bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional microglial activation differs across the cortex of patients in the Alzheimer's disease trajectory: a cross‐sectional study
Authors: Tuil Marie Emilie , Calsolaro Valeria , Crook Harry , Femminella Grazia Daniela , Pasqualetti Giuseppe , Buckley Christopher , Trigg William , Gentleman Steve , Brooks David J , Jogaudaite Simona , Abarrategui Javier Alegre , Hinz Rainer , Edison Paul
Published: January 2025

Background

Microglial reactivity and neuroinflammation are crucial pathological processes in Alzheimer’s Disease (AD). Several attempts to develop a treatment by supressing the immune response in AD have been made, yet these yielded very limited results. Recent studies suggest contrasting effects of microglial reactivity, indicating a biphasic response with both beneficial and deleterious effects at distinct stages of AD. We evaluated the regional differential influence of microglial reactivity on neuropathological processes across AD trajectory.

Method

48 patients were divided by diagnosis into control (11), Mild Cognitive Impairment (MCI, 14), and AD (23) groups. They underwent TSPO‐PET imaging, magnetic resonance imaging (MRI), and neuropsychological testing. The spectral analysis generated a TSPO‐PET impulse response function at 90 minutes (IRF90), reflecting its volume of distribution. Region of interest and voxel‐level analyses were performed, and grey matter (GM) volume was calculated using FreeSurfer and voxel‐based morphometric analysis. Additionally, post mortem brain tissue from 27 patients at Braak Stages IV‐VI was stained for CD32a and CD163, markers of pro and anti‐inflammatory activation respectively.

Result

The AD group showed increased microglial reactivity in the temporal, parietal, occipital, and medio‐temporal lobes, and the cingulate cortex compared to controls. Voxel‐wide analyses of AD and MCI patients yielded similar results across the cortex. The voxel‐wise analysis revealed both positive and negative clusters of association between tracer uptake and GM volume, with negative associations more often found in regions affected earlier in AD trajectory. This dual effect is further denoted by the presence of both CD32a‐positive and CD164‐positive microglia within the same regions in post mortem tissue.

Conclusion

The contrasting effects of reactive microglia on different pathological processes show regional disparities, with deleterious effects more closely associated with regions affected in the early stages of AD. This suggests a diverging response driven by both anti‐ and pro‐inflammatory reactivity profiles. The former, neuroprotective, would emerge locally alongside early pathology, while the later, neurotoxic, would only appear with more advanced pathology. Consequently, potential treatments should promote anti‐inflammatory polarization and supress pro‐inflammatory activation in microglia for an effective therapeutic strategy.
Event‐based modeling of T‐N mismatch reveals distinct spatio‐temporal trajectories of subtypes with likely co‐pathology in Alzheimer’s disease
Authors: Lyu Xueying , Yushkevich Paul A. , Hrybouski Stanislau , Li Yue , Duong Michael Tran , Xie Long , Wisse Laura E.M. , de Flores Robin , Irwin David J , Dickerson Bradford C. , Nasrallah Ilya M. , Das Sandhitsu R. , Wolk David A
Published: January 2025

Background

The heterogeneity of Alzheimer’s disease (AD) and lack of well‐validated markers of co‐pathologies present a substantial challenge for therapeutics. We previously found phenotypes defined by Tau (T) ‐ Neurodegeneration (N) discordance linked to non‐Alzheimer’s pathologies (e.g. TDP‐43, vascular disease). In this work, we aim to leverage T‐N mismatch for identifying distinct spatial‐temporal progression patterns of non‐AD pathologies.

Method

We performed T‐N regression on 1040 scan pairs (n = 722 individuals) from ADNI, using cortical thickness (N) and 18F‐Flortaucipir uptake (T) in 20 bilateral cortical regions of interest. As in previous work, residuals were identified as canonical (T∼N), vulnerable (N>T) and resilient (N<T). Here, we apply SuStaIn, a phenotype discovery and stage inference algorithm, to standardized T‐N residuals in canonical and vulnerable cases (n=608), expecting the latter would reflect co‐pathologies.

Result

Besides the "canonical" subtype (S0), SuStaIn identified three subtypes with distinct T‐N mismatch (N>T) progression profiles (Figure 1). Two exhibited different but progressively diffuse spatial patterns of T‐N mismatch — the anterior subtype (S1) starting from frontal, and the posterior subtype (S2) initiating from occipital/temporal regions. The third subtype (S3) exhibited temporal‐limbic mismatch patterns, with spreading to anterior limbic regions. The three mismatch subtypes had worse cognition, greater age and larger rate of amyloid positivity than canonical subtype (Table 1). SuStaIn‐identified stage was associated with age and worse cognition but not tau severity (Figure 2A‐C), indicating the stages do not represent AD progression. The anterior subtype had the largest white matter hyperintensity (WMH) volume, increasing with higher stages (Figure 2D), suggesting an association with vascular disease. The temporal‐limbic subtype demonstrated poorest memory performance (Figure 2E) and may be associated with TDP‐43 pathology, as suggested in our prior work. 90.1% with longitudinal scans did not change subtype or transitioned from canonical to mismatch subtypes (Figure 2F), supporting the stability of classifications.

