bluuebunny/crossref_metadata_2025 huggingface dataset:
Differences in sex distribution between genetic and sporadic FTD
Authors: de Boer Sterre C.M. , Van Der Lee Sven J , Diehl‐Schmid Janine , Riedl Lina , Piguet Olivier , Halliday Glenda M , Galimberti Daniela , Sorrentino Federica , Ducharme Simon , Fieldhouse Jay L.P. , Reus Lianne M. , Pijnenburg Yolande A.L.
Published: December 2021

Background

The reported sex distribution differs between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that have resulted in variable findings. Our aim was to determine the sex distribution in a large international retrospective cohort of sporadic and genetic FTD.

Method

We included patients with probable and definite behavioural variant frontotemporal dementia (bvFTD), non‐fluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA) and right temporal variant frontotemporal dementia (rtvFTD) from the Amsterdam Dementia Cohort, the Montreal Neurological Institute Cohort, the University of Ulm and Technical University of Munich Cohort (part of the German Consortium of Frontotemporal Lobal Degeneration), the Policlinico Milan Cohort and the Sydney FRONTIER Cohort. We compared sex distribution between genetic and sporadic FTD using χ2 tests.

Result

A total of 910 subjects were included (56.3% male), of whom 654 had bvFTD, 99 nfvPPA, 117 svPPA and 40 rtvFTD. Of these, 215 had genetic FTD and the sex distribution was equal (51.2% male), which did not differ significantly from sporadic FTD (57.8% male, χ2 p=0.081). In the sporadic bvFTD subgroup, we found a male predominance (61.6% males compared to 52.9% males in the bvFTD genetic group, χ 2 p=0.04). No sex distribution differences between sporadic and genetic cases were found in the other clinical FTD subgroups (all p>0.05).

Conclusion

Differences in sex distribution between genetic and sporadic behavioural variant of FTD may provide important clues for its differential pathogenesis and warrants further research.
Racial differences in AD CSF biomarkers in persons with MCI: Implications and insights
Authors: Garrett Stephanie L. , McDaniel Darius , Obideen Malik , Trammell Antoine R. , Shaw Leslie M. , Goldstein Felicia C. , Hajjar Ihab
Published: December 2021

Background

The implications for potential racial differences in tau CSF biomarkers for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are unclear for standard cutoffs used for determining enrollment criteria into novel clinical trials, and insight into interaction with markers of non‐biological determinants.

Method

Setting & Participants‐ Data presented were obtained from baseline assessment of a case control study conducted from March 1, 2016 through January 31, 2019. Participants were 50 years or older adult volunteers recruited from Atlanta, Georgia into the Brain Stress Hypertension and Aging Research Program (B‐SHARP, PI: Hajjar R01AG051633) at the Emory Goizueta Alzheimer’s Disease Research Center. Exposures‐ Self‐reported race and cognitive status per modified Petersen criteria. Outcome measures‐ CSF levels of Aβ1‐42, tau, P‐tau181, ratio of tau or P‐tau181 to Aβ1‐42, and hippocampal volume.

Result

362 study participants were analyzed (mean [SD] age, 65.6 [7.9] years of age), where 152 (42.0%) were African American, 230 (63.5%) were women, and 189 (52.2%) had MCI. After adjusting for multiple determinants, including age, sex, cognitive performance, body mass index (BMI), education, and family history of AD, results suggest Black Americans compared to white individuals with MCI had lower mean (SE) levels of CSF tau (52.4 [5.9] vs. 78.98 [5.02] pg/mL; P=.001) and P‐tau181 (15.42 [2.06] vs. 25.24 [1.75] pg/mL; P=.001). After adjusting for intracranial volume and other covariates in the total sample hippocampal volumes did not differ by race. However, using ROC analyses, AUC comparisons suggest that Aβ1‐42 (0.632 vs 0.779; P=.02) and P‐tau181 (0.638 vs 0.768;P=.03) had lower specificity and sensitivity in Black Americans to distinguish between MCI and normal cognition.

Conclusion

We recommend caution in using current biomarker cutoffs to determine enrollment criteria for potential Black American study cohorts. While we hypothesized that these differences could be explained by increased vascular contributors, our supposition was not supported; after adjusting for hypertension and diabetes, racial differences yet remained. Further investigation should clarify the impact of biological factors like vascular disease, interaction with more explicit and well‐defined environmental determinants like education quality and quantity, and their life‐course occurrence.
Early detection of mild cognitive impairment with convolutional neural network based on brain structural connectivity
Authors: Chen Qianyun , Yan Taiyu , Abrigo Jill , Chu Winnie C.W.
Published: December 2021

Background

Structural connectivity derived from diffusion tensor imaging (DTI) reflects white matter network changes during Alzheimer’s Disease (AD) progression, which can potentially serve as a biomarker for prediction. In this study we explored the ability of structural connectivity to predict mild cognitive impairment (MCI) by implementing a convolutional neural network (CNN).

Method

613 DTI scans (194 controls, 291 MCI and 128 AD) from 206 patients (113 male, 93 female; age range: 55‐91 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) Phase GO and 2 were included in this study. The clinical diagnosis at last ADNI follow‐up visit served as reference for prediction (average: 44.4 ± 26.7 months). DTI scans were acquired with 5 b0 and 41 diffusion weighted volumes with b=1000 s/mm2 at 2.7×2.7×2.7mm3 resolution. Preprocessing included eddy current correction and co‐registration to normalized T1‐weighted scans.

