequency coupling, and it may improve cognitive functioning. Future research will assess the effects of a longitudinal implementation of the intervention.
Association of synaptic density and glucose metabolism with cognitive performance in early Alzheimer's disease: a PET imaging study with [11C]UCB‐J and [18F]FDG
Authors: O'Dell Ryan S. , Mecca Adam P , Waszak Julia , Sharp Emily , Chen Ming‐Kai , Naganawa Mika , Toyonaga Takuya , Lu Yihuan , Chupak Anna , Cooper Emma , Lam Jessica , Miller Alyssa , Waldner Emma , Weibley Hannah , Zhao Yize , Nabulsi Nabeel B. , Huang Yiyun , Arnsten Amy F. T. , Carson Richard E. , van Dyck Christopher H
Published: December 2022

Background

Traditionally, [18F]FDG PET has been used in Alzheimer’s disease (AD) as a surrogate marker of disease progression and is highly correlated with cognitive and functional decline. Synaptic loss is an early pathological event and a major structural correlate with cognitive impairment, although this is based on limited post‐mortem studies at more severe disease stages. Recently, we have confirmed these neuropathologic studies in vivo, using [11C]UBC‐J PET to demonstrate significant correlations between synaptic density and cognitive performance in early AD. In this study, we examined the relationship between synaptic density, glucose metabolism, and cognitive performance in early AD using [11C]UCB‐J PET, [18F]FDG PET, and an extensive neuropsychological battery.

Method

[11C]UCB‐J and [18F]FDG binding was measured in 46 amyloid+ participants with AD (18 aMCI and 28 mild dementia) and 17 amyloid‐ cognitively normal participants aged 50‐85 years. Synaptic density was calculated as DVR and glucose metabolism as SUVR in a composite of AD‐affected regions, using a whole cerebellum reference region for both tracers. A validated neuropsychological battery assessed performance across six cognitive domains. Domain scores were calculated for each participant by averaging z‐scores within that domain, and global cognition scores averaged the domain scores.

Result

In a multiple linear regression model controlling for age, sex, and education, glucose metabolism was a stronger predictor of global cognitive performance compared to synaptic density in participants with AD (beta=2.90,eta2=0.38,P=0.000005 vs. beta=2.48,eta2=0.22,P=0.001), as well as executive function, language, processing speed, visual memory, and visuospatial ability. Synaptic density was a stronger predictor of verbal memory compared to glucose metabolism (beta=1.68,eta2=0.22,P=0.001 vs. beta=1.02,eta2=0.10,P=0.03). Using William’s tests, exploratory analyses demonstrated stronger correlations between medial temporal synaptic density and performance across all cognitive domains. In neocortical ROIs, glucose metabolism was more strongly correlated with cognitive performance across all domains with the exception of verbal memory, which demonstrated stronger correlations with synaptic density across all analyzed ROIs.

Conclusion

Consistent with a hypothesis of divergent synaptic loss and hypometabolism in early AD, these results demonstrate synaptic density is more strongly correlated with cognitive decline in medial temporal regions, while cerebral hypometabolism is more strongly correlated with cognitive decline in neocortical regions.
Biomarkers and clinical presentations in Creutzfeldt‐Jakob Disease
Authors: Shir Dror , Lazar Evelyn , Graff‐Radford Jonathan , Aksamit Allen , Cutsforth‐Gregory Jeremy , Jones David T. , Botha Hugo , Ramanan Vijay K , Prusinski Christian C , Porter Amanda , Day Gregory S
Published: December 2022

Background

The ability to detect malformed prion proteins using real‐time quaking‐induced conversion (RT‐QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt‐Jakob disease (CJD), facilitating earlier recognition of affected patients. Recognizing this, we evaluated the frequency of clinical features and biomarker results at initial evaluation in patients with CJD and determined the relationship between these early features and CJD diagnosis and prognosis.

