bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep and Neurocognitive Performance in Middle‐Aged Latina Women in an Agricultural Community: Insights from the CHAMACOS Maternal Cognition Study
Authors: Rojas Nadia , Calderon Lucia , Kogut Katherine , Rodriguez Maria Teresa , Romero Monica , Garcia Lizari , Rodriguez Hector , Guadamuz Jenny , Eskenazi Brenda , González Hector M , Torres Jacqueline M
Published: January 2025

Background

Latino adults face a 1.5‐to‐2‐fold increased risk of ADRDs compared to non‐Hispanic whites. Sleep disturbances among Latinos have been linked with worse neurocognitive function and a higher risk for ADRD. Limited research exists on sleep and neurocognitive function among middle‐aged Latinas. This study addresses these gaps by exploring the relationship between sleep duration, quality, nap frequency, and cognitive function in Latinas living in an agricultural community in California.

Method

Data come from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) Maternal Cognition study, which included 513 middle‐aged Latina women (mean age: 48.8) living in an underserved agricultural community in California. Average nightly sleep duration, sleep quality, and nap frequency were measured via self‐report. Participants completed the SOL‐INCA Neurocognitive Assessment, which yielded global and domain‐specific cognitive z‐scores (memory, executive function, verbal fluency). We separately estimated associations between each sleep measure and cognitive scores, controlling for socio‐demographic and health‐related covariates. In models of continuous hours of nightly sleep, we considered non‐linear associations.

Result

Participants reported a mean of 8.6 hours of nightly sleep; nap frequency was 64.8% no naps, 22.2% 1‐2 naps, 7.2% 3‐4 naps, and 5.9% 5+ naps. Sleep quality was 48.5% very sound or sound, 30.10% average, and 21.36% restless or very restless. We observed an inverted U‐shaped association between sleep duration and memory, executive function, and global cognitive z‐scores. Taking 1 or 2 naps per week (vs. zero naps) was associated with higher memory z‐scores (Coef: 0.21, 95% CI: 0.02, 0.39), while napping 5 or more times per week was associated with lower memory z‐scores (Coef: ‐0.61, 95% CI: ‐0.94, ‐0.29) and global cognitive function z‐scores (Coef: ‐0.25, 95% CI: ‐0.46, ‐0.04). We did not observe associations between self‐reported sleep quality and neurocognitive scores.

Conclusion

Our findings emphasize the significant connection between multiple measures of sleep duration, quality, and neurocognitive function. The results from this study can provide valuable insights for developing interventions targeted at improving sleep among Latinas living in rural settings. Interventions that target improved sleep may benefit neurocognitive function among middle‐aged Latinas living in agricultural settings.
Midlife physical activity and amnestic MCI: Impact on hippocampal volume
Authors: Tippett Lynette J , Merrick Jenna , Roberts Reece P , Morgan Catherine A , Melzer Tracy R , Kirk Ian J , Cawston Erin E , Williams Joanna M , Buchanan Sarah M , Cutfield Nicholas J , Dalrymple‐Alford John C , Anderson Tim J ,   The New Zealand‐Dementia Prevention Research Clinics, New Zealand
Published: January 2025

Background

The projected doubling of dementia prevalence by 2050 highlights the critical importance of altering the dementia trajectory and associated burden. Modifiable risk factors account for 40% of dementia risk (Livingston et al, 2020), including physical inactivity in late life. Protective effects of physical activity (PA) may be greater during earlier stages of neuropathological change, either directly by influencing the brain, or, indirectly by protecting against hypertension, obesity, and diabetes. We investigated whether midlife PA (i) differs in participants spanning the continuum from healthy older adults to clinically diagnosed early AD, and (ii) is related to hippocampal volume later in life.

Method

214 individuals from the New Zealand‐Dementia Prevention Research Clinics participated (31 healthy controls; 56 subjective cognitive decline; 107 amnestic mild cognitive impairment (aMCI) and 20 early AD dementia). Midlife physical activity was based on the Lifetime of Experiences Questionnaire, used to derive cumulative PA frequency scores, and weighted PA frequency‐by‐intensity composite scores. Hippocampal volume was computed from 3T MRI T1‐weighted images using SPM CAT12. ANCOVAs assessed between‐group differences on transformed PA variables. Groups were reduced to cognitively unimpaired (n = 87) and aMCI (n = 107) for multiple linear regressions that assessed whether midlife PA composite and frequency scores were associated with total hippocampal volume and whether these were moderated by gender and APOE status. Age, total intracranial volume and group were entered as predictors.

Result

There were no significant between‐group differences in transformed frequency or composite midlife PA measures (p‐values > .35). Midlife composite PA and frequency PA scores were associated with hippocampal volume, with associations moderated by gender (Beta gender X PA p‐values = .02 and .03), but not APOE status. Females showed the predicted positive association between midlife exercise and hippocampal volume, but males showed negative associations. Multiple regressions with only amnestic MCI participants revealed the same patterns of associations.

Conclusion

These findings suggest that the effects of midlife PA on hippocampal volume are detectable later in life in aMCI. Negative associations for males may relate to previous findings (human and animal) suggesting that leisure‐time PA is protective for the brain, but not occupational or “involuntary” exercise.
The Influence of Exercise on the Well‐being of Dementia Patients’ Caregivers
Authors: Sewerbidges‐Williams Linda B
Published: January 2025

Background

The demands of caregiving can exact a toll on unpaid caregivers’ physical and emotional well‐being. Caregivers of individuals with dementia frequently experience high levels of stress, anxiety, and depression. Physical activity is a promising intervention for promoting the well‐being of dementia caregivers. Little is known about the association between one’s level of physical activity and the well‐being of unpaid dementia patients’ caregivers. The aim of the study was to investigate the association between physical activity and well‐being of unpaid caregivers of dementia patients.

