bluuebunny/crossref_metadata_2025 huggingface dataset:
Religious Attendance, Childhood Trauma, and Later Life Depressive Symptoms
Authors: Britt Katherine C , Dong Fanghong
Published: December 2023

Background

Older adults who experienced childhood trauma are at higher risk of developing depression. Depression is linked with structural changes in the brain and alterations in neurotransmitters and inflammation, placing individuals with depression at 2 times as likely to develop dementia than individuals without depression. A growing body of literature supports religion and spirituality as protective factors for mental health, yet few studies have examined the mediating role of religious attendance on the association between childhood trauma and depressive symptoms in later life. Identifying modifiable protective factors to decrease depression and, potentially, dementia is needed to decrease the growing dementia burden.

Method

We analyzed data from the Health and Retirement Study in 2006‐2012 to examine the mediating role of religious attendance (in 2010) on the association of childhood trauma (in 2008) with later‐life depressive symptoms (in 2012) among older adults in the U.S. (N = 3,240) aged 60 years and older. A mediation analysis was conducted while controlling for covariates: sex, race, education, age, marital status, body mass index (BMI), and cognition.

Result

Aged 60‐104 years, participants had a mean age of 72.7 (8.45) years, were 57.9% female, and were 82.9% White. A significant association was found for childhood trauma using 4 self‐report items and self‐reported depressive symptoms using the Center for Epidemiological Studies‐Depression scale (CES‐D) (β = 0.2124, 95% CI [0.31, 0.1201], p<.001). There was a partial mediating effect of self‐reported religious attendance (high vs. low) between childhood trauma and depressive symptoms (β = 0.017, 95% CI [0.03, 0.003], p<.05) adjusting for sex, race, education, age, marital status, BMI, and cognition.

Conclusion

Religious attendance plays a partial mediating role in the relationship between childhood trauma and later‐life depressive symptoms in older adults. Clinical trials are needed to further examine the effect of religious attendance on depressive symptoms in older adults with a history of childhood trauma, with the potential to decrease the risk of dementia.
Association of Dietary Fat and the ApoE4 Allele with Cognitive Decline in a Biracial Population Sample
Authors: Liu Xiaoran , Beck Todd , Evans Denis A , Rajan Kumar B
Published: December 2023

Background

Intake of dietary fat has been linked with cognition. Apolipoprotein E plays a critical role in lipid metabolism; however, the potential interaction between ApoE ε4 carrier and dietary fat on cognition is not fully understood. We aim to examine the association of types of dietary fat and their relation to cognitive decline among those with and without the ApoE ε4 allele.

Method

The study included 3,528 participants from the Chicago Health and Aging Project (62% African Americans, 63% female). Global cognition was assessed using a composite score of episodic memory, perceptual speed, MMSE; and diet using a 139‐item food frequency questionnaire. ApoE genotype was assessed by hME Sequenom mass‐array platform. Longitudinal mixed effect regression models were used to examine the association of dietary fat and the ApoE ε4 allele with cognitive decline, adjusting for age, sex, education, smoking status, and calorie intake.

Result

Among varying types of dietary fat, including saturated fat (SFA), monounsaturated fat, and polyunsaturated fat, we found that a higher intake of SFA was associated with faster cognitive decline (p for trend 0.0274). Per 5% increase in calorie from SFA was associated with a 15% faster cognitive decline (β = ‐0.0064, p = 0.04). Participants in the highest quintile of intakes of SFA had a 34% faster cognitive decline than those in the lowest quintile (β = ‐0.0125, p = 0.0095).

In those with ApoE ε4 allele, per 5% increase in calorie from SFA was association with a 21% faster decline (β = ‐0.0197, p = 0.0038). Among participants with ApoE ε4 allele, individuals in the highest quintile of intakes of SFA had a 45% faster cognitive decline compared to those in the lowest quintile of intake (β = ‐0.0372, p = 0.0003). Higher SFA was not associated with cognitive decline among those without the ApoE ε4 allele nor other types of dietary fat.

Conclusion

Our study found a significant association of saturated fat with faster cognitive decline among those with the ApoE4 allele. Higher intake of saturated fat among the ApoE4 carriers might lead to significantly higher risk of cognitive decline in old age.
Dimensions of activities of daily living in subjective cognitive complaint elderly. The GERO Cohort
Authors: Slachevsky Andrea , Lillo Patricia , Sepúlveda Loyola Walter , Demanet Michele , Cerda Mauricio , Henriquez Fernando , Parrao Teresa , Zitko Pedro , Martínez‐Pernía David , Villagra Roque , Amieva Helene , Thumala Daniela
Published: December 2023

Background

Subjective cognitive complaint (SCC) is a risk factor of functional impairment in activities of daily living (ADL). ADL are divided from basic (BADL), instrumental (IADL), and advanced activities of daily living (a‐ADL), according to their cognitive complexity. These three dimensions of ADL have been scarcely explored in SCC The objective of this study was to analyze these three dimensions of ADL and their association with global cognition and sociodemographic factors in SCC.

Method

291 participants from the GERO prospective cohort study of community‐dwelling elderly with SCC, aged 70 or older, living in Santiago ‐ Chile were analyzed. ADL were evaluated with the Technology Activities of Daily Living Questionnaire (T‐ADLQ), an informant‐rated questionnaire measuring BADL, IADL and aADL (T‐ADLQ total score and dimension score range 0‐100, higher values meaning worse performance), global cognition with the Mini‐mental state (MMSE) and sociodemographic factors measured with age, gender, marital status, education, household‐income, working status. A multivariate logistic regression model was performed considering MMSE and sociodemographic factors as explanatory variables and the different dimensions of ADL as dependent variables. Results were evaluated with coefficient of regression and 95% confidence intervals.