Method

Clinical data were extracted from the electronic medical records of patients with probable or definite (pathologically confirmed) CJD assessed at Mayo Clinic from 2014‐2021. Diagnoses of probable CJD were established by clinical consensus, referencing the Centers for Disease Control and Prevention diagnostic criteria. Clinical features and biomarkers results were evaluated at presentation, and associations with CJD diagnosis and symptomatic disease duration determined.

Result

One‐hundred fifteen patients were included (40, [35%] with definite CJD). Mean age‐at‐symptom onset was 64.8±9.4 years; 68 patients were female (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD (e.g., stereotyped EEG abnormalities (16%), CSF 14‐3‐3 (60%)) was poor. Biomarkers with good diagnostic sensitivity included RT‐QuIC (93%), t‐tau levels >1149 pg/mL (88%), and characteristic signal abnormalities on MRI (77%). Multivariable linear regression confirmed shorter survival for patients with myoclonus (125.9 days, 95%CI 23.3‐15.5, p=0.026), visual/cerebellar signs (180.19 days, 95%CI 282.2‐78.2, p<0.001), positive 14‐3‐3 (193 days, 95%CI 304.9‐82.9; p<0.001), and elevated t‐tau levels (each 1000 pg/ml increase was associated with a nine‐day shorter time‐to‐death, 95%CI 1‐18; p=0.041).

Conclusion

CSF RT‐QuIC and elevated t‐tau levels, and stereotyped MRI abnormalities continue to be strongly associated with the diagnosis in the modern era, while other clinical findings (myoclonus) and biomarkers results traditionally ascribed to CJD (e.g., PSWC on EEG, 14‐3‐3) offered less value in the diagnostic evaluation. Detection of visual or cerebellar features, myoclonus, CSF 14‐3‐3, and t‐tau levels may predict disease duration, justifying inclusion in the evaluation of CJD‐suspected patients.
Examining an endogenous modulator of chaperone‐mediated autophagy in neurons across Braak stages of Alzheimer's disease
Authors: Weickhardt Alexander F. , Lee Yoo Bin , Piergies Antonia M. H. , Li Song , Lew Caroline , McCabe Mericka , Bourdenx Mathieu , Scrivo Aurora , Gavathiotis Evripidis , Cuervo Ana Maria , Grinberg Lea Tenenholz
Published: December 2022

Background

Defective clearance of tau by neuronal autophagy has been implicated in the accumulation of toxic forms of tau in Alzheimer’s disease (AD). A novel, endogenous activator of chaperone‐mediated autophagy (CMA‐modulator) was identified in cell culture experiments (Cuervo laboratory, unpublished data). It is unclear what role this endogenous CMA‐modulator plays in AD. We hypothesized that loss of the CMA‐modulator in neurons could lead to decreased clearance of abnormal tau monomers, promoting the accumulation of toxic forms of tau. This study examined the proportion of neurons with CMA‐modulator in postmortem brain tissue from subjects with a range of AD neuropathologic changes as well as both amnestic and non‐amnestic AD presentation.

Method

We used multiplex immunofluorescence (CMA‐modulator, NeuN for neurons, 1F3C for acetyl‐tau, AT100 for phospho‐tau) on tissue microarrays in the inferior temporal gyrus of 17 subjects (Table 1) and for each subject quantified neurons within a gray matter area of 7.4 ‐ 7.6 mm2 using digital pathology. To analyze the change in percentage of neurons positive for CMA‐modulator across Braak stages, we fit a linear regression model.

Result

In amnestic AD, the percentage of neurons positive for CMA‐modulator declined linearly with advancing Braak stage, but this trend was not statistically significant (slope = 2.42% loss per Braak stage, p = 0.086). The predicted percentage of positive neurons was 22.8% at Braak stage 0 and 8.25% at Braak stage 6 and amnestic presentation. All non‐amnestic cases were Braak stage 6, and the proportion of neurons positive for the CMA‐modulator varied greatly from 0.2% to 77.1%. There was no significant association between the percentage of CMA‐modulator positive neurons and either age or gender. Quantification for the acetyl‐tau and phospho‐tau markers is ongoing.