Methods

This cross‐sectional study included unpaid caregivers of dementia patients in Riverside, San Bernardino, Inyo, and Mono Counties, California. Utilizing a 31‐item questionnaire that included the International Physical Activity Questionnaire Short Form (IPAQ‐SF) and the Caregiver Self‐Assessment Questionnaire (CSAQ), participants provided insights into their physical activity levels and well‐being from July to October 2023. Logistic regression models were employed to analyze the relationship between physical activity (sedentary behavior, moderate physical activity, vigorous physical activity) and caregiver well‐being while controlling for demographic and health factors.

Results

The survey included 152 mostly female (82.8%) and married (72.8%) respondents, with an average age of 56 years (SD = 8.4 years). The majority were aged 60 or older (65.6%) and had been caregivers for 3.5 years on average. More vigorous physical activity was associated with better well‐being (p < 0.05), but sedentary lifestyle and walking frequency was not. Gender and level of education influenced the association between physical activity and well‐being. Another notable aspect is that 85% of caregivers exhibited low well‐being.

Conclusions

This study found an association between caregiver well‐being and vigorous physical activity but no association with sedentariness and frequency of walking. Designing personalized physical activity interventions maybe focusing on vigorous exercise can enhance the well‐being of dementia caregivers, thereby alleviating the burdens associated with dementia caregiving. Future research endeavors using longitudinal designs should be conducted to delve deeper into the underlying mechanisms driving these associations.
Cholinergic white matter pathways in Alzheimer’s disease, dementia with Lewy bodies, and other neurodegenerative diseases: a post‐mortem MRI study
Authors: López‐González Francisco J. , Nemy Milan , Rabano Alberto , Grothe Michel J. , Sanchez‐Juan Pascual , Ferreira Daniel
Published: January 2025

Background

In‐vivo magnetic resonance imaging (MRI) has recently shown that patients with clinically diagnosed Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) exhibit degeneration of the cholinergic nucleus basalis of Meynert and its white matter (WM) projections through the cingulum and external capsule pathways1. Here, we propose an imaging‐pathologic validation study aimed at investigating cholinergic WM pathways using post‐mortem MRI of autopsy‐confirmed AD, Lewy body dementia (LBD), and other neurodegenerative diseases (OTH).

Method

We included 53 brain donors (34 AD, 10 LBD, and 9 OTH, mainly including frontotemporal lobe degeneration and vascular disease, Table1). All donors underwent post‐mortem MRI in situ within 5 hours after death and were later subjected to neuropathological examination performed according to published consensus criteria. Post‐mortem MRI examination included 3D T1 structural imaging and diffusion‐weighted imaging acquired using a 3T scanner. Previously established masks of cholinergic WM pathways (i.e., cingulum and external capsule pathways) were transformed from standard MNI space to each individual’s b0 image in native space using the nonlinear SyN registration algorithm. Native space mean diffusivity (MD) maps were estimated for each donor using the FMRIB Diffusion Toolbox from FSL. Microstructural properties of each participant’s cholinergic WM pathway were then estimated by averaging the MD values within the back‐transformed masks in native space. Differences in age‐adjusted MD values between diagnostic groups were analysed using the Mann‐Whitney U‐test.

Result

AD donors were older than LBD donors (p = 0.007), and both groups were older than the OTH group. After adjusting for age, AD showed significantly higher MD values in cholinergic WM pathways when compared with OTH (Cohen’s d = 1.45, p<0.001) and LBD (Cohen’s d = 0.91, p<0.01) (Figure1). Elevated MD values in LBD compared to OTH did not reach statistical significance in this small sample (Cohen’s d = 0.85, p = 0.11).

Conclusion

We expanded previous in‐vivo MRI findings to post‐mortem MRI and confirmed the degeneration of cholinergic WM pathways in AD. Additionally, we highlighted the difference between AD and LBD donors, with a more severe cholinergic pathway degeneration in AD donors. References 1Schumacher J, et al. Cholinergic WM pathways in dementia with Lewy bodies and AD. Brain. 2022 Jun 3;145(5):1773‐1784.
Socioemotional dysfunction relates to financial exploitation vulnerability in Alzheimer’s disease and behavioral variant frontotemporal dementia
Authors: Lee Jayden J , Reeder Jerica E , Phan Tony X , Keener Lindsey C , Wang Siyi J , Darby R. Ryan
Published: January 2025

Background

Financial exploitation vulnerability (FEV) denotes the risk for falling victim to financial fraud and older adults reportedly lose an estimated $36 billion annually to scams. Socioemotional and cognitive impairments are potential risk factors for FEV in older adults with dementia. The present study examines whether the socioemotional measures of sensitivity to unfairness and self‐unawareness of socioemotional dysfunction and brain atrophy are associated with increased risk for FEV in Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD).

Method

25 AD and 39 bvFTD patients played the Ultimatum Game (UG), a social decision‐making task that assesses participants’ sensitivity to unfairness. FEV was measured by administering the Social Vulnerability Scale (SVS), an informant‐based questionnaire, comprising two factors for FEV (gullibility and credulity) and total financial vulnerability (SvsTotal). We evaluated patients’ unawareness of their own socioemotional dysfunction by administering the Interpersonal Reactivity Index to both patients and their informants and computed difference scores for perspective‐taking (patients’ score minus the informants’ score). Finally, we used voxel‐based morphometry to determine regional atrophy associated with FEV measures.

