bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of tubulin tyrosine ligase, a novel feature of sporadic and familial AD, is an enhancer of tau phosphorylation
Authors: Parato Julie , Qu Xiaoyi , Sproul Andrew , Pero Maria Elena , Bartolini Francesca
Published: December 2023

Background

We have recently shown that loss of tubulin tyrosine ligase (TTL) and subsequent disruption of a‐tubulin retyrosination is a feature of AD and a promoter of synaptic loss by inhibiting microtubule entries into dendritic spines. TTL+/‐ mice have cognitive deficits, altered LTP, synapse loss and increased levels of detyrosinated and D2 tubulin, two tubulin modifications that accumulate on non‐dynamic microtubules. We also found that low levels of phospho‐tau correlated with higher levels of detyrosinated and D2 tubulin in pyramidal neurons residing in the anterior hippocampal formation of human AD brains, raising the question of whether improper microtubule longevity drives early stages of tau hyperphosphorylation in AD. Here, we demonstrate that loss of TTL enhances both AMPK activation and tau phosphorylation in cultured rat hippocampal and human cortical neurons, and present preliminary evidence on the mechanisms by which this regulation may occur and contribute to TTL‐loss dependent synaptic dysfunction.

Method

Human cortical neurons derived from iPSC lines in which the London familial APP mutation V717I was knocked into one allele of the IMR90 control using CRISPR/Cas9, were used as a cellular model of familial AD. Lentiviral infection with shRNA against TTL was used to silence TTL expression. Microtubule dynamics were measured by confocal time‐lapse microscopy in neurons expressing EB3‐EGFP, a protein that tracks the growing plus ends of microtubules. Immunoblotting was performed to measure both unmodified and modified levels of TLL, tubulins, AMPK subunits, total tau, p262 and AT8 phospho‐tau.

Result

In the APP neurons, we found that a reduction in TTL levels correlated with an increase in p262/AT8 phospho‐tau variants and phospho‐AMPK, the active state of one of the kinases that phosphorylates serine 262, a key residue in the binding of tau to microtubules. Knockdown of TTL was sufficient to reduce microtubule dynamics and increase both active AMPK levels and phospho‐tau.

Conclusion

Our results indicate that loss of TTL alone reduces dynamic microtubules, triggers tau kinase activation, and results in hyperphosphorylated tau. Together with our previously published data, these findings suggest that reduced levels of TTL act as one of the early drivers of tau hyperphosphorylation in AD.
Deep learning based normative models identify structures that become abnormal with Alzheimer’s disease
Authors: Jaramillo Camilo , Trujillo Maria , Bernal Jose
Published: December 2023

Background

Improving dementia diagnosis is a major global concern, given that up to 20% of subjects are misdiagnosed. Normative modelling, which quantifies how far individuals deviate from healthy controls (HC), may help to better situate subjects along the spectrum. To determine whether this is the case, we implemented a deep learning based normative model and tested it on structural neuroimaging data from subjects with HC, mild cognitive impairment (MCI), and Alzheimer’s disease (AD).

Method

We developed an adversarial autoencoder (AAE) (Figure 1) leveraging FreeSurfer features, namely cortical surface area of 68 cortical subregions (34 by hemisphere; Desikan‐Killiany atlas) and volumes of 33 neuroanatomical structures (Aseg atlas). Our model not only returns individual “deviation” scores—divergence from HC—but also identifies regions of interest that contribute to said score, facilitating interpretability. We retrieved T1‐weighted MRI scans (n = 204) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (HC/MCI/AD 105/29/60; Table 1). We trained our AAE on 71 HC samples (n = 71) and tested it on the rest (n = 133). We used bootstrapping to compute confidence intervals (CI) for each point estimate and examined regions where scores differed for the considered groups [1].

Result

Deviation scores were lowest for HC (mean 0.74 [95%‐CI 0.63–0.88]), highest for AD (mean 1.21 [95%‐CI 1.03–1.50]), and intermediate for MCI (mean 1.04 [95%‐CI 0.88–1.27]), implying subjects indeed fell along the AD spectrum (Figure 2A). Said scores also enabled classifying subjects into HC, MCI, and AD with a mean area under the curve (AUC) of 75% (Figure 2B‐C; HC vs. MCI: 0.75 [95%‐CI 0.62–0.85]; HC vs. AD: 0.76 [95%‐CI 0.64–0.82]). According to the AAE, the hippocampus, parahippocampal cortex, ventricles, and inferior parietal lobe contributed to such differences (Figure 2D‐E).

Conclusion

Normative models can identify structures that become abnormal as the brain undergoes ageing and AD, in line with the literature. Further testing on a larger and more heterogeneous sample will reveal the potential of this tool and its potential deployment in clinics.