Conclusion

We identified distinct T‐N mismatch progression trajectories in AD, potentially reflecting progression of co‐pathologies. It is important to better define these groups in the context of anti‐amyloid therapies to better understand their effectiveness in populations with likely co‐pathology and whether these mismatch trajectories driven by non‐AD factors would continue independent of treatment.
The impact of late‐onset epilepsy as a co‐occurring condition of Alzheimer's disease on tau levels in older adults with Down syndrome
Authors: Queder Nazek , McMillan Liv , Sathishkumar Mithra , Taylor Lisa M. , Keator David B. , Doran Eric , Hom Christy L. , Krinsky‐McHale Sharon J. , Petersen Melissa , O'Bryant Sid E. , Brickman Adam M. , Head Elizabeth , Mapstone Mark , Silverman Wayne , Lott Ira T. , Yassa Michael A.
Published: January 2025

Background

There is an increased risk of epilepsy in Down syndrome (DS), especially after the age of 40. The onset of this co‐occurring disease is closely associated with Alzheimer’s disease (AD) related cognitive deterioration. Therefore, understanding the impact of late‐onset epilepsy on AD biomarkers in people with DS is crucial. Here, we aim to test the difference in tau levels and hippocampal volume in people with late‐onset seizures, childhood‐onset seizures, and no seizures.

Method

We analyzed data from 54 participants (52 +/‐ 6.5 years, 66% females) with DS enrolled in the Alzheimer’s disease Down syndrome study. A total of 18 participants had a history of seizures: 9 participants had recent onset of seizures in the last 5 years and 9 participants had childhood‐onset of seizures. A 2‐to‐1 match method was used to identify 36 control match participants based on age, sex, and dementia status. Magnetic resonance imaging (MRI) and flortaucipir (FTP) positron emission tomography (PET) were used to assess atrophy and tau accumulation respectively. Plasma ptau181 levels were assessed using the ultra‐sensitive single molecule array (Simoa) technology platform HDX imager. ANOVA was used to assess group differences.

Result

The results showed significant differences in ptau181 levels between individuals with late‐onset seizure disorder, individuals with childhood‐onset of seizures, and controls (F(2,51)= 9.649; p<.001). Post‐hoc analysis revealed that individuals with late‐onset seizure disorder had significantly higher levels of ptau181 compared to individuals with childhood‐onset (p<.001) and controls (p = 0.002), with no differences between childhood‐onset seizures and controls. No differences were observed in the hippocampus volume among the three groups. Differences in the temporal meta‐ROI tau SUVR were assessed in a subset of our sample. We observed a trend in individuals with history of seizures showing higher tau SUVR in the temporal meta‐ROI compared to controls.

Conclusion

Our findings suggest that the levels of ptau181 could be impacted by late‐onset seizure disorder. These results shed the light on the importance of assessing the impact of co‐occurring disorder on AD related biomarkers. Future research will explore the impact of late‐onset seizure disorder on AD‐related brain biomarkers longitudinally.
Metabolic PET brain networks predict clinical conversion prior to amyloid positivity in cognitively unimpaired individuals
Authors: Limberger Christian , Martins Gabriel Colissi , Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Peixoto Guilherme G. Schu , de Bastiani Marco Antônio , Machado Luiza Santos , Povala Guilherme , Pascoal Tharick A. , Rosa‐Neto Pedro , de Souza Débora Guerini , Zimmer Eduardo R.
Published: January 2025

Background

The default‐mode network (DMN) consists of brain regions with higher resting activity levels. Amyloid‐ß (Aß) deposition in Alzheimer’s disease (AD) occurs predominantly throughout the DMN, suggesting that activity within the network may facilitate disease processes. Indeed, increased neural activity is positively associated with Aß production. In this context, variations in DMN activity and associated metabolic networks may be linked to the risk of developing AD. However, how patterns of metabolic disruption relate to the progression of AD pathology remains unknown. Here, we investigated whether the metabolic brain networks (MBNs) architecture predicts clinical conversion in cognitively unimpaired (CU) individuals.

Method

We selected CU individuals negative to amyloid and tau (A‐T‐) from the ADNI cohort with [18F]FDG‐PET imaging data at baseline. These patients were divided in stable (non‐converters, n = 18) and clinical progressors (converters, n = 22). Individuals were age‐ and APOEe4‐matched (Table 1). The mean [18F]FDG standard uptake value ratio (SUVR, pons as reference) of brain regions of interest (ROIs) was extracted based on the DKT atlas. MBNs were assembled with a multiple sampling bootstrap scheme and corrected for group imbalance with the Adaptive Synthetic Sampling Approach for Imbalance (ADASYN) and for multiple comparisons using FDR (p < 0.05).

Result

[18F]FDG regional SUVRs presented no differences between groups (Figure 1). However, converters had a prominent brain PET metabolic hyperconnectivity compared to non‐converters, with a 1.5 fold‐change in connection density (p < 0.001, Figure 2A). Notably, this hyperactivation was not limited to the ROIs comprising the DMN; MBNs constructed with all brain regions reveal that the brains of converters typically display metabolic hyperactivity before the onset of CI (Figure 2B).