Result

Informant ratings for gullibility, credulity, and SvsTotal were significantly higher in bvFTD compared to AD patients (p<0.0001) while controlling for age, gender and disease severity. Greater acceptance of unfair offers in the UG was associated with higher gullibility (r = 0.42, p<0.03) and SvsTotal (r = 0.40, p<0.03) in both groups. bvFTD showed greater deficits in self‐awareness of perspective‐taking capability than AD patients (p<0.02). Unawareness of socioemotional dysfunction was associated with higher gullibility (r = 0.46, p<0.01) and SvsTotal (r = 0.56, p<0.005) in both groups. Increased gullibility in bvFTD was associated with gray‐matter volume loss in the left temporoparietal junction (LTPJ), a classic theory of mind region (p<0.01, FWE‐corrected).

Conclusion

Our results suggest that FEV is a more severe problem in bvFTD than AD but distinctly related to socioemotional dysfunction in both groups, including impaired self‐awareness and unwillingness to accept unfair offers in simulated social decision‐making tasks. LTPJ atrophy, critical to perspective‐taking, may also increase FEV susceptibility. Both socioemotional dysfunction itself, and a patient’s lack of awareness for their own deficits (i.e., anosognosia) may potentially be an important early risk factor for FEV.
The role of subcortical grey matter structures in neuropsychiatric symptoms from cognitively healthy tot mild cognitive impairment: a population‐based study
Authors: vom Hofe Ilse , Luik Annemarie I. , Vernooij Meike W. , Ikram M. Arfan , Wolters Frank J.
Published: January 2025

Background

Neuropsychiatric symptoms are common in the prodromal phase of dementia, and may be related to altered structure and function of subcortical grey matter involved in emotion regulation. We aimed to determine the association between subcortical grey matter volume and occurrence of neuropsychiatric symptoms in a population‐based study.

Method

Between 2009‐2015 dementia‐free participants from the population‐based Rotterdam Study underwent 1.5T brain MRI. Volumes of the accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus were determined using FreeSurfer 6.1. Symptoms of depression and anxiety were assessed using the Center for Epidemiologic Studies Depression (CES‐D) scale and the anxiety subscale of the Hospital Anxiety and Depression scale (HADS‐A). We determined cross‐sectional associations between subcortical volumes (per 1 standard deviation [SD] decrease) and continuous CES‐D and HADS‐A scores using linear regression, and with clinically significant symptoms (CES‐D=16;HADS‐A=8) using logistic regression. Models were adjusted for demographics, lifestyle factors, comorbidities and co‐medication use. We repeated analyses stratifying on cognitive status (healthy/subjective complaints/MCI).

Result

Of 3452 participants (mean age 69.3 years, 55.2% women), 284 (8.2%) scored positive for clinical depressive symptoms, and 270 (7.8%) for clinical anxiety symptoms. Smaller hippocampal volume was associated with higher odds of clinical depressive symptoms (odds ratio [95%CI]: 1.27[1.05‐1.52], p=0.01). In contrast, smaller volumes of the caudate were associated with less depressive symptoms (mean difference in log‐transformed score [95%CI] for caudate: ‐0.06[‐0.10;‐0.02], p<0.01, and pallidum: ‐0.04[‐0.08;0.00], p=0.05). Smaller volumes of the caudate and pallidum were also associated with less anxiety (caudate: ‐0.04[‐0.07;‐0.01], p<0.01, pallidum: ‐0.05[‐0.09;‐0.02], p<0.01), accompanied for the caudate by a lower odds of clinical anxiety symptoms (OR[95%CI]: 0.84[0.72;0.98], p=0.03). No associations were observed with the accumbens, amygdala, putamen, or thalamus. Associations were observed in cognitively healthy participants, as well as in those with subjective cognitive complaints or MCI.

Conclusion

In community‐dwelling older adults, volumes of the hippocampus, caudate, and pallidum are associated with neuropsychiatric symptoms, which do not differ by neurodegenerative disease stage. These findings support a complex role of subcortical volumes in the occurrence of neuropsychiatric symptoms in the older population.
Performance of the Amsterdam IADL scale in Assessing Functional Decline among Older People in Primary Health Care
Authors: Fawad Ayesha , Nilsson Maria H , Sikkes Sietske A.M. , Postema Merel C. , Stomrud Erik , Tideman Pontus , Hansson Oskar , Palmqvist Sebastian
Published: January 2025

Background

The Amsterdam Instrumental ADL Questionnaire (A‐IADL‐Q) has shown promising performance in detecting subtle impairment in IADL independency. Importantly, it has not been validated in older people in a primary care setting, i.e., where the initial work‐up and triaging of cognitive impairment occurs. The main aim was to examine the accuracy of the A‐IADL‐Q for estimating the cognitive stage in a primary care sample, both in the whole population and within the Alzheimer’s disease (AD) continuum. Secondary aims were to examine associations with the clinical dementia rating (CDR) scale and global cognition (MMSE), including the effects of non‐cognitive co‐morbidities and medications.

Method

This cross‐sectional study includes informants of 362 participants from the BioFINDER‐Primary care study. They completed the A‐IADL‐Q (higher scores = “better”) either on an iPad or at home on a computer. Cognitive stage was assessed by a dementia expert (blinded to A‐IADL‐Q scores). Amyloid status was determined using FDA‐approved CSF or PET measures. The main outcome was cognitive stage according to the NIA‐AA scale. Secondary outcomes were CDR‐sum of the boxes (CDR‐SOB) and MMSE. Receiver Operating Curves (ROC) analyses were used to calculate the area under the curves (AUCs).

Result

The mean age of participants (44.9% female) was 76.1 (SD 7.2) years. Out of which, 83 (23%) had subjective cognitive decline (SCD), 169 (47%) mild cognitive impairment (MCI), and 110 (30%) dementia. The AUC (95% CI) for differentiating between SCD versus MCI/dementia was 0.89 (0.85‐0.92), and it was 0.89 (0.85‐0.93) for SCD/MCI versus dementia. In amyloid positive participants (n = 303), AUCs were similar. Better A‐IADL‐Q scores were associated with worse results on CDR‐SOB (r = ‐0.73, p<0.001) and better global cognition (MMSE, r = 0.361, p<0.001). The effects of different co‐morbidities on the A‐IADL score, adjusted for cognitive stage, will be presented at AAIC.

