bluuebunny/crossref_metadata_2025 huggingface dataset:
A longitudinal analysis of cerebral blood flow changes in genetic frontotemporal Dementia: Results from genfi
Authors: Pasternak Maurice , Mirza Saira S. , Mutsaerts Henk‐Jan , Thomas David L , Cash David M , Bocchetta Martina , de Vita Enrico , Tartaglia Carmela , Mitchell Sara Berman , Black Sandra E. , Freedman Morris , Tang‐Wai David F. , Rogaeva Ekaterina , van Swieten John C. , Laforce Robert , Tagliavini Fabrizio , Borroni Barbara , Galimberti Daniela , Rowe James B , Graff Caroline , Finger Elizabeth , Sorbi Sandro , de Mendonça Alexandre , Butler Christopher , Gerhard Alexander , Sanchez‐Valle Raquel , Moreno Fermin , Synofzik Matthis , Vandenberghe Rik , Ducharme Simon , Levin Johannes , Danek Adrian , Otto Markus , Santana Isabel , MacIntosh Bradley J. , Rohrer Jonathan D. , Masellis Mario
Published: June 2023

Background

Mutations in the C9orf72, GRN, or MAPT genes are the most prevalent genetic causes of familial frontotemporal dementia (FTD). In a cross‐sectional study of genetic FTD, lower CBF was observed in presymptomatic FTD mutation carriers vs. controls from the same families in 6 regions of interest: the bilateral anterior cingulate cortex, the left medial temporal gyrus, the left and right insulae, and the left and right supramarginal gyri (Mutsaerts et. al. 2019). However, there have been no studies to date that identify longitudinal changes in CBF between FTD genetic subgroups (both presymptomatic and symptomatic) compared to controls.

Method

We compared longitudinal changes in CBF, as measured by ASL‐MRI, in 317 FTD mutation carriers (118 C9orf72, 141 GRN, and 58 MAPT) vs. 261 non‐carrier controls from the Genetic FTD Initiative (GENFI). Linear mixed effects models tested the main effect of carrier status, and its interaction with age, along with covariates of age, sex, site‐of‐scan against each subject’s mean regional cerebral blood flow within the regions of interest from Mutsaerts et al. (2019). Family membership was a random intercept in the model to control for similar genetic and environmental backgrounds.

Result

Differences between genetic subsets of FTD were apparent, with GRN carriers preferentially experiencing decreases within the salience network regions while MAPT carriers expressed differences within the left medial temporal gyrus and bilateral anterior cingulate gyrus. C9orf72 carriers only saw a decrease in CBF within the left insula. Significant interactions between carrier status and age were exclusively evident in MAPT carriers across all regions of interest.

Conclusion

Differentiating CBF signatures were found to exist between the genetic FTD subgroups, with the most prominent changes being seen in GRN and MAPT subsets. Evidence continues to mount that CBF may be a viable biomarker in the earlier detection and delineation of genetic FTD variants.

References: Mutsaerts, H. J. M. M. et al. Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study. Brain 142, awz039 (2019).
Changes of basal forebrain volume along the Alzheimer’s disease continuum in Down syndrome
Authors: Aranha Mateus Rozalem , Iulita Maria Florencia , Montal Victor , Pegueroles Jordi , Bejanin Alexandre , Grothe Michel J. , Carmona‐Iragui Maria , Videla Laura , Benejam Bessy , Valldeneu Sílvia , Barroeta Isabel , Altuna Miren , Fernandez Susana , Ribas Laia , Padilla Concepcion , Alcolea Daniel , González‐Ortiz Sofía , Bargallo Núria , Busciglio Jorge A , Cuello A. Claudio , Wisniewski Thomas , Blesa Rafael , Lleó Alberto , Fortea Juan
Published: June 2023

Background

Atrophy of basal forebrain (BF) cholinergic neurons is an early event in Alzheimer’s disease (AD) and is associated with cognitive impairment. Down syndrome (DS) is now recognized as a genetically determined form of AD. Therefore, people with DS represent a priority population to study biomarkers of AD pathology and neurodegeneration. Degeneration of BF neurons occurs both in sporadic AD and in DS brains with advanced AD pathology. However, the dynamics of BF atrophy and its changes with age and AT(N) biomarkers have not been studied in DS.

Method

We included 246 adults with DS (mean age 43.2 ±11.0 years; 43% female). Volumes of antero‐medial and posterior areas of the BF (amBF and pBF, respectively) were extracted from T1‐weighted 3T MR images using voxel‐based morphometry in SPM12 in combination with a stereotactic atlas of BF functional subdivisions (Figure 1). Differences in amBF and pBF volume in each AD clinical stage (Asymptomatic, Prodromal and Demented) were assessed with Kruskall‐Wallis and pairwise Wilcoxon tests. The relationship of BF volumes with age and AT(N) biomarkers in the cerebrospinal fluid (CSF) (amyloid‐β 42/40 ratio [aβ ratio], phosphorylated Tau 181 [pTau], total Tau [tTau] and neurofilament light [NFL]) was assessed in a subset of subjects (n = 161 [aβ ratio, pTau and tTau] and n = 95 [NFL]) with locally estimated scatterplot smoothing (LOESS) and linear regression in R, respectively.

Result

Volumes of amBF and pBF decreased significantly with age (Figure 2), with a steeper decline during the fifth decade of life. BF volumes also declined with AD clinical stage (Figure 3), and had significant correlations with CSF aβ ratio (p<0.001 r2 = 0.22), pTau (p<0.001 r2 = 0.20), tTau (p<0.001 r2 = 0.20) and NFL (p<0.001 r2 = 0.33) (Figure 4).