Result

Performances in T‐ADLQ total score ranged from 0 to 56; in BADL from 0 to 40; in IADL from 0 to 67 and a‐ADL from 0 to 100. T‐ADLQ total score was independently associated with MMSE (Coef: ‐0.24), age (Coef: 0.40) and marital status (Coef: 3.44), BADL with age (Coef: 0.14), IADL with age (Coef: 0.45) and marital status (Coef: 3.59), a‐ADL with marital status (Coef: 7.25). Results are presented in Table 1.

Conclusion

Impairment in ADL and their associated factors in SCC differ according to their complexity, being the aADL the most affected. Studying dimensions of ADL could contribute to better understanding functionality in SCC.

Slachevsky, A., …, Thumala, D. (2020). GERO Cohort Protocol, Chile, 2017‐2022: Community‐based Cohort of Functional Decline in Subjective Cognitive Complaint elderly. BMC geriatrics, 20(1), 505.

Slachevsky, A., … Hornberger, M. (2019). Mapping the neuroanatomy of functional decline in Alzheimer’s disease from basic to advanced activities of daily living. Journal of neurology, 266(6), 1310‐1322

Funding: ANID/FONDAP/15150012; ANID /FONDECYT/ 1231839 and ANID/PIA/ANILLOS ACT210096.
Caregiver Attributions of Cause to Behavioral Symptoms of Dementia
Authors: Winstead Vicki , Pickering Carolyn E , Yildiz Mustafa , Wang Danny
Published: December 2023

Background

Most individuals with Alzheimer’s disease and related dementias (ADRD)exhibit behavioral and psychological symptoms of dementia (BPSD) which can negatively impact quality of life for both caregiver and care recipient, yet there is a lack of knowledge on mechanisms of symptom development and triggers that can exacerbate a symptom. Thus, the aim of this study is to explore family caregiver perceptions’ of why a particular BPSD occurred.

Method

This study used a micro‐longitudinal design with family caregivers (N = 69) completing 8 days of diaries four times a day. Diaries were sent randomly three times a day and once in the evening. Data for this study were derived from the three random diaries (n = 982 responses) from the open‐ended question, “why do you think the behavior occurred?” This question was a follow‐up question to the caregiver’s report of the last observed behavioral symptom. Content analysis was used to identify initial codes for thematic analysis. Focused coding was used to further refine and organize into thematic categories.

Result

The sample was 54% African American and 69% female with a mean age of 74 caring for a close family member with dementia. Final analysis of data revealed 5 themes describing the caregivers’ perceptions of the cause of the behavioral symptom. These themes included describing the cause as: 1) the care recipient experiencing a loss of autonomy, 2) behavioral symptom as a direct result of the disease, “it’s Alzheimer’s, stupid.” 3) attributing negative emotions to the care recipient, anger, fear 4) environmental factors such as too much conversation, TV show, being cold 5) physical symptoms, “knee pain, “lack of rest,” ill‐fitting dentures. Responses among many of the individual caregivers varied daily from diary to diary based on the behavior reported or they simply answered, I do not know.”.

Conclusion

There are many interventions which aim to reduce caregiver stress and improve management of BPSD though they often have small effect sizes and do not sustain the effect over time. Incorporating insights from caregivers on how BPSD occur in daily life may provide for more ecologically valid interventions.
CSF AβX‐34 ‐ a new biomarker for amyloid‐related small vessel pathology in early Alzheimer’s Disease
Authors: Pålhaugen Lene , Kirsebom Bjørn‐Eivind , Tecelao Sandra , Jarholm Jonas Alexander , Gisladottir Berglind , Christensen Erik , Amundsen Line , Harrison Peter , Turton Michael , Grøntvedt Gøril Rolfseng , Skogseth Ragnhild E , Aarsland Dag , Selnes Per , Fladby Tormod
Published: December 2023

Background

Brain small vessel disease (SVD) increases Alzheimer’s disease (AD) risk. Impaired amyloid β (Aβ) clearance is linked to amyloid plaque formation and cerebral amyloid angiopathy (CAA). Aβ1‐40 is deposited in vessel walls, and Aβ with a C‐terminal 34' cut‐point is produced by perivascular cells. Evidence for SVD‐AD interactions in early AD is elusive, but incipient CAA putatively increases susceptibility for amyloid‐related imaging abnormalities (ARIA) in AD patients.

Here we compare the SVD MRI marker “peak width of skeletonized mean diffusivity” (PSMD) to cerebrospinal fluid (CSF) Aβ species and the neurodegeneration marker Neurofilament light chain (Nfl), assessing links between SVD and AD pathologies and Aβ species as potential markers for incipient CAA.

Method

Cross‐sectional data from the Dementia Disease Initiation (DDI) cohort were available, comprising (n = 112) cognitively normal (CN) and (n = 115) cases with mild cognitive impairment (MCI) (n = 227). CSF markers for AD A/T/N‐staging identified 134 cases with negative markers (A‐/T‐/N‐), 21 with amyloid positive markers (A+/T‐/N‐) and 72 with amyloid and tau‐positive markers (A+/T or N+) (see table 1 for sample descriptives). Multiple linear regression models were used with PSMD by lobe as the dependent variable, and NfL, Aβ1‐40 (MesoScale), Aβx‐34 (Bioventix, Pre Diagnostic) (separately) and interactions with A/T/N group as independent variables. Variables were log‐transformed and standardized.