Conclusion

Our findings suggest that the A‐IADL‐Q accurately estimates the cognitive stage among cognitively impaired older people (with high prevalence of comorbidities) in a primary care setting. This can aid primary care physicians in the diagnosis of cognitive impairment, clinical management/support, and as part of the work‐up for identifying eligible participants for anti‐amyloid treatment.
Connectivity to epicenters of tau accumulation contributes to regional synaptic loss in Alzheimer’s disease
Authors: Luan Ying , Wang Weiyi , Guan Yihui , Franzmeier Nicolai , Xie Fang , Ewers Michael
Published: January 2025

Background

Alzheimer’s disease (AD) is associated with substantial synaptic loss potentially due to synaptotoxicity of fibrillar tau, but the association between tau deposition and synaptic loss remains unclear. Based on previous observations that pathology spreads preferentially between closely connected regions, we tested in the current multi‐PET tracer study the hypothesis that synaptic loss propagates to regions closely connected to epicenters of high tau accumulation.

Method

We assessed 18F‐SynVesT‐1 PET as a measure of synaptic vesicle glycoprotein 2A (SV2A), and 18F‐flortaucipir tau‐PET in fourty‐five 18F‐florbetapir‐PET‐positive (Aß+) subjects with MCI or AD dementia, and 23 cognitivly normal (CN) Aß‐ controls. All PET scans were spatially normalized and parcellated into 200 ROIs. Adopting our previously established connectivity‐based prediction model (Franzmeier et al. Nat Commun 2020), we computed tau‐epicenter connectivity maps by projecting regions of highest tau‐PET SUVR (top 10% of group‐average tau‐PET ROIs) onto a normative resting‐state fMRI derived connectivity template from the Human Connectome Project. The tau‐epicenter connectivity map was projected onto the group‐average synaptic PET ROI w‐scores (standardized SUVR difference between Aß+ vs Aß‐ group) to test in linear regression analysis, epicenter connectivity as a predictor of synaptic PET w‐scores in connected ROIs. As a control, we conducted an additional regression analysis, using this time connectivity to cold spots of tau‐accumulation (10% of ROI with lowest tau‐PET uptake) instead of epicenter‐connectivity as a predictor. We repeated the analyses at the subject level, controlling for the effect of age, gender, clinical diagnosis and global amyloid‐PET uptake.

Result

Higher functional connectivity to the tau‐epicenter was associated with lower synaptic PET binding in the connected ROIs (ß = ‐0.380, p < 0.001, Figure 1A). In contrast, functional connectivity to the tau coldspot ROIs was associated with more preserved synaptic PET binding in the connected ROIs (ß = 0.396, p < 0.001, Figure 1B). Subject‐level analysis showed consistent findings (Figure 2 for tau‐epicenters).

Conclusion

Synaptic loss in AD occurs in a connectivity‐dependent manner, where closer functional connectivity to regions of high tau is associated with stronger loss in synaptic PET. Putative underlying mechanisms are the higher tau in tau‐epicenter connected regions or functional decline in the connected regions.
Resting State Functional Connectivity Assessment of Healthy Aging Trajectories in the Marmoset Brain
Authors: Bhik‐Ghanie Rebecca , Szczupak Diego , Zhang Bei , Papoti Daniel , Campos Vinicius , Dubberley Lauren R , Hitchens T Kevin , Yeh Fang‐Cheng , Schaeffer Lauren K Hayrynen , Carter Gregory W , Rizzo Stacey J Sukoff , Schaeffer David J , Silva Afonso C
Published: January 2025

Background

The common marmoset (Callithrix jacchus) is an important animal model in neuroscience and neurological diseases, presenting primate‐specific evolutionary features such as an expanded frontal cortex. We established a new consortium with funding support from the National Institute on Aging to generate, characterize, and validate MArmosets as Research MOdels of AD (MARMO‐AD). This consortium develops and studies gene‐edited marmoset models carrying genetic risk for AD, comparing them against wild‐type aging marmosets from birth throughout their lifespan, using non‐invasive longitudinal assessments. Here, we aim to characterize healthy aging trajectories by investigating their resting state functional connectivity in a population of marmosets.

Method

We imaged a cohort of 25 marmosets (17 males, 8 females) across the lifespan (8 to 150 months) using a dedicated 9.4T/30cm Bruker MRI scanner. The animals were acclimated to restrainers and head‐fixation helmets and imaged awake. EPI images (500 µm isotropic) were acquired for 1 hour and 20 minutes, yielding 2400 whole‐brain volumes. The images were pre‐processed for fMRI using AFNI and FSL. For each run, the first ten time points were removed for magnetization to reach a steady state. The images were despiked, and spatially aligned. Slice timing was corrected, and phase‐encoding distortion was corrected using FSL. Subsequently, brain images were registered to the Marmoset Brain Mapping V3 template, and brain‐wide connectomics were calculated using the GRETNA toolbox.

Result

Our group has shown through structural investigations (voxel‐based morphometry and white matter tractography) that several cortical clusters are affected by aging (Figure 1, Top Left). Here, with resting state fMRI, we show that many brain regions that change size with aging also show accompanying changes in their functional connectivity strength (Figure 1, Right). Integrating resting‐state fMRI with structural investigations will allow us to understand how these affected structures work together in a dynamic network.

