bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood astrocyte biomarkers in AD: a systematic review and meta‐analysis
Authors: Holper Sarah , Loveland Paula M , Churilov Leonid , Italiano Dominic , Watson Rosie , Yassi Nawaf
Published: January 2025

Background

We performed a systematic review and meta‐analysis of blood astrocyte biomarkers in Alzheimer's disease (AD).

Method

MEDLINE and Web of Science were searched without any restrictions on language, time, or study design, for studies reporting blood levels of the astrocyte biomarkers GFAP, YKL‐40, and S100B in AD patients. Pooled effect sizes were determined using Hedge's g method with a random effects model. The review was prospectively registered on PROSPERO (registration number CRD42023458305).

Result

The search identified 1186 studies; 36 met inclusion criteria (n=3366 AD patients, n=4115 cognitively unimpaired [CU]). Compared to CU individuals, AD patients had significantly higher GFAP and YKL‐40 levels (GFAP effect size 1.15, 95% CI 0.94‐1.36, P<.0001; YKL‐40 effect size 0.38, 95% CI 0.28‐0.49, P<.0001). Both biomarkers showed a trend towards a greater effect size in more advanced disease. No significant difference in blood S100B levels were identified.

Conclusion

Our findings reveal significant elevations in blood GFAP and YKL‐40 levels in AD patients across the clinical spectrum, suggesting that both biomarkers accurately reflect AD‐related pathology.
Comparison of [18F]MK6240 and [18F]Flortaucipir standardized uptake values (SUVs): the HEAD study
Authors: Tissot Cécile , Tsai Hsin‐Yeh , Tudorascu Dana , Lussier Firoza Z , Rahmouni Nesrine , Servaes Stijn , Therriault Joseph , Stevenson Jenna , Gordon Brian A. , Pascual Belen , Lowe Val J. , soleimani‐meigooni David N. , Oh Hwamee , Klunk William E , Rosa‐Neto Pedro , Jagust William J. , Pascoal Tharick Ali , Baker Suzanne L.
Published: January 2025

Background

Differences between on‐ and off‐target retention characteristics between [18F]MK6240 and [18F]Flortaucipir (FTP) complicate the harmonization across tracers. Our objective here was to separate the impact of the reference region by evaluating correlations between [18F]MK6240 (MK) and [18F]FTP standard uptake values (SUVs).

Method

Participants (Figure 1, n=90) received an amyloid‐β (Aβ) PET scan ([11C]PIB or [18F]NAV4694) and two tau‐PET scans: [18F]MK (90‐110 minutes post‐injection) and [18F]FTP (80‐100 minutes post‐injection). For all PET scans, the individual frames were realigned, averaged, and co‐registered to a Freesurfer 7.1‐segmented T1‐MPRAGE. SUVs were calculated in the reference region (inferior cerebellar gray), on‐target regions (entorhinal cortex, hippocampus, Braak III, Braak IV, Braak V, Braak VI) and off‐target regions (caudate, pallidum, putamen, thalamus, cerebellar white matter, choroid plexus, meninges, eroded white matter). We examined correlations between [18F]MK and [18F]FTP SUV values as a function of Aβ status, as well as their associations with age.

Result

All correlations (Figure 2) were significant at p<0.001. The interaction with Aβ status was significant for hippocampus, BraakIII‐V and the metatemporal region. In Aβ+ participants, [18F]FTP and [18F]MK6240 have similar SUVs in on‐target regions with a slope close to 1 except for in hippocampus and Braak VI. However, [18F]FTP SUVs, on average, were greater than [18F]MK SUVs in Aβ+ and Aβ‐ subjects in the reference region and all off‐target regions except for meninges, and in Aβ‐ subjects in the on‐target regions. Age correlated with [18F]FTP SUVs in Aβ‐ subjects in all regions (except the reference region, Braak VI and meninges) and [18F]MK SUVs in putamen and pallidum, but this correlation was only significant (p<0.01) when young and old subjects were included.

Conclusion

Despite [18F]MK’s higher affinity for tau and SUVR dynamic range being twice that of [18F]FTP, the SUVs in on‐target regions are similar. The higher [18F]FTP signal in the reference region appears to be the contributing factor to the lower dynamic range. The higher [18F]FTP signal in on‐target regions for Aβ‐ subjects may reflect the presence of off‐target signals in these subjects. Taking off‐target signals into account should improve correlations between the two tracers, especially when measuring the earliest deposition of tau.
Plasma phosphorylated tau 217 in relation to Alzheimer’s prevalence and cognition in Thailand
Authors: Hemachudha Pasin , Thanapornsangsuth Poosanu , Luechaipanit Watayuth , Hemachudha Thiravat
Published: January 2025

Background

Biomarkers for Alzheimer's disease (AD) in blood samples has the potential to facilitate early diagnosis and improve the accuracy of AD diagnosis. Plasma phosphorylated tau (p‐tau) is a key biomarker for AD; however, its utility for estimating the prevalence of AD and screening for cognitive impairment is still limited.

Method

The study recruited 71 participants over the age of 40. Plasma p‐tau 217 levels and neuropsychological data were measured. AD prevalence was estimated using a pre‐defined cut‐off derived from an independent cohort with biomarker‐defined AD status according to the current framework (Jack et. al., 2018). The correlation between plasma p‐tau 217 levels and neuropsychological data were also evaluated.

Result

The median age of participants was 62 years and overall clinical dementia rating of 0. The median Montreal cognitive assessment (MoCA) and Mini‐Mental State Examination (MMSE) score was 26 and 29 consecutively. Plasma p‐tau 217 levels showed a negative correlation with both neurocognitive tests (MoCA, Rho = ‐0.082, P = 0.5; MMSE, Rho = ‐0.26, P = 0.027). The estimated prevalence of AD was 16.9% (95% CI 9.9‐27.3) when using plasma p‐tau 217 as a biomarker, which was lower than the prevalence estimated using amyloid abnormalities of 30.1% (Jansen et. al., 2022).