Conclusion

Our findings suggest the existence of early metabolic alterations at the network level in amyloid negative converters. This corroborates the notion that early soluble forms of amyloid, considered synaptoxins, may trigger brain metabolic hyperconnectivity. MBNs hold promise as biomarkers for detecting individuals at risk of clinical progression, even before amyloid positivity status.
Heterogenous Tau Pathology in the Hippocampus of Progressive Supranuclear Palsy
Authors: Best Merci N , Levy Jonathan , Spencer Amber , Min Lia , Olafasson Einar , Pinarbasi Emile , Sexton Jonny , Jenkins Paul M , Carruthers Vernon B , Paulson Henry L
Published: January 2025

Background

Globose neurofibrillary tangles (NFTs) are found in subcortical areas of post‐mortem brain from individuals with the second most common primary tauopathy, progressive supranuclear palsy (PSP). The degree of cognitive impairment in secondary tauopathies such as Alzheimer’s disease (AD) correlates with the presence of NFTs, which originally appear in the entorhinal cortex before spreading throughout the hippocampus. In contrast, the degree of hippocampal tau pathology in PSP is thought to be limited, consistent with the view that cognitive impairment in PSP is predominantly subcortical. To better define the extent and variability of tau pathology in subregions of the hippocampus (dentate gyrus, CA4, CA3, CA2, CA1, subiculum, and parahippocampal gyrus), we examined PSP brains available through the Michigan Brain Bank.

Method

We identified 33 brains collected since 2011 where the primary neuropathology was PSP. For further analysis, we selected 15 brains (10 male), 14 of which lacked beta amyloid pathology. In 12 cases, clinical and neuropathological diagnoses of PSP were concordant (three other cases had been clinically identified as corticobasal degeneration or “other cognitive disorder”). Immunofluorescence microscopy and western blot analysis were performed with an antibody specific for phosphorylated tau, TaupS202/pT205. A semi‐quantitative scale was used to determine the degree of NFT pathology (0 = negative, 1 = sparse, 2 = intermediate, and 3 = robust) in hippocampal regions of PSP.

Result

Immunofluorescence demonstrated wide variability in the degree and range of tau pathology within the hippocampus. Five of 15 PSP brains demonstrated robust NFT pathology in at least one hippocampal subregion. Within the hippocampus, the CA1 and subiculum most commonly displayed denser NFT pathology whereas the dentate gyrus typically was spared. Western blot analysis likewise demonstrated marked heterogeneity in TaupS202/pT205 signal, ranging from 0 to 161 arbitrary units.

Conclusion

These findings support the view that hippocampal NFT pathology is not uncommon in PSP and may contribute to cognitive impairment in a subset of patients. Furthermore, the high variability in hippocampal NFTs nominates this region in PSP as a compelling brain area in which to assess correlations between tau accumulation and perturbations in neuronal cytoarchitecture.
Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes
Authors: Ottoy Julie , Su Min , Yin Eric , Rahmouni Nesrine , Stevenson Jenna , Soucy Jean‐Paul , Benedet Andrea L. , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. , Gauthier Serge , Black Sandra E , Rosa‐Neto Pedro , Goubran Maged
Published: January 2025

Background

In‐vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of Alzheimer’s disease (AD) patients. However, the extent and implication of microglia reactivity in white matter regions remains unclear. Here, we explored microglia reactivity in white matter using PET imaging of the translocator protein (TSPO) in relation to core AD biomarkers (amyloid, tau, and astrogliosis), microstructural damage, and cognitive decline.

Method

Ninety‐one participants from the Translational Biomarkers in Aging and Dementia cohort (45% Aß‐positive, 39% cognitively impaired) underwent diffusion‐weighted MRI, TSPO‐PET (11C‐PBR28), amyloid‐PET (18F‐NAV4694), tau‐PET (18F‐MK6240), and plasma Aß42/40, ptau181, ptau217, and ptau231. We investigated the associations of TSPO‐PET SUVR in white matter lobes (eroded by 2mm3) with each of the AD biomarkers, diffusion metrics, and cognition, adjusted for demographics and global cortical TSPO‐PET. Longitudinally, we investigated the interaction between time (up to 2y) and baseline white matter TSPO‐PET SUVR on cognitive decline, adjusted for demographics and cortical amyloid.

Result

White matter TSPO‐PET was increased globally with older age and frontally with male sex (p<0.05). In impaired individuals, TSPO‐PET was elevated in temporo‐occipital white matter regions compared to controls (p=0.01‐0.02). The occipital increases were associated with reactive astrogliosis (p=0.011) and higher‐Braak tau‐PET (p=0.003‐0.034 for Braak3‐4) and plasma ptau181 (p=0.014) (Figure 1A‐B), but not with Aß, ptau231 or ptau217. In addition, higher occipital TSPO‐PET was associated with lower fibre integrity (fractional anisotropy, p=0.025) but not free water. Finally, in relation to cognition, higher occipital and parietal TSPO‐PET was significantly associated with impaired memory and language, respectively, independent of Aß (Figure 1C). Longitudinally, within the same patient, higher white matter TSPO‐PET at baseline was significantly associated with favorable clinical outcome over time (Figure 1D).

Conclusion

Increased microglia reactivity (TSPO‐PET) in posterior white matter may indicate later‐stage AD associated with astrogliosis, tau, and dysfunction of the memory and language domains. Another novel finding is that individuals with higher white matter TSPO‐PET at baseline displayed better clinical prognosis over time. As such, assessing white matter inflammation could be promising to evaluate target engagement in clinical trials of anti‐inflammatory drugs and to subtype patients for better patient‐centric treatment outcome.
Evaluation of feasibility, added value and satisfaction of remote digital self‐assessment for mild cognitive impairment in primary and specialized routine care with the app neotivCare
Authors: Düzel Emrah , Schoettler Michael , Sommer Harriet , Griebe Martin
Published: January 2025

Background

Timely diagnosis of mild cognitive impairment (MCI) in Alzheimer’s disease (AD) is crucial for early interventions, but its implementation is often challenging due to the complexity and time burden of required cognitive assessments. Remote unsupervised self‐testing of cognition can potentially addres this health care challenge. We conducted the to date largest evaluation of feasibility and experienced added value of unsupervised digital remote assessment in primary and specialized health care in Germany.