Conclusion

Our work is the first to thoroughly describe the changes in resting state functional connectivity in the marmoset brain during normal aging, a valuable model for AD. This research will establish normative baselines for changes in marmoset brain connectivity with aging to evaluate our genetically engineered marmoset models of AD.
Exploring heterogeneity in Motoric Cognitive Risk Syndrome using Volumetric MRI‐guided Clustering
Authors: Nallapu Bhargav Teja , Blumen Helena M , Petersen Kellen K. , Lipton Richard B. , Pradeep V.G. , Srikanth Velandai K , Beare Richard , Beauchet Olivier , Milman Sofiya , Aleksic Sandra , Ezzati Ali , Verghese Joe
Published: January 2025

Background

The Motoric Cognitive Risk Syndrome (MCR) is a predementia stage characterized by slow gait speed and subjective cognitive complaints. Defining the heterogeneity of brain volumetrics in individuals with MCR will improve current dementia risk assessments.

Method

We used data from 6 cohorts from the MCR consortium (N=2,007). We used K‐means clustering algorithm guided by volumetric MRI to identify distinct subgroups of participants. We compared the differences in cortical and subcortical volumes, comorbidities, and gait speeds across the identified subgroups using one‐way ANOVA and post‐hoc pairwise group comparisons.

Result

The sample had a mean age of 71.89 (±7.05) years, 48.7% were women, 32.9% were White and 63.2% were Asian (see Table 1). Four subgroups (A to D) were identified through MRI‐based clustering with significant differences in brain region volumes (Figure 1A), gait speeds (Figure 1B) and proportion of individuals with MCR (Figure 2). Subgroups A and C had the least amount of atrophy in all brain regions and had the least proportion of MCR. Subgroup D had the highest proportion of MCR subjects and highest atrophy specifically in hippocampus and cortical regions. The average gait speed of Subgroup D was lower than other subgroups. Subgroup D also had the highest rate of hypertension and diabetes among the subgroups (Figure 2).

Conclusion

Our results validate the previous findings linking MCR syndrome to MRI evidence of neurodegeneration. Heterogeneity in cortical and subcortical signatures are present in older adults and provides insights into brain substrates of MCR.
Neurobiological correlates of grey matter morphometry changes in preclinical Alzheimer's disease
Authors: Pelkmans Wiesje , Cacciaglia Raffaele , Salvadó Gemma , Fauria Karine , Minguillón Carolina , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Molinuevo Jose Luis , Grau‐Rivera Oriol , Wilson Rachael E , Jonaitis Erin M. , Langhough Rebecca E. , Blennow Kaj , Zetterberg Henrik , Johnson Sterling C. , Suárez‐Calvet Marc , Gispert Juan Domingo
Published: January 2025

Background

The driving mechanisms of structural brain alterations in the earliest stages of Alzheimer's disease (AD) are not well understood. Previous heterogeneous findings in preclinical AD, including subtle atrophy and also increased grey matter (GM) volume, underscore the need for further exploration. This study uses an extensive fluid biomarkers panel to identify pathological drivers behind longitudinal GM changes in cognitively unimpaired (CU) adults.

Method

We investigated 632 CU individuals (age 61.8±6.3, mean±SD) from the ALFA+, Wisconsin ADRC, and WRAP cohorts (Table 1), with available longitudinal MRI and cerebrospinal fluid biomarkers of Aß42/40, p‐tau181, neurogranin, NfL, total‐tau, a‐synuclein, GFAP, YKL‐40, sTREM2, s100B, and IL‐6 measured using the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd). We used non‐negative matrix factorization to decompose biomarkers into latent components. The per‐subject component weights were associated with voxel‐wise GM volume changes (years 3.5±0.9, mean±SD) and longitudinal performance on the preclinical Alzheimer's cognitive composite (PACC) using mixed model analysis.

Result

Six biomarker components (C1‐C6) were identified (Figure 1). High expression of astrocyte biomarkers (C1) was related to GM volume increases in frontotemporal and subcortical regions, and faster cognitive decline in A+ individuals, while axonal damage with glial reactivity (C2) was associated with temporal atrophy. Microglial reactivity (C3) showed subtle associations with both increases and decreases in GM volume in different regions. A component primarily based on Aß pathology (C4) was strongly associated with widespread GM volume loss and faster cognitive decline. IL‐6 (C5) reflected non‐AD related inflammation. Finally, the co‐expression of tau pathology, neuronal injury, and synaptic damage (C6) showed robust associations with frontotemporal atrophy and cognitive decline in A+ individuals.

Conclusion

In a large longitudinal sample, we provide in vivo evidence that in the earliest stages of AD, Aß pathology is also a strong contributor to future neuronal loss and cognitive decline besides neurofibrillary tangles and neuroaxonal damage. Astroglial reactivity (i.e. GFAP, s100B) in preclinical AD was associated with an increase in GM volume, which may suggest a neuroinflammatory response, and was associated with worse cognitive performance. These findings underscore the dynamic nature of structural brain changes within preclinical AD, shaped by the contributions from diverse pathophysiological processes.
Prevalence of hypometabolism in AD‐related regions in real‐world FDG‐PET of the brain
Authors: Schwartz Trent , Robb W Hudson , Bishay Steven , Jackson T. Bryan , Jefferson Angela L. , Landman Bennett A. , Smith David Samuel , Hohman Timothy J. , Koran Mary Ellen I.
Published: January 2025

Background

Standard of care for many cancer workups includes whole‐body FDG PET/CT before, during, and after therapy. At Vanderbilt, these scans include the brain for every patient (>20,000 patients). Brain FDG PET is a validated assessment of neuronal health. We will use these standard of care FDG PET images as incidental screening opportunities to evaluate neuronal health to leverage in future electronic health record (EHR) research.