Conclusion

There may be a gradual loss of the endogenous CMA‐modulator across Braak stages in amnestic AD, but this study was underpowered to draw definitive conclusions. We are increasing the sample size.
Plasma phosphorylated‐tau181 is an indicator of early manifestations of neuropsychiatric symptoms in younger subclinical individuals
Authors: Gontrum Eva Q. , Saloner Rowan , Chan Brandon , Lago Argentina Lario , Rojas Julio C. , Casaletto Kaitlin B , Kramer Joel H.
Published: December 2022

Background

Neuropsychiatric symptoms (NPS) can be the first manifestations of Alzheimer’s disease (AD), predict faster disease progression, and are more prevalent in early‐onset AD. Plasma P‐tau181 is strongly linked to cognitive impairment due to AD, yet it is unclear whether plasma P‐tau181 similarly relates to NPS in non‐demented adults, and whether this association is age‐dependent.

Method

Plasma p‐tau181 concentrations (Quanterix Simoa) were measured in 265 non‐demented adults (212 cognitively unimpaired, 53 mild cognitive impairment; age = 74.4 [7.7], 51.5% female). NPS were measured via the informant‐based Neuropsychiatric Inventory Questionnaire (NPI‐Q) with the total severity score selected for analysis. Linear regression examined NPI‐Q score as a function of plasma P‐tau181, age, and their interaction, covarying for sex and diagnosis. To probe interaction effects, region of significance analyses identified the threshold along the distribution of age at which statistically significant plasma P‐tau181 and NPS associations emerged.

Result

NPI‐Q scores ranged from 0–15, with the largest proportion of total scores reflecting anxiety (35%), sleep disturbance (16%), depression (14%), and irritability (14%). In the full sample, higher plasma P‐tau181 related to higher NPI‐Q total severity scores (β = .21, p<0.001). Age moderated the relationship between plasma P‐tau181 and total severity scores (β = ‐.18, p < 0.02) such that higher plasma P‐tau181 was significantly related to higher NPS at younger ages, yet this association was no longer statistically significant after age 72.5.

Conclusion

Plasma p‐tau181‐related elevations in NPS were most prominent in mid‐life through early old age (50’s to early‐70’s), yet this association was attenuated at later age stages, suggesting that the emergence of NPS at younger ages may be more closely linked to tau pathology than late‐life NPS. Importantly, age‐dependent effects on plasma P‐tau181 on NPS were independent of diagnosis, possibly reflecting a unique link between tau pathology and the neurocircuitry underpinning NPS.
Effects of Masupirdine (SUVN‐502) on Agitation/Aggression and Psychosis in Patients with Probable Alzheimer’s Disease: A Post Hoc Analysis
Authors: Nirogi Ramakrishna , Jayarajan Pradeep , Abraham Renny , Tadiparthi Jayaprakash , Benade Vijay , Shinde Anil K , Rasheed Mohammed Abdul , Badange Rajesh Kumar , Goyal Vinod Kumar , Palacharla Veera Raghava Chowdary , Ravulu Jyothsna , Jetta Satish , Subramanian Ramkumar
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder in older people with manifestations of cognitive and functional decline and neuropsychiatric symptoms (NPS). Agitation/aggression and psychosis are regarded as the most distressing NPS.

Serotonin‐6 receptor (5‐HT6) is a G protein‐coupled receptor and is localized almost exclusively in the central nervous system regions which are important for control of mood regulation. Masupirdine is a potent and selective 5‐HT6 receptor antagonist. Masupirdine has been evaluated for its effects on cognition in patients with probable Alzheimer’s disease.

Method

Masupirdine has been evaluated in a phase‐2a proof‐of‐concept, 26‐week, randomized, double‐blind, placebo‐controlled, multicenter, parallel group clinical study in United States under active US IND. Subgroup analyses of phase‐2a study results was carried out to evaluate the beneficial effects of masupirdine on agitation/aggression, and psychosis using Neuropsychiatric Inventory (NPI‐12) scale.

Masupirdine was also evaluated in animal models to assess its effect on behavior and brain neurotransmitter modulations.

