bluuebunny/crossref_metadata_2025 huggingface dataset:
Melatonin to treat sleep disturbances in patients with Alzheimer’s disease
Authors: Sushko Viacheslav Viktorovich , Sushko Viktor Vasilievich
Published: January 2025

Background

Alzheimer’s disease can cause sleep disturbances in humans, which can worsen other symptoms of the disease.

Method

In our study, we examined the sleep patterns of 23 patients with Alzheimer’s disease, aged 65‐74 years (20 women and 3 men), over 4 months. All patients reported experiencing poor sleep, including difficulty sleeping in the ward, frequent awakenings during the night, early morning awakenings, and daytime sleepiness. To assess their sleep, we conducted a polysomnographic study in a specialized ward with continuous monitoring of indicators, video, and audio control. This was done both before the patients were included in the study and after a month of melatonin administration. During the diagnostic night, a nurse was present to continuously observe the polysomnography process. Based on the results of the polysomnography, we constructed a hypnogram, which is a curve that depicts the quality of sleep, the number and duration of sleep stages, and their structure. The patients were given a dose of 1.5 mg of melatonin (half a tablet) 30 minutes before bedtime for 4 weeks, with gradual withdrawal.

Result

In the initial polysomnographic study, all patients showed shortened phases of rapid eye movement (REM) and slow eye movement (SEM), with a rapid transition between them during sleep. They also experienced long periods before falling asleep and 3 to 4 nocturnal awakenings. However, after a month of melatonin administration, the majority of patients showed a normalization of REM and SEM phases, in line with their age norms, and an improvement in the duration of sleep. The number of nocturnal awakenings also decreased to 1‐2, mostly between 4 and 6 hours. Additionally, patients were able to fall back asleep after awakening, and the time it took for them to fall asleep decreased. However, even after a month of melatonin supplementation, some patients still experienced early morning awakenings and daytime sleepiness and reported feeling unrefreshed after a night’s sleep.

Conclusion

In conclusion, our study suggests that melatonin is effective in treating sleep disorders in patients with Alzheimer’s disease, and can help normalize the duration and frequency of REM and SEM phases during sleep.
Correlation between alterations in resting‐state functional alterations of brain and cerebrospinal fluid pathological markers in patients with Alzheimer's disease
Authors: Zhao Hui , Gong Cheng Bing
Published: January 2025

Background

The aim of this study was to explore the correlation between brain functional alterations and cerebrospinal fluid (CSF) pathological biomarkers in Alzheimer's disease (AD) patients.

Method

A total of 39 individuals were recruited, including 23 AD patients and 16 control subjects. All subjects underwent a battery of neuropsychological examinations, CSF measurement and multimodal magnetic resonance imaging scans. Independent component analysis was used to investigate the variations of functional connectivity (FC) between the two groups by utilizing the resting‐sate functional MRI (RS‐fMRI) data. Differences in ALFF and ReHo between the two groups were also calculated. Then correlation analyses were used to estimate the possible association between functional alterations and CSF β‐amyloid (Aβ1‐42.) and tau.

Result

Multiple inter‐ and intra‐network functional connections were altered in AD patients compared to the Non ADCI group. In the AD group, ALFF decreased in the right Superior Frontal Gyrus, Middle Frontal Gyrus, left superior temporal gyrus. and increased in the right cerebellum anterior lobe, and caudate nucleus as compared to Non‐AD CI group (p < 0.001). In addition, ReHo decreased in the right insula and left middle temporal gyrus (p < 0.001). Dynamic fluctuations of CSF Tau were observed to be associated with changes in FC between VN and PCC, FC of SMN, as well as the altered ReHo in the right insula and left middle temporal gyrus. Compared the AD group with the non‐AD CI group, the aforementioned altered functional brain connectivity, with the exception of FC in the PCC and VN, was significantly associated with a decrease in CSF Aβ1‐42.

Conclusion

AD patients have exhibited functional changes in more than one brain region. These changes are linked to the variations of Tau protein and Aβ1‐42 in CSF, with Aβ1‐42 having a particularly large impact on brain network function. From an imaging standpoint, this study validated the impact of pathological changes on brain function in AD.
Inter‐ and intra‐subject variability of quantitative EEG biosignatures and their effect on interpretation of normalized effect size
Authors: Meghdadi Amir H. , Berka Chris , Malek‐Ahmadi Michael H.
Published: January 2025

Background

Quantitative EEG measures can be used as biosignatures of disease conditions. As such, the effect of interventions/treatments can be studied by longitudinal analysis of changes in these measures. The consistency of these measures can be assessed by test‐retest reliability scores such as intra‐class correlation coefficient (ICC) that depends on intra‐ and inter‐subject variability. The magnitude of an effect can be described by a normalized effect size (i.e. normalizing the effect with respect to the sample variability). However, the inherent variability of EEG and its effect on interpretation of effect size is less explored. The aim of this work is to investigate inter‐ and intra‐subject variability of PSD‐based resting‐state EEG measures and their effect on analysis of change scores.

Methods

We collected 20‐channel longitudinal EEG data (initial visit and 1‐year follow‐up) from healthy volunteers (n=61, ages 40‐82). After artifact decontamination, we computed power spectral density (PSD) at 1‐40 Hz frequency bins. At each frequency, we computed inter‐ and intra‐subject variability of PSD as well as ICC. We simulated a hypothetical effect by adding a constant value to the 2nd visit’s data equivalent to half the standard deviation of the sample. We computed the normalized effect size (Cohen’s d) using both the pooled variance as well the variability in the change score. We compared these effect sizes for different frequencies.