References

:

[1] W. H. L. Pinaya et al., “Using normative modelling to detect disease progression in mild cognitive impairment and Alzheimer’s disease in a cross‐sectional multi‐cohort study”, Scientific reports, vol. 11 1, p. 15746, 2021.
Effect of multivitamin‐mineral supplementation on change in cognitive function in the COSMOS Clinical subcohort and meta‐analysis of COSMOS cognition studies
Authors: Vyas Chirag M. , Rist Pamela M. , Sesso Howard D. , Manson JoAnn E. , Okereke Olivia I.
Published: December 2023

Background

Few randomized clinical trials (RCTs) have investigated the effect of multivitamin‐mineral supplementation (MVM) on cognitive change among community‐dwelling older adults and effects remain untested using detailed in‐person, gold‐standard neuropsychological assessments; thus, we tested the effect of daily MVM vs. placebo on cognitive function among older adults enrolled in the in‐clinic component of COSMOS (COcoa Supplement and Multivitamin Outcomes Study). Furthermore, we conducted a meta‐analysis of the findings from the three COSMOS cognition studies: COSMOS‐Clinic (n = 603 for the detailed in‐person cognitive assessments), COSMOS‐Mind (n = 2262 for telephonic‐based cognitive assessments); and COSMOS‐Web (n = 3562 for computer‐based cognitive assessments) to provide a robust evaluation of the effects of MVM on cognition.

Methods

COSMOS is a 2×2 factorial RCT of cocoa extract supplements (Mars Edge; containing 500 mg/day flavanols) and/or MVM (Haleon, as Centrum Silver) for cardiovascular and cancer prevention. In COSMOS‐Clinic, n = 573 of n = 603 COSMOS‐Clinic participants completed all cognitive tests at baseline; n = 492 completed all cognitive tests at both baseline and 2‐year follow‐up. The primary outcome was global cognitive score [averaging z‐scores of 11 tests: general cognition (the Modified Mini‐Mental State), episodic memory (Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] word list learning and delayed recall tests; East Boston Memory Test immediate and delayed recall trials), CERAD word list recognition, and executive function/attention (two fluency tests; Trail Making Tests A and B; digit span backwards)]. Episodic memory and executive function/attention were examined separately. Finally, we used random‐effects models to meta‐analyze the findings of three COSMOS cognition studies.

Results

In COSMOS‐Clinic, we observed a signal for effect of MVM vs. placebo on improvement in global cognition over two years (mean difference = 0.06, 95% confidence interval [CI]: ‐0.003, 0.12). MVM vs. placebo led to significant improvement in episodic memory (mean difference = 0.11, 95% CI: 0.001, 0.23) but not in executive function/attention (mean difference = 0.04, 95% CI: ‐0.04, 0.11). The meta‐analysis of three COSMOS studies showed significant benefits of MVM on global cognition and episodic memory (will be presented in detail).

Conclusion

Daily MVM compared to placebo showed improvement in global cognition and episodic memory over 2 years among community‐dwelling older adults.
Masseter muscle volume measured by MRI correlated with cognitive function in a memory clinic
Authors: Muranaka Michiho , Tatewaki Yasuko , Thyreau Benjamin , Sakamoto Maya , Takano Yumi , Yamamoto Shuzo , Tomita Naoki , Nakase Taizen , Taki Yasuyuki
Published: December 2023

Background

“Oral frailty” which indicates a decline in oral function, has been focused on the fact that it can also affect cognitive function in the elderly population. Although Several studies have been attempted for establishing the utility of the cross‐sectional area or volume of masticatory muscles as objective indices reflecting oral frailty, no report has examined the relationship between masticatory muscles volume and cognitive function in detail. In this study, we aimed to clarify the relationship between size of masseter muscle, one of major masticatory muscles, and cognitive function in the elderly.

Method

A total of 349 subjects (mean age 77.3 +/‐ 9.2 years, 126 males and 223 females, 58 with subjective cognitive impairment, 88 with mild cognitive impairment, and 203 with dementia), who visited the Memory clinic of Tohoku University Hospital with a chief complaint of forgetfulness by March 2018 were included. Using 3D T1‐weighted images acquired on a 3‐Tesla MRI system, the bilateral masseter muscle cross‐sectional area was automatically calculated for all subjects using a custom deep‐learning image‐processing model trained on a subset of subjects to identify the relevant muscles and consistent section. Then, partial correlations with the MMSE score were conducted, adjusting for age and gender.

Result

The mean left and right masseter muscle cross‐sectional area are 399.3±84.7mm2 in subjective cognitive impairment, 387.9±106.5 mm2 in mild cognitive impairment, and 355.1±88.4 mm2 in dementia, respectively (p < 0.01). Adjusted for age and sex, they showed a significant correlation with MMSE (R = 0.151, p < 0.01). For post‐hoc stratified analysis, there was a significant correlation between mean masseter muscle cross‐sectional area and MMSE with female patients (R = 0.049, p < 0.05), whereas no correlation with male patients after adjusted age (R = 0.025, p > 0.05).

Conclusion

Our result revealed that the masseter muscle cross‐sectional area obtained from MRI may be related to cognitive function in the patients with complaint of forgetfulness. Therefore the masticatory function may reflect cognitive function in the elderly who are vulnerable in their memory, and the cross‐sectional area of masseter muscle based on MRI could be a potential indicator for predicting dementia risk.
The role of fibrinogen in neurodegeneration during a neuroinflammatory disease
Authors: Sulimai Nurul , Brown Jason , Lominadze David
Published: December 2023

Background

Fibrinogen is not only a marker of inflammation, but also a cause of inflammatory responses. We previously showed that when elevated during traumatic brain injury (TBI), fibrinogen increased cerebrovascular permeability mainly via caveolar transcytosis and, after extravasation and deposition in vasculo‐astrocyte interface, it activated astrocytes causing neurodegeneration that was associated with memory reduction.