Result

Masupirdine showed robust efficacy in agitation/aggression scores in patients who had baseline symptoms of agitation/aggression. In patients with baseline psychosis symptoms and/or symptom emergence, a significant reduction in psychosis scores were observed in masupirdine treatment arms. Behavioral observations from the animal models were also in accord with the post hoc observations from the masupirdine clinical trial.

Conclusion

Observations from the masupirdine clinical trial suggest the potential utility of masupirdine for the management of neuropsychiatric symptoms associated with agitation/aggression, and psychosis in patients with AD. Masupirdine is currently being evaluated for the management on agitation in patients with dementia of the Alzheimer’s type.
Using telepresence robots to support family virtual visits during the COVID‐19 Pandemic
Authors: Hung Lillian , Mann Jim , Wong Joey , Young Erika
Published: December 2022

Background

The COVID‐19 pandemic has disproportionately impacted older adults living with dementia in Long‐Term Care (LTC). Social isolation and loss of connections with families among residents have been detrimental and severely impacted quality of life.

Method

This project aims to enhance LTC homes' capacity to support virtual family visits using a telepresence robot. Research question: Is it feasible to implement robotic‐assisted virtual care in LTC homes? We applied a Collaborative Action Research (CAR) approach to work with stakeholders (frontline leaders, staff, patient and family partners) to explore the experiences of virtual family visits in four Canadian LTC homes. Guided by the Consolidated Framework of Implementation Research (CFIR), we conducted an online survey, interviews, focus groups, and observations to explore implementation experience.

Results

Our analysis identified three themes: (a) Relative advantage: Easy to visit, (b) Capacity for change: Readiness and organizational support, (c) Cultural safety for robot adoption: Champions leading the way during challenging times.

Conclusion

Our preliminary results suggest staff, residents, and families appreciated the robot for easy connection. Future research should apply inclusive methods to bring relevant stakeholders together to fully explore user experiences ‐ who is affected in what ways and the benefits, risks, and burdens of emerging technologies.
Decreased Peripheral Endothelial Function is Associated with Mild Cognitive Impairment and Lower Performance on Memory and Language
Authors: Cheng Michael L , Rogers Steven , Thomas Tiffany , Okafor Maureen , Seyfried Nick , Kulshreshtha Ambar , Goldstein Felicia C , Quyyumi Arshed , Hajjar Ihab
Published: December 2022

Background

The association between cardiovascular risk factors and cognitive decline is known, but the underlying mechanisms remain unclear. We investigated whether peripheral microvascular and endothelial function, measured by pulsatile arterial tonometry (EndoPAT), is associated with cognitive performance and mild cognitive impairment (MCI).

Method

This study is based on data from 340 participants (150 with MCI, 190 with normal cognition (NC); mean age 64.9 (SD: 7.7) years, 61% female, 48% African American) enrolled in the VAScular ContribUtors to prodromaL AlzheimeR’s disease (VASCULAR) study. Peripheral microvascular function was assessed using EndoPAT (Itamar Inc.), and a reactive hyperemic index (RHI) was derived after a 5‐minute arterial occlusion period and includes a continuous or discrete (dichotomous or tertile) variable. Cognitive assessment and diagnostic categorization performed at the baseline visit included Montreal Cognitive Assessment (MoCA), Boston Naming Test, Hopkins Verbal Learning Test‐Revised (HVLT‐R), and Trail Making Test. Groups were compared with a t‐test and multivariable logistic and linear regression analyses were performed to adjust for demographic and risk factor covariates.

Result

Participants with MCI had lower RHI, indicative of greater peripheral microvascular and endothelial dysfunction, compared to NC (mean 1.9 (SD: 1.4) vs 2.2 (0.7) AU, p=0.014), which remained significant after adjustment for age, education, sex, race, systolic blood pressure, history of diabetes, hyperlipidemia, and smoking (OR: 3.91 for each 1‐unit change in RHI (95% CI: 1.00, 7.08), p=0.03). When analyzed in tertiles, a lower RHI (<1.75 AU) was also associated with poorer expressive language (Boston Naming Test, p=0.03), and verbal memory performance (HVLT‐R delayed recall, p=0.01; HVLT‐R retention, p=0.02). Executive function (Trail Making Test) and overall cognitive status (MoCA) were not significantly associated with RHI.