Conclusion

In DS, BF volume decreases with age, AT(N) biomarkers and along the cognitive stages of the AD continuum.
Interference of different anesthetic agents on behavior and oxidative stress in the animal model of Aβ1‐42‐induced dementia in mice.
Authors: Garcez Michelle Lima , Macarini Bárbara Machado Naspolini , Medeiros Eduarda Behenck , Vargas Adrielly , Colombo Ana Carolina Nunes , Boaventura Amanda L , Zabot Gabriel Casagrande , Keller Gabriela Serafim , Rempel Lisienny Campoli Tono , Silveira Paulo Cesar Lock , Budni Josiane
Published: June 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. The animal model of AD‐like dementia induced by the peptide β‐amyloid 1‐42 (Aβ1‐42) is widely used. However, the animals have to be anesthetized and no studies are evaluating which anesthetic causes less interference in this model. This study aimed to evaluate the interference of different anesthetics on behavioral and oxidative stress in a mice model of Aβ1‐42‐induced dementia.

Method

Male and female BALB/c mice at 3‐ month‐old were used under three different protocols. Protocol 1 (inhalation): (1) 100% oxygen (isoflurane control); (2) artificial cerebrospinal fluid (ACSF) + isoflurane; (3) Aβ1‐42 + isoflurane. Protocol 2 (intraperitoneal): (1) saline; (2) ACSF + ketamine + xylazine; (3) ACSF + ketamine + dexmedetomidine; (4) Aβ1‐42 + ketamine + xylazine; (5) Aβ1‐42 + ketamine + dexmedetomidine. Protocol 3 (intraperitoneal): (1) saline; (2) ACSF + propofol; (3) Aβ1‐42 + propofol. After the anesthesia, mice were injected with Aβ1‐42 (400 pmol) free‐hand intracerebroventricular, then after 13 days, mice were submitted to the Y‐maze test (spatial memory), plus‐maze (anxiety), and open‐field (habituation memory); then, hippocampus were dissected to analysis.

Result

Isoflurane per se (protocol 1) caused no memory impairment, but caused an anxiolytic effect in males, in addition, to increased sulfhydryl content in males. In protocol 2, ACSF + ketamine + xylazine induced spatial memory impairment in males and habituation memory impairment in females; the anesthetics of protocol 2 increased 2',7' dichlorodihydrofluorescein (DCF) levels in females, and ACSF + ket + dex reduced levels of glutathione (GSH) in males. In protocol 3, propofol per se caused an anxiolytic effect in males and increased DCF levels in males and females, increased superoxide dismutase activity in males, and reduction in females, in addition, increased sulfhydryl content in males.

Conclusion

All anesthetic protocols evaluated caused alterations in the behavior and/or oxidative stress parameters; however, isoflurane seems to cause less interference in the animal model, followed by propofol. Protocol 3 seems to cause more interference, including in the Y‐maze (spatial memory), which is one of the main behavior tests to evaluate the mice model of Aβ1‐42‐induced dementia.
Impact of serum leptin and adiponectin levels on the development of brain infarcts in patients with mild cognitive impairment and Alzheimer’s disease
Authors: Carbone Giovanni , Palaia Maria Emiliana , Ercolano Erica , Santoro Maria Angela , Scognamiglio Francesco , Bencivenga Leonardo , Vitale Dino Franco , Rengo Giuseppe , Femminella Grazia Daniela
Published: June 2023

Background

The adipokines leptin and adiponectin have been associated with the development of atherosclerosis and the risk of cerebral infarctions. According to pre‐clinical studies, however, they play a protective role against ischemic brain damage. In this study we analysed the relationship between serum leptin and adiponectin levels and the onset or progression of silent brain infarctions in a population of subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).

Method

All data were extracted from the ADNI database. All patients with available serum leptin and adiponectin levels at baseline were selected. Demographic and anamnestic data, neuropsychological test results, tau, phosphotau and amyloid levels in CSF and regional brain metabolism with FDG‐PET data were also extracted. The determination of the number of silent cerebral infarctions was performed on baseline brain MRI. The final population includes 566 subjects, with 58 normal controls, 396 MCI and 112 AD.

Result

Leptin levels were significantly lower in patients with MCI than controls at baseline, while adiponectin levels were not different between the three groups. Multivariate regression analysis in patients with cognitive impairment (MCI + AD, 508 subjects) showed that leptin levels were significantly associated with BMI, arterial hypertension and female sex. By stratifying the three diagnostic groups by the presence or absence of baseline infarctions, leptin levels were significantly higher in patients with AD and brain infarcts than in patients with AD without brain infarcts. However, multivariate logistic regression analysis at baseline for the presence or absence of brain infarcts did not confirm the predictive value of leptin. Multivariate longitudinal analysis did not attribute predictive value to serum leptin levels on the development of silent brain infarcts in this MCI and AD population.

Conclusion

The evidence on the pathogenetic or protective role of adipokines on ischemic brain damage in the literature is mixed. In this population affected by MCI and AD, serum leptin and adiponectin levels are not associated with the development of brain infarctions; therefore, these results do not support the use of adipokines as biomarkers of cerebrovascular pathology in this population.
Risk prediction of Alzheimer’s dementia in mild cognitive impairment – Impact of AD biomarker disclosure on quality of life, mental health and risk knowledge: The PreDADQoL study
Authors: Rostamzadeh Ayda , Schwegler Carolin , Rosende‐Roca Maitee , Moreno Mariola , Canabate Pilar , Ortega Gemma , Schmitz‐Luhn Björn , Boada Mercè , Woopen Christiane , Jessen Frank
Published: June 2023

Background

Expanded technologies in early AD detection have led to an increasing number of individuals with mild cognitive impairment (MCI) asking for biomarker‐based risk prediction of Alzheimer’s dementia. However, standardized approaches for counseling and disclosure of individuals with MCI are lacking in clinical practice. First studies on cognitively healthy individuals and MCI patients have reported no major impact on psychological wellbeing after AD biomarker disclosure, but data on quality of life, health behavior changes and risk knowledge of individuals with MCI before and after AD biomarker disclosure is sparse.