Methods

Demographic data and FDG images were extracted from Vanderbilt’s EHR for the most recently imaged 1000 patients. Brain images were extracted, quality control was performed, and SUVR for an established AD meta‐region of interest (ROI) was calculated (Landau, et.al, 2011) as were SUVR for AD‐related ROIs including parietal and temporal lobes. We evaluated the prevalence of a positive AD metaROI (SUVR <=1.21) at staging and on post‐treatment images as well as change in ROI SUVR over time using a linear mixed effects model with subject specific slopes and intercepts, covarying for baseline age and sex.

Results

396 patients >=65 years old were included in this analysis. Most common indications for imaging included lymphoma, melanoma, and head and neck and lung cancers. 159 have >=2 FDG, with an average follow up time of 338 days between staging and follow‐up scans. 272 patients (68.6%) had a positive AD metaROI (<=1.21) at their initial staging PET, which increased to 296 patients (74%) on follow up. AD metaROI SUVR decreased over time in these patients (β(ΔSUVR/year)=‐0.013 and p=1.63x10‐4), and in the parietal (β=‐0.014/year and p=2.57x10‐5) and temporal (β(ΔSUVR/year)=‐0.010 and p=1.68x10‐4) lobes (Figure 1).

Conclusion

Incidental prevalence of a positive AD metaROI on FDG is high compared to expected prevalence of a clinical diagnosis of AD of ∼10%. Thus published cut‐points may not be applicable to PET of the brain captured during whole body imaging; different cut‐points may be required. FDG in AD‐related regions significantly decreased over time, consistent with expected age‐related changes. Incidental evaluation of the cerebral metabolism may hold important information on brain health. Evaluation of the entire cohort (n>20,000) and comparison to age‐matched controls is ongoing.
Dissociable spatial topography of neurodegeneration in Early‐onset and Late‐onset Alzheimer’s Disease: A head‐to‐head comparison of MRI‐derived atrophy measures between the LEADS and ADNI cohorts
Authors: Katsumi Yuta , Touroutoglou Alexandra , Brickhouse Michael , Eckbo Ryan , La Joie Renaud , Eloyan Ani , Nudelman Kelly N. , Foroud Tatiana M. , Dage Jeffrey L. , Carrillo Maria C. , Rabinovici Gil D. , Apostolova Liana G. , Dickerson Bradford C.
Published: January 2025

Background

Understanding how early‐onset Alzheimer’s disease (EOAD) differs from typical late‐onset AD (LOAD) is an important goal of AD research that may help increase the sensitivity of unique biomarkers for each phenotype. Building upon prior work based on small samples, here we leveraged two large, well‐characterized natural history study cohorts of AD patients (LEADS and ADNI3) to test the hypothesis that EOAD patients would show more prominent lateral and medial parietal and lateral temporal cortical atrophy sparing the medial temporal lobe (MTL), whereas LOAD patients would show prominent MTL atrophy.

Method

We investigated differences in the spatial topography of cortical atrophy between EOAD and LOAD patients by analyzing structural MRI data collected from 211 patients with sporadic EOAD and 88 cognitively unimpaired (CU) participants from the LEADS cohort as well as 144 patients with LOAD and 365 CU participants from the ADNI3 cohort. MRI data were processed via FreeSurfer v6.0 to estimate cortical thickness for each participant. A direct comparison of cortical thickness was performed between EOAD and LOAD patients based on W‐scores (i.e., Z‐scores adjusted for age and sex relative to CU participants within each cohort) while controlling for MMSE total scores. All patients underwent amyloid PET with 18F‐Florbetaben or 18F‐Florbetapir and amyloid positivity was centrally determined by quantification‐supported visual read.

Result

As expected, a direct comparison of cortical thickness between patients with EOAD and LOAD revealed a double dissociation between AD clinical phenotype and localization of cortical atrophy: EOAD patients showed greater atrophy in widespread cortical areas including the inferior parietal lobule (EOAD marginal mean W‐score ± SEM = ‐1.33±0.08 vs. LOAD = ‐0.52±0.09, p<.001, η2 = .097), precuneus (‐1.66±0.09 vs. ‐0.59±0.10, p<.001, η2 = .13), and caudal middle frontal gyrus (‐1.65±0.08 vs. ‐0.90±0.10, p<.001, η2 = .074), whereas LOAD patients showed greater atrophy in the entorhinal/perirhinal cortex and temporal pole (‐1.00±0.09 vs. ‐1.41±0.11, p<.008, η2 = .019).

Conclusion

These findings demonstrate a clearly dissociable spatial pattern of neurodegeneration between EOAD and LOAD, supporting our previously developed LOAD and EOAD signatures of cortical atrophy, which underlies the distinct episodic memory and other cognitive characteristics of these AD clinical phenotypes.
The Association between the Body Fat Localization, Insulin Resistance, and Amyloid Burden in Midlife
Authors: Dolatshahi Mahsa , Commean Paul K. , Naghashzadeh Mahshid , Nguyen Caitlyn , Lloyd LaKisha , Kasani Sara Hosseinzadeh , McBee‐Kemper Abby , Weeks Jake , Sirlin Claude , Ceriani Lael , Yifei Xu , Mittendorfer Bettina , Liu Jingxia , Benzinger Tammie L.S. , Ippolito Joseph E. , Morris John C. , Raji Cyrus A.
Published: January 2025

Background

Obesity in midlife is a risk factor for developing Alzheimer disease later in life. However, the metabolic and inflammatory effects of body fat varies based on its anatomical localization. In this study, we aimed to investigate the association of MRI‐derived abdominal visceral and subcutaneous adipose tissue (VAT and SAT), liver proton‐density fat fraction (PDFF), thigh fat‐to‐muscle ratio (FMR), and insulin resistance with whole‐brain amyloid burden in cognitively normal midlife individuals.