Method

This is a prospective, multicentric health care research evaluation survey called “re.cogni.ze”. Its goal is to evaluate physician satisfaction with a remote digital assessment solution (neotivCare) in primary and specialized routine care in Germany. Physicians in different regions of Germany have been recommending the app to approximately 1000 patients for a 12‐week self‐assessment of cognition. Last patient out is on 31st January 2024. The primary endpoint is the evaluation of physicians' and patients' overall satisfaction with neotivCare in comparison to neuropsychological questionnaires / standard procedures using a Likert scale. Secondary endpoints include user‐friendliness, qualitative assessment of acceptance, and potential improvements on medical routine services.

Result

This is first large scale assessment of feasibility, satisfaction and experienced added value of remote digital self‐assessment of MCI in routine care. The data will be analysed according to prespecified endpoints after data closure on the 31st January 2024.

Conclusion

The study results will provide insights into the feasibility, efficiency, and acceptance of new digital tools for MCI diagnosis in routine care. The re.cogni.ze survey will thus provide proof‐of‐concept information for the implementation of remote digital cognitive assessment apps for MCI into medical routine care.
ALZpath pTau217: Multi‐cohort performance, cross‐assay comparison, and clinical launch for the identification of Alzheimer’s Disease pathology
Authors: Chaby Lauren E , Borello Jacob , Vaughan Timothy , Portbury Stuart D , Frykman Hans , Mammel Anna , Encarnacion Mary , Serrano Geidy E , Wilson Rachael E , Du Lianlian , Jonaitis Erin M. , Johnson Sterling C. , Jeromin Andreas
Published: January 2025

Background

Blood‐based AD biomarker tests will be essential clinical tools to provide accessible and affordable screening and monitoring for AD disease‐modifying therapeutics (DMT) as well as advancing overall clinical care. Tau phosphorylated at position 217 (pTau217) is considered to have the highest accuracy in identifying Alzheimer’s disease (AD) pathology using blood. We describe a multi‐cohort evaluation of the Simoa ALZpath pTau217 assay in plasma, including memory clinic patients, as well as performance in the context of other commercially available pTau217 assays. Finally, we discuss the clinical launch of ALZpath pTau217 including pTau217 reference intervals and clinical cutoffs in the context of other pTau217 assays.

Method

The ALZpath pTau217 assay is an ultra‐sensitive blood‐based test developed on the semi‐automated single‐molecule array Simoa platform; it is the first commercially available pTau217 test and has been used in over 40 cohort studies with over 50,000 sample tests. To enable clinicians to leverage ALZpath pTau217 to inform care decisions, ALZpath Dx has been validated in partnership with Neurocode CLIA‐certified laboratory.

Result

We discuss multi‐cohort ALZpath pTau217 findings for the prediction of amyloid and tau burden, measured using PET imaging and post‐mortem histology. In a pTau217 cross‐assay evaluation, ALZpath pTau217 had the strongest relationship with amyloid load as measured by (PiB) PET in a population of healthy and MCI individuals in comparison with other blood‐based AD biomarker assessments including the integration of multiple biomarkers. We discuss pTau217 reference intervals derived from multiple normative populations and compare pTau217 levels detected across multiple pTau217 assays, demonstrating that reference intervals are currently highly assay specific, highlighting the importance of efforts underway to develop a pTau217 reference standard. Finally, we report the clinical launch of ALZpath Dx, including pTau217 clinical cutoffs derived from cross‐cohort analyses, and the implications for the dementia clinical care system.

Conclusion

Multi‐cohort findings support ALZpath pTau217 as a high performing diagnostic biomarker for Alzheimer’s disease with high accuracy in determining amyloid burden across all stages of AD continuum. ALZpath pTau217 performance capabilities can support timely AD identification and intervention and facilitate scalable DMT implementation.
Reducing Screen Failure Rates Due to Biomarker Cut‐offs in Early AD Trials with a Prognostic Model
Authors: Tam Angela , Laurent César , Dansereau Christian
Published: January 2025

Background

Alzheimer’s disease (AD) trials have high screen failure rates. Recent trials have enriched for individuals based on tau pathology in addition to amyloid pathology, which can exacerbate screen failures. We explored enrichment for decliners with a model that forecasts clinical progression, AD‐Px, while minimizing screen failures and avoiding strict tau cut‐offs.

Method

In amyloid‐positive early AD participants from ADNI (adni.loni.usc.edu), we quantified screen failure rates due to tau enrichment with CSF phosphorylated tau 181 (ptau‐181) measured by the Roche Elecsys assay at a 26.9 pg/mL cut‐off. That cut‐off best separated AD and cognitive unimpaired participants. We performed power analyses to estimate sample sizes for detecting 30% treatment effects at 80% power for two‐arm trials enrolling participants at this cut‐off. We compared the screen failure rates and sample size estimates of the ptau‐181 cut‐off against enrichment with decliners predicted by AD‐Px. AD‐Px is a machine learning model that uses APOE4 status, demographics, clinical assessments, and CSF biomarkers to predict individual risks of decline over 2 years. We replicated these analyses in an independent cohort of amyloid‐positive early AD participants from NACC (naccdata.org).