Result

Higher Nfl was related to higher PSMD independently of the Aβ species in all lobes. Although Nfl correlated with Aβ1‐40 (figure 1), no multicollinearity was observed in the model. In A+, lower Aβ markers were related to higher PSMD in all lobes, but particularly for the temporal lobe (figure 2). Aβx‐34 showed more robust relationships with PSMD in both A+ groups particularly in the temporal lobes (A+/T‐/N‐ b = .62, p = <.001, A+/T or N+ b = .52, p<.001) than Aβ1‐40. (A+/T‐/N‐ b = .66, p = <.01, A+/T or N+ b = .33, p<.001). Neither t‐ nor p‐tau measures were associated with PSMD (not shown).

Conclusion

Nfl independently related to PSMD, possibly reflecting amyloid‐independent neurodegeneration. CSF Aβx‐34 was in particular tightly linked to increased temporal lobe PSMD even in A+/T‐/N‐, pointing to early AD‐related SVD. This supports further evaluation of Aβx‐34 as a marker for CAA and susceptibility marker for ARIA.
Hippocampus‐associated tract degradation follows differential DTI patterns and is influenced by amyloid in MCI patients
Authors: Fleming Ben , Nowell Joseph , Edison Paul
Published: December 2023

Background

Diffusion tensor imaging (DTI) has been leveraged to understand microstructural alterations to limbic and cortico‐cortical tracts in Alzheimer’s disease (AD). However, investigation into the key changes and patterns of fractional anisotropy (FA) and mean diffusivity (MD) metrics in the early stages of MCI has not been widely investigated. This study aimed to establish whether the early DTI white matter tract changes in MCI patients are decoupled and whether amyloid positivity (Aβ+/Aβ‐) is associated with early tract degradation.

Method

171 participants (103 MCI & 73 CN) were recruited from the AD Neuroimaging Initiative (ADNI; adni.loni.usc.edu) database. For each participant, FA and MD maps were obtained at their baseline scan and voxel wise analysis was carried out using FSL (https://fsl.fmrib.ox.ac.uk/fsl/) and Tract‐Based Spatial Statistics (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/TBSS). Students t‐tests were conducted on the FA and MD changes in hippocampal WM tracts, previously identified as areas of potential early degradation. Comparisons between CN and MCI groups were made along Aβ+ and Aβ‐ groups.

Result

We found evidence for WM degradation, indicated by lower FA scores in MCI participants compared with controls, in the specific regions of interest of the fornix (p = 0.004) and tapetum (p = 0.012). Mean diffusivity was increased in the MCI group compared to CN in areas of the fornix (p < 0.001), consistent with FA alterations, yet differed from areas identified in FA changes owing to changes in the uncinate fasciculus (p = 0.022) and cingulum (p = 0.003). Comparison of DTI metrics in the fornix between amyloid status groups revealed that Aβ+ participants had significantly lower FA compared to Aβ‐ participants (p = 0.047), but MD did not significantly differ.

Conclusion

These results confirm the notion that WM tract integrity degradation in the tract apparatus surrounding the hippocampus occur early in the AD trajectory. However, results indicate that FA alterations occur in different patterns to that of MD and that amyloid may influence these patterns. This supports the idea that efforts to develop therapeutics which maintain WM tract integrity early may be key to slowing AD progression.
Does schooling attained by adult children affect parent’s cognitive function and decline in later life? An evaluation comparing observational and quasi‐experimental approaches
Authors: Gutierrez Sirena , Romero K. Renata Flores , Allen Isabel Elaine , Glymour M. Maria , Torres Jacqueline M
Published: December 2023

Background

A nascent body of research suggests that higher adult child educational attainment may have beneficial impacts on older parents’ cognitive aging. Children with higher education may offer both financial and non‐financial resources that help support healthy brain aging for older parents. The causality of these relationships is difficult to evaluate; quasi‐experimental approaches are needed to address the confounding bias expected for observational studies.

Method

We used data from the Mexican Health and Aging Study (n = 6741), a nationally representative cohort of adults aged ≥50 years (2012), with repeated measures of verbal memory and verbal fluency assessed in 2012, 2015, and 2018. We leveraged a 1993 national compulsory schooling law (CSL), which raised minimum schooling from six to nine years, as a source of quasi‐experimental variation in (adult) children’s education that is independent of confounders of the relationship between adult child education and parents’ cognition. We generated a binary instrumental variable based on the respondents’ oldest child’s birth cohort and used two‐stage least squares estimation (2SLS). We compared 2SLS estimates to those generated via ordinary least squares (OLS) regression and mixed linear models adjusted for respondent and family‐level characteristics.

Result

At baseline, participants (55.3% female) were on average 60.0 years old. OLS models suggested that more schooling among oldest adult children was associated with better baseline verbal memory (ß(95% CI): 0.017(0.012,0.022)) and verbal fluency z‐scores (ß(95% CI): 0.020(0.014,0.026)). Exposure to the CSL was associated with an increase in average educational attainment by 0.612 years (95% CI: 0.384, 0.842). However, estimates from 2SLS suggested no quasi‐experimental association between increased adult child schooling and older respondents’ verbal memory (ß(95% CI): ‐0.039(‐0.102,0.023)) or verbal fluency scores (ß(95% CI): ‐0.005(‐0.080,0.071)). In observational analyses, each year of increased schooling among oldest children was associated with slower decline in verbal memory z‐scores (ß(95% CI): 0.010(0.001,0.019)) per decade, but not with verbal fluency.

Conclusion

Our findings present promising, but inconclusive evidence that increases in schooling may have a beneficial effect on parents’ levels of cognitive performance. This work has important implications globally, given the massive increases in educational attainment achieved by recent generations in these settings.
Relationship Between P‐tau217 and Subjective Sleep Quality in MCI and Mild AD. A Preliminary Study
Authors: Price Ashley N. , Snyder Peter J , Strenger Jennifer , Thompson Louisa I , Jeromin Andreas , Sinoff Stuart , Alber Jessica
Published: December 2023

Background

Plasma‐tau217 (ptau217) has recently emerged as a biomarker for Alzheimer’s disease (AD). With sleep changes as an established feature of AD, previous studies suggest a link between sleep and tau pathology. We investigated whether overall subjective estimation of sleep quality is associated with p‐tau217 concentration (pg/ml) in a small sample population of older adults with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD).