Method

To define the possible mechanisms of fibrinogen‐induced activation of neurons, primary mouse brain cortical neurons from C57BL/6 mice were plated in poly‐d‐lysine‐ and laminin‐coated cell culture plates. Cells were treated for 1 hour with fibrinogen (0.5 or 1 mg/mL) in the presence or absence of a nuclear factor‐κB (NF‐kB) blocker, caffeic acid phenethyl ester (CAPE), or media alone (control). All groups contained hirudin to prevent the conversion of fibrinogen to fibrin. Levels of interleukin‐6 (IL‐6) and chemokine (C‐C motif) ligand 2 (CCL2) were assessed by qRT‐PCR. NF‐kB activity was measured in neuronal nuclear protein and cell extracts by the TransAMTM NF‐kB p65 protein assay and Western blot (WB). In parallel, using a cortical contusion injury (CCI), a mouse model of mild‐to‐moderate TBI was created in C576J mice. NF‐kB was detected with immunocytochemistry in cultured cells and brain samples collected 14 days after CCI. The specific association of fibrinogen with its neuronal receptors intercellular adhesion molecule‐1 (ICAM‐1) and cellular prion protein (PrPC) was assessed with a proximity ligation assay in cells.

Result

Fibrinogen specifically bound to neurons via its receptors ICAM‐1 and PrPC and increased NF‐kB levels. Fibrinogen caused upregulation of pro‐inflammatory cytokines IL‐6 and CCL2 mRNA. ELISA and WB NF‐kB p65 analysis demonstrated increased DNA binding by p65 and protein expression in fibrinogen‐treated neurons compared to that in control and CAPE groups. Fibrinogen caused translocation of NF‐kB p65 to the nucleus.

Conclusion

Results suggest that a specific interaction of fibrinogen with neurons results in neuroinflammation through activation of NF‐kB.
Day hospital for psychogeriatric patients: implementation of best practice
Authors: Bassitt Debora Pastore , Buchain Patricia Cardoso , Alves Tania Correa de Toledo Ferraz , Filho Geraldo Busatto
Published: December 2023

Background

Psychogeriatric day hospitals best practices deliver integrated patient and family centered care by multidisciplinary teams, providing a safer transition between acute psychogeriatric units to rehabilitation services and outpatients clinical care. This reduces inpatient length of stay and rehospitalization rates, favoring a successful daily routine care at home. We implemented in 2022 an elderly day hospital service at the Institute of Psychiatry USP Medical School, Brazil. This case report illustrates how day hospitals can contribute to a better clinical outcome.

Case report

64 year‐old male patient with bipolar disorder (BD), recurrent readmissions in our psychogeriatric unit due to either complications from bipolar disorder or clinical conditions and family burden (2020 for 90 days due to rapid cycling BD and 2021 to treat clinical conditions 4 days). When he was at home his family reported increased burden and difficulty in daily care. They asked for readmissions in this period .The cognitive impairment and functional decline were associated with neuroprogression in BD.The lack of adequate treatment worsened psychiatric, cognitive symptoms and the capacity to maintain his activities of daily living (ADL).

In 2022 he was admitted due to behavior symptoms (irritability and aggressivity) in our inpatient unit for 19 days. Transitioned to day hospital, he attended activities for two months, twice a week. The intervention provided cognitive and functional stimulation, caregivers training and psychoeducation. It was performed in groups and individually (patient and family).We observed improvement in cognition, basic daily life activities and social support. Admission and transition to outpatient care were CGI‐04‐04, MMSE 20‐23 and Katz 02‐04. We observed reduction in family burden and management of psychiatric and behavior symptoms.

Conclusion

Patient and family needs were identified and cared for, and we achieved an improved health outcome by creating a safe transition, reducing length of stay and preventing readmission. This present intervention demonstrates a clinical example of the coordinated approach in order to provide transitional care and enable rehabilitation (cognition, basic daily life and bipolar symptoms).The benefits of the patient‐ family centered care provides consistent recovery and decreased length of hospital stay and risk of readmission.
The interplay between White Matter Hyperintensities and regional β‐Amyloid on Defaults Mode Network
Authors: Ali Doaa , Bahrani Ahmed A , Khouli Riham H El , Gold Brian T. , Jiang Yang , Zachariou Valentinos , Wilcock Donna M. , Jicha Gregory A
Published: December 2023

Background

Cerebral small vessel ischemic disease (SVID) has been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Yet, the mechanistic role of SVID in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that axonal SVID influences amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults.

Method

Regional Standard Uptake Value ratios (SUVr) from Aβ‐PET, and white matter hyperintensity (WMH) volumes from 3D MRI FLAIR images were analyzed across a sample of 72 clinically‐unimpaired (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ‐PET SUVr in the connected cortical DMN regions were analyzed using linear regression models adjusted for age, sex, ApoE and total brain volumes.

Result

The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus (SLF) was associated with increased regional SUVr in the inferior parietal lobule (IPL) (p = 0.011).