Method

The transnational (Germany and Spain) project PreDADQoL recruited a total of 76 MCI patients and caregivers. Dyads received a standardized counseling on predictive biomarker‐based diagnosis of AD. MCI patients consenting to cerebrospinal fluid (CSF)‐biomarker testing received a standardized disclosure of their biomarker status and consecutive dementia risk. Following a mixed‐methods approach the empirical part of the project conducted follow‐up visits over 3 months to assess the effects of predictive AD diagnosis on various outcomes.

Result

Counseling on biomarker‐based AD detection and disclosure of dementia risk has no major impact on mental health and quality of life on MCI patients and their caregivers on short term follow‐up. Although the counseling included recommendations on lifestyle modification, individuals with MCI and caregivers reported a significantly less beneficial lifestyle 3 months after risk disclosure as compared to baseline. Despite adequate numeracy skills, the dementia risk perception in individuals with MCI did not correlate with the communicated risk, whereas caregivers’ risk perception correlated significantly with the communicated risk.

Conclusion

Our findings confirm that predictive AD diagnosis causes no major harm with regard to mental health and quality of life. However, despite the psychoeducational approach during the counseling and disclosure sessions with facilitating supplies, such as visual aids and take‐home material, the anticipated fostering effects on health behavior and risk knowledge remain modest. Our study contributes to the extended understanding of individuals with MCI and their caregivers when facing early AD detection. The PreDADQoL study will synergize empirical data with ethical and legal considerations for a guidance of good clinical practice in the field of predictive AD diagnosis.
Depression in older patients with dementia during COVID‐19 pandemics in Romania ‐ a geriatric center perspective
Authors: Oprea Violeta Diana , Sârbu Fabiola , Romila Aurelia
Published: June 2023

Background

A convincing body of evidence identifies depression as a risk factor for later life dementia, whereas later life depression should be considered as a prodrome for dementia. COVID‐19 pandemics highly affected elderly, and those suffering from dementia were among the most vulnerable populations to a severe evolution of SARS‐CoV2 infection as well as impacted by social isolation.

Method

We analyzed the association of depression in a study group of 162 geriatric patients, admitted due to complains of neurocognitive and psychiatric symptoms but also to other comorbidities, hospitalized in 2020‐2021 in our Geriatric Clinic after the pandemic was declared. All patients were evaluated using standard Mini Mental State Evaluation (MMSE) scale, Clock‐ Drawing Test (CDT) and Geriatric Depression Scale (GDS). Native cerebral CT‐scan imaging was used to assess if any neurobiological changes occurred.

Result

The incidence of dementia was 72.8% in the study group of 162 consecutive hospital admissions in the geriatric department. Out of the 118 cognitively impaired patients (out of which 9 were previously diagnosed with Alzheimer Disease), 73.7% had associated depression; other prevalent comorbidities in the geriatric lot were cardiovascular, neurologic, metabolic and musculoskeletal disorders. The relative risk of depression associated to dementia was 1.75. The complex relationship linking dementia and depression has also neuropathological underlying mechanisms‐ decreased cortical thickness and white matter loss were associated with both depressive symptoms and impairment of cognitive functions. In our study the majority of the patients (62.3%) presented structural abnormalities of different categories in cerebral CT‐scan imaging.

Conclusion

This high incidence reported on the association between dementia and depression in geriatric hospitalized patients is in line with the results of other studies, supporting the idea of standardizing a clinical assessment protocol for evaluating both cognitive dysfunction and depression in all elderly patients and monitoring their evolution. COVID‐19 conditions isolating elderly and restricting their access to medical services increased the risk of worsening their cognitive status and mental health. As the effective treatments for dementia remain scarce, clinicians could use a preventive approach by identification of high‐risk individuals ‐ one of the most relevant dementia risk factors being depression.
Olfaction and anxiety differently associated in men and women in cognitive physiological and pathological aging
Authors: Cieri Filippo , Zhuang Xiaowei , Ritter Aaron , Caldwell Jessica ZK
Published: June 2023

Background

Olfactory and affective factors are associated in a complex way, likely due to partial overlap in brain regions involved. Although the role of olfaction in disorders such as Parkinson Disease (PD) is documented, less clear is the association between olfaction and psychological symptoms, such as anxiety, in Mild Cognitive Impairment (MCI) and elderly cognitively healthy controls (HCs). Also, the role of sex differences in olfaction and psychological symptoms in healthy and pathological aging is poorly understood.

Methods

We included 117 subjects: 29 HCs (62.1% women), 43 MCI (34.9% women) and 45 PD (40% women), from the Center for Neurodegeneration and Translational Neuroscience. We assessed olfactory function with the Brief Smell Identification Test (BSIT) and anxiety with the State Trait Anxiety Inventory (STAI). We used a regression model for BSIT predicting STAI_Traits. We also used an interaction regression model to determine interaction between sex and olfaction predicting anxiety traits, in our three different groups.

Results

Loss of olfaction is related to greater anxiety traits in all our groups. Our regression model for BSIT predicting STAI_Traits is significant in HCs: p = 0.015; MCI: p = 0.001 and PD: p = 0.038 (adjusted for age, gender and education). Our interaction model olfaction*sex interaction to explore sex difference in the effect of olfaction on anxiety traits, showing that in HCs, for every unit increase in BSIT, trait anxiety decreased by 7.63 in men (p = 0.009) and 1.5 in women (p = 0.225); in MCI, for every unit increase in BSIT, trait anxiety decreased by 1.19 in men (p = 0.048) and 3.03 in women (p = 0.0036); in PD, for every unit increase in BSIT, trait anxiety decreased by 1.73 in men (p = 0.004) and 0.41 in women (p = 0.3632).

