bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral and central markers of inflammation increased in frontotemporal dementia and related conditions
Authors: Malpetti Maura , Swann Peter , Chouliaras Leonidas , Tsvetanov Kamen A , Jones P Simon , Cope Thomas E , Bevan‐Jones W Richard , Savulich George , Street Duncan , Whiteside David J , Rittman Timothy , Murley Alexander G , Stockton Katherine , Hong Young T , Fryer Tim D , Aigbirhio Franklin I , O'Brien John T , Rowe James B.
Published: December 2023

Background

Neuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and their relationship with central inflammation are limited. Here we assess inflammatory patterns of 41 serum cytokines from patients with FTD and related conditions, and their association with regional microglial activation (TSPO PET).

Method

Blood samples were obtained from 29 healthy controls, and 214 patients with a clinical diagnosis of behavioural variant FTD (bvFTD = 52), primary progressive aphasia (PPA = 51), progressive supranuclear palsy (PSP = 58) and corticobasal syndrome (CBS = 53). Serum assays used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to reduce dimensionality of cytokine data. A sub‐group of patients (bvFTD = 10, PPA = 17, PSP = 17) underwent PET imaging with [11C]PK11195 PET, as index of microglial activation. Kruskal‐Wallis and pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls. [11C]PK11195 non‐displaceable binding potential (BPND) was calculated in 83 regions of interest (ROIs) across the whole brain. Spearman correlations tested associations between cytokine components and regional [11C]PK11195 BPND.

Result

Sixteen cytokines were undetectable in >50% of participants and thus excluded. The first component identified by the PCA on the remaining 25 cytokines (explaining 19.7%) was strongly loaded by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on detected significant differences across the groups (χ2(4) = 11.0, p = 0.027), and the pairwise t‐tests identified significant differences between each patient cohort and controls (Figure 1, right). Spearman correlations identified regional positive associations between individual cytokine‐component scores and microglial activation in frontal and brainstem regions across the whole group (R≥0.25), and syndrome‐specific regional patterns (Figure 2).

Conclusion

This data‐driven approach identified a pro‐inflammatory profile across FTD and related conditions, which is positively associated with higher levels of microglial activation in syndrome‐related key brain regions. Blood‐based tests could greatly increase the scalability and access to neuroinflammatory assessment in dementia and experimental medicine studies.
Clinical and biomarker characteristics of amnestic MCI patients exhibiting a temporo‐limbic FDG‐PET pattern suggestive of LATE
Authors: Grothe Michel J. , Silva‐Rodríguez Jesús , Moscoso Alexis , Schöll Michael
Published: December 2023

Background

We have recently described a specific temporo‐limbic FDG‐PET signature that characterizes autopsy‐confirmed cases with limbic age‐related TDP‐43 encephalopathy (LATE), and have demonstrated its clinical utility for differential diagnosis of amnestic dementia patients. Here we assessed the utility of this pattern for patient stratification at a predementia disease stage, and further used tau‐PET data to study the degree to which this “LATE‐specific” FDG‐PET signature may correspond to a limbic‐predominant AD subtype.

Method

Individual FDG‐PET scans of 909 amnestic MCI (aMCI) patients from the ADNI cohort were screened for hypometabolic patterns being suggestive of LATE (sLATE) or typical AD (sAD) using automated pattern‐matching to autopsy‐confirmed pathology‐specific FDG‐PET signatures. sLATE and sAD patients were compared on clinical features, APOE4 genotype, and CSF biomarkers. Tau‐PET scans ([18F]Flortaucipir) were available in a smaller subsample (30%) and were analyzed for tau‐positivity using an FDA‐approved visual interpretation method as well as entorhinal SUVR (positivity‐threshold: SUVR≥2.1).