Conclusion

The results of this study suggest the possibility of plasma p‐tau 217 for estimating AD prevalence and cognition. It may represent those at risk of clinical onset. However, further studies are needed to investigate its utility in risk stratification, and cognitive performance assessment.
Plasma N‐terminal tau fragment is associated with cognitive status and AD biomarkers of tau and neurodegeneration in older adults
Authors: Rao Yiwen , Ostaszewski Beth L. , Anderson Amirah K. , Shirzadi Zahra , Liu Lei , Yang Hyun‐Sik , Chhatwal Jasmeer P. , Selkoe Dennis J. , Schultz Stephanie A. ,   ADNI
Published: January 2025

Background

The emergence of blood‐based biomarkers offers a cost‐effective and less invasive alternative to established neuroimaging and cerebrospinal fluid biomarkers. Newly developed fluid biomarkers, including N‐terminal tau fragment (NT1), have shown promise for identifying individuals at risk for Alzheimer’s disease (AD). Evidence has shown NT1 may be more abundant than full‐length tau across the AD continuum and has high sensitivity and specificity to separate cognitively normal (CN) individuals from those with mild cognitive impaired (MCI) and AD in discovery and replication cohorts. Here we quantify plasma NT1 in a large, well‐characterized cohort and examine the association between plasma NT1 and cross‐sectional clinical and biomarkers measures.

Methods

Seven hundred and seventeen individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who have plasma NT1, Aβ‐PET, MRI, and clinical (Clinical Dementia Rating; CDR) measures were included in this study (Table 1). NT1 was assessed using Quanterix Simoa HD‐X platform. PET, MRI, clinical, and other plasma measures were derived using previously described procedures in ADNI. Linear regressions were performed to assess the cross‐sectional association of NT1 with clinical and biomarkers measures, after adjusting relevant covariates.

Results

NT1 levels were elevated in cognitively impaired (MCI/AD; CDR>0) relative to CN (CDR=0) individuals (p=0.008, Figure 1A). Specifically, NT1 is elevated in the MCI group (CDR=0.5, MCI vs Aβ‐ CN group: p=0.005), but not the AD group (CDR>0.5, AD vs all other groups: p’s >0.206, Figure 1B). NT1 was associated with plasma phosphorylated (p)Tau‐181 (p=1.27x10‐9, Figure 2A) and plasma neurofilament light chain (NfL; p=5.68x10‐6, Figure 2B) but not hippocampal volume (p=0.239).

Conclusion

Plasma NT1 differentiated CN from MCI/AD individuals and was elevated particularly in the early symptomatic phase of disease. Plasma NT1 was associated with plasma markers of tau and neurodegeneration. Together these results suggest that plasma NT1 may be a useful biomarker of AD‐related tau pathology and neurodegeneration.
People with dementia as exercise video game testers: Gathering end‐user perspectives
Authors: Dove Erica , Wang Rosalie H. , Patterson Kara K. , Astell Arlene J.
Published: January 2025

Background

Commercially available exercise video games (‘exergames’) can be used by people with dementia with the right (human) prompting and support. However, more information is needed about what makes these systems and games technologically accessible for this population, considering their cognitive difficulties. This study explores what works and doesn’t work for people with dementia when introducing new exergame systems and games to broaden opportunities for physical activity.

Methods

Thirty‐two people living with dementia (mean Montreal Cognitive Assessment score: 12.75/30) were recruited from four community‐based adult day programs in Canada. Participants were recruited as ‘game testers’ once weekly for six weeks at each day program. Participants with dementia tried different exergame systems (e.g., Xbox Kinect, Nintendo Switch) and games (e.g., darts, boxing, dancing, etc.). Concurrently, gameplay video recordings and feedback via the talk‐aloud protocol and audio‐recorded post‐game group debriefs were collected. Data were analyzed descriptively and are currently undergoing analysis using behavioural coding software to examine in‐game prompts and player movements.

Results

In total, 292 gameplay turns occurred across the sessions. Some participants declined to play certain games after watching their peers experience accessibility challenges. Common reasons for ending a turn (beyond completing the game objective) included boredom, frustration, confusion, fatigue, and soreness. Systems with handheld controllers (e.g., Nintendo Wii) were less accessible for participants than gesture‐based controls due to the need to push buttons and attend to the controller while simultaneously performing physical motions. Additionally, games requiring multiple coordinated movements and those not accommodating additional age‐related impairments (e.g., range of motion impairments, mobility devices) were not widely accessible to this diverse group of participants.

Conclusions

This study highlights the importance of involving people living with dementia in game development. The findings reveal which elements of current exergames make them accessible or inaccessible for people living with dementia. These findings can help design new exergames to increase access to physical activity for people with dementia. The findings will also interest dementia service providers who want to use exergames to increase physical activity for people with dementia.
Understanding the variability in plasma biomarker levels in the context of established biomarkers of Alzheimer’s disease
Authors: Bluma Marina , Chiotis Konstantinos , Bucci Marco , Savitcheva Irina , Matton Anna , Kivipelto Miia , Jeromin Andreas , Santis Giovanni De , Molfetta Guglielmo Di , Ashton Nicholas J. , Blennow Kaj , Zetterberg Henrik , Nordberg Agneta K
Published: January 2025

Background

Plasma biomarkers are on the verge of being introduced as screening tools for detecting Alzheimer's disease (AD). Yet, previous studies yielded contradictory results regarding the extent to which distinct plasma biomarkers reflect the key pathological changes associated with AD. This study aims to investigate the specific relationship between core AD biomarkers, such as amyloid PET and CSF pTau, and the novel plasma biomarkers.