Results

Overall, absolute PSD exhibited high test‐retest reliability in the frequencies 2‐20 Hz (ICC>0.7) with 7‐9 Hz having the highest ICC (ICC>0.94). Inter‐subject variability was highest at 8Hz, and intra‐subject variability was lowest at 13‐15 Hz frequencies. For frequencies between 5 – 10 Hz (fast‐Theta/slow‐Alpha bands), the difference between the two types of normalized effect size ranged between 0.3 to 0.6.

Conclusions

Inter‐ and intra‐subject variability of PSD‐based EEG measures depend on frequency. As such, changes in PSD due to potential interventions should be interpreted with respect to the inherent variability of PSDs. In longitudinal analysis of paired data, normalized effect size should be reported using both population variability (inter‐subject) and change‐score variability (intra‐subject).
Nasal tissues from Alzheimer’s disease patients induces the formation of aggregates in a cellular model of tau propagation
Authors: Yanagisawa Daijiro , Arrozi Aslina Pahrudin , Kato Tomoko , Mizukami Tamio , Akatsu Hiroyasu , Yoshio Hashizume , Kaneda Daita , Tooyama Ikuo
Published: January 2025

Background

Abnormal protein depositions of amyloid β and tau are present in the nasal cavity in patients with Alzheimer’s disease. This finding raises an idea that nasal tissues would be a promising source of diagnostic biomarkers for Alzheimer’s disease. However, the amounts of amyloid β and tau are extremely small, making it difficult to quantify the levels using conventional methods such as ELISA, and thus it is challenging to utilize them for the diagnostic biomarkers. In the present study, we tested the nasal tissues as the source of diagnostic biomarkers using a cellular model of tau propagation.

Method

This study was approved by the institutional Ethics Committees. Postmortem nasal mucosa and brain tissues from patients with AD (n = 10) and normal subjects (n = 10) were collected with patient consent at the Fukushimura Brain Bank. Nasal and brain tissue homogenates were added to HEK293 cells expressing tau 3‐repeat domain with the L266V and V337M mutations (3RD∗VM) or 4‐repeat domain with the P301L and V337M mutations (4RD∗LM), which was fused with GFP at the C‐terminus.

Result

GFP fluorescence was detected uniformly within the cell bodies of HEK293T cells expressing 3RD∗VM‐EGFP and 4RD∗LM‐EGFP. There were no changes in the fluorescence after the additions of the brain homogenates from normal subjects. In contrast, a large number of fluorescent puncta was detected both in HEK293T cells expressing 3RD∗VM‐EGFP and 4RD∗LM‐EGFP at 4 days after the additions of the brain homogenates from patients with AD. Furthermore, the nasal tissue homogenates from patients with AD also induce the formation of fluorescent aggregates in HEK293T cells expressing 3RD∗VM‐EGFP and 4RD∗LM‐EGFP. Quantitative analysis revealed that the nasal tissue homogenates from AD patients significantly induced the aggregate formation, compared with normal subjects.

Conclusion

These results suggest that the nasal tissues from AD patients contain tau seeds with prion activity, similar to the brain. A cellular bioassay using nasal tissues would be great potential as an AD biomarker because of the usefulness of nasal tissue biopsy, and would provide an important contribution to the development of ex vivo diagnosis method for AD using the nasal extracts.
Quantitative‐ and visual read‐based flortaucipir PET T+ criteria for the pathophysiological assessment of Alzheimer’s Disease
Authors: Tunali Ilke , Kotari Vikas , Kennedy Ian A. , Burnham Samantha C. , Shcherbinin Sergey
Published: January 2025

Background

The revised NIA‐AA biological Alzheimer’s disease (AD) staging scheme considers various tau positivity (T+) rules based on global and regional neocortical tau PET uptakes. In AD clinical trials, various tau PET criteria (e.g., visual+quantitative [TauVQ], Mintun et al., 2021) have been employed to select eligible patients. In this study, we compared six T+ criteria in terms of their potential usefulness for biological staging and clinical trial eligibility.

Methods

N=296 symptomatic (189/107 MCI/AD‐dementia) subjects from AV‐1451‐A05 (NCT02016560) were included. Six different tau‐PET stratifications (T+/T‐) were employed: Two quantitative global neocortical uptake measures (CenTauR‐Universal, Villemagne et al., 2023, and AD‐signature weighted neocortical, Devous et al., 2018); two quantitative temporal‐based uptake measures (CenTauR‐Meta‐temporal, Villemagne et al., 2023 and Early Tau VOI, Kotari et al., 2023), a visual read‐based method (Fleisher et al., 2021) and TauVQ method. A dataset of young cognitively normal subjects (N=16) was utilized to determine T+ thresholds for quantitative measures (mean+2.5xSD SUVr). The tau stratifications were evaluated for their agreement with amyloid‐PET positivity and for AD‐related prognostic utility using signal‐to‐noise ratios (SNRs) of T+ for (1) Annualized change in AD Assessment Scale‐Cognitive (ADAS‐Cog11) and (2) 18‐month change in CenTauR‐Meta‐temporal SUVr.

Results

CenTauR‐Universal and CenTauR‐Meta‐Temporal derived T+ groups showed comparable SNRs (Figure 1A‐B) and agreement with amyloid positivity (Figure 2). The TauVQ‐ and the visual read‐derived T+ groups also performed similarly. The regional early tau VOI‐based T+ group, compared to the global AD‐signature neocortical‐based T+ group, showed a higher SNR for 18‐month change in CenTauR‐Meta‐temporal SUVr. However, a lower SNR for annualized ADAS‐Cog11 change and a lesser agreement with amyloid positivity were observed. Comparisons using PET‐to‐autopsy cohort will be presented.