Whole brain white matter fiber was tracked by deterministic tractography using DSI Studio under Q‐space diffeomorphic reconstruction scheme, which calculates the quantitative anisotropy mapping prior to normalization to standard space. An Automated Anatomical Labeling atlas 2 with 120 region‐of‐interests (ROI) was used to parcellate the brain, where each ROI represented a node of the network. The weight of the edge was calculated by number of tracts connecting two ROIs and normalized by medial length. Therefore a 120×120 structural connectivity matrix was generated for each scan. 80% of data was used for training and 10% of data for validation. The parameters that achieved highest accuracy on validation set was applied to the remaining 10% (hold‐out test set) for final evaluation. A seven‐layer CNN model was constructed for differentiating three groups. The performance was evaluated by accuracy and sensitivity.

Result

On an average of 3.7 years before the diagnosis, the prediction accuracy was 86.9% in validation set and 85.7% in hold‐out test set. The sensitivity to predict controls and MCI were 95.0% and 93.3%, respectively.

Conclusion

Using CNN, structural connectivity allowed good ability to predict MCI from cohorts at an early stage before diagnosis.
Brain atrophy and white matter hyperintensities are independently associated with plasma neurofilament light chain in an Asian cohort of patients with mixed pathology
Authors: Chong Joyce R. , Ashton Nicholas J. , Karikari Thomas K. , Hilal Saima , Saridin Francis , Tanaka Tomotaka , Schöll Michael , Blennow Kaj , Zetterberg Henrik , Lai Mitchell Kim Peng , Chen Christopher
Published: December 2021

Background

Recent studies on subjects with “pure” Alzheimer’s disease (AD) reported significant association between high blood neurofilament light chain (NfL) and AD‐related atrophy and poor cognition, but not with white matter hyperintensities (WMHs). In contrast, studies on non‐demented elderly with cerebral small vessel disease (CSVD) revealed a significant association between blood NfL and magnetic resonance imaging (MRI) markers of SVD including WMHs, lacunes and microbleeds. A major limitation of these studies is the lack of participants with mixed pathology to explore the potential independent and/or combined effects of brain atrophy, CSVD and amyloid burden (Aβ) on blood NfL.

Method

This study included 208 Singaporean participants of an ongoing longitudinal study, including non‐cognitively impaired controls (NCI; n=43), cognitively impaired no dementia (CIND; n=99), AD (n=44) and Vascular dementia (VaD; n=22). The presence of brain atrophy was defined by medial temporal atrophy scores ≥2. CSVD were determined by MRI markers. Brain Aβ was assessed by [11C]‐PiB PET SUVR. Plasma NfL (pNfL) was measured by Single molecule array (Simoa) immunoassay.

Result

pNfL concentrations were significantly increased in AD and VaD. In the full cohort, stepwise regression including neuroimaging markers (brain atrophy, WMH, cerebral microbleeds, lacunes and brain Aβ), vascular risk factors (hypertension, hyperlipidemia, diabetes, smoking and APOE ε4 carriership) and demographics (age, gender, education) as independent variables showed that brain atrophy, WMH, age, gender and presence of diabetes to be independently associated with pNfL (all p<0.05). Further univariate general linear models (Fig 1) showed that in the presence of brain atrophy (N+WMH‐) or high WMH (N‐WMH+) alone, pNfL was significantly increased after controlling for age, gender and presence of diabetes (p≤0.007). There was a trend of further increase in pNfL in the presence of both brain atrophy and high WMH burden.

Conclusion

The independent associations and potential combined effects of brain atrophy and WMH on pNfL, together with the high prevalence of SVD burden in the elderly, suggests that SVD needs to be considered when interpreting elevated pNfL in elderly patients.
Dissemination of person‐centered community care for mild dementia using local cooperatives in Korea during the COVID‐19 pandemic
Authors: Park Myonghwa , Go Younghye
Published: December 2021

Background

To promote aging in place and improve the quality of life for persons with mild dementia during COVID‐19 pandemic, there is a need to support them in their community in‐person approach. Therefore, person‐centered community care for individual service and support in the community is an urgent priority. This study aimed to develop a person‐centered community service for mild dementia patient to collaborate with local cooperatives and test its feasibility.

Methods

This study was done from March to December, 2020. The person centered community service manual was developed based on previous guidelines and studies. The manual guided person‐centered assessment, tailored intervention, and outcome evaluation based on six domains; person‐hood, daily life, cognitive health, physical activity, safety, and community support. The local cooperatives for community care participated to provide comprehensive needs assessment and individualized service to the community residents with mild dementia. The staff visited the patient’s home and provide individual service. The feasibility study was tested with the staff and patients.

Results

This study found that the service was effective for initial rapport, comprehensive assessment, individualized planning, person‐centered service provision, referral to community service, and outcome evaluation. However, service provider’s increased workloads and the time for home visiting and completing the service were identified as barriers during pandemic period. In addition, service providers still experienced lack of knowledge and skills in enhancing safety such as precaution and social distancing.