Conclusions

Olfaction and anxiety are correlated in physiological and pathological aging, but differently in men and women. We show a closer relationship in men compared to women. In HC and PD olfaction is more closely and significantly correlated in men compared to women. In MCI we note an opposite pattern, with women show a slightly closer link between anxiety and olfaction.
Impact of disease stage and reference region selection on longitudinal tau 18F‐MK6240 PET in Alzheimer’s disease
Authors: Krishnadas Natasha , Dore Vincent , Robertson Joanne , Ward Larry , Fowler Christopher J , Masters Colin L. , Bourgeat Pierrick , Fripp Jurgen , Villemagne Victor L. , Rowe Christopher C.
Published: June 2023

Background

Tau PET imaging enables prospective longitudinal observation of the rate and location of tau accumulation in Alzheimer’s disease (AD). 18F‐MK6240 is a newer, high affinity tracer for the paired helical filaments of tau in AD. It is widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the impact of two reference regions on the magnitude and effect size of regional change.

Method

One hundred and fifty‐eight participants: 83 Aβ‐ cognitively unimpaired (CU), 37 Aβ+ CU, 19 Aβ+ MCI, 19 Aβ+ AD had annual 18F‐MK6240 PET imaging for a mean of 1.6 years. Standardized uptake value ratios (SUVR) were generated for three in‐house composite ROI: mesial temporal (Me), temporoparietal (Te), and rest of neocortex (R), and a Free‐Surfer derived meta‐temporal (MT) ROI. Two reference regions were examined: cerebellar cortex (SUVRcb) and eroded subcortical white matter (SUVRwm).

Result

Figure 1 shows the annual rate of tau SUVR change in composite ROI. In Aβ+ CU, tau accumulation was greatest in Me (2.8‐3.2%/ year) (vs Aβ‐ CU, Cohen’s d = 0.30 SUVRcb, 0.24 SUVRwm) and MT (3.2‐3.6%/year) (vs Aβ‐ CU, d = 0.36 SUVRcb, 0.31 SUVRwm). In Aβ+ MCI, tau accumulation was greatest in Te (2.3‐3.7%/year) (vs Aβ‐ CU, d = 0.34 SUVRcb, 0.41 SUVRwm). In Aβ+ AD, greatest increase was in Te and R, with a decrease in Me. In Aβ+ AD, SUVRcb showed marginally greater increase in these regions (e.g. 3.8%/year compared to 2.68%/year SUVRwm in R) (vs Aβ‐ CU, d = 0.60 SUVRcb, 0.27 SUVRwm). In the young Aβ+ AD dementia group, spill‐over from adjacent high cortical binding or an increase in white matter binding elevates signal in the reference region.

Conclusion

The rate of tau accumulation varies according to brain region and baseline tau. Change is greatest in the MTL in preclinical AD, in the MTL and lateral temporal cortex in MCI, and Braak V‐VI regions in AD dementia. The PET measured change is greater and less variable using an eroded white matter reference region, except in AD dementia, where spill‐over from adjacent high cortical binding or increase in white matter binding elevates the reference region.
Medial temporal lobe (MTL) – default‐mode network (DMN) functional connectivity disruption in the early stages of the progression of Alzheimer’s disease in a multimodal ADNI3 MP‐RAGE and EPI‐BOLD Basic cohort
Authors: Grajski Kamil A
Published: June 2023

Background

A cross‐sectional same‐session multi‐modal analysis (T1, rsfMRI) was applied to identify potential biomarkers of the progression from cognitively normal (CN) to significant memory concern (SMC) and early and late mild cognitive impairment (EMCI, LMCI) in Alzheimer’s disease.

Methods

An ADNI3 EPI‐BOLD Basic sub‐population (N = 133) with baseline diagnosis CN (N = 45), SMC (N = 46), EMCI (N = 22), and LMCI (N = 20), matched for age (p = 0.61), education (p = 0.26), gender (p = 0.26), morphometric (FreeSurfer 7), and fMRI (AFNI) measurements, was processed with a hybrid a priori data‐driven method that identified anchor‐target ROI pairs in rsfMRI [1]. ROI pairwise correlations were False Detection Rate (FDR) corrected in a parallel group‐level one‐way four‐factor (CN, SMC, EMCI, LMCI) ANOVA and post hoc pairwise t tests were performed for significant tests only.

Results

A 3‐mm grid of ROI (r = 6mm) seeds in left MTL yielded 488 ROI “anchors”. 3D (Fisher Z‐transformed) correlation maps were computed for each subject for each anchor ROI and input to a group‐level one‐way four‐factor 3D ANOVA. Cluster analysis (Nvox = 20; p = 0.02; P = 3.45) of the 3D F statistic maps yielded 1,774 target ROIs. An r = 6mm ROI was placed at the center of mass of each target cluster. ROI anchor‐target pair correlations were input to a group‐level one‐way four‐factor ANOVA FDR corrected (q = 0.005; p* = 0.0035, permutation, N = 1000) which identified 1,179 significant tests. Post hoc pairwise t tests only on the significant ANOVA tests were FDR‐corrected (q = 0.005) and yielded 163 significant SMC‐CN tests (p* = 6.8×10−4); 158 EMCI‐CN tests (p* = 6.6×10−4); and 120 LMCI‐CN tests (p* = 5.1×10−4). The significant target ROI masks were summed which identified 35‐44 clusters. The same hybrid a priori data‐driven method was then applied in independent runs using as anchor regions the left amygdala, thalamus, substantia nigra, and accumbens area. The resultant spatial distribution of significant target ROI masks predominantly, but not uniformly coincided with DMN‐associated regions. An independent analysis of right hemisphere yielded similar results.