Conclusions

Our analyses suggest using CenTauR‐Meta‐temporal and visual read‐based regional T+ criteria may identify a larger subgroup of symptomatic patients exhibiting similar amyloid positivity prevalence and clinical decline compared to those determined by corresponding global T+ criteria. Among examined methods, the early tau VOI‐based T+ criterion possibly captures the earliest pathologic stage. Lastly, CenTauR‐based T+ groups showed lower SNRs for tau and clinical progression, suggesting flortaucipir‐specific criteria might be more sensitive for prognostic evaluations. Further validations using different datasets and cut points are warranted.
Learning from Real‐World Data Platforms: Insights into Care and Representation in Research Through ALZ‐NET and New IDEAS
Authors: Windon Charles , Dilworth‐Anderson Peggye , Wilkins Consuelo H. , Carrillo Maria C. , Apgar Charles , Edelmayer Rebecca M. , Gatsonis Constantine , Hanna Lucy , Hillner Bruce E , March Andrew , O'Bryant Sid E. , Rafii Michael , Rissman Robert A , Siegel Barry A. , Snyder Heather M , Whitmer Rachel A. , Rabinovici Gil D.
Published: January 2025

Real‐World data platforms for Alzheimer’s Disease (AD) offer a unique opportunity to improve health equity through better understanding of health disparities and inclusivity in research, which is critical to translatability of research findings. AD research in the US and globally remains largely inaccessible to many individuals due to individual‐level, study‐level, investigator‐level and larger systemic barriers. ALZ‐NET, a US‐based registry to evaluate longitudinal outcomes of patients being evaluated for or treated with novel FDA‐approved AD therapy, and New IDEAS, an observational US‐based longitudinal study of amyloid PET clinical utility, both offer opportunities for examining care, inclusivity, and disparities.

ALZ‐NET (Alzheimer’s Network for Treatment and Diagnostics) is a national, provider‐enrolled, patient registry collecting longitudinal regulatory grade clinical data. It also features a diagnostic imaging and biospecimen repository. Providers at clinical sites across the US enroll and longitudinally follow patients being considered for Food and Drug Administration (FDA)‐approved AD therapies according to local site practice standards. Clinical practice sites across the US are eligible for ALZ‐NET participation, allowing a greater diversity of participating patients. Registry data is maintained using centralized, secure electronic data capture and management systems that will allow for co‐enrollment of participants into affiliated clinical trials, merging of data with existing databases, and data sharing to facilitate additional research studies.

NEW IDEAS (Imaging Dementia ‐ Evidence for Amyloid Scanning) has enrolled cognitively impaired Medicare beneficiaries at memory clinics across the US since 2020. New IDEAS features a dedicated recruitment and engagement strategy that leverages community partnerships and liaisons in 9 targeted, highly diverse US metro areas to specifically address barriers to participation in traditional research. New IDEAS has identified and developed novel methodology that can inform future studies in successfully increasing representation in AD research on a large scale, with >40% of the current patient population consisting of individuals historically not included in research. New IDEAS also offers insights into rates of amyloid pathology by in vivo biomarkers among diverse populations.

Real world data platforms like ALZ‐NET and New IDEAS serve an important role in fostering greater understanding of health disparities and inclusivity in research to improve care.
Distinguishing Early Mild Cognitive Impairment from Late Mild Cognitive Impairment through Free‐Water Diffusion Tensor Imaging: A Comparative Analysis
Authors: Bergamino Maurizio , McElvogue Molly M. , Stokes Ashley M.
Published: January 2025

Background

Mild Cognitive Impairment (MCI) represents an intermediate stage between normal age‐related cognitive decline and more severe degenerative conditions such as Alzheimer's disease. Understanding the differences between Early‐MCI (EMCI) and Late‐MCI (LMCI) is crucial to facilitate early diagnosis and future clinical interventions. This study employed free‐water diffusion tensor imaging (FW‐DTI) to explore the differences in white matter alterations between EMCI and LMCI. Additionally, voxel‐based correlations between FW‐DTI metrics and Mini‐Mental State Examination (MMSE)/Geriatric Depression Scale (GDS) were studied.

Methods

In this study, a total of 56 healthy controls (HCs) with a mean age  of 74.2 (±6.5) years, 43 individuals with EMCI with  of 72.1 (±8.1) years, and 28 subjects with LMCI with  of 73.8 (±6.0) years were included. Magnetic resonance imaging (MRI) data, acquired at 3T, were downloaded from the ADNI database. Pre‐processing steps included denoising, brain extraction, correction for eddy current, and alignment of diffusion data. FW‐DTI metrics were computed using a custom Matlab script. Statistical analysis was conducted using ANCOVA, employing a linear model with gender and age as covariates (significance for FDR<0.05). Linear models were also used for correlations.

Results

Statistical differences between EMCI and LCMI were found for MMSE (Z=4.275;p<0.001). No differences were found for GD (Table 1). Figure 1 depicts group‐wise differences in the free‐water fraction (f) and FW‐Fractional Anisotropy (FW‐FA) across all study cohorts. Differences in the f index (f‐EMCIFW‐FA‐LMCI) were observed in the forceps major, corpus callosum, right sagittal stratum, and right fornix, shedding light on specific white matter tracts implicated in the progression from early to late MCI stages. Voxel‐based correlations between FW‐DTI metrics and MMSE/GD are illustrated in Figure 2.