Conclusion

The person‐centered community service can be useful to enhance the safe and sustainable community services during COVID‐19 pandemics. Collaboration with local cooperatives can be the best practices through the well‐designed manual.
Correlates of subjective cognitive decline (SCD) in a Canadian sample of midlife and older adults
Authors: Hopper Shawna , Hammond Nicole G , Stinchcombe Arne
Published: December 2021

Background

Subjective cognitive decline (SCD), a self‐perceived decline in memory among otherwise cognitively healthy older adults, has been linked to increased risk of Alzheimer’s disease (AD). It is believed that SCD may be a first symptomatic expression of preclinical AD. Identification of SCD precursors may allow for early identification and implementation of intervention to prevent cognitive decline.

Method

Using data from the Canadian Longitudinal Study on Aging (CLSA), a national study of over 50,000 participants ages 45‐85 at baseline, we sought to identify potential risk and protective factors for SCD. Participants with diagnosed AD at baseline were excluded. Exposures were measured at baseline and SCD was measured three years later, at first follow‐up, with the question: “Do you feel like your memory is becoming worse?”. A multivariable logistic regression model was used to estimate odds of SCD (analytic sample: n=36,885).

Result

Results indicated that 56.1% participants reported SCD. Participants with a post‐secondary education had increased odds of SCD compared to those with less than a secondary school graduation (OR=1.20, 95% CI: 1.09, 1.33). Hearing problems (OR=1.46, 95% CI: 1.36, 1.56) and vision problems (OR=1.14, 95% CI: 1.05, 1.24) were associated with increased odds of SCD. Alcohol consumption also increased the odds of SCD, with infrequent drinkers (OR=1.08, 95% CI: 1.00, 1.16), regular drinkers (OR=1.13, 95% CI: 1.05, 1.22) and frequent drinkers (OR=1.16, 95% CI: 1.07, 1.25) more likely to self‐report SCD than never drinkers. Participants who consumed five or more servings of fruits/ vegetables had reduced odds of SCD (OR=0.95, 95% CI: 0.91, 0.99), when compared to those who consumed <5 servings. Compared to participants who never smoked, former smokers had increased odds of SCD (OR=1.13, 95% CI: 1.08, 1.12), whereas current smokers had reduced odds of SCD (OR=0.91, 95% CI: 0.84, 0.98). Lastly, individuals with diagnosed mood and anxiety disorders had higher odds of SCD compared to those without (OR=1.42, 95% CI: 1.34, 1.50).

Conclusion

This study sheds light on prospective correlates of SCD in a large population‐based sample of older Canadians. Many of the factors associated with SCD may be modifiable therefore amenable to early intervention.
Neurodegenerative diseases and lifetime seizure risk: A study of autopsy proven cases
Authors: Vöglein Jonathan , Kostova Irena , Arzberger Thomas , Noachtar Soheyl , Dieterich Marianne , Herms Jochen , Schmitz Peer , Ruf Viktoria , Windl Otto , Roeber Sigrun , Simons Mikael , Höglinger Günter , Danek Adrian , Giese Armin , Levin Johannes
Published: December 2021

Background

In the neurodegenerative conditions Alzheimer disease (AD), Lewy body disease (LBD) including the neuropathologically indistinguishable Parkinson disease and dementia with Lewy bodies, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) figures for seizure risk are inconsistent, rare or lacking. This is particular true if neuropathologically confirmed diagnoses are stipulated. Therefore, our goal was to determine the lifetime risk for epileptic seizures and to investigate associated clinical parameters in neuropathologically diagnosed neurodegenerative diseases.

Method

Cases from the Neurobiobank Munich, Germany, were matched with information from clinical files regarding the occurrence of epileptic seizures. The aforementioned diseases were compared for lifetime seizure risk. The predictive value of the first clinical symptom regarding lifetime risk for seizures was analyzed and associations between the occurrence of seizures and survival was investigated.

Result

We analyzed 454 neuropathologically diagnosed cases with sufficient clinical data available. 144 had AD, 103 LBD, 93 PSP, 53 FTLD, 36 MSA, and 25 CBD. Lifetime risk for epileptic seizures was 31.3% in AD, 20.0% in CBD, 12.6% in LBD, 11.3% in FTLD, 8.3% in MSA and 7.5% in PSP. Patients with AD had a statistically significantly higher lifetime risk for seizures compared to patients with FTLD (p=0.005), LBD (p=0.001), MSA (p=0.005) and PSP (p<0.001). An increased lifetime seizure risk was found in patients with cognitive first symptoms when compared to those with non‐cognitive first symptoms (21.1% vs. 11.0%). A decreases lifetime risk for seizures was observed in cases with motor first symptoms when compared to those with non‐motor first symptoms (10.3% vs. 20.5%). MSA patients with seizures survived longer when compared to those without (12.3 vs. 7.0 years; p = 0.017).