Method

A total of 49 cognitively normal midlife individuals (Age: 50.65±5.77 years, 61.2% female, BMI: 32.0±67.34, 57.1% obese) underwent brain PET scan, body MRI, and metabolic assessment. Homeostatic Model Assessment for Insulin Resistance (HOMAIR) was used for measuring insulin resistance. Dynamic amyloid imaging was performed with a bolus injection of ∼15mCi [11C]PiB, followed by a 60‐min scan. Data from the 30‐60 minute post‐injection window was used for calculating whole‐brain amyloid centiloid. VAT and SAT were semi‐automatically segmented using an in‐house MATLAB‐based software. A trained U‐Net convolutional neural network (CNN) model was used to calculate the hepatic PDFF maps from abdominal T1‐weighted images. After preprocessing and N4ITK bias correction on mid‐thigh slices between the ischial ramus and the medial knee condyle, a MATLAB program was used for segmenting thigh total fat including subcutaneous, inter‐, and intra‐muscular fat, and muscle volumes. Total thigh fat‐to‐muscle ratio (FMR) was calculated. Using Spearman correlation test, the association between whole‐brain amyloid centiloid and BMI, HOMAIR, VAT, SAT, PDFF, and FMR was assessed, with age and sex as covariates.

Result

Obese individuals had a higher amyloid burden compared to the non‐obese (p = 0.011). Whole‐brain amyloid centiloid values were significantly associated with VAT (rho = 0.62, p<0.0001) and HOMAIR (rho = 0.56, p = 0.013), but not other fat metrics. A mediation analysis showed significant direct effect of VAT (p = 0.02) on amyloid burden, while the indirect VAT effects mediated by HOMAIR were non‐significant (p = 0.28).

Conclusion

Obesity, higher visceral fat and insulin resistance, but not BMI, subcutaneous abdominal fat, liver fat, or thigh fat, are associated with higher whole‐brain amyloid burden in midlife. This highlights the importance of anatomical characterization of body fat for Alzheimer disease risk, where visceral fat shows a strong relationship with amyloid pathology.
Confounding factors to Alzheimer's disease plasma biomarkers in patients from a memory‐clinic cohort
Authors: Rodrigues Matheus Scarpatto , Oliveira Markley , Lussier Firoza Z , Ferreira Pamela C.L. , Bauer‐Negrini Guilherme , Povala Guilherme , Felix Cynthia , Abbas Sarah , Zalzale Hussein , Soares Carolina , Saha Pampa , Madeiros Marina Scop , Hong Chang Hyung , Roh Hyun Woong , Karim Helmet T. , de Oliveira Jade , Zimmer Eduardo R. , Karikari Thomas K , Bellaver Bruna , Son Sang Joon , Pascoal Tharick A.
Published: January 2025

Background

Blood‐based biomarkers for Alzheimer’s disease (AD) are increasingly prevalent and accessible beyond research environments. Consequently, it is crucial to determine whether confounding factors, particularly highly prevalent comorbidities, influence the levels of these blood biomarkers, thereby refining their clinical interpretation. In this study, we examined the impact of comorbidities on plasma AD biomarker levels within a memory‐clinic cohort.

Method

We analyzed 832 individuals (CU: 101, CI: 731) from the BICWALZS cohort with available information of comorbidities and plasma biomarkers measurements. The effect size of each comorbidity to plasma p‐tau217, neurofilament light chain (NfL) protein, glial fibrillary acidic protein (GFAP) and amyloid‐ß (Aß) 42/40 ratio was accessed by the ß‐estimate and 95% CI values of linear regression models adjusted by clinical diagnosis, age, and sex. Comparison of biomarkers between comorbidities was carried out by ANOVA.

Result

Among the evaluated comorbidities, plasma creatinine levels, BMI index, sleep disorder, and the presence of kidney disease were the primary comorbidities linked to variations in plasma biomarker concentrations (Figure 1). Analyzing the levels of the biomarkers according to the presence of comorbidities, we observed that individuals with increased plasma creatinine exhibited significantly higher plasma levels of p‐tau217, NfL and GFAP in comparison to the individuals with normal levels of creatinine (p < 0.05, Figure 2A, B, C). The mean of p‐tau217 and NfL, but not of GFAP, was elevated between those with kidney disease (p < 0.05, Figure 2A, B). High plasma NfL levels were observed in individuals with diabetes and hypertension (p < 0.05, Figure 2B). On the other hand, high BMI index was associated with lower plasma p‐tau217, NfL and GFAP compared to individual with normal BMI (Figure 2A, B, C). We also observed that individuals with sleep disorder exhibited decreased plasma p‐tau217 levels (Figure 2A). Plasma Aß42/40 ratio was not affected by the analyzed comorbidities (Figure 2D).

Conclusion

Our findings indicate that elevated creatinine levels, a higher BMI index, and the presence of kidney disease are the most significant confounding variables associated with alterations in AD plasma biomarkers. Together, our results shed light on the impact of different comorbidities to the interpretation of biomarker values in real‐world populations.
Longitudinal changes in amyloid, glucose, and glial reactivity imaging biomarkers in a transgenic rat model of amyloidosis
Authors: Lazzarotto Gabriela , Spelta Lidia Emmanuela Wiazowski , Vera Cleinando Clemente da Silva , da Rocha Andreia Silva , de Souza Débora Guerini , Faria Daniele de Paula de Paula , Zimmer Eduardo R.
Published: January 2025

Background

Imaging biomarkers have helped to reconceptualize Alzheimer’s disease pathophysiology. More specifically, positron emission tomography (PET) radiopharmaceuticals for non‐invasively assessing amyloid‐beta (Aß) plaques, glucose metabolism, and glial reactivity allow for tracking disease progression in a temporally ordered manner. However, whether transgenic models recapitulate biomarker‐related changes remains elusive. Here, we longitudinally evaluated Aß, glucose metabolism, and glial reactivity using PET in a transgenic amyloid rat model.