Conclusion

Peripheral microvascular endothelial dysfunction, measured as RHI, was associated with MCI and with lower performances on measures of language and memory. These data highlight the importance of systemic microvascular health in cognitive health. Strategies targeting microvascular endothelial function may need further investigation in cognitive therapeutics.
How does a diagnosis of mild cognitive impairment impact everyday behaviours, quality of life and healthcare utilisation? A systematic review of people with MCI and their carers.
Authors: Connolly Evie Margaret , Slight Sarah , Ardle Ríona Mc
Published: December 2022

Background

The UK National Dementia Strategy was developed to improve professional and public attitudes and understanding around dementia, and to ensure through all stages of dementia that patients receive high‐quality care and support(1). Mild cognitive impairment (MCI) is a prodromal stage of dementia that can impact on patients’ everyday behaviours and quality of life (QOL). Carers may undertake additional responsibilities, which may ultimately impact on their health. We conducted a systematic review on the impact of an MCI diagnosis on the lives of both the individual and carers/families, focusing on everyday behaviours, QOL, and healthcare utilisation.

Method

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews (PRISMA) checklist. We searched five large databases including Web of Science, Scopus, Medline, Embase and Psychinfo for studies published after Jan 2004, using appropriate key terms. Titles, abstracts and full texts were screened against set inclusion criteria. Data were extracted onto a customized data extraction sheet, and a narrative synthesis of all eligible studies was undertaken. This review was registered with PROSPERO (no CRD42021291995).

Results

Ten papers were included. Patients diagnosed with MCI and cares/families described a lack of understanding of the term MCI itself, particularly around ‘mild’ and the anxiety around further cognitive decline. There was a perceived lack of information provided to both patient and carers around the diagnosis, with carers not perceiving themselves as carers up until that point. Carers also reported increased levels of depression and distress as they undertook more caring responsibilities. Carers experienced frustration with loved ones, who denied that they had memory problems and took longer to process and do things; this led to increased family conflict.

Conclusion

This review identified the functional and psychosocial impact of a MCI diagnosis on people and carers. There is a critical need to combat stigma, increase information and support for people with MCI, and provide psychosocial interventions for people and carers post MCI diagnosis to enhance them to better cope and potentially reduce related depression, anxiety, and carer burden.

1 Banerjee S. Living well with dementia–development of the national dementia strategy for England. Int J Geriatr Psychiatry. 2010;25:917‐922.
Brain insulin signaling and neurodegeneration: IRS‐1 isolated from neuronal enriched extracellular vesicles associates with frontal lobe gray matter volume in cognitively unimpaired adults
Authors: Peter Darby , Ennis Gilda E. , Eren Erden , III Doug C Dean , Oh Jennifer M. , Asthana Sanjay , Johnson Sterling C. , Kapogiannis Dimitrios , Bendlin Barbara B.
Published: December 2022

Background

Brain insulin signaling, as measured by insulin signaling proteins in neuronal enriched extracellular vesicles (nEVs), has previously been associated with gray matter (GM) volume in the temporal lobe of nondemented older adults and in multiple brain regions in those with Alzheimer’s clinical syndrome (Walker et al, 2021; Mullins et al, 2017). We sought to extend these findings by performing a voxel‐wise analysis to test the relationship between whole‐brain GM volume and nEV tyrosine phosphorylated IRS‐1 (pY‐IRS‐1) in a cognitively unimpaired sample enriched for AD risk.