Conclusion

In this clinical neuropathological correlation study, nearly every third AD patient and approximately every fifth patient with a neurodegenerative disease experienced epileptic seizures in the disease course. Therefore, epileptic seizures are an important comorbidity in neurodegenerative conditions, in particular in AD. Assessment of the first clinical symptom may improve early estimation of the lifetime seizure risk in the studied neurodegenerative diseases.
The circadian rest‐activity patterns in mild‐moderate Alzheimer’s disease patients
Authors: Targa Adriano , Benitez Ivan David , Dakterzada Faride , Araujo John Fontenele , Minguez Olga , Huerto Raquel , Tahan Nuria , Barbe Ferran , Piñol‐Ripoll Gerard
Published: December 2021

Background

Alterations in the circadian rhythms are present in the presymptomatic phase of Alzheimer’s disease (AD), possibly contributing to its pathogenesis. However, it is unknown whether such alterations could be associated with worse outcomes once the individuals are diagnosed with the disease. We aimed to evaluate the association between the rest‐activity rhythm and AD‐related outcomes in patients with mild‐moderate AD.

Method

The cohort included 100 individuals with mild‐moderate AD. The rest‐activity rhythm was assessed through the use of actigraphy for 14 days. Cerebrospinal fluid was obtained to determine the levels of distinct pathological markers of the disease and neuropsychological evaluation was carried out at the beginning of the study and after 12 months of follow‐up.

Result

We observed that older age was associated with increased fragmentation of the rest‐activity rhythm (per 1 SD increase, change [SD] of 0.311 [0.096]; p = 0.002) whist female sex was related to higher synchronization between the endogenous rhythm and the zeitgebers (per 1 SD increase, change [SD] of 0.780 [0.193]; p < 0.001). The rest‐activity rhythm was also associated with disease‐related outcomes. Accordingly, there was an association between higher NF‐L levels an increased relative amplitude (per 1 SD increase, change [95% CI] of 240.480 [59.176 to 421.784]; p = 0.010). In addition, increased fragmentation of the rhythm at the baseline was associated with enhanced cognitive decline after one year of follow‐up independently of age, sex, ApoE4 status, educational level, and pharmacological treatment (per 1 SD increase, change [95% CI] of ‐0.576 [‐1.148 to ‐0.005]; p = 0.048).

Conclusion

Our results suggest a potential role for the rest‐activity rhythm in predicting both molecular and clinical outcomes in patients with mild‐moderate AD. Further studies are warranted to confirm these findings and to elucidate whether there is causality among the observed associations. In case of a positive response, the circadian rest‐activity rhythm could be a promising target to prevent the cognitive decline.
HIV‐associated neurocognitive disorder: An investigation using structural neuroimaging in a c‐ART treated Tanzanian cohort
Authors: McDonald Lucy , Koipapi Sengua , Howlett William , Dekker Marieke , Urasa Sarah , Kalaria Rajesh , Walker Richard , Firbank Michael J , Paddick Stella‐Maria
Published: December 2021

Background

There is a newly emergent ageing population of people living with HIV (PLWH) in Africa. However, there is little research into HIV‐associated neurocognitive disorder (HAND) in this population. Existing research suggests HAND is prevalent however the aetiology remains unclear. This study aims to determine whether HAND is truly prevalent and explore potential causes in PLWH on c‐ART using objective structural measures.

Method

A systematic sample of PLWH aged ≥ 50 receiving combination antiretroviral treatment (cART) according to local guidelines were recruited from a HIV clinic in Kilimanjaro, Tanzania. Demographic data and comorbidities were self‐reported. HIV‐disease management data were obtained from detailed clinic data sheets. HIV viral load and CD4 count were measured. A detailed low‐literacy neurocognitive battery, informant history for functional impairment and neurological examination were conducted and HAND diagnosis made by consensus panel using AAN criteria. Cerebral atrophy (brain and ventricle volume) and WMH were measured using quantitative analysis of 1.5T MRI.

Result

This cohort (n=91, 100% on cART, 64.8% female) had well‐managed HIV (75.9% suppressed viral load, median CD4 507 cells/ul). However, 66.7% had gross atrophy on their MRI scan, and HAND had a prevalence of 63.7%. The significant independent predictor (IP) of decreased brain volume was older age at HIV diagnosis (p=.001), and of increased ventricle volume was increased age (p<.0001), male gender (p<.0001) and increased frailty (p<.0001). The significant IPs of increased WMH volume were increased age (p<.0001) and smoking (p=.021). Only memory impairment independently predicted all structural measures.

Conclusion

This is the first MRI study of older c‐ART treated PLWH in Africa. Despite c‐ART and good disease management, HAND was objectively prevalent and unrelated to measures of HIV disease severity. Cerebral atrophy and WMH were associated with factors of neurodegeneration. Cerebral atrophy was associated with male gender and older age at diagnosis. Association with older age at diagnosis may be 'legacy effect' of early CNS effect of the HIV virus rather than current management.
Distinctive effect of biological sex in AD‐related CSF and plasma biomarkers
Authors: Milà‐Alomà Marta , Brinkmalm Ann , Rodriguez Juan Lantero , Karikari Thomas K. , Ashton Nicholas J. , Kvartsberg Hlin , Grau‐Rivera Oriol , Sala‐Vila Aleix , Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M. , Brugulat‐Serrat Anna , Akinci Muge , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Suridjan Ivonne , Kollmorgen Gwendlyn , Stoops Erik , Vanmechelen Eugeen , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose , Suarez‐Calvet Marc ,   for the ALFA study
Published: December 2021

Background

Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women. Although previous studies reported sex differences in fluid biomarkers, there is a need for a comprehensive analysis across the disease continuum. The aim of this study was to compare AD‐related biomarkers in cerebrospinal fluid (CSF) and plasma between women and men in middle‐aged cognitively‐unimpaired individuals at risk for AD.