Method

We examined participants (mean age = 69) with MCI (n = 14) and mild AD (n = 2). MCI participants had CDR 0.5 and MoCA scores ranging 17‐28. Mild AD participants had CDR of 1.0 and MoCA scores of 17. pTau217 was measured with a novel validated SIMOA assay, developed by one of us (A.J.) for ALZPath, Inc. The Pittsburgh Sleep Quality Index (PSQI) was used as a subjective measure of sleep quality. Pearson correlation coefficient was used to test the association between ptau217 and the global score of PSQI, and spearman’s rho was used for each of the 7 subscales of the PSQI.

Result

The global score (total score) of the PSQI was found to be significantly correlated with ptau217 concentration, such that poorer sleep was associated with increased ptau217 (r = ‐.587, p<.05). Partial correlations revealed that this correlation remained after controlling for age, sex, and years of education (all p<.05).

Conclusion

Global scores on the PSQI were associated with ptau217 concentration in MCI and mild AD participants, such that poor reported sleep quality was associated with increased plasma tau. Future studies in larger samples and longitudinal investigations using objective sleep data (actigraphs) would serve to confirm these findings.
Sex‐specific transcriptome alterations in the cingulate cortex of Lewy body dementia cases
Authors: Olney Kimberly C. , Wojtas Aleksandra , Rabichow Benjamin E. , DeTure Michael , Dickson Dennis W. , Chang Rui , Ross Owen A. , Fryer John D.
Published: December 2023

Background

Lewy body dementia (LBD) is one of the most common causes of dementia and is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of alpha‐synuclein in the form of Lewy bodies and neurites. Many of these individuals also have concomitant neuropathological changes such as vascular disease, tangles, and TDP‐43. Like in Alzheimer’s disease, APOE4 is the most significant genetic risk factor for the development of LBD. We sought to survey the landscape of transcriptional changes in the cingulate cortex from a large cohort of LBD cases (>400) compared to normal controls of both sexes.

Method

We performed bulk tissue RNAseq and aligned reads to a human reference genome that is informed on the sex chromosome complement of the sample. Differentially expressed genes were determined after genome‐wide correction.

Result

We found a core set of transcriptional changes that were shared between both sexes in pathways related to neuronal functions and inflammation. However, we also identified numerous changes in genetic female samples that were not significantly altered in genetic males, or that were significantly altered but in the opposite direction. Similar male‐specific changes were also found. These alterations were present for genes on both sex chromosomes as well as autosomes. Though cohort sizes were smaller, we also compared this dataset to Alzheimer’s disease and found shared but unique transcriptional alterations.

Conclusion

Overall, genetic males and females exhibit sex‐shared and sex‐specific gene expression patterns in dementia with Lewy bodies. We are currently assessing splice alterations, running causal gene network analysis, and performing histological validation.
Characterization of various type of cognitive impairment using multiomics – a pilot imaging study from a local institution
Authors: Cheung Eva YW , Mak Henry , Chau Anson CM , Chiu Patrick Ka‐Chun , Shea Yat Fung , Kwan Joseph SK
Published: December 2023

Background

In addition to clinical diagnosis, multi‐modal imaging has been employed for early detection of various types of dementia. Image features from various types of images provided information for accurate diagnosis. This study aimed to evaluate the role of multiple imaging, including MRI T1W, T2W, resting state functional MRI (rs‐fMRI) and 18‐F Flutemetamol PET image in diagnosis of various types of cognitive impairments.

Methods

56 participants (16 Alzheimer’s Disease (AD), 10 AD type Mild Cognitive impairment (A‐MCI), 18 vascular type MCI (V‐MCI), 12 Vascular dementia (VD) and 25 Healthy Control (HC) were recruited in an local memory clinic. All types of images were re‐orientated, segmentation and normalized to the whole brain mask template. 45 brain regional volumes (Vol) were calculated from T1w using Freesurfer. Brain regional white matter hyperintensities (WMH) were obtained from T2w images. Interhemispheric functional connectivity (IFC) of brain regions were measured from rs‐fMRI. Standard uptake value (SUV) were measured and calculated from the PET images. Also, patient demographics including age, sex and HK‐MoCa score (Demo) were recorded. 70% of each group of participants were assigned to the training group, whereas the rest 30% were assigned to test group. The neural network toolbox of MATLAB was employed to build four characterization models: Model 1 based Vol and WMH; Model 2 based on Vol, WMH and IFC; Model 3 based on Vol, WMH, IFC, and demo; Model 4 based on Vol, WMH, IFC, demo and SUV.

Results

The receiver operating characteristics (ROC) curves showed that the Model 1, 2 and 3 achieved satisfactory accuracy, with 79%, 68% and 70% respectively. While Model 4 achieved excellent accuracy of 100%. The sensitivity and specificity of each model for each group was over 75% to 100%. The model with more image features attained higher accuracy in dementia diagnosis.

Conclusion

Artificial neural network model with multiomics can accurately differentiate AD, A‐MCI, V‐MCI, VD and HC. Further study is suggested with more participants for models verification.
Together Stronger: A creative arts program for children of a parent with young onset dementia
Authors: Moiseyeva Darya , Goodman Janet , Heath Phillippa , Harrison Lizzie , Draper Charlie , Astell Arlene
Published: December 2023

Background

Working age individuals who develop dementia experience significant challenges to their ability to keep working. This has wide ranging impacts not only on the individual but also for their families, many of which include young children. Presently there is limited knowledge of the impact on children of having a parent with YOD or of resources to support these children.