Conclusions

A hybrid a priori data‐driven approach applied to anchor ROIs in MTL and multiple subcortical regions identified target ROIs that were predominantly, but not uniformly associated with DMN.

[1] Grajski, K. A., Bressler, S., and ADNI. (2019). Neuroimage Clin. 2019;23:101860.
Effectiveness of a virtual health coach intervention for caregivers of persons with frontotemporal degeneration
Authors: Massimo Lauren M , Hirschman Karen , Fisher Lauren , Sharkey Michelle , Aryal Subhash , Riegel Barbara
Published: June 2023

Background

Frontotemporal degeneration (FTD) is a common cause of young‐onset dementia. A tremendous burden is placed on caregivers who often sacrifice their own self‐care needs in order to manage the cognitive decline and subsequent functional impairments of their loved one, contributing to extraordinarily high levels of stress and depression. Health coaching is a support intervention that is personalized and multidimensional, providing support for coping with stress while fostering self‐care. Here we report on the efficacy of a virtual health coach intervention (Virtual Caregiver Coach for You; ViCCY) aimed at increasing self‐care behaviors and reducing stress in FTD caregivers.

Method

In this pilot randomized control trial, 30 caregivers of persons with behavioral variant FTD (bvFTD) were randomly assigned to either the intervention group (ViCCY) which included 10 coaching sessions over 6 months plus targeted health information through the internet or the control group receiving standard care augmented with the targeted health information through the internet. Caregiver self‐report measures on self‐care (primary outcome), stress, depression and coping were collected at enrollment, 3 and 6 months. Using linear mixed‐effects models, we evaluated differences in change over time between the intervention and control groups.

Results

There were no significant differences in baseline characteristics between the groups. There was a significant group‐by‐time interaction for self‐care monitoring (t58 = 2.37, p = 0.0210) and self‐care confidence (t58 = 2.32, p = 0.0239) on the Self‐Care Inventory, demonstrating that caregivers who received the ViCCY intervention improved in their self‐care over time. The intervention group also reported lower self‐neglect over time compared to the control group (Health Care Self Neglect Scale: t58 = ‐2.38, p = 0.0417). No differences were observed between the groups on the secondary outcome measures of stress, depression and coping.

Conclusions

bvFTD caregivers are a unique population who defer their own self‐care in response to the stress of caregiving. This RCT shows promise for remotely delivered health coaching as an innovative way to increase support that is urgently needed to reduce poor outcomes in this distressed and underserved caregiver population.
Disentangling the heterogeneity of brain atrophy in Alzheimer’s Disease
Authors: Liu Hangfan , Toledo Jon B. , Grothe Michel J. , Rashid Tanweer , Launer Lenore J. , Shaw Leslie M. , Snoussi Haykel , Heckbert Susan R. , Weiner Michael W. , Trojanowski John Q , Seshadri Sudha , Habes Mohamad
Published: June 2023

Background

Alzheimer’s disease (AD) is the most common cause of dementia. In AD patients, structural MRI analyses have identified various brain atrophy patterns, which are likely the result of differences in regional pathology distribution and variable presence of co‐pathologies.

Method

We included 496 ADNI participants and applied our robust collaborative clustering approach (RCC) to the MRI scans of the Aβ+ participants. RCC removes noise while simultaneously clustering subjects and features. Group comparisons were performed applying Kruskal‐Wallis analyses for quantitative variables and chi‐square tests for categorical variables (Table 1). Power transformations were used to normalize the distribution of quantitative variable for linear regression analyses. APOE ε4 presence and white matter hyperintensity (WMH) volume were included as predictors. P‐values <0.05 were considered statistically significant.

Result

We identified three distinct atrophy clusters among the Aβ+ participants (Table 1). A “limbic predominant” atrophy cluster showed greater cingulate and right hippocampus, inferior and middle temporal lobe atrophy than the cognitively unremarkable (CU) Aβ‐ reference group (Figure 1). The diffuse atrophy cluster showed greater parieto‐occipital‐temporal atrophy. The “hippocampus sparing” atrophy cluster showed a similar neocortical atrophy pattern except for less atrophy in the temporal lobe. The limbic predominant cluster participants had a higher APOE ε4 prevalence than the hippocampal sparing cluster participants (Table 1, 2). The three clusters had higher baseline ADAS‐Cog13 and flortaucipir SUVR binding in all the Braak staging‐defined areas than the CU Aβ‐ reference group (Table 3). The diffuse atrophy cluster had higher ADAS‐Cog13 scores, florbetapir composite scores, and flortaucipir SUVRs in all the Braak staging‐defined areas than the two other atrophy clusters. The hippocampal sparing atrophy cluster participants were older and had higher WMH volumes than the limbic predominant atrophy cluster and the CU Aβ‐ reference group participants.

Conclusion

Our clustering method discovered three reproducible atrophy patterns in AD, including typical and atypical presentations. This finding likely reflects different combinations of co‐pathology leading to the development of AD, some of which are captured with MRI. Mainly, WMH contributed to the heterogeneity of AD and the atypical neocortical variant.
Prediction of brain amyloidosis: a multi‐site machine learning analysis
Authors: Fan Shuyang , Ha Sung Min , Xiao Pan , Schindler Suzanne E. , Gordon Brian A. , Raji Cyrus A. , Fagan Anne M. , Xiong Chengjie , Cruchaga Carlos , Aschenbrenner Andrew J. , Hassenstab Jason J. , Benzinger Tammie L.S. , Bateman Randall J. , Morris John C , Ances Beau M. , Sotiras Aristeidis
Published: June 2023

Background

Position emission tomography (PET) imaging and cerebrospinal fluid (CSF) analysis are the gold standards for evaluating brain amyloidosis in vivo, but their utility is limited by invasive procedures, high costs of PET, and limited accessibility to PET facilities. Prior research has used machine learning to assess amyloidosis based on non‐invasive and easily accessible information such as cognitive test scores and genetic data, but past accounts have typically used a single cohort to train and test their models, which may undermine their generalizability. Importantly, most studies have imputed amyloidosis of symptomatic participants without evaluating their models on cognitively unimpaired (CU) individuals. Accordingly, we aimed to develop algorithms that estimate risks for amyloidosis and validate them on CU participants from an external cohort.