Method

We analyzed plasma pTau181, pTau217, pTau231, GFAP, NfL, CSF pTau181, Aβ‐PET scans, and MRI/CT visual reads of atrophy (MTA and GCA) in a cohort of memory clinic patients (N=138) who underwent comprehensive clinical assessments at the Memory Clinic, Karolinska University Hospital, Stockholm, Sweden. Patients were classified according to the ATN system, for the presence of Aβ‐deposition (A), tau aggregation (T), and neurodegeneration (N) based on Aβ‐PET, CSF pTau and MRI/CT measurements, respectively. We utilized methods based on multiple linear regression to evaluate the distinct contributions of Aβ‐PET, CSF pTau, and neurodegeneration, on plasma biomarker levels, while also considering demographic variables.

Result

We found significant (p<0.05) positive associations between Aβ‐PET and plasma pTau181, pTau217, pTau231, GFAP, but not NfL. Similarly, significant positive associations were observed between CSF pTau and plasma pTau isoforms and GFAP. After accounting for the effect of Aβ‐PET, only plasma pTau217 and pTau231 remained significantly associated with CSF pTau. Among all, plasma pTau217 and GFAP exhibited the greatest effect sizes to distinguish between A+/A‐, whereas plasma pTau231 and pTau217 for distinguishing T+/T‐. Plasma NfL showed the highest effect size for distinguishing N+/N‐ among all plasma biomarkers. Dominance analysis indicated that Aβ‐PET had the highest relative importance in predicting pTau isoforms and GFAP values, followed by CSF pTau. Notably, pathology‐related AD biomarkers (Aβ‐PET and CSF pTau) explained the largest portion of variance in plasma pTau217(56%), GFAP (24%), pTau181(16.2%), pTau231(17%), but not NfL(0.6%).

Conclusion

Amyloid burden primarily drove changes in levels of the tested plasma biomarkers, except for NfL where atrophy played a role. Unlike plasma GFAP and pTau181, where the effect of CSF pTau was attenuated by the effect of Aβ‐PET, both pTau231 and pTau217 reflected changes in CSF pTau levels. Variance in plasma pTau217 levels appeared to be well explained by AD‐related pathological changes.
In‐vivo plasma biomarker concentrations correlate with postmortem AD‐neuropathology in the oldest old
Authors: Lorenz Linda M.C. , Rohde Susan K. , Luimes Maruelle C. , Fierro‐Hernández Patricia , Rozemuller Annemieke J.M. , Bank Netherlands Brain , Hoozemans Jeroen J.M. , Teunissen Charlotte , Holstege Henne
Published: January 2025

Background

There has been ongoing uncertainty to what extent plasma biomarkers are representative of neuropathological markers of AD pathology in the oldest old. A complicating factor is that with increasing age, Aβ‐ and Tau pathologies accumulate in the brains of cognitively healthy individuals to highly variable levels (Zhang & Ganz et al., 2022). The unique availability of both antemortem plasma biomarker concentrations and postmortem neuropathology in self‐reported cognitively healthy oldest old, offers a chance to explore whether levels of plasma biomarkers can serve as in‐vivo proxy of AD neuropathology.

Methods

We evaluated postmortem neuropathology of 48 centenarian brains, with a median MMSE score of 26 (range:16–30) at blood draw. We quantified plasma biomarkers Aβ40, Aβ42, Aβ42/40, pTau181, NfL and GFAP on the Simoa platform. The median interval between blood‐sample collection and brain donation was 1.3 (range:0–5.1) years. In addition to conventional spatio‐temporal staging systems such as Thal‐Aβ phase (median 2, range:0‐5) and Braak‐NFT stage (median 3, range:2‐5), we also quantified pathological load by measuring the percentage area of immunopositivity for total Aβ (range:0–9.0%), Aβ40 (range:0–3.3%), Aβ42 (range:0–11.5%), pTau‐217 (range:0–1.8%) and AT8 (pTau‐202/205; range:0–49.2%) in the cortex of the temporal pole. Partial Spearman correlations were conducted adjusted for age, sex, and time interval.

Results

Plasma pTau‐181 correlated with Aβ pathology loads, namely Aβ40 (r=0.48, p<0.001), Aβ42 (r=0.41, p=0.005) and total Aβ (r=0.48, p<0.001), as well as with spatio‐temporal Thal‐Aβ phase (r=0.45, p=0.003). Plasma pTau‐181 correlated with quantitative pTau pathology loads, specifically pTau‐217 (r=0.48, p=0.001) and AT8 (r=0.41, p=0.005), but not with spatio‐temporal Braak‐NFT stage (r=0.17, p=0.290). Furthermore, both plasma NfL and plasma GFAP also correlated with pTau‐217 load in the brain (r=0.30, p=0.0496; r=0.30, p=0.044, respectively). Plasma Aβ40, Aβ42, Aβ42/40 did not correlate with any neuropathology measure.

Conclusions

Results reveals plasma pTau‐181, but not plasma Aβ, as a reliable indicator for both Aβ and pTau pathology loads in the temporal pole of the oldest old. The 100‐plus study cohort provides a promising opportunity to study the correlation between different pTau epitopes and the presence of pTau levels, as well as the presence of Tau pathology, including NFTs, neuropil threads, pre‐tangles and ARTAG.
Discriminating Alzheimer's Pathologic Changes from Dementias: A Multi‐Factor Blood Biomarkers Diagnostic Model Using the AT(N) System
Authors: Wang Tianyi , Shang Li , Mao Chenhui , Sha Longze , Dong Liling , Liu Caiyan , Lei Dan , Li Jie , Wang Jie , Huang Xinying , Li Bo , Huang Yixuan , Bao Jialu , Qiu Yuyue , Chu Shanshan , Jin Wei , Zhu Zhaohui , Sui Huimin , Hou Bo , Feng Feng , Peng Bin , Cui Liying , Wang Jianyong , Xu Qi , Gao Jing
Published: January 2025

Background

To assess the diagnostic efficacy of plasma biomarkers in distinguishing Alzheimer's pathologic changes from other forms of dementia, our study focused on examining plasma biomarkers in accordance with the AT(N) system.