Result

In ADNI, 36.2% of participants failed to meet the ptau‐181 cut‐off, and 453 individuals were required to power a trial. AD‐Px screened out only 16.7% of participants, while maintaining equivalent statistical power with a sample size estimate of 453. Compared to the ptau‐181 cut‐off, AD‐Px had a 53% smaller screen failure rate (p < 0.001) (Fig. 1). In NACC, the ptau‐181 cut‐off screen failed 42.1% of participants and a power analysis estimated a sample size of 518 individuals. Selecting AD‐Px decliners in NACC, however, screen failed only 11.6% patients and required a sample size of 508 individuals. In NACC, AD‐Px had a 72% smaller screen failure rate compared to ptau‐181 (p < 0.001) (Fig. 2).

Conclusion

AD‐Px effectively reduces screen failure rates caused by restrictive biomarker cut‐offs, enabling more flexible inclusion criteria while maintaining statistical power. By substantially reducing screen failure rates, AD‐Px can accelerate patient enrollment, lower screening costs, and shorten trial durations without compromising sample quality.
Investigating retrotransposon‐derived eccDNA as a source of innate immune activation in tauopathy
Authors: Lambert Morgan Elizabeth , Ramirez Paulino , Sun Wenyan , Frost Bess
Published: January 2025

Background

Retrotransposon‐derived extrachromosomal circular DNA (eccDNA) was extracted and sequenced from brains with Alzheimer’s disease, progressive supranuclear palsy, or healthy controls. Retrotransposon‐derived DNA was visualized outside of the nucleus in these phenotypes with phospho‐STING. Drosophila were used as a model to study extranuclear retrotransposon DNA.

Method

DNA was extracted from post‐mortem human patients with AD (n = 6), PSP (FTD) (n = 6), or no pathology (n = 6). The DNA was treated with exonucleases to degrade linear DNA and the circular DNA was isolated. Post‐mortem cryosections of AD, PSP, or healthy control brains were used for fluorescent in‐situ hybridization (FISH) of retrotransposon sequences. Co‐immunofluorescence of phospho‐STING was performed on FISH tissue. Drosophila brains were also used for FISH of retrotransposons. Digital qPCR was used to measure copy number of retrotransposons in human and fly tissue.

Result

Preliminary data suggests an increase in phospho‐STING in AD and PSP brains compared to controls. Preliminary data also suggests an enrichment of retrotransposon DNA in circular DNA sequencing in tau pathology compared to controls.

Conclusion

Retrotransposon‐derived eccDNA may be an activator of the cGAS‐STING pathway in AD and PSP.
LATE‐NC IN THE VERY ELDERLY– THE POPULATION‐BASED VANTAA 85+ ‐STUD
Authors: Mikhailenko Elizaveta , Colangelo Kia , Tuimala Jarno , Kero Mia , Savola Sara Emilia , Raunio Anna , Kok Eloise H , Tanskanen Maarit , Mäkelä Mira , Puttonen Henri , Mäyränpää Mikko I. , Kumar Darshan , Kaivola Karri , Paetau Anders , Tienari Pentti , Polvikoski Tuomo , Myllykangas Liisa
Published: January 2025

Background

Population‐based cohort studies play a crucial role in unraveling the underlying causes of dementia among older individuals. While previous research has indicated an increase in limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) with age, only limited investigations have delved into this phenomenon within a population‐based context. In this study, we examined the prevalence of LATE‐NC and its correlations with other brain pathologies and cognitive function in individuals aged > 85 years.

Method

Evaluation of the Vantaa 85+ study cohort, comprising 601 individuals aged >85 years residing in Vantaa, Finland in 1991, formed the basis of our investigation. Neuropathological assessments were conducted on 304 subjects (51%), with LATE‐NC staging feasible for 295. Dementia status and Mini‐Mental State Examination scores were established during baseline and three follow‐up assessments spanning from 1994 to 1999. LATE‐NC staging relied on TDP‐43 immunohistochemistry, following recently updated guidelines. Digital evaluation of arteriolosclerosis involved calculating the average sclerotic index of five randomly selected small arterioles in the amygdala, hippocampal regions, and frontal white matter. Fisher’s exact test, along with linear and logistic regression models, were employed to analyse associations between LATE‐NC, arteriolosclerosis, previously identified neuropathological variables (such as Alzheimer’s disease neuropathological change, Lewy‐related pathology, hippocampal sclerosis, and cerebral amyloid angiopathy), and cognitive metrics.

Result

Among the 295 subjects, LATE‐NC was present in 189 (64%), with stage 2 being the most prevalent (29%) followed by stage 3 (13%), while stages 1a, 1b, and 1c were less frequent (10%, 5%, and 8%, respectively). Stages 1a (P< 0.01), 2 (P< 0.001), and 3 (P< 0.001) were significantly associated with dementia and lower Mini‐Mental State Examination scores. LATE‐NC exhibited strong associations with Alzheimer’s disease neuropathological change (P< 0.001), hippocampal sclerosis (P< 0.001), diffuse neocortical Lewy‐related pathology type (P< 0.001), and amygdala arteriolosclerosis (P< 0.006). Across all six multivariate models, LATE‐NC emerged as one of the most robust independent predictors of dementia. Notably, LATE‐NC commonly co‐occurred with other neuropathological changes, with only a negligible percentage (<0.5%) of cases attributing dementia solely to LATE‐NC.