Result

734 aMCI patients showed evidence of significant regional hypometabolism, and of these 92 had a pronounced temporo‐limbic hypometabolic pattern classified as sLATE, whereas 68 had a classical temporo‐parietal pattern classified as sAD(Fig‐1). Compared to sAD, sLATE patients had similar MMSE and memory scores but more preserved executive function scores, and they showed generally slower cognitive decline over follow‐up (p<0.001)(Fig‐2). They were also significantly older (d = 0.83, p = 0.01), less often APOE4 carriers (39% vs 64%, p<0.001), and had less abnormal CSF Aβ42 (d = 0.60, p = 0.001) and p‐tau181 levels (d = ‐0.40, p = 0.01). With regards to tau‐PET, 9/30 sLATE (30%) and 9/10 sAD (90%) patients were visually positive and similar proportions were seen for entorhinal SUVR (40% vs 90%).

Conclusion

The majority of amnestic MCI patients exhibiting a LATE‐typical temporo‐limbic FDG‐PET pattern show clinical and biomarker features that deviate from prodromal AD. A smaller subset of these patients shows elevated tau‐PET signal and could thus represent a limbic‐predominant AD subtype.
Imaging genetics based dementia risk prediction using deep survival neural network
Authors: Yu Jing , Vernooij Meike W , Ikram M. Arfan , Niessen Wiro J. , Roshchupkin Gennady V.
Published: December 2023

Background

Dementia has a large impact on people’s lives and is one of the leading causes of death. Therefore, accurate risk assessment is essential for improving early diagnostics and intervention. Previous studies have proposed various models for dementia risk prediction, based on imaging biomarkers and genetic factors. However, most of them have linear, unimodality or low‐dimensional nature due to model limitations and computational challenges of integrating such heterogeneous and high‐dimensional domains as images and genotype data. Recent development of Artificial Intelligence, specifically neural networks, enabled such integration, yet focused on classification problems, not risk prediction. We present a deep survival neural network to meet the purpose.

Method

Data were obtained from the Rotterdam Study. Individuals with complete data and available brain MRI before dementia diagnosis were included. MRI scans were pre‐processed using voxel‐based morphometry according to Good et al. into gray matter images. We included ApoE‐ε4 and 76 top‐risk SNPs based on most recently published GWAS (Bellenguez et al.). We developed the model combining Convolutional Neural Network and Survival Analysis, with the maximum‐likelihood estimator and C‐index of cox proportional hazard (Cox) model as the loss function and metric. To evaluate model performances, we used Cox model as comparisons: one baseline model with gender, age, genetic inputs and one extended model with additional extracted brain measurements. We performed 10 cross‐validation by stratified sampling to reveal the true differences.

Result

Table1 shows little performance differences among the models, as expected age is already the strongest predictor. However, we see that raw gray matter and genetics inputs contribute to prediction additionally in all models. Furthermore, using the method from Tsang et al. we show strong interactions among image, age and genetic features (Fig.1). Fig.2 visualizes the most important brain regions for prediction on 3D image using GRAD‐CAM.

Conclusion

We developed a deep survival model for dementia risk prediction which do not outperform classical model with brain measurements at present. However, our model is able to integrate high‐dimensional MRI and genetic data, detect and visualize the importance and interactions among input data, which may give additional insight for dementia prediction and etiologic research.
High‐salt diet enhances Helicobacter pylori infection and increases the prevalence of Alzheimer’s disease
Authors: Balendra Vyshnavy
Published: December 2023

Background

The American Heart Association recommends that adults consume less than 2,300 milligrams of salt (sodium chloride) daily; anything surpassing this limit is classified as a “high‐salt diet (HSD)” [1]. Research has shown that excessive salt intake stimulates the gastric mucosa, favoring Helicobacter pylori (Hp) colonization [2]. In this review, the relationship between HSD and the susceptibility to Hp infection will be discussed. It is proposed that increased salt consumption will cause neurodegeneration, i.e. Alzheimer’s disease (AD) by way of increased expression of Hp strains in the gastric mucosa.

Methods

A complex and specific literature search was conducted across various scientific, international databases for English, peer‐reviewed articles and reviews published in the last decade using the following terms: Helicobacter pylori, amyloid‐β, high‐salt diet, and Alzheimer’s disease. Case reports were excluded. The main objectives were predominantly focused on animal‐based studies.