Method

Eight children aged between 8‐19 took part in Together Stronger, a community based creative arts programme for children of a parent with young onset dementia. Hosted by the Museum of English Rural Life (MERL) the program ran in a hybrid format over eight bi‐weekly sessions. Activities included willow weaving, storytelling with museum artefacts, and baking together. The impact on the children’s wellbeing and social engagement was assessed using mixed methods.

Result

Qualitative results suggest an overall improvement in the wellbeing of the children whilst quantitative wellbeing results were inconclusive. The children were overwhelmingly positive about the creative activities and wished the group would continue. They particularly liked that the group did not focus on their parent’s dementia but instead was about creative activities. The children enjoyed the social aspect and appreciated the opportunity to spend time with other people in the same situation.

Conclusion

This community‐based project for children of parents with young‐onset dementia shows promising results in terms of feasibility, acceptability and impact. Participants' feedback on the structure and contents of the sessions provides useful recommendations regarding future service provision.
Mapping of validated apathy scales onto the apathy diagnostic criteria for neurocognitive disorders
Authors: Bawa Kritleen Kaur , Sankhe Krushnaa , Md Daniel Bateman , Cummings Jeffrey L. , Ereshefsky Larry , Husain Masud , Ismail Zahinoor , Manera Valeria , Mintzer Jacobo , Moebius Hans J. , Mortby Moyra E , Porsteinsson Anton P. , Robert Philippe , Miller David S. , Lanctôt Krista L.
Published: December 2023

Background

Diagnostic criteria for apathy (DCA) in neurocognitive disorders were developed in 2021. As next steps, we assessed whether commonly‐used validated apathy scales map onto the DCA and identified which scales map best.

Method

Using a modified Delphi process, mapping of the Neuropsychiatric Inventory‐Clinician (NPI‐C) Apathy domain and the Apathy Evaluation Scale (AES) onto the DCA were assessed by surveying apathy experts. For each item on the scales, experts were asked to evaluate the degree of correspondence to the DCA globally, and the 3 DCA dimensions [diminished initiative, interest, and emotion]. Respondents voted “not at all” (scored as 0), “weakly” (scored as 1), or “strongly” (scored as 2). For each item, if the mean score was <0.5, the item was considered not mapped, for scores >1.5, the item was considered mapped, and items with scores 0.5‐1.5 were discussed further in a virtual consensus meeting. The surveys were then sent to other scientific community members, and the interrater reliability between the two groups was assessed using Cohen’s kappa.

Result

The surveys were completed by 12 experts. For NPI‐C apathy, 10/11 (90.9%) questions mapped primarily onto one dimension of the DCA: 2 onto “Initiative”, 6 onto “Interest”, and 2 onto “Emotion”. Of NPI‐C Apathy domain items, 9/11 (81.8%) mapped globally onto the DCA. For the AES, 7/18 (38.9%) questions mapped onto different dimensions of the DCA: 4 onto “Initiative”, 2 onto “Interest”, and 1 onto “Emotion”; 6/18 (33.3%) items mapped globally onto the DCA. The mean mapping scores of NPI‐C were significantly higher than those of the AES (t (27) = 2.25, p = 0.032) indicating better performance of NPI‐C in this exercise. These findings were confirmed in a consensus discussion. There was substantial agreement (kappa = 0.621) between the experts and the community group regarding mapping of NPI‐C but only moderate agreement (kappa = 0.553) regarding mapping of AES on the DCA.

Conclusion

More questions from the NPI‐C Apathy domain mapped strongly and uniquely both globally, and onto the 3 dimensions of the DCA, compared with the AES. Future research using the DCA, NPI‐C Apathy domain, and AES in clinical and research settings are needed to confirm these results.
Synaptic dysfunction, Tau pathology and Neurodegeneration
Authors: Soares Carolina , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Aguzzoli Cristiano Schaffer , Rohden Francieli , Ferrari‐Souza João Pedro , Zalzale Hussein , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Benedet Andrea Lessa , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Soucy Jean‐Paul , Gauthier Serge , Souza Diogo O. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R , Pascoal Tharick A.
Published: December 2023

Background

Tau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration in the same brain regions. Our study aims to map in the brain the association of synaptic markers with tau and degeneration.

Method

We evaluated 147 individuals from the TRIAD cohort with CSF GAP43, SYT1, SNAP25, neurogranin (Ng), ptau217, neurofilament light protein (NfL) quantification, as well as tau positron emission tomography (PET), magnetic resonance imaging, and clinical assessments. One‐way ANOVA tested group differences on synaptic levels. Spearman correlation tested the association among synaptic proteins. Linear regressions tested the association between biomarkers. Voxel‐based morphometry (VBM) was considered as an index of neurodegeneration.

Result

We observed an increase in synaptic markers across age and the AD spectrum, reaching a plateau when cognition is affected (Figure 1A). Among the synaptic markers, SNAP25 showed the greatest magnitude of change, on average, between young, aged cognitively unimpaired, mild cognitive impaired, and AD individuals (mean 62.44%). (Figure 1B‐C). In addition, we found that all synaptic markers are significantly intercorrelated (Figure 1D). Moreover, CSF ptau217 correlated with all synaptic biomarkers, GAP43 (β = ‐044), SYT1 (β = ‐0.41), SNAP25 (β = ‐0.59) and Ng (β = ‐0.25). Conversely, CSF NfL was strongly but only correlated with GAP43 (β = 0.62) (Figure 2). Voxel‐wise correlation revealed that tau tangles measured by [18F]‐MK6240 PET, was positively associated with SNAP25 in AD‐related regions, and VBM was associated with all synaptic markers, but more closely with GAP43. Furthermore, the interaction between synaptic markers and temporal meta‐ROI [18F]‐MK6240 on VBM was significant for Ng and GAP43 (Figure 3).