Method

A total of 156 participants were recruited from the PUMCH dementia cohort. This comprised 55 non‐AD (A‐) and 101 Alzheimer's pathologic changes (A+) individuals. Among the latter group, there were 40 AD‐like(A+T‐) and 61 AD(A+T+). Biomarker diagnoses were relied on cerebrospinal fluid (CSF) biomarkers and amyloid PET results. Plasma biomarkers were quantified using single molecule array (SIMOA).

Result

Plasma Aβ40, Aβ42, GFAP, NfL, and pTau181 were compared among A‐, A+T‐, and A+T+ groups. Significant reductions in plasma Aβ42/40, along with elevated levels of plasma pTau181 and GFAP, were observed in both A+T‐ and A+T+ groups compared to the A‐ group. However, no significant differences were found between the A+T‐ and A+T+ groups. Additionally, plasma Aβ42/40, pTau181, and GFAP exhibited significant correlations with multiple CSF biomarkers, especially with CSF Aβ biomarkers, whereas plasma Aβ42, Aβ40, and NfL did not. None of the plasma biomarkers were indicative of disease severity in A+ dementia patients. Finally, a high accuracy diagnostic model in predicting Alzheimer's pathologic changes in dementia patients could be generated using plasma biomarkers.

Conclusion

Plasma levels of Aβ42/40, pTau181, and GFAP present valuable indicators in distinguishing Alzheimer's pathologic changes from other forms of dementia. The integration of multiple plasma biomarkers into a diagnostic model can significantly enhance diagnostic accuracy, thereby providing valuable support for clinical practice.
Cardiorespiratory Fitness Modifies the Association Between Cerebral Pulsatility on Amyloid Burden and Core CSF Biomarkers of Alzheimer’s Disease
Authors: Breidenbach Brianne M. , Brach Talia L. , Glittenberg Matthew P , Paulsen Adam J , Symanski Leah E , Naren Tarun , Driscoll Ira , Lose Sarah R , Gallagher Catherine L. , Johnson Sterling C. , Asthana Sanjay , Betthauser Tobey J. , Rivera‐Rivera Leonardo A. , Hermann Bruce P , Sager Mark A. , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Cook Dane B. , Wieben Oliver , Okonkwo Ozioma C
Published: January 2025

Background

Increasing evidence supports the notion that vascular dysfunction contributes to the evolution of Alzheimer’s disease (AD). Cerebral pulsatility index (PI) is reportedly higher in AD and MCI compared to age matched controls and has been associated with greater beta‐amyloid (Aß) burden. Higher cardiorespiratory fitness (CRF) positively affects vascular function and is associated with lower PI in several large cerebral vessels. Our objective was to examine whether CRF modifies the relationship between PI, Aß burden, and core AD cerebrospinal fluid (CSF) biomarkers.

Method

Cognitively unimpaired adults (n=33, MeanAGE=64.0) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who met study criteria were included. Aß burden was measured as global cortical PiB‐PET. CSF biomarkers were measured with the NeuroTookKit, a panel of robust prototype assays (Roche Diagnostics International Ltd). PI from bilateral MCA vessels were measured using 4D flow MRI and averaged (PI‐MCAAVG). CRF was indexed as VO2peak during a graded exercise treadmill test. A single multivariate regression, (covariate‐adjusted for sex, age, and APOE4) examined whether CRF modifies the impact of PI‐MCAAVG on Aß burden and core‐AD CSF biomarkers [phosphorylated Tau 217 (pTau‐217), total Tau (tTau), Aß42/Aß40, pTau/Aß42]. When significant, the PI*CRF interaction term would indicate a differential effect of PI on Aß burden or CSF biomarker as a function of CRF.

Result

There was a significant interaction between PI and VO2peak on PET Aß burden (ß = ‐0.05, p= 0.04), Aß42/ Aß40 (ß=0.006, p=0.03), pTau (ß= ‐3.4, p=0.03), tTau (ß ‐29.8, p=0.04) and pTau/Aß42 (ß= ‐0.006, p=0.02), indicating less Aß burden and more favorable profiles for all core CSF biomarkers with increasing VO2peak despite elevated PI.

Conclusion

Our findings support the hypothesis that greater CRF modifies the effect of cerebral PI on PET Aß burden and core AD CSF biomarkers, indicating that improved VO2 seems to be protective against cerebrovascular alterations known to contribute to AD‐related biomolecular changes.
Associations between blood‐based biomarkers, synaptic density and Alzheimer’s disease hallmarks in the brains of nondemented elderly
Authors: Meyer Steffi De , Alali Soha , Laroy Maarten , Casteele Thomas Vande , Cauwenberge Margot Van , Goossens Julie , Rocker Charlotte De , Vanbrabant Jeroen , Vanmechelen Eugeen , Dupont Patrick , Laere Koen Van , Vandenbulcke Mathieu , Emsell Louise , Poesen Koen
Published: January 2025

Background

Synaptic loss is a critical early pathological hallmark of neurodegeneration, in particular in Alzheimer’s disease (AD), as evidenced by in vitro as well as in vivo PET studies. To date, it is not clear how blood‐based synaptic and AD biomarkers relate to synaptic density in the brains of non‐demented elderly, including those diagnosed with depression.