Method

We measured Aβ42, Aβ40, Mid (M)‐p‐tau 181, N‐terminal (N)‐p‐tau 181, N‐p‐tau 217, M‐p‐tau 231, t‐tau, NfL, neurogranin, SNAP25, GAP43, synaptotagmin1, sTREM2, YKL40, GFAp, S100B, IL6, sVCAM1, sICAM1, MCP1 and α‐synuclein in CSF; and N‐p‐tau181, NfL, GFAp, MCP1, sICAM1 and sVCAM1 in plasma. Biomarker measurements were performed using immunoassays (colorimetric, MSD, Elecsys®, Simoa and the exploratory Roche NeuroToolKit robust prototype assays) and mass spectrometry. We tested sex differences in demographic variables (using t‐test or Chi‐squared) and in cardiovascular factors (using ANCOVA adjusted for age and APOE‐ε4 status). Sex differences in biomarkers were assessed with 3 different ANCOVA models, adjusted for (i) age, (ii) age and CSF Aβ42/40 and (iii) age and cardiovascular factors that showed sexual divergence.

Result

We studied 384 participants of the ALFA+ cohort. Men had higher education, APOE‐ε4 prevalence, physical activity, diastolic blood pressure, BMI, glucose and triglycerides than women. In contrast, women had higher vitamin B12, LDL, HDL and total cholesterol as compared to men. In CSF (Table 1), men had higher NfL, GFAp, MCP1, sICAM1 and sVCAM1, while women had higher neurogranin, synaptotagmin‐1 and N‐p‐tau 217, after adjusting for age (Model I). These differences remained significant after adjusting for CSF Aβ42/40 (Model II). In plasma (Table 2), we observed an opposite pattern compared to results in CSF: women showed higher NfL, GFAp and sICAM1 after adjusting for age (Model I) and for CSF Aβ42/40 (Model II). Sex differences in CSF NfL, sICAM1, sVCAM1, and plasma sICAM1 remained significant after adjustingg for cardiovascular factors (Model III).

Conclusion

AD‐related fluid biomarkers of neurodegeneration and neuroinflammation/endothelial dysfunction differ between women and men, but these differences have an opposite direction for some biomarkers in CSF and plasma. These results highlight the importance of considering sex differences in AD‐related fluid biomarkers.
Association between telomere length and cognitive function among cognitively unimpaired individuals at risk of Alzheimer’s disease
Authors: Rodríguez‐Fernández Blanca , Vilor‐Tejedor Natalia , Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M , Minguillón Carolina , Fauria Karine , DeVivo Immaculata , Navarro Arcadi , Gispert Juan Domingo , Molinuevo Jose , Sala‐Vila Aleix , Crous‐Bou Marta ,   for the ALFA study
Published: December 2021

Background

Telomere length (TL) is an objective biomarker of biological aging and it has been proposed to play a crucial role in Alzheimer's disease (AD) progression by impairing cognitive resilience. However, published studies show inconsistent results and a very limited number of studies have evaluated the role of TL in aging and midlife individuals. The main objective of this study was to evaluate the association between TL and cognitive performance in middle‐aged cognitively unimpaired individuals at increased risk of AD.

Methods

The study included 1,079 participants from the ALFA (ALzheimer and FAmilies) cohort. Relative TL was determined by qPCR from DNA extracted from peripheral blood leukocytes. TL values were normalized by computing z‐scores. A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing and executive function. Further, episodic memory, executive function and global cognitive composites were calculated by averaging normalized raw scores of all subtests in each domain. Generalized linear models with Poisson/quasi‐binomial distributions and linear regression models were implemented to assess the cross‐sectional association between TL and cognitive subtests as well as TL and cognitive composites, respectively. All models were adjusted by sex and age. Additionally, stratified analyses by APOE‐ɛ4 status were conducted. Statistical significance was set at P≤0.05.

Results

Longer TL at baseline was associated with better performance on executive function subtests related to visual processing, attention/working memory and reasoning only in APOE‐ɛ4 non‐carriers [Table 1]. Similarly, APOE‐ɛ4 non‐carriers showed a significant association between longer TL and better scores on executive function composites [Table 2]. In contrast, no associations between TL and memory‐related tests were observed.

Conclusions

Our results suggest a potential role for telomeres on maintaining cognition in aging, specifically in individuals at low genetic risk of AD. Further longitudinal analyses are warranted to better understand the role of the APOE‐ɛ4 genotype on these associations and their potential impact on cognitive resilience in the context of the AD continuum.
Cerebral amyloid angiopathy and visuospatial functioning: Analysis of the clock drawing test
Authors: MacLean Davis , Zwiers Angela , Cox Emily , Ismail Zahinoor , Camicioli Richard , Smith Eric E.
Published: December 2021

Background

Cerebral amyloid angiopathy (CAA) contributes to cognitive impairment as well as dementia in the elderly. In clinical cohorts, symptomatic CAA is associated with impairments in executive function and processing speed. Because CAA severity tends to be highest in the occipital and posterior temporal and parietal lobes, it may also affect visuospatial function. We hypothesized that participants with a clinical diagnosis of CAA will have impaired performance on tests of visuospatial function when compared to control, mild cognitive impairment (MCI) and Alzheimer’s disease (AD) participants.