Method

Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 987) and the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) (n = 688) were used. The examined predictors for amyloidosis were demographic factors, body mass index (BMI), apolipoprotein E (APOE) genotype, and performance on cognitive tests (Table 1). Random forest models were trained with nested cross‐validation (CV) on the ADNI cohort before testing on the Knight ADRC cohort for a reliable assessment of generalizability. The outer CV loop enabled unbiased measurement of prediction performance, and the inner loop hyperparameter optimization.

Result

The model achieved an area under the receiver operating characteristic curve (AUC) of 0.81 [0.79, 0.84] on the ADNI cohort (Table 2), and its performance generalized well to the Knight ADRC participants. When only CU participants are considered, performance was overall lower than that for the full cohort, which we expect given that they have less over pathology. The model was nonetheless able to achieve an AUC of 0.78 [0.75, 0.81] on the Knight ADRC CU participants.

Conclusion

Machine learning models can predict brain amyloidosis with a moderate degree of accuracy on asymptomatic individuals and generalize well to external cohorts. Our models can be used to screen for individuals likely to be Aβ PET‐positive, thus reducing preclinical AD trial recruitment cost by avoiding unnecessary PET scans.
Levels of blood memory CD8 T cells that induce AD‐like pathology in mice correlate with decreased Aβ42 and increased total Tau in CSF of AD patients
Authors: Wheeler Christopher J. , Van Dam Debby , Vermeiren Yannick , De Reu Hans , De Deyn Peter Paul
Published: June 2023

Background

We previously engineered mice to accumulate elevated levels of age‐related, antigen‐specific memory CD8 T cells as in humans. These mice spontaneously develop all major hallmarks of AD with aging. Analogous T cells reactive to an epitope on Amyloid Precursor Protein (APP) were found in aging humans, accumulated in AD brain, and decreased in AD blood. Here, we examine whether their levels are associated with established AD biomarkers in CSF.

Method

Antigen‐specific CD8 T cells in blood were quantified by flow cytometric analysis after staining with anti‐CD8, anti‐KLRG1 and APP peptide‐HLA‐A2 multimers in normal aging, MCI with or without AD biomarkers, and confirmed late‐onset AD patient cohorts (n = 50). Aβ1‐42, total Tau, and pTau181 were quantified in CSF, and cognitive performance assessed by MMSE.

Result

Percentage of APP‐specific memory CD8 T cells was significantly decreased with dementia (0.68 + 0.29% for MMSE <25; 1.63 + 0.32% for MMSE >24), reaching minimal levels in AD blood, which precluded meaningful correlations in AD patients. Nevertheless, increasing levels of APP‐specific memory CD8 T cells in blood from all subjects combined corresponded with increased CSF Aβ1‐42 (r = 0.373, P < 0.0004) and decreased total Tau but not pTau181 or MMSE (r = ‐0.234, P < 0.0292; r = ‐0.208, P < 0.0531; and r = ‐0.009, P < 0.9410, respectively). Decreases in the larger parental (KLRG1+) memory CD8 T cell population also correlated with decreased CSF Aβ1‐42 in AD patients alone (r = 0.511, P = 0.003 for % KLRG1+ of CD8 T cells; r = 0.682, P < 0.00009 for % KLRG1+CD8+ cells; n = 31).

Conclusion

Our results reveal that age‐related memory CD8 T cells in blood decrease with dementia, and in proportion to decreased CSF Aβ1‐42 and total Tau in all patients, while their parental KLRG1+ population is directly proportional to Aβ1‐42 in AD patients only. This validates our previous findings that loss of APP‐specific memory CD8 T cells from blood accurately tracks the AD continuum, and support the notion that antigen‐specific memory CD8 T cells are associated with the earliest detectable pathologic changes in AD.
Activation of D1 receptor improved learning and memory and synaptic plasticity in Alzheimer’s model
Authors: Bakhtiarzadeh Fatemeh , Shahpasand Koorosh , Fathollahi Yaghoub , Najafi_Zadeh Javad Mir
Published: June 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with complex etiology. Among the neurotransmitter abnormalities that have been investigated in AD, the dopaminergic system has been intensively studied as a key neurotransmitter system involved with emotion and cognition. The dopaminergic system undergoes several changes during the neuropathological aging process. In general, some studies suggested that dopamine plays a major role in synaptic plasticity mechanisms. Interestingly, in AD, the dysfunction of dopaminergic transmission has been hypothesized as a new player in the pathophysiology of AD. On the other hand, stimulation of dopaminergic input to the hippocampus, ventral tegmental area, improved working and spatial memory in mice model of Alzheimer’s disease. In this study we assessed the effect of dopamine receptors on learning and memory and synaptic plasticity in Alzheimer’s like disease mice model.

Method

One month after bilaterally intra hippocampal injection of cis‐ P tau, adult male mice received D1 and D2 receptor antagonist, after 5 minute, induced high‐frequency ventral tegmental area stimulation for 30 min/ 5 day, and animals were assessed for changes in learning and memory. Short term and long term memory was assessed respectively by Y maze and Barnes maze and also synaptic plasticity was studied by in vitro evoked‐ field potential recording.