Conclusion

The findings suggest that the relation between Aβ parietal cortex is partially driven by SVID in downstream axonal pathways in pAD. The biological relationships and interplay between Aβ and white matter microstructure alterations that precede overt WMH development across the continuum of AD progression warrants further study.
Serum biomarkers indicate sex differences in response to pathology inhibition in aged mice with tau pathology
Authors: Chowdhury Anisuzzaman , Collins Jessica M , Perry Sharn , Breadmore Michael , Shigdar Sarah , King Anna E
Published: December 2023

Background

The failure of some clinical trials using drugs that remove brain amyloid to prevent progression of dementia suggest that neurodegenerative disease may not progress in a linear fashion and threshold levels of one pathology may initiate alterations that are unable to be reversed upon removal of the initiating pathological process. We used the inducible Tg4510 mouse tauopathy model to determine whether neurodegeneration could be halted following removal of transgene expression in mice aged to 18 months

Method

Pathology was induced in mice from 8 weeks until 18 months of age (n = 20 equal male/female; both tau transgenic and non‐transgenic) by removal of doxycycline (dox) diet. Dox diet was returned to half the animals from 18‐23 months to inhibit pathology. Levels of serum Nfl were measured using SIMOA assay throughout disease progression and p‐tau181 along with other serum biomarkers were measured at endpoint. Immunohistochemical assays were performed to quantitate numbers of neurons (NeuN) and tau load (PHF‐tau) in hippocampus.

Result

Serum Nfl increased over aging in all mice and was significantly higher in tau transgenics relative to non‐transgenics at 18 months (p<0.05). Between 18 and 23 months, the rate of serum Nfl increase was significantly(p<0.05) reduced in male transgenic mice on dox compared to female transgenic mice, so that by 23 months levels were not different from non‐transgenic mice. Similarly, the numbers of neurons in the hippocampus of male mice on dox at 23 months was significantly higher than their female counterparts (p<0.05). When looking at levels of serum p‐tau181 at 23 months, there was significantly (p<0.05) higher levels in male mice on dox than female mice

Conclusion

These data suggest that aged female mice have ongoing neurodegeneration following removal of pathology induction that is similar to mice with continued pathology induction. The differences in serum p‐tau‐181 may indicate that female mice fail to clear pathological tau from the brain. Further studies will examine the relationship between histopathology and blood biomarkers and determine whether female mice on dox have a higher tau pathology load than their male counterparts.
Trajectories of white matter degeneration in frontotemporal dementia: new insights using fixel‐based analysis
Authors: Landin‐Romero Ramon , Quang Halle , Matis Sophie , D'Souza Arkiev , Calamante Fernando , Piguet Olivier
Published: December 2023

Background

The three clinical presentations of frontotemporal dementia (FTD), behavioral‐variant FTD (bvFTD), progressive non‐fluent aphasia (PNFA), and semantic dementia (SD), are caused by abnormal aggregation of protein pathologies and progressive brain atrophy that precede the emergence of clinical symptoms. Neuropathology shows a ‘prion‐like’ propagation along white matter pathways before aggregating in the neuronal cell bodies of the grey matter. The in‐vivo mapping of upstream white matter trajectories of degeneration can improve disease staging and understanding of disease mechanisms in FTD, but longitudinal white matter studies are rare due to methodological challenges. Here, we develop a novel neuroimaging approach to map white matter changes in FTD using fixel‐based analysis (FBA), a new diffusion weighted imaging technique.

Method

Sixty FTD patients (23 bvFTD, 15 PNFA and 22 SD) were matched with 30 heathy controls. Participants underwent a comprehensive annual clinical assessment and high‐resolution multimodal MRI (median 2 years; range 1‐6 years). Time‐varying changes in white matter fibre density and cross‐section were computed with MRtrix3, FreeSurfer 7.1.1 and Spatiotemporal Linear Mixed Effects models.

Result

All FTD syndromes showed more extensive white matter changes at baseline than previously reported. In bvFTD, atrophy extended posteriorly over time, encroaching in tracts connecting subcortical and motor‐associations regions (Fig 1). In PNFA, baseline left‐lateralized atrophy extended anteriorly and inferiorly and into the contralateral hemisphere, eventually mirroring patterns of atrophy at presentation (Fig 2). In SD, the focal left temporal baseline atrophy extended posteriorly and laterally along the inferior and superior longitudinal fasculi, and involving the right hemisphere with disease progression (Fig 3).

Conclusion

The FBA approach enabled the identification of new white matter bundles in FTD, with syndrome‐specific effects and improved biological interpretability compared to traditional tensor imaging methods. Our method can be extended beyond FTD to other neurodegenerative disorders to inform better models of disease staging and provide useful targets for patient stratification and monitoring in trials of disease‐monitoring interventions.
Impact of multidomain lifestyle intervention on white matter integrity: theSUPERBRAIN exploratory sub‐study
Authors: Moon So Young , Kim Sohui , Hong Chang Hyung , Park Yoo Kyoung , Na Hae Ri , Song Hong‐Sun , Park Hee Kyung , Lee Jong‐Min , Jeong Jee Hyang , Choi Seong Hye
Published: December 2023

Background

In the SoUth Korean study to PrEvent cognitive impaiRment and protect BRAIN health through lifestyle intervention in at‐risk elderly people (SUPERBRAIN), we evaluated the impact of a 24‐week facility‐based multidomain intervention (FMI) and home‐based MI (HMI) on white matter integrity.