Method

Participants with CAA presented with lobar intracerebral hemorrhage, transient focal neurological episodes, or mild cognitive impairment; met Boston criteria for probable CAA; and did not have dementia. Clocks were scored based on a published 20‐point system (Mendez, JAGS 1992). Clock items were subcategorized by general contours, number items, and hand items (Mendez, JAGS 1992); and by a subset of 9 items correlated in prior literature with visuospatial function and temporal‐parietal hypoperfusion (visuospatial items).

Result

Data from 53 CAA without dementia, 43 MCI, 30 AD with mild dementia (MMSE ≥20), and 40 control participants were analyzed (mean age 71.6 [SD 7.5]; 47% women). Compared to controls, CAA participants performed significantly worse on total score, hand items, and visuospatial items (Table 1). AD participants performed worse than controls on all components except general contour, and MCI participants did not differ from controls. Among CAA participants, total and visuospatial scores did not correlate with history of stroke, number of microbleeds, or white matter hyperintensity volume (p>0.10).

Conclusion

Mean performance on the clock drawing test is lower in CAA patients without dementia than controls, suggesting visuospatial impairment. This impairment may be related to vascular amyloid deposition in posterior brain regions; however, it was not correlated with typical markers of CAA severity suggesting it may be an early but not necessarily progressive feature. Future research should investigate the mechanisms of visuospatial impairment in CAA—including whether it is related to posterior white matter damage or parieto‐occipital atrophy—and its association with daily function and risk for cognitive decline.
Endogenous control miRNAs for normalization in plasma samples of Alzheimer’s disease patients from a discovery and validation cohort
Authors: Dakterzada Faride , Targa Adriano , Benitez Ivan David , Torres Gerard , ElKhayat Leila Romero , Moncusi Anna , Huerto Raquel , Barbe Ferran , Piñol‐Ripoll Gerard
Published: December 2021

Background

Several studies had explored the role of miRNAs in Alzheimer’s disease (AD). The identification of endogenous controls (ECs) would contribute to the standardization of these biomarkers in AD but they have not yet been established. The objective of the study was to identify miRNAs that can be used as ECs in AD.

Method

We evaluated 145 patients divided into two different cohorts. One was a discovery cohort of 19 women diagnosed with mild to moderate AD (Mini‐Mental State Examination (MMSE) score ≥ 20) and with confirmed pathologic levels of Aβ42 in CSF. The stability assessment cohort consisted of 126 individuals: 24 control subjects, 25 subjects with MCI and negative for CSF biomarkers, 22 subjects with MCI and positive for CSF biomarkers and 55 subjects with AD and positive for CSF biomarkers.

In the discovery cohort, a profile of 384 miRNAs was determined in plasma by TaqMan Low Density Array. The best EC candidates were identified by mean‐centering and concordance correlation restricted normalization methods. The stability of the EC candidates was assessed using the GeNorm, BestKeeper and NormFinder algorithms.

Result

Nine miRNAs (hsa‐miR‐324‐5p, hsa‐miR‐22‐5p, hsa‐miR‐103a‐2‐5p, hsa‐miR‐362‐5p, hsa‐miR‐425‐3p, hsa‐miR‐423‐5p, hsa‐let‐7i‐3p, hsa‐miR‐532‐5p, and hsa‐miR‐1301‐3p) were identified as EC candidates in the discovery cohort. The validation results indicated that hsa‐miR‐103a‐2‐5p was the best EC, followed by hsa‐miR‐22‐5p, hsa‐miR‐1301‐3p, and hsa‐miR‐425‐3p, which had similar stability values in all three algorithms.

Conclusion

We identified a profile of four miRNAs as potential plasma ECs to be used for normalization of miRNA expression data in studies of subjects with cognitive impairment.
Lifestyle and behavior changes during the COVID19 pandemic in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Lehtisalo Jenni , Ngandu Tiia , Mangialasche Francesca , Hemiö Katri , Solomon Alina , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta L , Tuomilehto Jaakko , Soininen Hilkka , Kivipelto Miia
Published: December 2021

Background

Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a randomized trial that showed beneficial effect on cognition with a 2‐year multidomain lifestyle intervention. During the post‐intervention follow‐up, COVID19 pandemic emerged resulting in lockdown and reduced services. Our aim is to investigate how lifestyle and behavior changes during the pandemic are related to lifestyle earlier in the study.

Method

The FINGER cohort included 1260 individuals aged 60‐77 years at baseline and at risk of dementia, randomized into multidomain intervention or control groups. A postal survey was sent to all eligible participants from the FINGER study in June 2020 (end of the first wave of the pandemic in Finland), on average 10 year after the baseline. 859 (68%) were still alive and eligible for the survey.