Method

This cross‐sectional study included 61 older adults with no history of dementia (age [mean±SD] = 71±6 years, MMSE (median[IQR] = 28[3], 64% female, 38% late‐life depression) from the Leuven late‐life depression (L3D) study. Plasma as well as [11C]UCB‐J PET (synaptic vesicle protein 2A [SV2A]) were acquired from all participants. Subgroups underwent [18F]MK6240 (tau load, n = 51) and [18F]flutemetamol (amyloid‐β [Aβ] load, n = 48) PET. Plasma SNAP25, VAMP2 and pTau181 were quantified using Homebrew Simoa assays developed by ADx Neurosciences. Plasma GFAP, Aβ1‐42 and Aβ1‐40 were quantified using the Quanterix N4PE Simoa kit. Associations between biomarkers and SV2A density were evaluated using voxelwise regression models adjusted for age, sex and depression diagnosis at peak‐level Puncorrected <.05 and cluster‐level PFWE <.05. If significant clusters were detected, Spearman correlations were calculated across the identified clusters for each biomarker. Global brain Aβ and tau load were assessed in Aβ‐ and tau‐vulnerable regions and also correlated with plasma biomarkers.

Result

High GFAP levels associated with low synaptic density within temporal regions (GFAP cluster 1) as well as the precuneus and cingulate gyrus (GFAP cluster 2) with ρGFAP = ‐0.39 (P =.002, Figure 1A). High VAMP2 levels were associated with lower synaptic density within temporal and frontal and – to a lesser extent – occipital regions (ρVAMP2 = ‐0.55, P <.001, Figure 1B). For the Aβ1‐42/Aβ1‐40 ratio as well as pTau181 and SNAP25 levels, no associations with synaptic density were observed. Of note, study participants overall demonstrated low global Aβ and tau pathology (Figure 2) and no correlations were found with global Aβ nor tau load for any of the plasma biomarkers.

Conclusion

Plasma levels of GFAP and VAMP2 reflect synaptic density independently of pathological AD hallmarks in nondemented elderly with low evidence of AD pathology.
Physical exercise prevents age‐related changes in [11C]PK11195 uptake in a mouse model of Down Syndrome
Authors: Righini Chiara Maria , de Souza Larissa Estessi , Brizola Jean Marques , Spelta Lidia Emmanuela Wiazowski , de Paula Faria Daniele de Paula
Published: January 2025

Background

Down syndrome (DS) is associated with mitochondrial dysfunction leading to higher levels of oxidative stress and cell degeneration. This fact, together with the overexpression of AD‐related genes in trisomy 21, increases the risk of developing Alzheimer's disease (AD). Thus, it is important to look for interventions that could prevent mitochondrial damage before symptoms occur. Physical activity is a non‐pharmacological intervention that provides an anti‐inflammatory response and increases the levels of neurotrophic factors that are beneficial for brain health. Therefore, the aim of this study is to evaluate the effect of physical activity on microglial function during the aging process in a transgenic mouse model of DS using [11C]PK11195 positron emission tomography.

Method

Ts65Dn male and female mice (euploid and trisomic) were used in this study (CEUA 1292/2019). Animals were subjected to physical activity on a treadmill from 2 to 20 months of age, 3 times per week. [11C]PK11195 PET images were acquired at 5, 14, and 20 months of age. For image acquisition, animals were injected intravenously with [11C]PK11195. Images were acquired in a small animal PET scanner 30 min after tracer injection, and acquisition took 20 min, with animals kept under anesthesia throughout the acquisition. PET images were co‐registered to a T2‐MRI template and the standardized uptake value (SUV) was calculated in the whole brain.

Result

Throughout the aging process, a decrease in the [11C]PK11195 uptake was observed in the trisomic animals at 20 months of age, when compared to the age of 5 months (‐60.7%, 0.56±0.13 vs. 0.22±0.1, p<0.05); and 14 months (‐55.1%, 0.49±0.09 vs. 0.22±0.1, p<0.01). However, the exercised trisomic animals did not present a decrease in the [11C]PK11195 uptake at 20 months being comparable (no statistical differences) to the euploid animals (exercise and non‐exercise groups).

Conclusion

Our data suggest that physical activity could prevent a possible deleterious effect of accelerated aging in mitochondrial function, in the presence of the trisomy 21, since lower [11C]PK11195 uptake could be associated with mitochondrial dysfunction and reduced expression of the TSPO protein.
Multisensory stimulation in advanced dementia: Insights from a case study
Authors: Chrysostomou Savvina , Tziannarou Antonia , Hadjiloizou Andrea , Moza Sotiria
Published: January 2025

Background A 92‐year‐old retired seamstress, born in 1932, with 12 years of education, had been residing in a long‐term care facility since 2019, following a fall and hip fracture. Post‐admission, her cognitive function gradually declined and she did not participate in residential home activities. This study explores the outcomes of an 8‐month, multisensory remediation program. Methods The individual participated in bi‐weekly, multisensory, group therapy sessions spanning eight months from April to December 2023. The stimuli comprised a blend of visual, tactile, and auditory elements, such as constructive wooden puzzles, knitting wool, sensory balls, kinetic sand, exposure to fabric and clothing, classical music songs, language engagement through discussions, and reminiscence activities. Results Over the course of 8 months, the individual demonstrated qualitative improvements, including active participation in dialogues with neuropsychologists, expressing preferences for stimuli, and displaying increased engagement and willingness to attend sessions. Clinic personnel also noted positive changes in mood, cooperation, interest in interactive activities within the clinic, and enhanced language abilities. These improvements led to the patient relocating to a more team‐oriented table in the common area. As a result of these observed positive changes in the clinical profile, the Mini Mental State Examination (MMSE) was administered in December 2023, yielding a score of 6 out of 30 (points achieved in, naming, reading, orientation and following instructions). Discussion Multisensory therapy may show promise in regard to language and communication skills in elderly individuals with advanced dementia. These positive outcomes may contribute to the patients’ overall well‐being and serve as valuable indicators for treatment evaluation. The study is ongoing to explore long‐term effects and broader implications.
Contribution of White matter Hyperintensities Lesion Burden to Cognitive Impairment in Older Adults with Epilepsy
Authors: Reyes Anny , Prabhakaran Divya , Farid Nikdokht , Punia Vineet , Struck Aaron F , Wang Irene , Ferguson Lisa , Almane Dace , Jones Jana , Busch Robyn M , Hermann Bruce P , McDonald Carrie R
Published: January 2025