Method

Totally, 152 participants, aged 60‐79 years without dementia, were randomly assigned to the FMI, HMI, or control groups. Among them, 55 participants (20 FMI, 19 HMI, and 16 controls) underwent brain MRI at baseline and 24 weeks. The dtifit tool was used to fit the diffusion tensor model and computed diffusion scalar maps for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Individual FA, MD, AD, and RD at baseline were compared among groups using one‐way analyses of covariance (ANCOVA) with age, sex, years of education, and imaging site effects added as covariates of no interest. In addition, to compare changes in the FA, MD, AD, and RD from baseline to the study endpoint, we used two statistical analyses. First, ROI‐wise paired t‐tests were used to analyze longitudinal changes in white matter integrity for control and intervention group. The statistical significance level was set at bonferroni corrected p‐value < 0.05. And then, significant brain image measures in previous paired t‐test were compared between each group pair (FMI vs. control; HMI vs. control; FMI+HMI vs. control) using ANCOVA with changes as dependent variables and age, sex, education, and site as covariates.

Result

The FA, MD, AD, and RD at each ROI at the baseline were not different among groups after bonferroni correction. In cingulum regions, the FA and AD were increased and the MD and AD were decreased significantly in the intervention group. The AD in right uncinate fasciculus was also increased in intervention group. Finally, among the significant regions in paired t‐test, compared with the control group, the FMI, HMI, and intervention group yielded significantly more beneficial effects on the AD of the cingulum regions

Conclusion

The change of white matter integrity in the intervention group suggests that multidomain lifestyle intervention may be beneficial through structural neuroplastic changes in highly complex tract.
Associations between neighborhood environment and computerized cognitive performance among older Black adults
Authors: Allan Alexa C , Gamaldo Alyssa A. , Thorpe Roland J. , Roberts Jennifer D , Evans Michele K , Zonderman Alan B
Published: December 2023

Background

Studies have suggested that neighborhood quality is associated with health outcomes beyond individuals’ socioeconomic characteristics (Kind & Buckingham, 2018; Ludwig et al., 2011). Limited research has explored how subjective neighborhood quality is associated with cognitive functioning, particularly among socioeconomically diverse Black adults. The current study examined the cross‐sectional association between perceived neighborhood characteristics and cognitive functioning among Black adults.

Method

This study included 1,079 community‐dwelling, socioeconomically diverse Black adults (Mage = 56.64, SDage = 9.14; 59% female) from wave 4 of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. Neighborhood quality was assessed using three scales about built environment disorder (e.g., litter, graffiti, and crime), social cohesion (e.g., close‐knit neighborhood, neighbors can be trusted), and social control (e.g., neighbors take action for children disrespecting adults). Cognitive functioning was assessed using the computerized Joggle battery. Multivariable linear regression analyses were conducted with each cognitive measure as the outcome measure. Models were adjusted for age, sex, education, reading literacy, poverty status, and depressive symptoms.

Result

In the adjusted models, higher built environment disorder was associated with slower performance (p < .05) on an attention and visual orientation measure and fewer correct responses (p’s < .05) on attention, executive function, and speed measures. High social cohesion was associated with faster performance (p < .05) on attention, visual orientation, executive function, and speed measures. Additionally, high social cohesion was associated with greater numbers of correct responses (p < .05) on an attention and executive function measure. Interestingly, high social control was associated with slower performance on executive function. Significant interactions were observed between neighborhood quality and covariates. For example, higher perceived social cohesion was associated with slower average reaction time on memory and attention, particularly for individuals with higher depression total scores. In contrast, higher perceived social cohesion was associated with faster average reaction time on executive functioning, particularly for men.

Conclusion

These findings underscore the importance of environmental characteristics for cognitive performance among Black adults. Further, these findings support the continued assessment of contextual factors as mechanisms or avenues for understanding how to improve cognitive functioning.
The Australian Dementia Network Registry: A Nationwide Clinical Quality Registry to monitor and improve dementia diagnosis and care
Authors: Ward Stephanie Alison , Brodaty Henry , Rowe Christopher C , Wallis Kasey , Ahern Susannah
Published: December 2023

Background

Many Australians live with dementia, yet limited evidence suggests there are unacceptable variations in clinical care. Until now there had been no systematic collection of high‐quality clinical data that benchmarks practice and helps drive improvements.

Method

The Australian Dementia Network (ADNeT) Registry, a clinical quality registry designed to close this gap, recruits sites involved in dementia diagnosis, such as memory clinics, and collects a minimum dataset from clinicians at the time of diagnosis of either dementia or mild cognitive impairment (MCI). The Registry later sends information to patients (and/or caregivers), including on how to withdraw if preferred, and collects co‐designed patient and/or caregiver outcome and experience measures by survey. The Registry oversees data analysis, generates clinical quality indicators (CQIs), and facilitates timely access for providers to this data.