Conclusions

In conclusion, our study reveals critical insights into the white matter changes associated with EMCI and LMCI, with significant implications for future research and clinical practice. The observed correlations between diffusion metrics and cognitive scores, mainly in LMCI group, underscore the potential of the FW‐DTI in enhancing our understanding of MCI progression and informing early diagnostic strategies.
Plasma biomarkers in dementia with Lewy bodies: evidence from memory clinic settings
Authors: Vrillon Agathe , Bousiges Olivier , Götze Karl , Demuynck Catherine , Muller Candice , Ravier Alix , Schorr Benoit , Philippi Nathalie , Cognat Emmanuel , Hourregue Claire , Dumurgier Julien , Lilamand Matthieu , Cretin Benjamin , Blanc Frédéric , Paquet Claire
Published: January 2025

Background

Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain.

Method

We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n=104), Alzheimer’s disease (AD, n=76) and neurological controls (NC, n=27). Measured biomarkers included plasma Aβ ratio, p‐tau181, NfL and GFAP using SIMOA and plasma YKL‐40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n=90) were stratified according to their CSF Aβ profile.

Results

DLB patients displayed altered plasma Aβ ratio, p‐tau181 and GFAP levels compared with NC and altered plasma Aβ ratio, p‐tau181, GFAP, NfL and sTREM2 levels compared with AD patients (Figure 1, a‐f). Plasma p‐tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC]=0.80) and NC (AUC=0.78) and combining biomarkers did not improve diagnosis performance. Plasma p‐tau181 was the best standalone biomarker to differentiate amyloid‐positive from amyloid‐negative cases (AUC=0.75) and was associated with cognitive status. Combining plasma Aβ ratio, p‐tau181 and NfL increased performance to identify amyloid copathology (AUC=0.79). Principal component analysis identified different segregation patterns of plasma biomarkers in AD and DLB groups (Figure 1, g‐h).

Conclusion

Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p‐tau181 has potential contribute to identify Aβ copathology in DLB.
Synaptic proteins in pre‐symptomatic Alzheimer's disease: genes implicate synaptic biomarkers to the early detection of cognitive decline
Authors: Ao Jiarui , Labonté Anne , Picard Cynthia , Brinkmalm Ann , Blennow Kaj , Breitner John C.S. , Zetterberg Henrik , Villeneuve Sylvia , Poirier Judes ,   PREVENT‐AD Research Group
Published: January 2025

Background

The heterogeneous etiology of “sporadic” Alzheimer’s disease (sAD) includes genetic influences. To better understand synaptic dysfunction in AD pathogenesis, we used protein quantitative train loci (pQTL) assessments and a polygenic risk score (PRS) to examine the relationship between synaptic integrity and longitudinal cognitive performance in the presymptomatic phase of the disease.

Method

The PREVENT‐AD cohort includes symptom‐free elderly participants at risk of AD because of their family history. A second resource, the Quebec Founder Population (QFP) brain bank, derives from the descendants of the 17th and 18th century French settlers in Eastern Canada. We used Olink Proximity Extension Assays to measure the soluble synaptic proteins ADAM 22 (post‐synaptic) and ADAM23 (pre‐synaptic) in 120 CSFs, while immunoprecipitated SYT1 (pre‐synaptic) and SNAP25 (pos‐synaptic) were analyzed in 141 CSF samples using a quadrupole–orbitrap mass spectrometer. The Repeatable Battery for Assessment of Neuropsychological Status (RBANS) indicated cognitive trajectory. Genotyping was performed using the Illumina Infinium Omni 2.5M‐8 array. Cortical RNAs (n=86) from the QFP cohort were processed using GeneChip WT Pico Kit. Statistical analyses included sex, education and APOE e4 status as covariates.

Result

Among PREVENT‐AD participants who remained cognitively unimpaired over the past 11 years, we observed significant correlations between a PRS constructed from pQTL ADAM 22 CSF concentrations and delayed memory (R2 = 0.06, p = 0.0132), visuospatial constructional memory (R2 = 0.274, p = 0.00408) and total index scale (R2 = 0.202, p = 0.0454), but only trend‐levels association with immediate memory (R2 = 0.1, p = 0.0747). We also found similar correlations between PRS constructed from of CSF ADAM 23, CSF SYT1, CSF SNAP25 concentrations and the different RBANS subscales. Significantly lower cortical mRNA levels for ADAM22 (p = 0.062), ADAM23 (p = 0.0030), SYT1 (p = 0.033) and SNAP25 (p = 0.0036) were found in the autopsied AD brains compared to autopsied control brains.

Conclusion

CSF synaptic protein levels show promising correlations with emerging cognitive deficits and provide insights toward a possible compensatory mechanism in the early presymptomatic phase of the disease.
Comparison of olfactory and cognitive measures to neuroimaging biomarkers in the prediction of cognitive decline and dementia in the MCSA cohort
Authors: Devanand Davangere , Lee Seonjoo , Knopman David S. , Vassilaki Maria , Luchsinger Jose A. , Motter Jeffrey N
Published: January 2025

Background

Inexpensive, non‐invasive tests may improve the identification of persons at increased risk for cognitive decline and dementia. We compared impairment in odor identification and global cognition with neuro‐imaging biomarkers to predict cognitive decline and dementia in the population‐based Mayo Clinic Study of Aging (MCSA).