Conclusion

This population‐based inquiry underscores the significant role of LATE‐NC as an independent determinant of dementia within the general late‐life population.
Economics of Dementia Prevention: Why the 2023 World Health Global Guidelines on Dementia May Not Reduce the Dementia Epidemiology in Developing Countries
Authors: Mostert Cyprian M
Published: January 2025

Background

In 2023, the World Health Organization (WHO) presented the Mental Health Gap Action Programmes to avert Dementia. In this publication, the WHO presented a high certainty that physical activity interventions prevent Dementia. The organization presented low levels of certainty that psychosocial interventions, non‐pharmaceutical interventions, depression, and anxiety treatments are effective for Dementia prevention in low‐income and middle‐income countries (LMICs). This policy paper utilizes Global evidence, Continental perspective, Regional insight, and County outlook and presents the potential global policies that can avert Dementia, which were omitted in the 2023 WHO report.

Method

This review uses World Bank, World Health Organization, and United Nations datasets. We also comprehensively searched the medical literature for published articles on social and commercial determinants of Dementia.

Result

We demonstrate that the current WHO report does not comprehensively present policies that may yield positive returns in averting Dementia for developing countries. Physical activity is high in LMICs and may do little to prevent Dementia. Countries need to reduce poverty, hunger, tobacco consumption, alcohol consumption, sugar consumption, and other substances as crucial risk factors that drive Dementia outcomes in LMICs. Other policies that may improve Dementia epidemiology are welfare programs presented in Figure 1. These policies have robust chance of averting sixty percent of the Dementia cases.

Conclusion

There is a significant risk of failing to improve Dementia outcomes if the current 2023 WHO report is not amended. Policymakers must address both the social and commercial determinants factors of Dementia as countries seek to achieve healthy brain aging.
Potential roles for BACE inhibitors in AD therapeutic trials
Authors: Aisen Paul S.
Published: January 2025

Background

Now, at the beginning of the era of disease‐modifying drugs for AD, many questions must be addressed in the effort to optimize benefits. Important issues remain regarding the timing and duration of amyloid‐removing immunotherapy and the potential advantages of combination therapies. Anti‐fibrillar amyloid antibodies effectively remove amyloid but may not be appropriate for maintenance of the low amyloid state; secretase inhibition is a reasonable alternative. Evidence suggests that the earlier amyloid is removed the larger the benefit; by extension, beginning anti‐amyloid therapy before plaque accumulation may be optimal but may require targeting the generation of amyloid monomers. The toxicity of diffusible amyloid species suggests that combining immunotherapy with secretase inhibition may provide additive benefit. As reviewed in this session, the availability of substantial pre‐clinical and clinical data on BACEi therapy suggests that this approach can provide fine‐tuned reduction in amyloid peptide generation while avoiding the reversible cognitive toxicity associated with this class of drug.

Methods

Findings from trials with amyloid‐removing antibodies and various BACE inhibitors along with growing data on accurate plasma markers of AD neurobiology inform considerations of the next generation of trials needed to clarify the role of BACEi therapy for disease‐modification.

Results

Experience from ongoing clinical trials indicates that plasma biomarkers, particularly mass spectroscopy assays of abeta and ptau217 ratios, accurately predict amyloid levels by PET below the normal range. Further, changes in plasma ptau assays precede reaccumulation of fibrillar amyloid after cessation of amyloid‐lowering immunotherapy. These findings suggest that marrying accurate monitoring of plasma markers to BACEi therapy can provide a path to optimization of anti‐amyloid therapy. Future studies may demonstrate that screening individuals in late‐middle age with these plasma measures facilitates management of amyloid dysregulation at the pre‐plaque stage for primary prevention of AD.

Conclusion

Coupled with plasma biomarkers of AD pathology, BACE inhibitor therapy may provide a feasible approach to the optimization of anti‐amyloid therapy for established AD as well as primary prevention of the disease.
Plasma synapse proteins discriminate between AD, DLB, and FTD dementias and closely predict memory dysfunction
Authors: Taddei Raquel N , Kivisäkk Pia , de Geus Matthijs B , Klein Charles N , Zetterberg Henrik , Gomez‐Isla Teresa , Arnold Steven E
Published: January 2025

Background

Robust biomarkers are urgently needed to detect, diagnose, and predict memory decline in the three most common neurodegenerative dementia syndromes, Alzheimer disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). The currently used diagnostic and therapeutic compounds target the disease‐defining neuropathologic signatures (amyloid, tau, alpha‐synuclein, TDP43) but show limited efficacy. Growing evidence suggests that synapses form the anatomical basis of cognition and that synapse dysfunction closely predicts dementia onset and progression in these dementing disorders. Yet, the plasma synapse signatures characterizing the three most common neurodegenerative dementia syndromes remain unexplored.