Results

Experimental data shows HSD enhances Hp growth in mice. The subsequent microglial activation containing H. pylori‐specific IgG, IL‐8 and TNF‐α in the cerebrospinal fluid, induces oxidative damage in neuronal cells. In addition, urease in Hp increases cytosolic [Ca2+] apoptosis and autophagy of neurons. Hp filtrate induces tau hyperphosphorylation at AD‐tau phosphorylation sites such as Thr231 and Ser404. Hp ‐infected mice show a significantly larger GFAP‐positive astrocyte area than non‐infected mice. Immunostaining reveals microglia and astrocytes to be found adjacent to amyloid‐β plaques in Hp‐infected AD model mice. Injection of Hp filtrate impairs the maturation of dendritic spines, increasing Aβ42 production in the hippocampus and cortex, and enhancing expression of PS‐2, resulting in delayed spatial learning and impaired memory in rats.

Conclusion

This review provides comprehensive evidence of potential synergistic effects of HSD and Hp on the brain resulting in neurodegeneration and AD progression. Understanding the pathologic consequences of salt consumption on this infection may be key in the prevention of dementia and AD. Thus, further research is required for substantiation of causality, the role of antibiotics and to examine other novel therapeutics.
C9orf72 dipeptides trigger neuroinflammation via the NLRP3 inflammasome
Authors: Auty Jack , Hoyle Chris , Pointer Ayesha , Pickering‐Brown Stuart , Brough David , Ryan Sarah
Published: December 2023

Background

The most common cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a repeat expansion in C9orf72. The expansion is translated to produce five toxic dipeptides (DPRs), which aggregate in patient brain. Neuroinflammation is observed in patients, with increased microglial activation and elevated levels of pro‐inflammatory cytokines in CSF. However, the causes of this inflammation are unknown. Here, we investigated whether DPRs activate immune cells and contribute to neuroinflammation.

Method

Primary macrophages or microglia were treated with synthetic C9orf72 dipeptides and levels of pro‐inflammatory cytokines released into the culture media were analysed by ELISA and Western blot. Cytotoxicity was measured by LDH assay. Mouse organotypic hippocampal slice cultures were also treated with DPRs and cytokine release measured.

Result

One of the DPRs, GR, caused secretion of the pro‐inflammatory cytokine, interleukin (IL)‐1β, from macrophages, microglia and in hippocampal slice cultures. GR also caused significant toxicity. IL‐1β secretion was prevented by pre‐treatment with MCC950, a drug which inhibits the NLRP3 inflammasome. The inflammasome is a protein complex which forms in the cytosol of immune cells is response to “danger” stimuli, resulting in cleavage of caspase‐1 and subsequent release of IL‐1β. We confirmed that caspase‐1 was cleaved in macrophages following GR treatment. In addition, knockout of NLRP3 prevented IL‐1β secretion in response to GR. Finally, we showed that several drugs which are clinically approved for use in other conditions rescued GR‐induced NLRP3 activation.

Conclusion

Here, we demonstrate that C9orf72 dipeptides could directly contribute to neuroinflammation in FTD/ALS via the NLRP3 inflammasome. Furthermore, we demonstrate that this can be inhibited pharmacologically, highlighting NLRP3 as a potential therapeutic target in FTD/ALS.
Body Mass Index, but not Visceral Abdominal Obesity and Insulin Resistance, Negatively Impacts White Matter Microstructure in Midlife
Authors: Raji Cyrus A. , Dolatshahi Mahsa , Rahmani Farzaneh , Commean Paul K. , Nguyen Caitlyn , Ippolito Joseph , Benzinger Tammie L.S.
Published: December 2023

Background

Midlife obesity, as evidenced by high body mass index (BMI), is increasingly understood as a risk factor for development of Alzheimer’s disease. Importantly, visceral fat, by producing adipokines, contributes to inflammation as well as insulin resistance, mechanisms involved in development of Alzheimer’s disease. Herein, we aimed to assess association of white matter microstructure, measured by Diffusion tensor imaging (DTI), with obesity and abdominal adipose tissue composition at midlife.