Result

Hippocampal cis‐ P tau injection as a new mice model of Alzheimer’s disease produced spatial and working memory impairment and also disrupted long term potentiation in striatum radiatum of hippocampus. Applying VTA‐DBS ameliorated memory impairment, with no effects in the control group. Further, in vitro evoked field potential recording showed a restoration of long term potentiation (LTP).

Using D2 receptor antagonist, has no effect on learning and memory improvement after stimulation of ventral tegmental area but using D1 receptor antagonist impaired learning and memory. Applying dopamine on hippocampal slice restored LTP and D1 receptor antagonist had no effect on LTP disruption, but D2 receptor antagonist restore LTP.

Conclusion

These results indicate that ventral tegmental area stimulation might mitigate memory dysfunction and synaptic plasticity in cis‐P tau accumulation by D1 receptor and phasic release of dopamine.
Alzheimer’s disease risk alleles of PICALM gene may accelerate cognitive (memory and attention) performance in middle‐aged healthy APOE‐ε4 carriers
Authors: Dzianok Patrycja , Kublik Ewa
Published: June 2023

Background

The APOE (allele ε4) and PICALM (SNPs rs541458: allele T; and rs3851179: allele G) genes were recognized as risk factors for late‐onset Alzheimer’s disease (AD). However, effects of these risk genes on the cognitive functions of healthy individuals are still not determined and their possible interactions have never been studied. We investigated the preclinical influence of both genes on brain cognitive functions in a healthy middle‐aged population.

Method

Seventy three healthy adults (50‐63 y/o) completed computer tasks measuring attention, cognitive control and memory. MSIT task included an easy‐control condition and an attentionally demanding condition with combined cognitive conflicts. Sternberg’s task included an easy condition (there is a need to memorize 4 letters strings) and a hard‐one (with 8 letters strings). APOE (rs429358/rs7412) and PICALM (rs3851179 and rs541458) alleles were determined using a traditional Sanger sequencing protocol. The data was divided according to the genetic tests results (control group: absence of ε4 and less‐risky PICALM alleles; the double risk group: ε4‐carriers, and homozygous carriers of high‐risk PICALM alleles; single risk group: ε4‐carriers and less‐risky PICALM alleles). ANOVA was used to determine the effects of genetic variants on task performance (reaction time (RT) and accuracy for easy/hard MSIT and Sternberg conditions).

Result

Results revealed that while the groups did not differ in accuracy or RTs for easy conditions, they did differ significantly on hard conditions (p<0.05). The single‐risk group showed longer RTs than the control group in both tasks. The effect was preserved when performing the analysis of covariance (ANCOVA) with the age as a covariate.

Conclusion

AD risk genes, APOE and PICALM, can affect cognitive abilities even in healthy individuals. APOE‐ε4‐carriers needed longer time to process difficult stimuli but surprisingly an addition of PICALM risk alleles seemed to reverse this tendency. Further studies are needed to unambiguously determine the effects of the PICALM and its interactions with other risk genes (including APOE) in modulating the cognitive abilities of still healthy individuals.

[Supported by National Science Centre, Poland, no. 2018/31/N/HS6/03551.]
The eighteen months’ follow‐up, second version, after the intervention using a rehabilitation program of physical and cognitive rec‐Xercise (REPCREC) for the elderly with mild cognitive impairment (MCI)
Authors: Kanemaru Akiko , Kato Takayuki , Kawaji Yoshie , Honda Takuya , Makita Ayaka , Goto Takahiro , Uno Shizuna , Uemura Honoka , Higuchi Wakana , Shimizu Aya , Enomoto Yoji , Kanemaru Kazutomi
Published: June 2023

Background

To prevent or slow down the age‐related cognitive decline is an important issue. Therefore we have conducted intervention study with our rehabilitation program of physical and cognitive Rec‐Xercise (REPCREC) for the elderly with MCI.

Method

Seventy‐six cases, out of seventy‐nine enrolled individuals, have undergone our evaluation and intervention program (REPCREC). The subjects have been divided into four groups; group A the cognitive REPCREC, group B physical REPCREC, group C both cognitive and physical REPCREC and group D control. The design of this study is a non‐randomized controlled trial. Intervention groups have received the each session once per week up to twelve times. Before and after the intervention, and 3‐, 6‐, 12‐ & 18‐months after the intervention, we have evaluated the following items: physical function, GDS, POMS2, neuropsychological tests [MMSE, RBMT, TMT, Ravenʼs Colored Progressive Matrices(RCPM), Rey‐Osterrieth Complex Figure Test(ROCF), story retention, coding and Miyake’s paired verbal associate learning test(MPVALT)]. A one‐day booster program has been provided at the time of evaluation. For statistical analysis, Fisher’s exact test and Kruscal‐Wallis test for the baseline data, and linear mixed model(LMM) analysis have been performed.

Result

The median age is 79, median MMSE scare is 27.5, and the numbers of each group are A18, B24, C27, and D7 cases. At the baseline, no difference between groups except POMS‐F (p = 0.026). LMM analysis revealed the significant differences: 1) before REPCREC; RCPM of group A (p = 0.013), story retention delayed (p = 0.001) of group A (p = 0.011)▪C (p = 0.037), story retention immediate (p = 0.022), MPVALT (non‐related) (p = 0.048) and ROCF (recall) (p = 0.006), 2) after REPCREC; coding (p = 0.011) of group A (p = 0.049)▪C (p = 0.032) and ROCF(recall) (p = 0.018), 3) 3 months after REPCREC; TMTB (p = 0.031) of group A (p = 0.032) and story retention delayed of group A (p = 0.011).