Method

At the 2008 assessment, 647 participants who were ≥ 55 years old with at least one follow‐up had the following procedures: modified Blessed Information‐Memory‐Concentration Test (BIMCT), 12‐item Brief Smell Identification Test (BSIT), brain magnetic resonance imaging (MRI), and Positron Emission Tomography (PET) amyloid imaging with 11C‐Pittsburgh compound B (11C‐PiB). A subsample (n=556) also had 18F‐fluorodeoxyglucose (18F‐FDG) PET scans. The utility of these baseline measures to predict cognitive decline (cognitively unimpaired to mild cognitive impairment [MCI] or dementia, or MCI to dementia) was examined during follow‐up (mean 8.1 SD 3.4 years). Transition to dementia was a secondary outcome.

Result

Among 647 participants without dementia (mean age 74.0 SD 8.1 years; 54.4% male) at baseline, 102 participants manifested cognitive decline and 34 participants transitioned to dementia. In Cox regression survival analyses for cognitive decline, PiB PET showed the strongest predictive utility (hazard ratio HR 5.05, 95% CI = 3.32‐7.69, p<.001). Impaired BSIT (HR 3.46, 95% CI = 2.34‐5.11, p<.001), impaired BIMCT (HR 3.63, 95% CI 2.46‐5.36, p<.001), MRI and FDG measures were also significant predictors. After adjusting for age, sex and education, these predictors remained significant with attenuated effects (PiB HR 3.89, 95% CI 2.54‐5.95, p<.001; BSIT HR 2.77, 95% CI 1.85‐4.14, p<.001; BIMCT HR 3.3, 95% CI 2.21‐4.95, p<.001). After adding these demographic variables in the model, the combination of BSIT and BIMCT showed strong predictive utility (C‐index=0.85), similar to PiB PET (C‐index=0.84). Combining all predictors showed a C‐index of 0.89. These measures showed similar but stronger results for dementia transition.

Conclusion

Tests of global cognition and odor identification provide a brief, non‐invasive, inexpensive method comparable to PET amyloid imaging for identifying community‐dwelling persons likely to decline cognitively or transition to dementia. Other potential uses for this combination include identification of persons likely to benefit from disease‐modifying medications and determination of eligibility for prevention trials.
The relationship between amyloid burden, hippocampus, and cholinergic integrity
Authors: Lee Li‐Hua
Published: January 2025

Background

Hippocampal atrophy and degeneration of cholinergic pathways are prominent neuroimaging findings in early Alzheimer’s disease (AD). However, whether these image findings are related to amyloid accumulation is still debated.

Method

From 2021 to 2023, we recruited 116 participants from memory clinic in Cardinal Tien Hospital, Taipei, Taiwan. All our participants received complete neuropsychological tests, 3.0 T brain MRI and amyloid positron emission tomography (PET). Hippocampal volumes were measured through high‐resolution T1 weighted images. DTI metrics such as MD (mean diffusivity) or FA (fractional anisotropy) values were derived from DSI studio. In this study, we use cingulum bundle, external capsule and uncinate fasciculus to simulate cholinergic pathway.

Result

Our study included 41 healthy individuals, 61 with mild cognitive impairment (MCI), and 14 with mild dementia. Significant differences were observed across these groups in hippocampal volumes, MD values of cholinergic tract, and amyloid SUVR values. Our linear regression analysis, which adjusted for variables including sex, age, and education level, demonstrated that these three neuroimaging markers are significant predictors of cognitions. Notably, the analysis revealed that hippocampal volume, amyloid SUVR and the MD values of the cholinergic pathways independently predict the severity of cognition. When evaluating the association between amyloid SUVR, hippocampal volume and cholinergic integrity by multilinear regression models which were controlled with age, sex, and presence of APOE4 carrier status, we found that hippocampal volume is significantly associated with the amyloid burden (β = −0.215; p = 0.022), while cholinergic MD values are not related to amyloid SUVR.

Conclusion

Amyloid accumulation is associated with hippocampal atrophy, but not cholinergic integrity in our study. The impairment of cholinergic integrity may be due to etiologies other than amyloid. Neuroimaging markers focusing on cholinergic integrity should be closely observed independently from others. Multitargeting treatments, in addition to anti‐amyloid, may be required for better efficacy in the prevention and treatment of cognitive decline in AD.
Therapeutic effects of class I HDAC inhibitor CI‐994 in Alzheimer’s disease
Authors: Lu Wenyan , Kawatani Keiji , Jeevaratnam Suren , Bu Guojun , Kanekiyo Takahisa , Li Yonghe
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common cause of age‐related dementia, and the presence of amyloid‐β (Aβ) plaques and tau‐containing neurofibrillary tangles is associated with the neurodegeneration and cognitive impairment in this incurable disease. Growing evidence shows that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in AD, and HDACs have been highlighted as a novel class of anti‐Alzheimer targets. Moreover, restoring Wnt/β‐catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy for AD. CI‐994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI‐994 can cross the blood‐brain barrier and is a cognitive enhancer.

Method

We evaluated the therapeutic potential of CI‐994 in human patient‐specific iPSC‐derived neurons and cerebral organoids with APOE ε4/ε4 genotype or carrying MAPT p.P301L mutation.

Result

We found that CI‐994 is not only a potent class I HDAC inhibitor but also a novel modulator of Wnt/β‐catenin signaling, and that activation of Wnt/β‐catenin signaling by CI‐994 is associated with elevated Wnt co‐receptor LRP6 protein level. Moreover, CI‐994 increased synaptic protein levels, enhanced spontaneous synaptic firing and network formation, and decreased tau phosphorylation in iPSC‐derived neurons. Finally, CI‐994 significantly increased histone acetylation, activated Wnt/β‐catenin signaling, and decreased Aβ production and tau phosphorylation in AD patient‐specific iPSC‐derived cerebral organoids.