Method

We analyzed plasma samples from 100 individuals with autopsy‐confirmed neurodegenerative dementias (24 AD, 30 DLB, 30 FTD) and 16 controls without dementia or neuropathological abnormalities enrolled in the Massachusetts ADRC longitudinal cohort. Samples were obtained ≤3 years prior to death and analyzed using unbiased mass‐spectrometry (ProteographTM Seer Inc.). Plasma proteins were cross‐referenced with the SynGO database to select synaptic, and with the Human Protein Atlas to include brain‐expressed proteins. ANOVAs, Bonferroni corrections, and t‐tests were applied using R functions on log‐transformed data. Linear correlation analyses evaluated associations of synapse protein levels and cognitive scores (MoCA, CDR‐global, CDR‐SoB) in each dementia syndrome.

Result

We detected >80 synaptic proteins in the plasma of the 100 cases. A subset of 14 plasma synapse proteins significantly differed between dementia cases and controls. Some synapse proteins were increased across dementia syndromes (HABP4, RAP2A), while subsets of them were selectively altered in only one specific neurodegenerative condition (ARL8A, WASF3, AP1S1 in AD; ADDB, L1CAM in DLB; SRGP2, PP2BA, MADD, DEMA, NCAN in FTD). Significant correlations with memory scores were found for some synapse proteins (ARL8A, RAB3C in AD, ADDB in DLB, and DEMA in FTD).

Conclusion

Synapse‐associated proteins are altered in the plasma of AD, DLB, and FTD, compared with non‐demented control cases. Select synapse protein signatures may serve as biomarkers to detect global cognitive dysfunction in various dementing diseases, and to accurately discriminate between dementia syndromes. The future investigation and validation of plasma synaptic biomarkers may provide an unprecedented tool for the detection and differential diagnosis of neurodegenerative dementia syndromes in research and clinical settings.
Topography and Predictitve Value of Enlarged Perivascular Spaces in Patients with Cognitive Impairment beyond Aneurysmal Subarachnoid Hemorrhage
Authors: Gong Li , Liu Xueyuan
Published: January 2025

Background

To explore the correlation between the topography of EPVS and cognitive impairment after aSAH.

Method

Patients clinically diagnosed as aSAH by DSA and CT; Head magnetic resonance imaging was performed between 1 week and 1 month after onset, combined with clinical and neuroimaging variables to assess the incidence of hydrocephalus and delayed cerebral ischemia after aneurystic subarachnoid hemorrhage. Follow‐up was performed at 3 months, and the patients' prognosis and cognitive function were evaluated by mRS and the Montreal Cognitive Assesement (MoCA), respectively. The clinical characteristics of aSAH patients with EPVS <10 and EPVSV10 in basal ganglia and centrum semioval were compared, and a binary Logistic regression model was used to study the severity of EPVS and its correlation with DCI, subacute hydrocephalus, poor prognosis and cognitive impairment.

Result

BG‐EPVS predominance pattern (BG‐EPVS > CSO‐EPVS) was more common in the aSAH group (53.8%) than in other primary SAH patients without aneurysm(15.8%). A total of 159 patients completed 3‐month MoCA assessment, of which 63 (39.6%) were diagnosed with cognitive impairment (MoCA<22). EPVS >10 (no matter CSO or BG) was associated with unfavorable functional outcomes at 3 months. BG‐EPVS >10 linked to subacute hydrocephalus and DCI, but not with cognitive impairment after adjusting for established predictors. In contrast, CSO‐EPVS>10 predicted worse cognitive function after adjustment for established variables.

Conclusion

CSO‐EPVS is associated with cognitive impair beyond aSAH, but not with subacute hydrocephalus and DCI, suggesting distinct lymphatic drainage and mechanism after an attack of aSAH.
Therapeutic Poetry Program for Indigenous People Living with Dementia
Authors: Guzman Antonio Paniagua
Published: January 2025

Background

Due to its accessibility and connection with cognitive and linguistic abilities, poetry has been used to study diverse characteristics of experiential and emotional outcomes of people living with dementia (PLWD). Previous studies have shown that the practice of poetry has the potential of improving health, cognitive, and communicational outcomes of PLWD. Also, it is supportive in understanding the experiences and needs of PLWD and has proved to be an effective mechanism to improve the relationships between PLWD and their caregivers. Even though much needed poetry interventions have been developed and implemented to serve diverse populations in the United States, no culturally safe programs specifically for Indigenous PLWD have been developed.

Method

Using a community‐based participatory research (CBPR) framework and Indigenous methodologies, this study is based on the development and implementation of a pilot therapeutic poetry program for Indigenous PLWD and their caregivers in an Indigenous Nation in Minnesota, through the adaptation of existing techniques used to deliver poetry‐based therapy for PLWD. Aligned with CBPR principles, this pilot program will be facilitated and evaluated by community members.

Results

N/A

Conclusion

With the participation of 12 Indigenous dyads, this project aims to (a) implement a sustainable program that can be replicated in other communities; (b) assess the effects of the program on dyads’ relationships, quality of life, intra‐community relationships, cultural performance, and Indigenous identity; and (c) identify mechanisms that improve quality of life, quality of care, relationships, and the regulation of behavioral issues for PLWD in the Indigenous context.
Unraveling Pathways in Alzheimer’s Disease: Insights into Rap1 Signaling Associations with Focal Adhesion and Shigellosis
Authors: Garg Meher , Lee Inhan
Published: January 2025

Background

Existing therapeutic approaches in Alzheimer’s disease (AD) targeting beta‐amyloid and tau proteins have shown limited success. Shigellosis, an intestinal infection caused by Shigella, is capable of colonizing the human intestinal epithelium and has been associated with focal adhesions. Rap1 signaling is associated with cancer and cell adhesions. Upregulation of the RAP1 signaling pathway and its interactions with other signaling pathways could contribute to synaptic dysfunction, neuronal damage, and cognitive deficits and has emerged as a candidate pathway for study in Alzheimer’s disease. Associations between the Rap1 signaling pathway, focal adhesion and shigellosis could shed further light on pathogenesis of AD.