Result

Total of 735 responders (85% of the eligible participants) were on average 78 years old. They were younger, had higher baseline cognition, and were more often from the former control group than non‐responders (p<0.05 for all). The intervention allocation showed no association with self‐reported lifestyle changes during the pandemic in diet, exercise, or cognitive activity. Among older participants (>78 y), the intervention group reported more increase in remote contact with friends and relatives (p=0.013) and health care (p=0.042) than the control, and also less pandemic‐related reduction in overall contact with friends (p=0.045). Among all, reductions in physical exercise were reported among those who were less physically active earlier in the study. Both increase and decrease in contact with friends and family were reported by those more cognitively active earlier in the study. They also had more increase in remote contacts. Changes in diet were positive (increase in fruit and vegetable intake), but they were not related to earlier diet.

Conclusion

The FINGER participants reported only minor change in their lifestyle and behavior during the first wave of the COVID pandemic related lockdown. For physical activity, the pandemic appeared to have negative effect particularly among those with lower levels earlier, possibly adding inequalities. Intervention was related to more remote contacts, probably due to better computer literacy after the cognitive training.
Exposure to ambient air pollution and cognitive decline: Results of the prospective Three‐City study
Authors: Duchesne Jeanne , Gutierrez Laure‐Anne , Chen Jie , Vienneau Danielle , de Hoogh Kees , Helmer Catherine , Tzourio Christophe , Jacquemin Benedicte , Berr Claudine , Mortamais Marion
Published: December 2021

Background

Growing epidemiological evidence suggests an adverse relationship between exposure to air pollutants and cognitive decline. However, there is still some heterogeneity in the findings, with inconsistent results depending on the pollutant and cognitive domain considered. We aimed to evaluate if air pollution was associated with global and domain‐specific cognitive decline.

Methods

We used data from the French Three‐City prospective cohort on 6380 participants aged 65 and older at recruitment and followed up for 12 years. Participants did cognitive tests at baseline and every 2 years, to assess global cognition (Mini Mental State Examination, MMSE), visual memory (Benton Visual Retention Test, BVRT), semantic fluency (Isaacs Set Test, IST) and executive functions (Trail Making Tests A and B, TMTA/B). Land‐use regression models were used to estimate fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC) exposure at participants’ residential address over the 5‐year preceding the baseline visit. Linear mixed models were performed for each pollutant to evaluate their association with cognitive decline.

Results

Participants median age was 73.4 (IQR 8.0), and 61.5% were women. Baseline median scores were 28 (3) for MMSE, 12 (3) for BVRT, 48.0 (14.0) for IST, 0.5 (0.2) for TMTA, and 0.2 (0.2) for TMTB. We found a significantly worse decline in global cognition among participants with higher PM2.5 exposure: for PM2.5 levels ranging from 19.6 to 30.4 µg/m3, an IQR increment in PM2.5 (1.5) was associated with greater MMSE decline (β: 0.003 [0.0006;0.006] per year). Other associations were inconsistent in direction and of small magnitude. For instance, an IQR increment in PM2.5 was associated with a 0.03 (‐0.002;0.060) change in IST decline and a ‐0.0003 (‐0.0009;0.0003) change in TMTA decline.

Conclusion

We found an adverse association between PM2.5 exposure and decline in global cognition. No significant associations were observed for the other pollutants and cognitive domains.
Estimating attrition in mild‐to‐moderate Alzheimer’s disease and mild cognitive impairment clinical trials
Authors: Ritchie Marina , Gillen Daniel L. , Grill Joshua D.
Published: December 2021

Background

Participant retention directly affects the validity and generalizability of clinical trial results. Investigators need information about expected attrition when planning trials of varying durations.

Method

Using the Alzforum and clinicaltrials.gov databases we reviewed 351 phase 2 and 3 placebo‐controlled trials conducted since 1998. Eighty‐six mild‐to‐moderate Alzheimer’s disease (AD) and eleven Mild Cognitive Impairment (MCI) trials met criteria for inclusion in this study. We first assessed the frequency with which trial arms differed in overall retention. When trials included more than one active arm, we combined those arms into a single group. To model associations between trial duration and retention, we used binomial regression.

Result

Figure 1 illustrates differences in the observed proportion of participants completing in each trial between active and placebo arms for mild‐to‐moderate AD (Figure 1A) and MCI trials (Figure 1B). For each trial, a 95% confidence interval for the true difference between arms is provided. Since there was no consistent difference between arms, subsequent analyses combined active and placebo arms. Figure 2 illustrates the completion rate by trial duration for mild‐to‐moderate AD (Figure 2A) and MCI trials (Figure 2B). A local smoother along with uncertainty regions is added for visual aid. In general, trials with longer study duration had lower retention rates. Using binomial regression with robust variance estimates to account for within‐trial correlation, we estimated that a 6‐month increase in trial duration is associated with a 34% decrease in the odds of trial completion (OR=0.66; 95% CI: 0.58, 0.75; p<0.001) among mild‐to‐moderate AD trials and a 20% decrease (OR=0.80; 95% CI: 0.68, 0.93; p=0.004) among MCI trials. From the binomial regression model, the proportion of participants completing 6, 12, and 18‐month trials were estimated to be 82.9%, 76.3%, and 68.0% for mild‐to‐moderate AD trials and 82.6%, 79.1%, and 75.2% for MCI trials, respectively.