Method

A total of 34 middle‐aged (age: 51.27 ± 6.12 years, BMI: 32.28 ± 6.39 kg/m2), cognitively normal participants, underwent bloodwork, brain and abdominal MRI. Insulin resistance status was assessed using Homeostatic Model Assessment for Insulin Resistance. Abdominal visceral and subcutaneous adipose tissue (VAT, SAT) were automatically segmented using VOXel Analysis Suite (Voxa) and VAT/SAT ratio was calculated. A diffusion spectrum imaging scheme with a total of 98 diffusion samplings and a voxel size of 2 mm was acquired. Using DSI studio (https://dsi‐studio.labsolver.org/), the diffusion data were reconstructed using generalized q‐sampling imaging and the tensor metrics were calculated. Fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, RD, respectively) for white matter tracts were compared across study groups using one‐way ANOVA. Multiple regression models with sex, age, and education as covariates were used to assess the association of BMI, VAT/SAT ratio, and HOMA‐IR with DTI metrics.

Result

Our data showed that BMI was negatively associated with AD values in right inferior fronto‐occipital fasciculus, tapetum and forceps major of Corpus Callosum (CC), superior and middle cerebellar peduncle, and bilateral reticular tract. The negative association of BMI with AD values in tapetum of CC was significant only in women. Right reticular tract MD and superior cerebellar peduncle MD and RD values were also significantly associated with BMI. There were no significant associations between neither of diffusion metrics and VAT/SAT ratio or HOMA‐IR.

Conclusion

Association of midlife obesity with lower axonal diffusivity, reflective of lower white matter integrity, with differential patterns in men and women especially in CC, is in line with previous findings in healthy individuals. Reduced axonal diffusivity in reticular and brain stem pathways could be indicative of early dysregulations observed in Alzheimer’s disease.
Feasibility of cognitive assessments post‐emergency department (ED) discharge: A longitudinal pilot study of Medicare‐enrolled adults 65 +
Authors: Dawson Walter D , Spoden Natasha , Gothard Sarah , Kaye Jeffrey , Wright Kirsten M
Published: December 2023

Background

50% of US adults living with Alzheimer’s disease and related dementias (ADRD) never receive a formal diagnosis. This compromises the wellbeing of persons living with ADRD and their care partners, increases health services utilization, and the costs‐of‐care. Wider screening and assessment for ADRD may increase access to supportive care that prevents or delays disease progression, ameliorates care partner burden, and alleviates costs.

Method

A sample of Medicare‐enrolled individuals 65+ (n = 149) presenting to the Oregon Health & Sciences University (OHSU) emergency department (ED) in Portland, Oregon between May 2022 and January 2023 were recruited and administered the Telephone Interview for Cognitive Status (TICS) up to one‐month post‐discharge. Study participants were queried about their physical health via the modified cumulative illness rating scale (M‐CIRS), while their cognitive health was assessed via the PROMIS Cognitive Measure Questions on Mental Clarity. Care utilization patterns were measured via review of subjects’ electronic health records (EHR) for three years prior to study enrollment date focusing on total hospitalizations, ED visits, and primary care (PC) visits. These reviews measured health care utilization across three groups comparing individuals with (A) un‐diagnosed cognitive impairment with (B) cognitively healthy individuals, and (C) individuals with a formal ADRD diagnosis.

Result

Study enrollment rate was 25.8% (n = 149) of individuals meeting eligibility requirements. Enrollment was limited to patients with an OHSU PC affiliated provider excluding the majority (ineligible n = 1681, 74%) of Medicare‐enrolled ED patients (total ED users available for recruitment was n = 2,258). Of those contacted, 10% declined participation due to lack of interest and 4% declined due to cognitive or health restraints. Time to administer instrument suite ranged between 26‐33 minutes.