Result

Commencing in 2020, ADNeT Registry has so far collected data from 55 clinics, representing all Australian states, including from regional and rural areas, and public and private providers. Data on the 2250 participants to date, 1552 (69%) with dementia and 698 (31%) with MCI, indicates a median time from referral to diagnosis of 126 days. For dementia and MCI, respectively, mean ages (SD) at diagnosis are 78.7(8.7) and 76.8 (8.8) years, and mean MMSE scores are 20.7(5.3) and 26.1 (2.8). The most common dementia subtype diagnosed is Alzheimer’s Disease (76%), whilst the CQIs showing most substantial variation nationally are for cholinesterase prescription and appointment wait‐times. The Registry has an 11% opt‐out rate, receives 48% of patient/caregiver surveys sent, has published three site and one annual report, and continues to grow.

Conclusion

The ADNeT Registry’s early experience is that a clinical quality registry for dementia in Australia is feasible to implement and provides value to participating clinicians. We anticipate that, over time, feedback to clinicians and benchmarking of their data compared to their colleagues’ will drive improvements in diagnostic practices and care. Additional Registry attributes, such as facility to enable research study participation, and expansion of dataset to enable uptake and outcome monitoring of new diagnostics and therapeutics, has made it attractive to governmental, regulatory, professional, consumer and pharmaceutical bodies.
Are the predictions of phenotypic cognitive scores by polygenic cognitive scores driven by the cognitive complexity of the phenotypic measures? A meta‐analysis
Authors: Nijenhuis Jan te , Balaji Kannappan , Lee Kun Ho
Published: December 2023

Background

Intelligence is highly heritable and plays an important role in behavioral genetic research. Recent genome‐wide association studies (GWASs) have identified inherited genomic variants that account for a modest portion of the heritability of intelligence. There are many studies where cognitive polygenic scores (PGSs) are used to predict scores on intelligence tests; the resulting rs are all over the place. Various explanations are offered for this high variability in resulting rs, but none of them are convincing.

There is another approach, building upon a fundamental finding from intelligence research, namely that the most important difference between intelligence tests is their difference in cognitive complexity. We hypothesize that the predictions of phenotypic cognitive scores by polygenic cognitive scores are a function of the cognitive complexity of the phenotypic cognitive scores.

Method

We carried out a meta‐analysis of studies reporting 1) cognitive polygenic scores (IQ, Cognitive achievement, Educational attainment) and 2) the correlation between cognitive polygenic scores and at least four cognitive test scores. We computed the cognitive complexity of the cognitive tests. We then computed the correlation between 1) the cognitive complexity of the cognitive tests and 2) the correlation between cognitive polygenic scores and at least four cognitive test scores. A strong positive correlation means that the predictions of phenotypic cognitive scores by polygenic cognitive scores are strongly driven by the cognitive complexity of the phenotypic measures.

Result

A substantial number of studies were found and many of them were based on a large number of subjects. The studies analyzed so far show large to very large correlations, strongly confirming the hypothesis.

Conclusion

Based on an analysis of a subset of the studies in the meta‐analysis, cognitive polygenic scores predict most strongly for difficult IQ tests and least strongly for easy IQ tests. So, we conclude that the predictions of phenotypic cognitive scores by polygenic cognitive scores are strongly driven by the cognitive complexity of the phenotypic measures.
Dementia caregiving in Nigeria: is stigma a motivator for care, a barrier to care, or both?
Authors: Nwakasi Candidus , Esiaka Darlingtina
Published: December 2023

Background

Some Nigerians struggle to make sense of symptoms resulting from Alzheimer’s disease and related dementias (ADRD). This may not be surprising as there is no word for dementia in its over 500 local languages. Thus, some Nigerians use words to explain ADRD symptoms that may stigmatize people living with dementia and their families.

Method

Our qualitative descriptive study while focusing on the everyday understanding of dementia, aims to highlight the influence of stigma on the caregiving experiences of informal female Nigerian dementia caregivers. Semi‐structured interviews were conducted with a purposive sample of 12 adult informal female caregivers in Nigeria. We analyzed the interview transcripts for themes. Then, the findings were shared with focus groups of 21 adult Nigerians residing in the United States to gain more contextual insight on the initial findings.

Result

The three major themes identified in the study include: 1) misconceptions about ADRD symptoms, 2) stigma as a negative motivator, and 3) stigma weakens family support.

Conclusion

Overall, we argue that a combination of limited ADRD knowledge and awareness, and traditional beliefs drive ADRD‐related stigmatization. This consequently affects access to caregiving and family support. Strategies such as culturally appropriate ADRD awareness campaigns and formal long‐term care policies are urgently needed. These would help reduce the risk of ADRD‐stigmatization and strengthen informal dementia caregiving in Nigeria.
Dissociating recollection precision from success in healthy older adults and mild cognitive impairment
Authors: Hill Paul , Ekstrom Arne
Published: December 2023

Background

Age‐related variance in episodic memory can be accounted for in part by the retrieval of less precise mnemonic representations, independently of age differences in recollection success. Whether these selective deficits in memory precision are exacerbated in older adults with mild cognitive impairment (MCI) is unknown.