Conclusion

Our results support a heterogenous role of synaptic markers in the AD continuum and suggest that synaptic dysfunction in the presence of tau pathology may not be driving atrophy.
Sulfanegen, a 3‐mercaptopyruvate sulfurtransferase substrate, as a therapeutic option for Alzheimer’s disease
Authors: More Swati S , Rao Swetha Pavani , Xie Wei , Kwon Christopher , Juckel Nicholas , Vince Robert , Lee Michael K
Published: December 2023

Background

The oxidative stress evident in the Alzheimer’s disease (AD) brain leads to compromised 3‐mercaptopyruvate sulfurtransferase (3MST) function, one of the endogenous hydrogen sulfide (H2S) producing enzymes.1,2 Impaired 3MST function is expected to contribute toward potentiation of oxidative stress by depleting cellular glutathione (GSH) stores, and exacerbation of AD pathology by enhancing Aβ aggregation resulting in neurodegeneration. Preclinical studies with H2S donors such as NaSH have been promising,3,4 however further clinical translation efforts are thwarted due to their poor chemical stability, bioavailability, and dose‐limiting toxicities. We have developed a stable, bioavailable prodrug of 3MST substrate 3‐mercaptopyruvate, named sulfanegen, which can supplement the enzymatic reaction releasing H2S.2 Thus provision of sulfanegen could prove beneficial in mitigating AD‐related neurodegenerative consequences.

Method

Aged, symptomatic cohorts APP/PS1 mice (7 and 12 month old) were treated with saline (N = 8) or sulfanegen (75 mg/kg, i.p., N = 8) for 12 weeks. Cognitive behavioral assessments (T‐maze) were conducted 10‐11 weeks after treatment initiation. Equal numbers of both sexes of mice were used as much as possible. The harvested brain tissues were analyzed biochemically for cortical/hippocampal Aβ1‐42 burden, oxidative stress and inflammatory markers (protein carbonyls, lipid peroxidation, glutathione assay, TNF‐α and IL6. Quantitative stereological analysis of Aβ pathology, neuroinflammation and progressive neurodegeneration were also conducted.

Result

Treatment of symptomatic Alzheimer’s mice with sulfanegen prevented cognitive impairment resulting from AD pathology (Figure 1).2 This was corroborated by reduced brain amyloid load as well as the reversal of oxidative stress and neuroinflammation. Neuropathological analysis also displayed modest, but significant effect of sulfanegen on Aβ levels, reactive astrogliosis and microglial reactivity. More importantly, sulfanegen caused attenuation of progressive degeneration of noradrenergic system in the LC. Additionally, administration of sulfanegen supplemented brain 3MP levels, resulting in restoration of brain 3MST function.

Conclusion

Collectively, our results show that the provision of a 3MST substrate, sulfanegen, exhibits neuroprotective effects, along with restoration of cognitive function in an AD mouse model. This study suggests an important role of 3MST in AD pathophysiology and potential therapeutic utility of sulfanegen as a disease‐modifying treatment.
Distinct Neural Correlates of Anxiety and Depression in Subjective Cognitive Decline versus Healthy Aging, a Microstructural Diffusion MRI Study
Authors: Flaherty Ryn , Sui Yu Veronica , Masurkar Arjun V. , Rusinek Henry , Lazar Mariana
Published: December 2023

Background

A common criticism of considering Subjective Cognitive Decline (SCD) as a preclinical stage of Alzheimer’s Disease is that it may be explained by depression or anxiety1. We used NODDI, a diffusion microstructural model2, to explore the pathophysiology of depression and anxiety in SCD versus controls.

Method

325 participants in the Cam‐CAN study 3 (127 SCD) older than 55 were included in the analysis. Diffusion imaging data was collected on a 3T Siemens TIM Trio scanner with a 32‐channel head coil for 0, 1000 and 2000 s/mm2 b‐values and 30 gradient directions. Preprocessing and calculation of the NODDI metric Intracellular Volume Fraction (ICVF) were completed using MRTrix3, AMICO and MATLAB. The hippocampal cingulum bundle and fornix regions of interest (ROIs)4 were extracted from the ICBM‐DTI‐81 atlas. Depression and anxiety were assessed using the Hamilton Anxiety and Depression Scale (HADS). Linear regression models were completed in R. Gender and age were included as nuisance variables.

Result

There were no differences in gender or age distribution between cohorts, however participants with SCD were more depressed and anxious on average (Table 1). There was a significant interaction effect between depression and cohort in the fornix (Figure 1), as well as between anxiety and cohort in the hippocampal cingulum (Figure 2). In post‐hoc analyses, only the SCD group showed a correlation between depression and ICVF in the fornix (Figure 1) while only controls showed a correlation between anxiety and ICVF in the hippocampal cingulum (Figure 2), indicating different pathophysiology underlying psychiatric symptoms in the two groups.

Conclusion

Anxiety and depression appear to be associated with different microstructural features in SCD versus controls, suggesting anxiety and depression in SCD is a phenomenon distinct from anxiety and depression in healthy aging. Future work will explore the relationship between anxiety and depression and risk of conversion to mild cognitive impairment.