Conclusion

Medicare‐enrolled adults 65+ recently discharged from the ED appear to be an acceptable population to administer cognitive assessments. Findings during the recruitment process show success at enrolling this population to the study and administration times did not appear burdensome in duration for those enrolled. This study provides preliminary evidence supporting a focus on older ED patients to administer cognitive assessments, linking outcomes to the EHR, and ultimately providing a platform for future research on the impact of under‐diagnosed ADRD on health outcomes and utilization.
Neurovascular Coupling in Hypertensive COVID‐19 Survivors Medicated With Different Classes of RAS Inhibitors: A Pilot Study
Authors: Guthrie Sarah E , Jacoby John R , Mellen Sarah F , Valencia Emily M , Maina Katherine N , Michel Christa B , Yadav Shrikanth M , Howard Casey M , Salat David H , Sitnikova Tatiana A
Published: December 2023

Background

Hypertension poses an increased risk of Alzheimer’s disease (AD). Coronavirus disease 2019 (COVID‐19) may exacerbate this risk by affecting the Renin‐Angiotensin system (RAS), which contributes to the regulation of neurovascular coupling (NVC). NVC is a mechanism that optimizes cerebral blood flow (CBF) to meet the metabolic and waste‐removal needs of the brain. Disrupted NVC may predispose individuals to AD through hypoxia‐related protein changes and suboptimal protein‐waste removal from the brain. Several studies reported reduced CBF in long‐haul COVID‐19 patients. Among antihypertensive medicines that target the RAS, angiotensin receptor blockers (ARBs), but not angiotensin‐converting enzyme inhibitors (ACEIs), were previously found to regulate CBF. Therefore, we hypothesized that, if taken during and after a COVID‐19 episode, ARBs rather than ACEIs would be protective against long‐term CBF dysregulation.

Method

We quantified NVC through a novel analysis paradigm that takes advantage of simultaneous resting‐state electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). We obtained scans from older adult participants (aged 55‐80), including healthy controls and hypertensive COVID‐19 survivors medicated with ARBs or ACEIs during their COVID‐19 infection (occurring 3‐27 months before scanning). Hidden Markov modeling on source‐localized EEG was used to detect transient electrophysiological activity in distinct neural networks. A rapid event‐related fMRI analysis deconvolved the blood oxygenation level‐dependent (BOLD) changes evoked by the network‐specific electrophysiological activations. NVC was measured as the slope of vascular BOLD changes over the time‐locked electrophysiological neural changes.

Result

In this pilot study, the default mode network (DMN) showed differences in NVC between the hypertensive COVID‐19 survivors and the healthy control group. Crucially, the ARB‐medicated subgroup, like the control group, showed the BOLD response in the DMN regions time‐locked to the DMN electrophysiological activations; NVC differences between the ARB‐medicated and control groups did not reach significance. In contrast, the ACEI‐medicated subgroup showed a reduced NVC in the DMN relative to the control group.

Conclusion

The DMN, which is linked to memory dysfunction in AD, may be vulnerable to NVC disruptions, given its high metabolic demands. Hypertension management with ARBs may reduce COVID‐19’s effects on cerebrovascular regulation, preventing ischemic stroke, vascular dementia, and AD. Results replication is warranted.
Oral tributyrin supplementation attenuates Alzheimer’s disease‐associated neuropathology and prevents cognitive and behavioral deficits in the 3xTg‐AD mouse model
Authors: Chilton Paula M. , Ghare Smita S. , Charpentier Benjamin T , Myers Scott A. , Rao Aakarsha V. , Greenwell J Caleb , Tyagi Neetu , Behera Jyotirmaya , Wang Yali , Sloan Lucy J , Zhang JingWen , Gobejishvili Leila , Whittemore Scott R , Shields Christopher B , Cooper Gregory , McClain Craig J. , Barve Shirish
Published: December 2023

Background

Dysbiosis of the gut microbiome is associated with various diseases, including Alzheimer’s Disease (AD). A decrease in intestinal butyrate‐producing bacteria has been indicated by pre‐clinical and clinical studies in AD; therefore, we assessed the effects of long‐term oral administration of tributyrin (TB: a butyrate pro‐drug) on the development of memory and neuromuscular deficits, and CNS pathology in 3xTg‐AD (3xTg) mice.

Method

Oral gavage with tributyrin (2 mg/kg) was given twice weekly to female 3xTg mice between 6‐ and 17‐months of age. Treatment was stopped and mice were tested for spatial memory (Y‐maze and novel object recognition test‐NORT) and neuromuscular function (RotaRod and grip tests). Brains from untreated (2‐, 12‐, or 18‐month‐old untreated or TB treated 18‐month‐old mice were formalin‐fixed, paraffin‐embedded for microscopic analysis of AD‐associated pathology, neuroinflammation, and oxidative stress markers.