Method

Healthy older adults and adults with MCI recalled item‐location associations in a circular space. Distance errors between the remembered and true location of each item were fit with a probabilistic mixture model to determine the probability that a given response belonged to a Gaussian distribution with a mean distance error of zero (indicating memory success), or to a uniform distribution comprising the full range of possible responses (indicating memory failure). We defined memory precision as the variability in distance errors during successful retrieval trials (i.e., belonging to the Gaussian component).

Result

Item recognition and source memory accuracy were reduced in the MCI cohort relative to healthy older adults. By contrast, the precision of successfully retrieved item‐location associations did not differ between the two groups.

Conclusion

Retrieval success and mnemonic precision represent dissociable sources of variance in memory performance in older age and mild cognitive impairment.
The association between the area deprivation index and dementia in a Veteran Population
Authors: Dintica Christina S. , Bahorik Amber L , Xia Feng , Kind Amy J. , Yaffe Kristine
Published: December 2023

Background

Residence in a disadvantaged neighborhood is associated with adverse health exposures and outcomes, and may increase risk for cognitive impairment and dementia. We investigated the association of the area deprivation index (ADI) with dementia in in a sample of the national Veteran population.

Methods

We examined data from the Veterans Health Administration (VHA), the largest integrated health care system in the United States. We studied 1,613,337 patients who obtained VHA care from 10/1/1999 to 9/30/2021, (n = 1,395,872 White; n = 147,530 Black) aged ≥55 years (mean: 68.6, SD: 7.7), 98% male. We characterized neighborhood deprivation with the ADI, a validated measure that combines 17 specific indicators (e.g., income, education, employment and housing) into an index of disadvantage. Participant zip codes from residential addresses were geocoded and assigned an ADI national rank according to their census block group. We used these data to categorize participants into ADI rank quintiles, where higher ADI rank quintile corresponds with more deprivation. We estimated adjusted incidence rates of dementia (International Classification of Diseases, 9th and 10th Edition codes) using Cox proportional hazards regression with age as the time scale.

Results

During a mean follow‐up of up to 11 (SD 4.8) years, 208,909 participants (12.8%) developed dementia. Compared to the least disadvantaged neighborhood quintile, all other groups had an increased risk of developing dementia in models adjusted for sex, race/ ethnicity, and psychiatric and medical comorbidities. The association was dose‐dependent, with the most disadvantaged quintile demonstrating the greatest risk (Quintile 2 HR: 1.09 95% CI: 1.07, 1.11; Quintile 3 HR: 1.14, 95% CI: 1.12, 1.16; Quintile 4 HR: 1.17, 95% CI: 1.16, 1.19, Quintile 5 HR: 1.24, 95% CI: 1.22, 1.26, Quintile 1 reference group). Repeating our main analysis using competing risks regression led to similar results.

Conclusion

We found a dose‐dependent association between ADI and dementia The ADI may be a valuable tool for identifying high‐risk communities for dementia intervention.
Contrasting longitudinal changes in amygdala integrity in early Alzheimer’s disease and frontotemporal dementia subtypes
Authors: Huang Mengjie , Landin‐Romero Ramon , Dalton Marshall Axel , Piguet Olivier
Published: December 2023

Background

The amygdala is a complex and heavily connected subcortical brain structure. It plays a central role in regulating social, emotional and cognitive processes. Amygdala atrophy has been previously reported in Alzheimer’s disease (AD) and in frontotemporal dementia (FTD), although the findings are inconsistent. In addition, the trajectories of atrophy progression over time are unclear. The aim of this study was to determine the structural changes of the amygdala in early AD and FTD and map their changes over time.

Method

Patients clinically diagnosed with amnestic AD (n = 20) or with FTD (behavioural variant FTD (bvFTD) = 20; semantic dementia (SD) = 20, primary nonfluent aphasia (PNFA) = 20), and 20 matched healthy controls (HC) completed whole brain structural MRI annually across multiple time points. Automated regional parcellation of the amygdala into three subregions was performed with FreeSurfer 7.1.1 using the T1‐weighted images. Linear mixed effects models were applied to identify changes in amygdala volumes over time.

Result

At baseline, bvFTD, SD and AD, but not PNFA, displayed significant overall amygdala volume loss compared with HC. Atrophy was most severe and asymmetrical (Left > Right) in SD. No subregional differences emerged across the clinical groups. Longitudinal analyses revealed a significantly greater amygdalar atrophy rate overall in all patient groups compared with HC. The greatest volume reduction was found in the right amygdala, which was significantly most pronounced in SD, across all subregions. In contrast, only the AD and PNFA groups showed a significant change over time in the left amygdala.

Conclusion

These findings identified global amygdala changes in AD and FTD. Importantly, these changes have a different time and location signature depending on the disease. In FTD, they occur early and more severely in SD and bvFTD, but later in PNFA. In AD, atrophy seems to take a more protracted course. In all groups, the right amygdala was affected later than the left. These findings have implications for the diagnosis and monitoring of these dementias. Future analyses will examine the relations of these alterations in amygdala integrity with social cognition and emotion regulation, functions known to be variably compromised in AD and FTD.
Amyloid β Induces Lipid Droplet‐Mediated Microglial Dysfunction in Alzheimer’s Disease
Authors: Prakash Priya , Manchanda Palak , Paouri Evangelia , Bisht Kanchan , Sharma Kaushik , Wijewardhane Prageeth , Randolph Caitlin , Clark Matthew , Fine Jonathan , Thayer Elizabeth , Prayson Richard , Zhang Chi , Davalos Dimitrios , Chopra Gaurav
Published: December 2023

Background

Several microglia‐expressed genes have emerged as top risk variants for Alzheimer’s disease (AD) that are involved in lipid droplet (LD) formation and processing. Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD‐risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. LD accumulation in aging (Nat Neurosci. 23(2),194‐208, 2020) appears to increase microglial inflammatory responses, while inflammatory challenges increase LD formation, thereby potentially setting up a feed‐forward injury that could contribute to the relentless progression in AD.