Background

Older adults with epilepsy represent the largest and fastest‐growing segment of individuals with epilepsy and harbor risk factors for pathological aging, including cerebrovascular risk factors (CVRFs) and Alzheimer’s disease (AD)‐related pathology. In fact, several community‐based studies have reported up to a 3‐fold increased risk for dementia including AD among individuals with epilepsy. Despite this, identification of risk factors for AD and related dementias (ADRD) remains largely unexplored in epilepsy, which has critical implications for patient care and dementia risk stratification. Here, we examine the relationship between white matter hyperintensities (WMH) as a marker for vascular brain injury, a common contributor to the ADRD spectrum (i.e., biomarker of non‐AD co‐pathology), and sociodemographic, clinical, and cognitive profiles in older adults with epilepsy.

Method

Forty‐nine older adults with epilepsy without dementia (average age=66.6, average education=15.1, 52.8% female, 86.8% non‐Hispanic white) completed cognitive testing, a comprehensive lipid panel, and MRI that included 3D FLAIR. The 3D FLAIR was analyzed to quantify WMH lesion burden (LB) using the LesionQuant software. Stepwise regressions were used to examine the contribution of sociodemographic, clinical, and vascular risk factors to WMH‐LB. The association between cognitive scores and WMH‐LB was analyzed with Spearman rho.

Result

Older age, male sex, non‐White race, hypertension, and diabetes were associated with increased periventricular (adjusted R2= .518, p=.016) and whole brain WMH‐LB (adjusted R2= .456, p=.025). Smoking was associated with increased juxtacortical WMH‐LB (β= .684, p=.025). Higher juxtacortical WMH‐LB was associated with poorer performance on measures of visual immediate (rho=‐.374, p=.010) and delayed memory (rho=‐.408, p=.004), delayed list recall (rho=‐.363, p=.011), processing speed (rho=‐.364, p=.010), confrontation naming (rho=‐.314, p=.010), and lower scores on the MoCA (rho=‐.350, p=.014) and more errors on the ADAS‐Cog (rho=.372, p=.008).

Conclusion

In a group of older adults with epilepsy, greater WMH burden was associated with a worse cognitive profile and with the presence of CVRFs. The etiology of dementia in epilepsy remains understudied, and here, we provide evidence for WMH burden as a potential contributing factor to cognitive decline in this population. Older adults with epilepsy with evidence of vascular pathology would benefit from targeted interventions focused on the management of modifiable vascular risk factors.
Intersection of co‐occurring α‐synuclein and tau seeds in Lewy body and other neurodegenerative diseases
Authors: Zamore Hannah , Manca Matteo , Coughlin David G , Standke Heidi , Browne Danielle F. , Smirnov Denis , Thomas Olivia R. , Swanberg Caitlin , Galasko Douglas R. , Hiniker Annie , Kraus Allison
Published: January 2025

Background

Distinct amyloid structures characterize specific proteinopathies, including tau and α‐synuclein based neurodegenerative diseases. However, how protein seed co‐occurrence and other pathologic features account for clinicopathological heterogeneity observed within and between proteinopathies is unclear. Here, we quantify α‐synuclein and isoform‐specific tau seeds across neurodegenerative diseases, including in Lewy body disease (LBD), AD neuropathologic change (ADNC), and 4R tauopathy cases to inform how co‐occurring seeds may impact disease presentation and trajectory.

Method

Real‐time quaking‐induced conversion (RT‐QuIC) assays with fM sensitivity were used to estimate α‐synuclein and tau isoform specific seeding doses in LBD (n=21), ADNC (n=47) across a range of Braak stages, and in 4R tauopathy (CBD=6; PSP=15) in mid‐frontal lobe and hippocampus.

Result

α‐synuclein seeding doses were observed in the mid‐frontal lobe of all LBD cases, increasing with Lewy body stage (F=69.8, p<0.001) and reaching up to 105 and 106 seeding doses. Co‐occurring α‐synuclein seeding was noted as prevalent (50%) in AD, albeit typically at multi‐log lower levels than that quantified in LBD. 100% of AD with amygdala‐predominant α‐synuclein (N=4) and 30% of AD cases without Lewy bodies (N=10) had detectable α‐synuclein seeding. 3R/4R tau seeds were nearly ubiquitously detected well before overt neuropathology across all cases, and α‐synuclein seeding was also observed occasionally without α‐synuclein neuropathology. Markedly, 3R/4R tau and α‐synuclein seeding activities correlated in LBD while controlling for Braak stage (R2=0.72, p<0.001). 4R tau seeds confirmed 4R tauopathy and occurred to some extent, albeit with lower frequency than 3R/4R tau, in non‐4R tauopathy.