Conclusion

The program REPCREC showed the better effects after REPCREC on non‐verbal intelligence, visuospatial abilities, memory, attention, planning, working memory etc. [RCPM, ROCF (recall), MPVALT] in especially the cognitive REPCREC (group A). And group A showed the significant improvement in TMTB and story retention delayed, even three months after REPCREC. That may indicate the prolonged efficacy of the REPCREP in shift of attention and coherent memory for MCI
Levels of plasma neurofilament light and pTau‐181 predict for steeper cognitive decline in Typical AD and Hippocampal‐sparing compared to Limbic‐predominant AD subtype
Authors: Bucci Marco , Naudet Léa Delphine Christelle , Nordberg Agneta K
Published: June 2023

Background

Recent studies suggest plasma neurofilament light (p‐NFL) and phosporylated‐Tau‐181 (p‐pTau181) are valuable biomarkers for detecting faster cognitive decline in patients with Alzheimer’s Disease (AD) dementia. Recently, AD subtyping has been used to subgroup patients into AD phenotypes with possibly different cognitive prognoses. The aim of this study was to investigate the interaction between p‐NFL and p‐pTau‐181 and different AD subtypes to predict decline in episodic memory.

Method

In total, 357 non‐AD (Aß‐) (Cognitive Normal and Mild Cognitive Impairment) and 73 AD subjects (Aß+, according to mainly Amyloid‐PET or ‐CSF) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Subjects had at least one plasma sample and one MRI scan. The latter was used to subtype AD patients (Risacher et al. 2017). AD subjects were subtyped in Limbic‐predominant (18%), typical AD (67%) and Hippocampal‐sparing (15%) subtypes. The ADNI_MEM composite score was used as proxy for cognition. Linear mixed models were tested to predict cognitive decline up to 4.5 years of follow up (27.7±13.1 months) including the interaction between time, AD subtype and p‐NFL and p‐pTau‐181. Age, gender, education, and ApoE4 status were included in the models. Models were selected incrementally through model comparison (AIC, BIC). The final model included both p‐NFL and p‐pTau‐181.

Result

The AD subtypes did not differ in cognition (‐1±0.6 for the whole group) or age (74±8 ys for the whole group), but in gender. Higher p‐NFL levels in patients with Hippocampal‐sparing and Typical AD subtypes showed faster decline in cognition compared to non‐AD patients (p<0.05, both), while Limbic‐predominant did not. For p‐pTau‐181, the interaction with Limbic‐predominant was significant and the model showed stronger separation of cognitive decline across all AD subtypes than p‐NFL. Combining both biomarkers improved the model but only the interactive effects of pTau‐181 for Hippocampal‐sparing and typical AD subtypes were significant (p<0.05, both).

Conclusion

In the Limbic‐predominant AD subtype the levels of the two plasma biomarkers p‐NFL and p‐pTau‐181 did not predict for progressive cognitive decline (episodic memory), suggesting that this AD subtype with late disease onset (contrary to the Hippocampal‐sparing subtype), cannot be early detected with plasma p‐NFL and p‐pTau‐181.
Longitudinal trajectories of self‐reported subjective cognitive decline in relation to objective cognitive performance in a population‐based cohort
Authors: Street Rebecca E , Lu Kirsty , Nicholas Jennifer M , Keuss Sarah E , Pavisic Ivanna M , James Sarah‐Naomi , Baker John , Buchanan Sarah M , Wagen Aaron Z , Storey Mathew , Harris Matthew J , Parker Thomas D , Lane Christopher A , Keshavan Ashvini , Freiberger Tamar , Murray‐Smith Heidi , Cash David M , Coath William , Wong Andrew , Richards Marcus , Fox Nick C , Crutch Sebastian J , Schott Jonathan M
Published: June 2023

Background

Subjective Cognitive Decline (SCD) may represent the onset of cognitive decline before impairment on standard cognitive tests occurs (Jessen et al., 2014). Previous cross‐sectional studies were shown to have limited ability to capture objective differences in cognitive performance between groups with and without SCD (Cacciamani et al., 2017). Understanding the interplay between changes in subjective memory ratings and objective cognitive function over time may have utility in identifying people at risk of dementia.

Method

370 cognitively normal (CN) individuals with complete cognitive data (Table 1 for characteristics) from Insight 46, a longitudinal neuroscience sub‐study of the MRC National Survey for Health and Development (the British 1946 Birth Cohort), underwent cognitive, clinical, and physical assessments, and neuroimaging (combined MRI/18F‐Florbetapir‐PET). SCD was measured using MyCog (Rami et al., 2014) a validated tool, from the SCD‐Questionnaire, where higher scores indicate greater subjective complaints. Linear regression models were used to test whether longitudinal cognitive change as measured using the Preclinical Alzheimer Cognitive Composite (PACC) and a visual short‐term memory binding task were influenced by baseline MyCog and whether there are parallel associations between rates of change in MyCog and longitudinal cognitive change. Covariates were sex, age at baseline visit, childhood cognitive ability, educational attainment, and adult socioeconomic position.

Result

Baseline MyCog scores did not predict rates of change in PACC or visual short‐term memory binding outcome measures (Table 2). Rates of MyCog change alone did not predict rate of change in PACC, localisation error, total correct number of trials or proportion of misbinding errors (Table 3). However, we observed an interaction effect with baseline amyloid‐b status, whereby greater rates of subjective memory concerns predicted faster rates of decline in the proportion of misbinding errors in amyloid‐b positive participants only (Table 3; Figure 1).

Conclusion

These findings suggest that higher amyloid‐b burden in CN individuals with subjective memory complaints is associated with faster rates of decline in visual working memory. Corroborating previous reports that feature binding tasks can objectify subtle cognitive deficits found in SCD (Koppara et al., 2015) and serve as a promising tool for identifying people at risk of dementia.