Method

LD formation is dependent upon age and disease progression, and is more prominent in the hippocampus in brains from human patients and the AD mouse model 5xFAD. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD‐laden microglia exhibited a deficit in amyloid‐beta (Aβ) phagocytosis evaluated using AβpH ‐ a human Aβ1‐42 analog that exhibits fluorescence upon lysosomal internalization (Chem Sci. 12, 10901‐10918, 2021). Extensive unbiased lipidomic and metabolomic profiling in microglia identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation.

Result

We show that microglia form LDs upon exposure to Aβ, and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. Mechanistically, Aβ alone is sufficient to induce LD formation in microglia and that this conversion requires a specific metabolic conversion of FFAs to TAGs (the building blocks of LDs). This conversion is likely protective for the brain and microglia, as we recently showed that long‐chain saturated FFAs can be neurotoxic (Nature 599,102‐107, 2021), but it is not without cost for microglial phagocytic abilities. We demonstrate that a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting it improved microglial uptake of Aβ.

Conclusion

These findings identify a new lipid‐mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.
Comparison of Baseline Cognitive Testing Results in Mild Cognitive Impairment Subtypes in the NACC Database
Authors: Lerner Alan J. , Appleby Brian , Elkasaby Mohamed , Leverenz James B , Malone Joseph , Miller‐Scott Lindsay J , Murphy Tamara B , Ogrocki Paula K. , Pillai Jagan A. , Duffy Charles
Published: December 2023

Background

Mild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living. MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamestic single domain (NASD), or Nonamnestic multi‐domain (NAMD). Previous studies have suggested Nonanmestic subtypes demonstrate more likely represent non‐AD prodromes, but conclusions have been limited by small sample sizes. The present study attempts to see correlates of htese proposed differences as evident by cognitive testing battery.

Method

Using the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with subtyping. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. Baseline demographic, clinical features, Neuropsychiatric symptoms, and AD biomarkers were collected. One‐way ANOVA analyses were used to compare cognitive performance on all UDS cognitive tests across MCI subtypes.

Result

9852 individuals with MCI on baseline UDS visits were analyzed: 45.4% AMD, 33.7% ASD, 12.6% NASD, 8.2% NAMD. There were significant differences (P<.001 or greater) on all measures which is not unexpected given large sample size. Notable differences between ASD/AMD, NASD/NAMD were prominent on Trails B, Craft story immediate and delayed recall, and Benton immediate recall minus delayed recall. See table for complete summary of scores.Trails B, mean (SD) times were ASD (113±62), AMD (157±82), NASD (143±78),NAMD (171±83). Craft story showed clear differences between groups on immediate recall (ASD14.9 (6.4)/AMD 14.2 (6.76)/NASD 18.0 (8.0/NAMD 17.9 (6.9)) and delayed recall (ASD 9.9 (7.0)/AMD 10.1 (6.7)/NASD 15.2 (6.4)/NAMD 15.5 (6.2)). Benton immediate minus delayed recall differences were ASD 8.1/AMD 7.9 versus NASD 4.2, NAMD 4.9)

Conclusion

Nonamnestic MCI subtypes are characterized by lower performance on executive tasks such as Trails B. Conversely, memory tasks show lower performance in NACC UDS participants with amnestic subtypes of MCI. This would support the concept that Nonamnestic MCI may represent prodromal stages of non‐AD dementia more frequently.
Specific serum autoantibodies predict the development and progression of Alzheimer’s disease with high accuracy
Authors: Shen Lu , Fang Liangjuan , Jiao Bin , Cao Liqin , Tang Beisha
Published: December 2023

Background

Autoimmunity plays a key role in the pathogenesis of Alzheimer’s disease (AD); however, whether autoantibodies in peripheral blood can be used as biomarkers has not been reported.

Method

Serum samples were obtained from 767, 146, and 255 patients with AD, mild cognitive impairment (MCI), and other neurodegenerative diseases, respectively, and 518 healthy controls. Specific autoantibodies were measured using a custom‐made immunoassay. Multivariate support vector machine models were employed to investigate the correlation between serum autoantibody levels and disease states.

Result

Seven candidate AD‐specific autoantibodies were identified, and a classification model with high accuracy (area under the curve (AUC) = 0.94) was established. Importantly, these autoantibodies could distinguish AD from other neurodegenerative diseases and out‐performed amyloid and tau protein concentrations in cerebrospinal fluid in predicting cognitive decline (P < 0.001).

Conclusion

AD onset and progression are associated with an unappreciated serum autoantibody response. Therefore, future studies could optimize its application as a convenient biomarker for the early detection of AD.