Method

Cognitively‐unimpaired adults (n=47) from the Wisconsin Registry for Alzheimer’s Prevention underwent MRI and blood collection (Table 1). nEVs were isolated from plasma samples by immunoprecipitation targeting neuronal marker L1CAM. pY‐IRS‐1 was measured in nEVs using an electrochemiluminescence assay (Meso Scale Discovery, Rockville, Maryland) (Mustapic et al, 2017). T1‐weighted images were analyzed using the FMRIB Software Library (FSL), where images were first normalized to MNI space and segmented into WM, GM, and CSF using FSL’s FLIRT, FNIRT, and FAST tools and resulting GM maps were smoothed with a Gaussian kernel (sigma = 3.5mm). General linear models and non‐parametric testing (FSL randomise) were used to assess voxelwise associations between nEV pY‐IRS‐1 concentration and GM volume, while controlling for sex and age effects. Significant associations between GM volume and nEV pY‐IRS‐1 were defined as p < 0.01, uncorrected.

Result

We observed lateralized positive associations between nEV pY‐IRS‐1 and GM volume in the right frontal lobe (Figures 1 and 2). After correcting for multiple comparisons, we observed no significant relationships between nEV pY‐IRS‐1 concentration and GM volume.

Conclusion

Previous studies indicate that lower nEV pY‐IRS‐1 is associated with lower GM volume in regions such as the temporal and parietal lobes. Here, we determined that lower nEV pIRS‐1 concentrations were associated with lower GM volume laterally in the right frontal lobe of healthy middle‐aged and older adults. Future studies are needed to determine the mechanism by which disrupted insulin signaling in the brain may cause GM loss in these regions.
Meta‐analysis of age‐related cognitive decline reveals a novel locus for the attention domain and implicates a COVID‐19 related gene for global cognitive function
Authors: Acharya Vibha , Fan Kang‐Hsien , Snitz Beth E , Ganguli Mary , DeKosky Steve , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas
Published: December 2022

Background

Cognition is a highly complex polygenic trait. A limited number of studies have explored the genetic basis of cognitive decline in aging populations using cognitive domain specific measures.

Method

To identify genetic markers for cognitive decline, we conducted a genome‐wide association meta‐analysis and gene‐based tests on five different cognitive domains (attention, language, executive function, visuospatial abilities, memory) and global cognition on 3,068 older individuals (≥65 years) of European ancestry derived from three prospective cohorts: Gingko Evaluation Memory Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). All subjects completed a comprehensive neuropsychological battery of tests covering the examined domains. A linear mixed effects model was used to estimate the longitudinal decline in cognitive scores after adjusting for sex, baseline age and education. Global cognitive decline was defined as a decline in average performance in neuropsychological tests across the five domains.

Result

Genome‐wide significant association of APOE*4 was observed with decline in the memory domain (p= 8.93E‐09) and global cognitive function (p= 2.69E‐08).We identified a novel locus for decline in the attention domain on chromosome 9 in an intergenic region between RASEF/FRMD3 (p = 3.17E‐08). Gene‐based analysis identified TMPRSS11D as the top gene for decline in global cognition (Bonferroni corrected p= 2.48E‐06). TMPRSS11D plays a role in host‐defense system and recent studies have shown that it activates spike protein of SARS‐CoV‐2 and facilitates viral entry to cell (Viruses 2021;13:384; J Biol Chem 2021; 296:100135).

Conclusion

We have identified a novel locus for longitudinal decline in the attention domain, replicated the association of APOE*4 with the global and memory domains, and potentially implicated the role of TMPRS11D in cognitive decline through gene‐based analysis. The association of TMPRSS11D with cognitive decline might help to explain cognitive impairment observed in some patients after COVID‐19 infection (Br J Anaesth 2021; 25:e54; JAMA Netw Open 2021; 4(10):e2130645 ). While functional studies might help to understand the underlying molecular mechanism of the associated loci, cognitive decline studies with larger samples are essential to establish these findings.
Biological characterization of the therapeutic role of Rab10 modulation in the development of Alzheimer’s disease
Authors: Murcia Josue D Gonzalez , Mollard Alexis , Bearss David
Published: December 2022

Background

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. The continuous genetic research done on this disease demonstrates the vast complexity of the genetic architecture. The most recent whole‐genome sequence analysis (GWAS)included 1.1 million individuals and identified 38 loci associated with AD status with seven novel loci. However, there is no reliable therapeutics to combat the late stages of AD as of late. The identified rare variants in the RAB10 gene show protective effects against developing AD. This work demonstrates that inhibition of the expression of RAB10 yields better outcomes in terms of the amyloid‐beta ratio and cognition. In addition, we demonstrated that RAB10 modulates the NLRC4 inflammasome complex and their derived products IL‐1‐beta, IL‐18, and TNF‐alpha.