Method

TGF344‐AD (APP/PS1) and wild‐type rats were scanned at 6, 9, and 12 months with [18F]FDG, [11C]PK11195 and [11C]PIB. Images were manually co‐registered in a rat magnetic resonance template. Standardized uptake values (SUV) were calculated for [18F]FDG and [11C]PK11195, and SUV ratio (SUVR) was calculated for [11C]PIB using the pons as the reference region. The results were normalized using Z‐Score and statistical significance was determined at Z>2 (p < 0.05).

Result

At 6 months, no differences between groups were observed. At 9 months, however, we detected significant amyloid load, glucose hypermetabolism, and increased glial reactivity. At 12 months, animals presented increased Aß load while still presenting signs of brain glucose hypermetabolism. By contrast, glial reactivity did not present alterations compared to 9‐month‐old rats.

Conclusion

Our findings indicate that in the early phases of detectable Aß deposition, there is a joint increase in brain glucose metabolism and glial reactivity. These findings suggest that amyloid deposition triggers early neuroinflammatory response. We and others have provided evidence that early FDG‐PET hypermetabolism is an indicator of glial reactivity.
Functional brain network organization supports cognitive function in patients with Alzheimer's Disease‐related pathological burden and brain atrophy
Authors: Zhang Ziwei , Chan Micaela , Winter‐Nelson Ezra , Wig Gagan S
Published: January 2025

Background

Alzheimer’s disease (AD) is defined by the accumulation of Aß plaques and tau neurofibrillary tangles. The consequences of these pathologies include neurodegeneration and cognitive dysfunction. However, the process by which AD pathologies leads to cognitive impairment remains unclear. Some individuals can harbor pathological burden yet be cognitively unimpaired; these observations have led to ideas about cognitive reserve (Stern, Lancet, 2012). Dominant models of AD biomarkers do not include direct measures of brain function. To address this gap, we tested whether resting‐state brain system segregation explains discrepancies between AD‐related pathology, structural atrophy, and cognitive function. System segregation changes across the adult lifespan, is stratified in relation to life course exposures, and relates to cognitive function (Wig, Trends in Cognitive Sciences, 2017).

Method

Participants were recruited through the Alzheimer’s Disease Neuroimaging Initiative. Cognitive impairment was quantified using clinical dementia rating (CDR). The participant group included 184 healthy (CDR=0) adults, 101 very mild dementia (CDR=0.5), 24 mild dementia (CDR=1) and 2 moderate dementia (CDR=2) patients (age range: 55–96 years). Functional brain networks were generated using resting‐state fMRI time series. Network edges were defined as correlations between time series of each pair of nodes. Brain system segregation was calculated to quantify functional brain network organization for each participant (Chan et al., PNAS, 2014).

Result

Multiple linear regression analyses were used to test whether Aß and tau relate to brain system segregation, with age, gender, education, and head motion included as covariates. Neither Aß nor tau burden was associated with brain system segregation (Aß: p=0.45; tau: p=0.55). Among individuals exhibiting positive pathological burden (either Aß, tau, or both) based on cut‐off values, individuals with higher system segregation were less cognitively impaired (Aß+: p=0.007; tau+: p=0.021; Aß and tau+: p=0.03). Finally, system segregation explained unique variance with respect to CDR status over and above Aß, tau, and cortical thickness. Brain system segregation was negatively related to CDR status (p=0.003), while accounting for these other factors.

Conclusion

Functional brain network organization supports observations of cognitive reserve, and explains unique variance with respect to AD‐related cognitive impairment independent of AD‐related pathology and neurodegeneration.
Benzofuroisoquinoline derivatives reverse amyloidogenesis and amyloid‐associated memory impairments in acute and transgenic mouse models of Alzheimer’s disease
Authors: Park InWook , Park Sohui , Jeon Hanna , Kim Kyeonghwan , Yoon Soljee , Shin Jisu , Kim Hye Yun , Kim Ikyon , Kim YoungSoo
Published: January 2025

Background

Alzheimer’s disease (AD) is predominantly caused by the aggregation of amyloid‐β (Aβ) peptides into neurotoxic plaques. Current therapeutic approaches using monoclonal antibodies, like aducanumab and lecanemab, have shown promise in reversing Aβ aggregation. However, these treatments are expensive and challenging to administer. Small molecules offer a more accessible alternative but face specificity hurdles. Our study explores a library of hybrid compounds, integrating structures known to affect Aβ aggregation, to find potential small molecule therapeutics for AD.

Method

We utilized a thioflavin T (ThT) fluorescence assay to measure the inhibitory effects of YIAD compounds on Aβ aggregation. Compounds were tested at varying concentrations with preformed Aβ aggregates. For analysis of Aβ species post‐inhibition, SDS‐PAGE coupled with photocrosslinking (PICUP) and silver staining were employed. In vivo efficacy was assessed using an Aβ‐infused mouse model and a 5XFAD transgenic mouse model, with cognitive function measured by a Y‐maze test and Aβ plaque burden by thioflavin S (ThS) staining.

Result

ThT assays indicated that certain YIAD compounds significantly inhibited Aβ aggregation. SDS‐PAGE analyses confirmed changes in Aβ species distribution upon compound treatment. Aβ aggregate dissociation was demonstrated with ThT assays, indicating potential for plaque clearance. YIAD‐0405 and 0407 significantly improved spatial memory in the Y‐maze test and reduced plaque burden in 5XFAD mice, as evident from ThS staining.

Conclusion

Our findings suggest that YIAD compounds, specifically YIAD‐0405 and 0407, effectively inhibit and dissociate Aβ aggregates in vitro and in vivo. These compounds improve cognitive function and decrease plaque burden, positioning them as promising candidates for oral AD therapeutics. Further studies will explore their mechanistic pathways and long‐term efficacy in treating Alzheimer’s disease.