1. Mitchell AJ, Beaumont H, Ferguson D, et al. Acta Psychiatrica Scandinavica. 2014;130(6):439‐51.

2. Daducci A, Canales‐Rodriguez EJ, Zhang H, et al. Neuroimage. 2015;105:32‐44.

3. Shafto MA, Tyler LK, Dixon M, et al. BMC neurology. 2014;14(1):1‐25.

4. Kantarci K. Frontiers in Aging Neuroscience. 2014;6.
The contribution of leisure activities to cognitive health in adults with chronic stroke
Authors: Hernández‐Gamboa Rebeca , Dao Elizabeth , Falck Ryan S , Liu‐Ambrose Teresa
Published: December 2023

Background

Stroke doubles one’s risk for dementia. Therefore, stroke survivors represent a target population in need of intervention strategies to promote cognitive function and prevent dementia. Engagement in leisure activities, such as social, physical, and cognitive enrichment activities, are beneficial for healthy cognitive aging. Thus, we hypothesize that higher levels of leisure activities are associated with better cognitive performance in adults with chronic stroke and may be a promising approach to promoting cognitive health post‐stroke.

Method

A cross‐sectional analysis of baseline data from the Vitality study – a randomized controlled trial examining the effects of exercise training or complex mental and social activities on cognitive function in community dwelling older adults (aged 55+ years) living with chronic stroke (i.e., stroke sequelae ≥1 year). Our primary cognitive outcome was the Alzheimer’s Disease Assessment Scale–Cognitive Subscale‐Plus (ADAS‐Cog Plus: 13‐item ADAS‐Cog and additional cognitive tests). We indexed participation in leisure activities using the Nottingham Leisure Questionnaire (NLQ); this questionnaire is specific for stroke survivors. We first investigated the bivariate correlation between leisure activities and ADAS‐Cog Plus score, and then performed multiple regression analyses to examine the independent contribution of leisure activities to explain variance in ADAS‐Cog‐Plus scores, after controlling for age, sex, education, and Montreal Cognitive Assessment (MoCA) score.

Result

Forty‐three females and 72 males were included in this analysis (mean age = 70.69 ±8.68, MoCA = 21.83±4.20, and NLQ = 22.84±7.26). Higher NLQ score was significantly associated with better ADAS‐Cog Plus score (r = ‐0.31; 95% CI: [‐0.47 ‐0.14]; p< 0.001). Importantly, the multiple linear regression indicated that higher NLQ scores were independently associated with better ADAS‐Cog Plus performance (b = ‐0.02 ± 0.007; p = 0.01). The adjusted R2 for the model including NLQ was significantly higher than the model without NLQ scores (F = 6.45, p<0.05).

Conclusion

Our findings suggest that higher levels of leisure activities are associated with better cognitive performance in adults living with chronic stroke. Future studies should explore the types of leisure activities that are most beneficial to preserve cognition and prevent dementia onset post stroke. Different physical and cognitively demanding activities may differentially affect cognitive function.
White Matter Correlates of Speech in Cerebrovascular Disease
Authors: Broberg Dana N , Haddad Seyyed MH , Aveni Katharine , Havens Alexander , Orange Joseph B , McLaughlin Paula , Binns Malcolm , Roberts Angela C , Bartha Robert
Published: December 2023

Background

Analyses of spoken discourse (speech beyond single words or sentences) can detect cognitive impairment in cerebrovascular disease (CVD) [Roberts, et al. (2021). Top Lang Disord 41(1):73‐98]. However, the neurological basis for altered spoken discourse in CVD is poorly defined. This study examined the association between spoken discourse and visible white matter damage detected using structural magnetic resonance imaging (MRI) and potential early‐stage damage in normal‐appearing white matter (NAWM) detected using diffusion tensor imaging (DTI) to better define the link between CVD‐related neurodegeneration and altered speech.

Method

Spoken discourse and 3T MRI data were obtained from the CVD cohort of the Ontario Neurodegenerative Disease Research Initiative (n = 127). Spoken discourse analyses were completed previously [Roberts et al., 2021]. White matter hyperintensities (WMH) and the NAWM portions of the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus – parietal (SLFp) and temporal (SLFt) endings, and uncinate fasciculus (UNC) were segmented in each hemisphere (Figure 1). Mean values of fractional anisotropy (FA) and mean diffusivity (MD) within NAWM, and normalized WMH volume were calculated for each of the white matter tracts. Three canonical correlation analyses examined associations between 10 spoken discourse measures and the imaging metrics (WMH volume, FA, MD) in each tract.

Result

Canonical correlations were significant for FA (rc
= 0.51, p<0.05) and MD (rc
= 0.56, p<0.05) but not WMH volume (rc
= 0.42, p = 0.69). Among the white matter tracts, the strongest canonical loadings were seen for FA and MD in the left SLFp (FA: 0.80; MD: ‐0.61) and left SLFt (FA: 0.60; MD: ‐0.40) (Figure 2). Higher FA and lower MD in the left SLFp and left SLFt were associated with fluency, information content, and syntax performance.

Conclusion

Spoken discourse performance was associated with microstructural integrity of NAWM but not visible white matter damage. These results suggest that DTI metrics provide a more relevant assessment of white matter tract function in relation to speech than a volumetric measure of tract lesion load. Of the white matter tracts investigated in this study, spoken discourse performance in CVD was most strongly linked to white matter microstructure in the parietal and temporal endings of the left superior longitudinal fasciculus.
Increased CSF GAP‐43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease
Authors: Franzmeier Nicolai , Dehsarvi Amir , Steward Anna , Biel Davina , Dewenter Anna , Roemer Sebastian Niclas , Wanger Fabian , Brendel Matthias , Ewers Michael , Moscoso Alexis , Blennow Kaj , Zetterberg Henrik , Schöll Michael
Published: December 2023

Background

Animal and in vitro studies of Alzheimer’s disease (AD) found that tau spreads trans‐synaptically in an activity‐dependent manner, suggesting that synapses are key routes for tau spread. Importantly, amyloid‐beta (Ab) induces synaptic remodeling and aberrant synaptic activity, which may accelerate trans‐synaptic tau spread. In AD patients, we found previously that PET‐assessed tau spreads from circumscribed epicenters across functionally connected brain regions. Yet, it remains unclear whether connectivity‐associated spread of tau in AD is accelerated by Ab‐related synaptic changes. The presynaptic growth‐associated protein 43 (GAP‐43) is implicated in synaptic plasticity and is consistently increased in cerebrospinal fluid (CSF) in AD, suggesting that GAP‐43 captures deviations in synaptic integrity such as aberrant synaptic activity. We therefore tested whether higher GAP‐43 is associated with faster Ab‐related tau spread.