Method

In‐vitro experiments were carried out using human neuroblastoma (N2A) cell lines transfected with a mammalian plasmid to overexpress the APP gene and the immortalized microglia HMC3 cell line. We used the compound reference MLi2 and house compounds HT4253 and HT4403 to inhibit the expression of the RAB10. We used ELISA protocols to test the amyloid‐beta 40 and 42 ratios, IL‐1‐beta, IL‐18, and TNF‐alpha secretion. Western blots immunocytochemistry allowed us to determine the phosphorylation of RAB10 and LRRK2, LAMP1, and ASC. In‐vivo behavioral experiments were done using APP/PS1 mice. Hippocampus tissue was collected to run RNA sequence and total proteomics analysis.

Result

A higher dosage of compound HT4253 and HT4403 inhibits phosphorylation of RAB10 with an IC50 of 82 nM and 63 nM, respectably. The inhibition of RAB10 and LRRK2 activates a higher expression of the LAMP1 protein. The incubation with a high compound dosage improved the secretion of the amyloid‐beta 42/40 ratio. The additional experiments and results will be presented at the conference.

Conclusion

This work provides insights into the protective role of RAB10 against AD and neuroinflammation. RAB10 could be a promising therapeutic target for AD prevention.
Efficacy evaluation of a novel vectorized anti‐tau antibody, targeting a C‐terminal phospho‐tau epitope, using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies.
Authors: Liu Wencheng , Paranjpe Maneesha , Holth Jerrah , Clarke Blaise , Thompson Jeffery , Clement Joe , Knoll Elisabeth , Chung Charlotte , Adeluyi Adewale , Powers Alex , Kurella Vinodh , Kavanagh Dillon , Ezell Brian , Fiore Timothy , Grant Kyle , Hou Jay , Bales Kelly R. , Paul Steven M. , Carter Todd
Published: December 2022

Background

Anti‐tau immunotherapy has become a promising therapy for Alzheimer’s disease (AD) and tauopathies. With the hypothesis that tau pathology spreads via cell‐to‐cell transmission, including trans‐synaptic propagation, success of anti‐tau immunotherapy relies, in part, on the identification of efficacious antibodies and their delivery to affected or vulnerable brain regions with sufficient or enhanced exposure in the CNS. We have previously demonstrated broad distribution and expression of vectorized anti‐tau antibodies in the mouse brain using a blood brain barrier penetrant capsid, VOY101, administered intravenously (IV).

Method

Several novel anti‐tau antibodies that met the target profile have been generated and are being evaluated in vivo (Liu et al, submitted as a separated abstract in AAIC 2022).

Result

One of the antibodies discovered, antibody 1, exhibits strong affinity for PHF‐tau, demonstrates specific binding to tau pathology on brain sections of AD and PSP patients, and potently prevents PHF seeding and propagation in vitro and in vivo. This antibody recognizes a phospho‐specific epitope in the C‐terminal region of tau and shows significant reduction of tau pathology in an AD‐PHF induced P301S hippocampal seeding and propagation model. Furthermore, we have vectorized antibody 1 into an AAV expression vector with by BBB penetrant capsid and are evaluating it in two independent mouse models of tauopathy.

Conclusion

This gene therapy‐based approach has potential advantages over traditional passive immunization, including 1) continuous expression of antibody in the central nervous system (CNS) after a single gene therapy administration compared to repetitive administrations of high dose of antibody by passive immunotherapy; 2) increased CNS exposure of tau antibody relative to passive immunotherapy; and 3) the potential to target intracellular tau aggregates which are less effectively accessed by passively delivered antibody. These results add to accumulating evidence that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.