Conclusion

Protein seed co‐occurrence is prevalent, including at early stages of both tau and α‐synuclein based disease. RT‐QuIC assays can selectively amplify, with multi‐log differentiation, α‐synuclein or tau seeds related to distinct α‐synuclein or tau structures characteristic of LBD, AD, and 4R tauopathies. Pervasive, but quantitatively distinct α‐synuclein seeding activity occurred in frontal cortex in LBD and AD, including detectable α‐synuclein seeds in some AD cases without identifiable Lewy body neuropathology. Regression analysis of seeding activities revealed quantitatively similar levels of α‐synuclein and tau seeding in LBD suggesting a possible novel role for α‐synuclein‐tau interaction in LBD, which we will explore in future studies.
Joint Contribution of NfL and PSMD for Improved Risk Stratification of VCID
Authors: Luckey Alison M. , Beiser Alexa S , Himali Jayandra J. , Gaona Carlos A. , Zeynoun Joy , Rodriguez Luis A. Mendez , Habes Mohamad , Kautz Tiffany F. , Seshadri Sudha , Aparicio Hugo J. , Satizabal Claudia L
Published: January 2025

Background

Advancing therapeutic and prevention strategies for vascular contributions to cognitive impairment and dementia (VCID) warrants identifying novel biomarkers. However, due to the high heterogeneity underlying dementia pathology, a single marker may not fully risk‐stratify for VCID. A blood‐based biomarker of neuroaxonal injury, neurofilament light chain (NfL), and a neuroimaging‐based biomarker of white matter microstructural damage on diffusion weighted imaging, peak width of skeletonized mean diffusivity (PSMD), have been related to worse general cognition and proposed as robust biomarkers for cerebral small vessel disease (cSVD). We investigated the joint contribution of NfL and PSMD for improved specificity/sensitivity to identify persons at risk for VCID.

Method

Dementia‐free participants from the Framingham Offspring Study with cognitive, neuroimaging, and NfL data were included (N=969). NfL was measured in plasma, and PSMD was derived from MRI diffusion weighted imaging. Executive function and general cognitive function were assessed from a neuropsychological battery. NfL and PSMD were dichotomized by the top quartile and combined to indicate a high cSVD burden. The high NfL‐PSMD risk category was related to cognitive function using linear regression adjusting for age, age‐squared, sex, education, renal function (eGFR), and total intracranial volume. Additional analyses incorporating amyloid PET uptake in 64 participants were performed to discern Alzheimer’s disease pathology from VCID.

Result

Higher NfL‐PSMD was significantly associated with worse executive (Beta±SE, ‐0.06±0.02, p=0.002) and general cognitive function (‐0.15±0.07, p=0.02). Additionally, amyloid PET over‐predicted NfL levels in those with PSMD below the median (observedpredicted, 0.06 (0.33)). Although results were not significant (p=0.15) due to the limited sample, they suggest that amyloid pathology does not explain cSVD burden measured with NfL and PSMD.

Conclusion

Our findings suggest combining NfL and PSMD can better risk‐stratify those with VCID and poorer cognitive function. This NfL‐PSMD multi‐biomarker has potential to discriminate vascular dysfunction from Alzheimer’s pathology, improving identification of persons better suited for VCID clinical trials. Utilizing a multi‐biomarker approach may improve accuracy for risk stratification of persons bearing covert cerebral vascular injury. Further studies are underway to confirm these findings in larger, diverse samples.
Gut microbiome features co‐occur in different groups of Alzheimer’s disease phenotypes and genotypes
Authors: Kang Jea Woo , Khatib Lora A. , Dilmore Amanda H. , Heston Margo B. , Ulland Tyler K. , Johnson Sterling C. , Asthana Sanjay , Carlsson Cynthia M. , Chin Nathaniel A. , Knight Rob , Kaddurah‐Daouk Rima , Rey Federico E. , Bendlin Barbara B. ,   Alzheimer's Gut Microbiome Project Consortium (AGMP)
Published: January 2025

Background

Gut microbiome features are known to be different in Alzheimer’s disease (AD) patients compared with cognitively normal. Evidence suggests that the gut microbiota may be related to the pathology of AD. We examined the association between the gut microbiome and AD phenotypes and genotypes.

Method

Cross‐sectional analysis was performed on the filtered microbiome count table including 246 participants from the Microbiome in AD Risk Study. The filtered taxonomic count table was used to analyze differential abundance using the BIRDMAn pipeline. To determine the differences in the microbiota features derived from each cognitive, amyloid, and ApoE4 group, we implemented statistical models that had microbiome features as outcome variables and each cognitive, amyloid, and ApoE4 group as predictor variable adjusting for covariates including age, sex, BMI, Bristol type, and age difference between fecal collection and measurements of each predictor variable.

Result

Each cognitive, amyloid, and ApoE4 group showed differentially abundant microbiota features. Top microbial features (more abundant in AD, amyloid +, ApoE4 +) that co‐occurred with all three groups were mostly Bacteroides spp., Collinsella spp., and Fusobacterium spp. Bottom microbial features (less abundant in AD, amyloid +, ApoE4 +) that co‐occurred with all three groups were mostly Dialister spp. and Prevotella spp.

Conclusion

The same microbial species were more abundant and less abundant in clinical, preclinical, and genetic risk groups. These results suggest candidate microbes that can be stratified in analyses that involve associations between gut microbiome and AD pathology.
Pathways towards Cognitive resilience in the context of amyloid pathology: a longitudinal matched study design
Authors: Aguillar Pablo , Akinci Muge , Palpatzis Eleni , Bejanin Alexandre , Arenaza‐Urquijo Eider M
Published: January 2025

Background

Cognitive resilience can be defined as better‐than‐expected cognitive performance in the context of Alzheimer’s disease (AD) pathologies or increased AD risk. We investigated pathways associated with cognitive resilience trajectories in amyloid positive (A+) and/or APOE4 cognitively unimpaired (CU) older adults including brain resilience, resistance to AD pathologies and vascular pathology.