Methods

We included longitudinal [18F]Flortaucipir tau‐PET (follow‐up∼3.21±1.48yrs), baseline [18F]Florbetapir amyloid‐PET and CSF GAP‐43 from 93 subjects (i.e., cognitively normal [CN] controls Ab‐, n = 54; CN/Mild Cognitive Impairment Ab+, n = 33/21). To model connectivity‐associated tau spread, we determined a connectivity template across 200 cortical regions (i.e., Schaefer atlas) using 3T multi‐band resting‐state fMRI in 42 age‐ and sex‐matched Ab‐/tau‐ controls. All statistical models were controlled for age, sex and diagnosis.

Results

Using linear regression, we found that higher CSF GAP‐43 levels were associated with faster Ab‐related tau‐PET increase in pre‐defined ROIs (centiloid x GAP‐43 interaction, global/temporal‐meta‐ROI: b = 0.0019/0.0028; p = 0.009/0.007, Fig.1) as well as in the personalized Q1 ROI (b = 0.0024; p = 0.004) that summarizes regions most closely connected to subject‐specific tau epicenters with highest baseline tau‐PET (Fig.2A). Importantly, this centiloid x GAP‐43 interaction decreased across regions less strongly connected to tau epicenters (Q2/Q3/Q4: b = 0.0017/0.0008/0.0002; p = 0.009/0.080/0.344, Fig.2B‐D, 3A). Further, we quantified subject‐specific connectivity‐associated tau spread (i.e., the regression‐derived association between epicenter connectivity and tau‐PET increase in remaining brain regions). Here, higher CSF GAP‐43 was associated with a stronger association between Ab and connectivity‐associated tau spread (centiloid x GAP‐43 interaction, b = ‐0.0031; p = 0.037, Fig.3B).

Conclusions

Higher CSF GAP‐43 is associated with faster Ab‐related tau spread across interconnected brain regions in AD, suggesting that AD‐related synaptic abnormalities are associated with accelerated tau spread rendering synaptic changes a potential treatment target to attenuate tau spreading.
ATH‐1105, a small molecule positive modulator of the HGF/MET system, is neuroprotective and attenuates TDP‐43 protein pathology in ALS and frontotemporal dementia‐relevant preclinical models
Authors: Johnston Jewel L , Berthiaume Andrée‐Anne , Reda Sherif , Kleist Kayla N. , Setti Sharay E. , Wu Wei , Church Kevin J.
Published: December 2023

Background

Frontotemporal dementia (FTD) is a neurodegenerative disorder marked by loss of neurons in the frontal and temporal lobes, leading to cognitive and behavioral changes. Common pathological features include neuroinflammation and intracellular inclusions of TDP‐43, which are found in approximately 50% of people with FTD. Positive modulation of the hepatocyte growth factor (HGF)/MET system has been shown to protect against several drivers of neurodegeneration and may represent a therapeutic strategy for FTD. Here, we assess the effects of ATH‐1105, a small molecule positive modulator of HGF/MET, in preclinical models that capture components of FTD, including neurodegeneration, inflammation, cognitive impairment, and TDP‐43 pathology.

Method

To evaluate the neurotrophic effects of ATH‐1105, neurite length and synaptic count were measured in rat hippocampal neurons after treatment with ATH‐1105. The neuroprotective effects of ATH‐1105 were assessed in rat cortical neurons subjected to neurotoxic insults including 1‐methyl‐4‐phenylpryidinium, glutamate, lipopolysaccharide (LPS), or hydrogen peroxide. Anti‐inflammatory effects of ATH‐1105 were evaluated by measuring secreted proinflammatory cytokines in LPS‐stimulated THP‐1 differentiated macrophages. To assess pro‐cognitive effects after neuroinflammatory insult, adult mice received a single intraperitoneal injection of LPS followed by daily doses of ATH‐1105 for 14 days. Cognitive performance was assessed in the T‐maze spontaneous alternation task. Finally, Prp‐TDP43A315T mice, a model of ALS/FTD, were given daily oral treatment with 20 mg/kg ATH‐1105 or vehicle for two months, starting from one month of age. Plasma was evaluated for levels of proinflammatory cytokines and neurofilament light chain. At study termination, TDP‐43 inclusions in the sciatic nerve were measured by immunohistochemistry.

Result

Treatment with ATH‐1105 increased neurite outgrowth and synaptic count in primary hippocampal neurons and protected against all cytotoxic insults in primary cortical neurons. ATH‐1105 mitigated cytokine release in LPS‐stimulated THP‐1 macrophages and attenuated LPS‐induced cognitive impairment in vivo. In TDP‐43A315T mice, treatment with ATH‐1105 reduced plasma biomarkers of inflammation and neurodegeneration. Additionally, after two months of treatment, ATH‐1105 reduced intra‐axonal TDP‐43 inclusions in the sciatic nerve.

Conclusion

The data presented provide preliminary evidence that ATH‐1105 is protective against several pathological mechanisms common to FTD, including TDP‐43 protein pathology, and support its continued evaluation as a therapeutic for FTD.