Method

We leveraged the Gene Expression Omnibus (GEO) GSE109887 dataset, available on the NIH’s GEO2R website, comprising microarray RNA expression data from medial temporal gyrus of 46 AD patients and 32 controls. Differential gene expression analysis was conducted using GEO2R. Gene interaction analysis and identification of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed using STRING‐DB. Gene function insights were obtained from Gene Cards. Statistical analysis and heatmap visualization were conducted using R/R Studio.

Results

After analyzing using STRING, the top 250 expressed genes in AD patients were associated with upregulated KEGG pathways. The Rap1 signaling pathway had a false discovery rate (FDR), p‐value of 0.0212, strength of 0.64, and count in network of 10/201. The shigellosis pathway had a FDR of 0.00088, strength of 0.71, and count in the network of 13/218. The focal adhesion pathway had a FDR of 0.0212, strength of 0.65, and count in network of 10/195. The upregulated genes present in Rap 1 signaling and shigellosis were ITGB1, TLN2, PLCB1, PLCE1, and PLCG1. The genes found in Rap 1 signaling and focal adhesion were ITGB1, TLN2, RAF1, PDGFRB, and PRKCG.

Conclusion

Our findings provide valuable insights into the molecular mechanisms underlying AD. The dysregulated pathways in AD show an association between Rap1 signaling and focal adhesion and shigellosis. Upregulation of the Rap1 signaling, focal adhesion and shigellosis pathways could be a biomarker/potential therapeutic target and should be evaluated in future study.
Adapting healthcare infrastructure for disease‐modification in early Alzheimer’s disease
Authors: Rothwell Simon , Polotti Enea , Eksteen Christine
Published: January 2025

Background

With the emergence of disease‐modifying therapies (DMTs) for early Alzheimer’s disease (AD), evolution of healthcare infrastructure is needed to identify patients eligible for treatment with an AD DMT, and to adequately treat and monitor patients throughout. Our research aimed to assess current practices and available infrastructure, to identify bottlenecks, and to propose solutions to increase patient access to AD DMTs in the EU4+UK.

Methods

We searched publicly available information (to August 2023) to derive a foundational understanding of the current level of healthcare infrastructure in each country. Subsequent primary research with 11 neurologists and 39 hospital administrators across the 5 countries informed an assessment of AD diagnostic, infusion, and monitoring capacity.

Results

Magnetic resonance imaging (MRI) is recommended for differential dementia diagnoses and will be required for monitoring patients throughout treatment with an AD DMT. However, in most countries, capacity is expected to bottleneck due to shortages in MRI machinery, trained staff, and limited allocation of scans to AD. Optimizing the use of MRI will be key to expanding patient access to AD DMTs. Confirming amyloid positivity via cerebrospinal fluid testing/ lumbar puncture or positron emission tomography (PET) is recommended for AD diagnoses and a requirement for AD DMT eligibility. Amyloid PET is not widely conducted due to a lack of dedicated centers and/or reimbursement in some countries, whereas lumbar puncture is not expected to be associated with major access challenges. AD DMTs require administration via infusion; however, current neurology units are adapted for infusions of DMTs for multiple sclerosis. Infusion capacity may also be limited by trained staff shortages and lack of dedicated outpatient infusion units for AD. There is potential to repurpose some infusion capacity to AD.

Conclusions

European healthcare system infrastructure can adapt to improve access to AD DMTs. Establishing and/or expanding country‐wide networks of accredited hospitals and external/private partnerships could allow patients greater access to services across multiple locations and individual hospitals to better leverage external resources. At an organizational level, more resources can be allocated towards AD and efficient resource planning can help to optimize healthcare for patients with early AD.
Implication of Chronotherapy in mouse models of Alzheimer’s Disease
Authors: Shi Yu , Salinas Ricardo , McRoberts William , Rozen Stephen , Swint Jordan , Bloom George S , Güler Ali
Published: January 2025

Background

Sleep disturbances are commonly observed in early‐stage Alzheimer’s Disease (AD) patients and correlate with their cognitive performance over time. Sleep in mammals is governed by the central circadian system, which responds to environmental cues like light and aligns with daily routines such as eating.

Method

In this study, we developed a regimen with a shortened light phase (LD = 8:16), time‐restricted feeding, and exercise (LiFE) to strengthen the circadian system and enhance sleep quality in 5xFAD and 5xFAD‐PS19 AD mice.

Result

This approach enhanced cognitive performance in Morris water maze and novel object recognition tests. The LiFE treatment did not reduce amyloid plaques or tau phosphorylation.

Conclusion

Our study shows that, independent of AD histopathological changes, LiFE chronotherapy enhances cognition in AD model mice, with the potential to improve cognition in human AD patients. We are currently exploring the neural mechanisms and biological processes impacted by the LiFE treatment.