Conclusion

Our findings indicate that CI‐994 is a novel potential therapeutic candidate for AD.
Multichannel template‐based spatial normalization precision in older adult brain QSM
Authors: Abid Rasheed , Niaz Mohammad Rakeen , Ridwan Abdur Raquib , Wu Yingjuan , Evia Arnold M , Bennett David A. , Arfanakis Konstantinos
Published: January 2025

Background

Quantitative Susceptibility Mapping (QSM) offers significant potential for studying metal and iron homeostasis in the brain and serves as a diagnostic tool for various pathologies, such as Alzheimer’s disease. However, the precision of QSM spatial normalization for older adults depends on the quality and representativeness of the chosen template and the type of information used during image registration. This study compares three available QSM templates in terms of their representativeness and precision of inter‐subject matching for older adult QSM data.

Method

The study used 3D T1‐weighted MPRAGE and multi‐echo 3D GRE data from 100 non‐demented older adults (aged 67.8‐97.2 years). QSM templates from the recently developed MIITRA templates were compared with two other publicly available templates (HybraPD and MuSus‐100). Five registration pipelines using ANTS image registration toolbox were employed. Single‐channel registration of the susceptibility maps to QSM templates, multichannel registration of T1‐weighted images and susceptibility maps to T1‐weighted and QSM templates (at 25%, 50% and 75% weights correspondingly) and finally, single‐channel registration of T1‐weighted images to T1‐weighted templates. Average log‐Jacobian maps of deformations were generated for each participant. Finally, inter‐subject pairwise (100x99/2 = 4950 pairs) normalized cross‐correlation of magnetic susceptibility maps of participants in template space was calculated for each registration approach.

Result

Spatial normalization of older adult brains required less deformation when registering to MIITRA templates compared to other templates, indicating that MIITRA templates are more representative of the older adult brain (Figure 1). Furthermore, pairwise normalized cross‐correlation was higher when using single‐channel registration of susceptibility maps to QSM templates than other methods (Figure 2). Overall, the highest spatial matching of magnetic susceptibility maps of the older adult brains was achieved when using single‐channel registration of magnetic susceptibility maps to MIITRA‐QSM template.

Conclusion

The study highlights the importance of template and registration pipeline selection in spatial alignment of magnetic susceptibility maps of the older adult brain. The MIITRA atlas proved more representative of the older adult brain, as evidenced by lower deformation requirements. Single‐channel registration of magnetic susceptibility maps of older adult brains to the MIITRA‐QSM template allowed higher inter‐subject spatial matching compared to other available templates.
Application of blood biomarkers for the future anti‐Aβ antibody therapy in Japan
Authors: Kasuga Kensaku , Tsukie Tamao , Igarashi Kazuya , Ishiguro Takanobu , Miyashita Akinori , Onodera Osamu , Ikeuchi Takeshi
Published: January 2025

Background

With the approval of Lecanemab in Japan following the U.S., biomarker‐based diagnosis of AD will be required in daily practice. However, PET or CSF are limited by cost, low availability, and invasiveness. In addition, frequent MRI is required to monitor amyloid‐related imaging abnormalities (ARIA), an adverse event unique to anti‐Aβ antibodies. Blood biomarkers are expected to be inexpensive, less invasive, and acceptable for frequent testing in daily practice.

Method

Of the cases analyzed for AD‐related CSF biomarkers for diagnostic purposes from Department of Neurology, Niigata University and related facilities, 217 plasma available cases were included. Of the 217 cases, 113 were clinically diagnosed as Alzheimer's clinical syndrome (ACS) and 104 as non‐ACS, including 6 cerebral amyloid angiopathy related inflammation (CAAri) cases. CSF Aβ42/40 ratio, phosphorylated tau (pTau181), neurofilament light chain (NfL), and plasma pTau181 and NfL were measured. According to the research framework, AD was determined when both CSF Aβ42/40 ratio (as A marker) and CSF pTau181 (as T marker) were positive. The ROC curve was used to verify the accuracy of plasma pTau181 in differentiating AD from non‐AD, and the accuracy of plasma NfL in differentiating AD from CAAri, which has been suggested to share a common pathology with ARIA.

Result

Plasma pTau181 differentiated AD group (CSF A+T+) from non‐AD group with high accuracy (AUC = 0.867). Plasma pTau181 also differentiated A+ group from A‐ group with high accuracy (AUC = 0.913, sensitivity 89.7%, specificity 82.9%). When the low‐risk threshold was made more stringent (Sensitivity 90%, 95%, 100%), negative predict value increased (78.1%, 88.9%, 100%). When the high‐risk threshold was made more stringent (Specificity 90%, 95%, 100%), positive predictive value increased (78.1%, 88.9%, 100%). However, as a trade‐off, the number of the intermediate risk group increased (16%, 35%, 81%). Plasma NfL discriminated CAAri group from AD group (ACS and CSF A+T+) with high accuracy (AUC = 0.947).