Conclusion

While decisions related to expected trial attrition are guided by several factors, these estimates may assist investigators designing trials and suggest that trial attrition is frequent and related to trial duration.
A phase 1b, randomized, double‐blind, placebo‐controlled, parallel cohort safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy study of intravenously infused BIIB092 in patients with four different primary tauopathy syndromes
Authors: Ljubenkov Peter A. , Vandevrede Lawren , Rojas Julio C. , Tsai Richard , Koestler Mary , Graham Danielle , Dam Tien , Boxer Adam L.
Published: December 2021

Background

Aggregation of insoluble tau is a key autopsy finding in several neurodegenerative conditions including corticobasal syndrome (CBS), non‐fluent variant primary progressive aphasia (nfvPPA), frontotemporal lobar degeneration due to microtubule‐associated protein tau (MAPT) mutation, and traumatic encephalopathy syndrome (TES). Monoclonal‐antibody (mAb) therapies may promote clearance of pathogenic tau species, but differing protein isoforms and conformations may limit the affinity of mAbs for tau epitopes in distinct tauopathy syndromes. A “basket trial” allows for efficient investigation of drug target engagement in distinct diseases sharing common causative molecular alterations. We assessed the safety, tolerability, pharmacokinetic profile, and pharmacodynamic effects of BIIB092 (gosuranemab), a mAb targeting an N‐terminal tau epitope, in a basket trial enrolling participants with 4 different tauopathy syndromes: CBS, nfvPPA, symptomatic MAPT mutations, and TES. We also explored BIIB092’s effects on CSF, MRI and clinical measures of disease severity.

Method

N=25 participants were randomized approximately 3:1 to monthly intravenous infusions of 2000 mg BIIB092 (8 CBS, 4 nfvPPA, 4 MAPT, 2 TES) or placebo (CBS, 2 nfvPPA, 1 MAPT, 1 TES) for up to 6 months of double‐blind therapy. Subsequently 14 participants received monthly open label infusions for up to 6 months. Plasma, CSF, exploratory clinical measures, and volumetric imaging were collected at baseline, week 12, and week 24 of the double‐blind portion of the trial.

Result

The study was terminated by Biogen in December 2019 (following negative results in a phase 2 in progressive supranuclear palsy), prior to completion of planned enrollment or treatment in recruited participants. Adverse events were more frequent in participants randomized to BIIB092 (83%) compared to placebo (28%), though no adverse events were attributed to study drug. In all patients randomized to BIIB092, we observed 90% reduction in detectable CSF N‐terminal tau epitopes at weeks 12 (mean ‐96.9%, SD 2.0) and 24 (mean ‐97.0%, SD 1.9) of the blinded treatment period. Analyses of other secondary and exploratory endpoints are underway.

Conclusion

Six months of BIIB092 treatment was well tolerated and appears to bind to the N‐terminal epitopes in individuals with four different tauopathy syndromes.
Trajectories of self‐rated concerns in individuals developing cognitive decline
Authors: Gagliardi Geoffroy Pierre , Diez Ibai Palacio , Bueichekú Elisenda , Farrell Michelle E. , Kuppe Madeline K , Marshall Gad A , Amariglio Rebecca E. , Sepulcre Jorge , Sperling Reisa A. , Vannini Patrizia
Published: December 2021

Background

Subjective perception of cognitive decline is identified as an important marker related to the risk of progression to Alzheimer's disease. However, loss of awareness has also been observed in predementia stages, potentially reducing the validity of the subjective experience. The aim of this study was to characterize the trajectories of complaints in cognitively normal (CN) individuals who later developed cognitive decline, as well as investigate differences in demographics, brain pathology and clinical progression between individuals aware and unaware of these changes.

Method

We included participants (CN at baseline) from the Harvard Aging Brain Study. Linear Mixed effect models were used to compute individual longitudinal changes of memory complaints (7 questions questionnaire) and cognition (Preclinical Alzheimer’s Cognitive Composite, PACC5). Participants who demonstrated a statistically significant PACC5 decline over time were divided into two groups: an Unaware (N=36) group defined as individuals with statistically significantly decreasing or displaying low (<2.5/7) complaints, and a Heightened (N=14) group defined as individuals with significantly increasing or displaying high (>2.5/7) complaints (Fig 1). Participants who did not decline in memory were assigned to the Stable group (N=248). Kaplan‐Meier survival analysis was performed to determine the rate of progression from CN to clinically impaired (MCI or dementia diagnosis) across groups.

Result

No group differences were found for gender, education, depressive symptoms or Apolipoprotein E4‐carrier status (Tab 1). Unaware participants were significantly older than the Stable group (p<0.001). The Heightened and Unaware groups demonstrated equivalent amyloid burden, which was significantly greater than the Stable group (p<0.01). The survival analysis revealed significant differences between all groups (p<0.001,Fig 2). Heightened participants had the fastest rate of clinical progression, followed by the Unaware group.

Conclusion

Participants with heightened awareness demonstrated the fastest rate of progression from cognitively normal to MCI or dementia. Importantly, among the individuals with a subsequent cognitive decline, a number of individuals (72%) were unaware of their decline. These individuals had the same demographic profile and amyloid burden as the individuals with heightened awareness. Future research will investigate the mechanisms of self‐awareness and potential dysfunction of systems underlying the loss of awareness, as it can be essential for the preservation of individual autonomy.