Method

We included 534 CU ADNI participants with available cognitive data, longitudinal amyloid‐PET ( [18F]florbetaben and [18F]florbetapir) and structural MRI (gray matter volumes) and, as ubset with tau‐PET ( [18F]AV1451) (n = 287) and white matter hyperintensities (n = 467) volume data (n = 534). We performed a one‐to‐one matched design, aligning participants by their baseline amyloid levels, MMSE scores, and age within an average follow‐up time of 6 years (68.18 ±32 months). We identified 44 CU participants ‐ defined as cognitive resilient ‐ who were A+ and/or APOE4 carriers and remained CU and 44 CU A+ matched participants who converted to MCI or AD (non‐resilient). To assess brain resilience, resistance to pathologies and vascular pathways, at baseline, t‐test were performed with gray matter volumes, amyloid (n = 44), tau (n = 12) and WM measurements (n = 27) as outcomes of interest. Longitudinally, linear mixed effect models were used to examine the interaction between cognitive resilient status (resilient vs non) and time on regional amyloid and tau deposition, and gray matter volume.

Result

At baseline, cognitive resilient participants were characterized by lower tau burden in temporal regions (Figure 1). Longitudinally, cognitive resilient participants showed lower tau accumulation in medial temporal and limbic areas, including the insular and anterior cingulate cortices, and lower volume loss in fusiform, inferior temporal and entorhinal cortex (Figure 2). Unexpectedly, cognitive resilience participants showed greater amyloid increases notably in the anterior cingulate, although both groups showed increased amyloid accumulation. Sensitivity analysis adjusting by conversion time, to rule out the impact of varying accumulation rates due to disease progression, rendered similar results.

Conclusion

Our results suggest that processes downstream amyloid deposition including resistance to tau and brain maintenance might be key to maintain cognitive function in the presence of amyloid pathology.
The impact of polygenic cardiovascular risk on Alzheimer’s‐like brain changes
Authors: Lenhoff Sarah‐Alexis , Page Frederick A , Nowell Joseph , Edison Paul
Published: January 2025

Background

A growing body of evidence demonstrates the relationship between cardiovascular risk and the risk of dementia development. Researchers have identified several genetic links between cardiovascular diseases and Alzheimer’s disease, including the apolipoprotein E and methylenetetrahydrofolate reductase (MTHFR) genes. Here we evaluated the impact of cardiovascular polygenic risk on pathological brain changes associated with Alzheimer’s disease, to elucidate the potential mechanism by which cardiovascular risk induces brain damage.

Methods

n ≈ 30,000 participants were evaluated from the UK Biobank database. The standard cardiovascular polygenic risk score was acquired for all participants. Where data was available the following data was downloaded; hippocampal volume and total grey matter volumes, white matter hyperintensity volume, whole brain grey matter and temporal cerebral blood flow, and diffusion‐weighted imaging outcomes. Linear regressions were performed to evaluate the influence of cardiovascular polygenic risk on brain changes in various regions implicated in Alzheimer’s disease.

Results

A higher cardiovascular polygenic risk demonstrated the strongest association with an increased deep white matter hyperintensity volume. Increased polygenic risk was additionally associated with a reduced total grey matter volume. In the parahippocampal part of the cingulum, higher polygenic risk was associated with increased mean diffusivity and reduced orientation dispersion. No association was shown with cerebral blood flow.

Conclusion

Genetic cardiovascular risk was demonstrated to be associated with several Alzheimer’s‐like neurodegenerative changes. A strong association was shown with white matter hyperintensities and decreased total brain volume, indicating the vulnerability to cognitive impairment in those with higher cardiovascular risk. Screening cardiovascular genetic risk at mid‐life could provide a useful tool to implement therapeutic intervention, not only to reduce the risk of cardiovascular disease but to prevent the development of Alzheimer’s disease.
The Relationship between Subjective Visual Impairment and Domain‐Specific Cognitive Performance in Cognitively Normal Older Adults and MCI Patients
Authors: Sergio Jordan P , Dubois Abigail , Thompson Louisa I. , Strenger Jennifer , Price Ashley N. , Stradtman Megan , Sinoff Stuart , Snyder Peter J. , Alber Jessica
Published: January 2025

Background

Age is the greatest risk factor for self‐reported visual impairment (VI) and Alzheimer’s Disease (AD). While prior studies demonstrate associations between VI and cognitive screening measures in older adults, the relationship between VI and specific cognitive domains remains unexplored. We examined the relationship between subjective VI and executive function, attention, visuospatial construction, episodic memory, and processing speed.

Method

Participants were older adults aged 55‐80: 58 cognitively unimpaired (CU) (MoCA>=26, CDR=0) and 19 MCI patients (MoCA>19, <24, CDR=.5). Subjective VI was measured with the National Eye Institute Visual Function Questionnaire (NEI‐VFQ). A neuropsychological battery including the MoCA, CDR, Digit Symbol Substitution Test (DSST), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and Free and Cued Selective Reminding Test (FCSRT) was administered to assess cognition. Partial correlations controlling for age and years of education compared subjective VI scores to cognitive scores. A multivariate, repeated measures ANCOVA was run on a subset (N=23) of participants with 1 year follow‐up data to determine whether group performance differed over time on NEI‐VFQ and DSST.

Result

There were significant correlations between scores on the composite NEI‐VFQ and both the DSST and visuospatial sub‐scale of the RBANS in the CU and patient groups (p<.05). CU adults showed a greater practice effect over time on the DSST than the patient group, who declined in performance. Specifically, CU APOE E4 carriers had a larger increase in DSST score over 12 months than non‐carriers, along with a larger increase in subjective VI on the NEI‐VFQ.

Conclusion

Attention, processing speed, visuospatial construction, and executive function performance was related to a standardized measure of subjective VI in CU older adults and MCI patients. After 12 months, CU APOE E4 carriers showed a stronger practice effect than CU non‐ carriers on the DSST, concomitant with increase in subjective VI. Subjective measures of VI may serve as a tool in early detection of cognitive impairment, although increases in VI over time co‐occurred with increased practice effects in CU APOE E4 carriers. Longitudinal studies are ongoing to examine the predictive value of subjective VI on cognitive impairment.