Conclusion

In Japanese clinical practice, plasma pTau181 is considered to be useful for detecting AD pathology, and is expected to be utilized for screening of anti‐Aβ antibody therapy. Plasma NfL may also be useful in screening for adverse events of anti‐Aβ antibodies.
Increased levels of Matrix Metaloproteinase‐10 and Adenosine Deaminase in blood are associated with reduced cognition
Authors: Michopoulou Sofia , Amin Jay , Kipps Christopher , Sussams Rebecca , Lunnon Katie , Holmes Clive , Teeling Jessica
Published: January 2025

Background

Neuroinflammation and activation of the immune system can influence Alzheimer’s disease (AD) progression. This is mediated by inflammatory molecules, which exacerbate the production of β‐amyloid, the propagation of tau pathology, and neuronal loss. By measuring CSF markers of inflammation in a heterogeneous clinical cohort we found that levels of Adenosine Deaminase (ADA) and Matrix‐Metaloproteinase‐10 (MMP‐10) increase in patients with AD.

Despite promising results of immune markers in CSF, a substantial limitation for wide clinical application is the requirement for a lumbar puncture, which is an invasive procedure only available in specialist settings. Using alternative fluid markers, such as blood sample measurements, would enable wider use of immune markers in AD diagnosis.

Here we evaluate if measurement of ADA and MMP‐10 markers in blood samples is associated with cognitive decline.

Method

Blood samples from 98 participants, including 41 healthy controls and 57 patients with amnestic mild cognitive impairment (aMCI) in the ICOS study were analysed. Participants were monitored at six‐monthly intervals over two years. Blood samples obtained during the third monitoring visit at 12 months post recruitment were analysed in this study. The levels of MMP‐10 and ADA in these samples were measured using the OLINK platform. Correlation analysis and Receiver Operator Characteristic (ROC) curves were used to evaluate if these markers of inflammation are associated with cognitive function.

Result

ADA, an enzyme that regulates immune homeostasis, showed a weak but statistically significant increase in blood concentration with decreasing MoCA cognitive test scores (Rho=‐0.2, p=0.023). MMP‐10, an enzyme involved in blood brain barrier function, also showed a weak but statistically significant increase with decreasing MoCA scores (Rho=‐0.25, p=0.006).

ROC analysis indicates that both ADA and MMP‐10 are weak predictors of amnestic MCI. They can differentiate between healthy controls (MoCA 26‐30) and patients with aMCI (MoCA 18‐25) with Areas Under the Curve of only 0.57 and 0.64, respectively.

Conclusion

In this study, blood levels of ADA and MMP‐10 were significantly associated with cognitive impairment. Their predictive ability of aMCI is weak and further work is required to establish the prognostic capabilities of immune markers in blood samples in larger patient cohorts.
Assessment of inflammatory biomarkers in Alzheimer's disease
Authors: Santos Gustavo A A
Published: January 2025

Background

Neuroinflammation can be considered a risk factor for the onset or progression of Alzheimer's dementia. In a neuroinflammatory process, the death of neurons may accelerate, favoring the progression of Alzheimer's disease. The release of pro‐inflammatory proteins can, for example, cause synaptic dysfunction and impede neurogenesis.

Method

76 participants were invited to participate in this experiment, arranged as follows: Elderly Group without AD: 26 cognitively healthy elderly individuals without a diagnosis of AD, aged 65 years or over. Adults without AD group: 25 adult and non‐elderly individuals, cognitively healthy and without a diagnosis of AD, aged between 19 and 59 years old. Elderly group with AD: 25 patients diagnosed with probable AD, aged 65 years or over. The concentrations of cytokines (IL‐4, IL‐6, IL‐8, IL‐10 and TGF‐β) present in saliva were measured through enzymatic assays (ELISA), using the following kits, respectively: IL‐4, IL‐6, IL‐8, IL‐10 ‐ HCYTOMAG‐60K‐04 CYTOKINE PANEL WITH 04 PLEX (IL4, IL6, IL8 AND IL10); E‐EL‐H0110 ‐ Human TGF‐1(Transforming Growth Factor Beta 1), ELISA Kit

Result

We identified important changes in IL‐4, IL‐6, IL‐8 and TGFb1, with increased expression in participants with AD and a reduction in healthy ones, except for TGFb1, which had exactly the same levels found in participants without AD, except for women, where it was increased, a fact to be investigated

Conclusion

For IL‐10 Cytokines we did not find any type of variation, however IL‐8 was elevated in patients with AD and reduced in patients without AD; IL‐6, IL‐4 and TGF‐b are also elevated in AD patients and reduced in healthy subjects. These findings support the hypothesis that AD is an inflammatory process.
An EEG study of neurophysiological markers of cognitive reserve
Authors: Katayama Osamu , Stern Yaakov , Habeck Christian G , Coors Annabell , Lee Sangyoon , Harada Kenji , Makino Keitaro , Tomida Kouki , Morikawa Masanori , Yamaguchi Ryo , Nishijima Chiharu , Misu Yuka , Fujii Kazuya , Kodama Takayuki , Shimada Hiroyuki
Published: January 2025

Background

Cognitive reserve (CR) is a property of the brain trait that allows for better–than–expected cognitive performance, relative to the degree of brain change over the life course. However, the neurophysiological markers of CR require further investigation. Electroencephalography (EEG) may provide an appropriate neurophysiological marker of CR. Therefore, we tested whether activity in the dorsal attention network (DAN) and the ventral attention network (VAN), as measured during resting–state EEG, moderates the relationship between hippocampal volume and episodic memory.

Method

Participants from the National Center for Geriatrics and Gerontology–Study of Geriatric Syndromes, were included; all underwent determined hippocampal volume using MRI and episodic memory was measured using word lists. After testing the effect of hippocampal volume on memory performance using multiple regression analysis, we evaluated the interactions between hippocampal volume and DAN and VAN network activity. We used the Johnson–Neyman technique to quantify the moderating effects of the DAN and VAN network activity on the relationship between hippocampal volume and word list memory, and to identify specific ranges of the DAN and VAN network activity with significant hippocampal–memory associations.

Result

A total of 449 participants were included in this study. We found significant moderation of DAN with a slope of β = ‐0.0001 (95% CI: ‐0.0002; ‐0.00001, p = 0.041) and VAN was significant, with a slope of β = 0.0001 (95% CI: 0.00001; 0.0003, p = 0.032). We found that larger hippocampal volume was associated with better memory performance, and this association became stronger the lower the DAN activity. However, when the DAN activity was > 944.9, the hippocampal volume was no longer significantly related to word list memory performance. For VAN, we found higher hippocampal volume was more strongly associated with better memory performance when VAN activity was higher. However, when the VAN activity was < 914.6, the hippocampal volume was no longer significantly associated with word list memory.

Conclusion

Our results suggest that attention network helps maintain memory performance in the face of age related structural decline, meeting criteria for a neural implementation of cognitive reserve.
Large‐scale Proteomic Analyses of Incident Alzheimer's Disease Reveal New Pathophysiological Insights and Biomarkers
Authors: Zhang Yi , Guo Yu , YOU JIA , He Yu , Yu Jin‐Tai
Published: January 2025

Background

The pathophysiological evolutions involved in early‐stage Alzheimer’s disease (AD) are not well understood.

Methods

We used data of 2,923 plasma proteins from 51,296 non‐demented middle‐aged adults in the UK Biobank with 15 years of follow‐up. We first identified AD‐associated proteins using Cox proportional hazard models and then delineated their temporal sequences to characterize the pathophysiological evolution. The predictive value and potential as drug targets for proteins were finally estimated.

Results

We identified 48 AD‐related proteins, with CEND1, GFAP, NEFL, and SYT1 being top hits in both near‐term (HR:1.15‐1.77; P:9.11×10‐65‐2.78×10‐6) and long‐term AD risk (HR:1.20‐1.54; P:2.43×10‐21‐3.95×10‐6). In trajectory modeling, these four proteins increased 15 years before AD diagnosis and progressively escalated, indicating early and sustained dysfunction in synapse and neurons. Proteins related to extracellular matrix organization, apoptosis, innate immunity, coagulation, and lipid homeostasis also showed early disturbances, followed by malfunctions in metabolism, adaptive immunity, and final synaptic and neuronal loss. We uncovered non‐linear alterations in human plasma proteome with AD progression, and proteins with escalating abnormalities showed stronger correlations with AD signature brain measures. Combining CEND1, GFAP, NEFL, and SYT1 with basic demographic data generated desirable predictions for 10‐year (AUC=0.901) and over‐10‐year AD (AUC=0.864), which were comparable to full model with proteomic and demographic data. In addition, CEND1 and SYT1 were potentially novel drug targets, as supported by Mendelian randomization (P<0.001) and colocalization analyses (Posterior Probability>0.8).

Conclusions

Proteins that first reached defined abnormality and progressively escalated were good predictive markers and potential treatment targets. Our findings highlight the importance of exploring the pathophysiological evolutions in early stages of AD, which is essential for the development of early biomarkers and precision therapeutics.
Prediction of long‐term treatment outcome in Alzheimer's disease based on EEG connectivity
Authors: Youn Tak , Park Hea Jeong , Jun Hyong Sook
Published: January 2025

Background

It is difficult to predict of long‐term treatment response of AD to medical treatment when starting medication. We explored EEG brain connectivity as a potential biomarker for long‐term medication outcomes in patients with AD.

Methods

Resting‐state EEG was recorded from a total of 56 AD patients (mean age = 73.23±6.39) when starting medication after diagnosis of AD. EEG was recorded in 32 channels. We divided the patients into two groups, good and poor respondent groups according to clinical evaluation after treatment and dosage changes of AD medication with MMSE score change. Starting dosage of AchE inhibitor, donepezil was 7.75±3.85mg and the mean treatment period is 104.05±57.93 weeks. The mean final medication dosages are donepezil 13.23±6.93mg and memantine 9.52±9.68mg. Initial MMSE scores of good respondent group (n=32, M=11, F=21) is 20.06±4.35 and poor respondent group (n=24, M=7, F=17) is 19.63±4.07. We analyzed brain EEG connectivity among the 246 cortical regions defined by the Brainnetome atlas.

Results

Our study found that the difference in brain EEG connectivity, especially intrahemispheric regional connectivity in gamma frequency bands, is increased at multiple regions of right hemisphere such as between Brodmann Area 44 and 39, such as DLFPC and hippocampal areas, DLFPC and caudate nucleus, middle frontal and inferior parietal areas in poor respondent group (p<0.00001). In alpha frequency band, EEG connectivity between right DLPFC(BA 9/46) and right paracentral lobule of frontal lobe (BA 4) is increased in good respondent group (p<0.0001). In theta frequency band, EEG connectivity in the areas of frontal lobe (BA 4 and 6) is decreased in good respondent group (p<0.0001).

Conclusions

This study shows increased gamma bands EEG connectivity between right anterior and posterior areas in poor respondent group. In general cortical gamma‐band activity is increased by selective attention in normal populations and related to cholinergic system. Elevated gamma band power was observed in AD when compared to MCI and control subjects was reported in a previous study. Our results suggest the potential of the gamma EEG connectivity of initial EEG when starting treatment as a biomarker to predict long‐term medical treatment for AD medication.