Result

Short‐term, episodic memory and spatial memory along with balance and coordination and grip strength were all significantly decreased in untreated 3xTg mice at 17‐months of age compared to 2‐ or 10‐month‐old mice. TB treatment, however, attenuated these effects in 17‐month mice. TB treatment did not affect the accumulation of either Aβ or Tau in the subiculum at 18‐months. However, pTau hyperphosphorylation—as indicated by co‐staining with both pTau(Ser404) and AT‐8 pTau (Ser202/Thr205) mAb—was effectively prevented with TB treatment. Similarly, significant age‐dependent neuroinflammation indicated by IBA1 (microglia) and GFAP (astrocytes) staining was increased in the hippocampus of 18‐month 3xTg mice and was effectively prevented by TB treatment. Additionally, markers of oxidative stress, 4‐HNE and acrolein adducts, were also increased in the molecular layer of the hippocampus and attenuated in TB treated mice.

Conclusion

These studies demonstrate that TB treatment after initiation of Aβ deposition in the subiculum dramatically abrogates the loss of neurologic function in 3xTg mice as demonstrated by increased memory, cognition, and neuromuscular function. Moreover, these increases coincide with attenuated AD‐associated pathology in the hippocampus of TB‐treated 3xTg mice. Importantly, these data indicate that treatment with a butyrate pro‐drug can be integrated into treatment strategies to preserve cognitive and neuromuscular functions in patients in the prodromal phase of AD.
EEG‐based neural biomarker for diagnosis and assessment of mild cognitive impairment and Alzheimer’s disease
Authors: Jiao Bin , Li Rihui , Tang Beisha , Shen Lu
Published: December 2023

Background

Electroencephalogram (EEG) has emerged as a non‐invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimer’s disease (AD). However, the effectiveness of EEG in the precise diagnosis and prediction of AD and its preclinical stage, mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD.

Method

A total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting‐state EEG recordings for a three‐level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of predictive models by combining participants’ EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for predicting the disease progression and individual’s cognitive function.

Result

The identified EEG biomarkers achieved over 70% accuracy in the three‐level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD‐linked neurodegeneration on EEG metrics were localized at parieto‐occipital regions. Noteworthy, the absolute theta power of channel O2 was negatively correlated with Aβ42 (r = ‐0.358, p < 0.001) and positively correlated with p‐tau (r = 0.442, p < 0.001). In terms of cognitive assessment, the Hjorth mobility of channel O1, O2 and P4 were found to be positively associated with MMSE and MoCA scores (r = 0.416‐0.464, all p < 0.001). In the predictive analyses, the optimal EEG features were more effective than the CSF + APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG + CSF + APOE measures achieved the best performance for all targets of prediction.

Conclusion

Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.
Time for Living & Caring: An Online Intervention to Support Dementia Caregivers’ Use of Respite
Authors: Utz Rebecca , Thompson Amber , Wong Bob , Iacob Eli , Sparks Catharine , Terrill Alexandra , Caserta Michael
Published: December 2023

Background

Because of the demanding care needs associated with dementia, family caregivers often have increasing anxiety and burden over time. Respite, defined as time away from caregiving, is the most requested type of caregiver support and is hypothesized to benefit caregiver wellbeing. However, many caregivers report low respite satisfaction, feeling as though they wasted their time or that they did not know how to use their respite time in a way that benefited them.

Method

Time for Living and Caring (TLC) is a virtual coaching “app” that helps caregivers schedule and plan their respite time. With funding support from NIA (R01‐AG061946), we conducted a pilot test with dementia caregivers (n = 159), randomized into one of two delivery methods – an immediate group that could access all features and functions of the app for 16 weeks, and a delayed‐attention group that received initial instructions on calendaring for 8 weeks and then the more interactive coaching features during the second 8 weeks. This additive “dosing” model where the immediate group received “2 doses” in the first 8 weeks while the delayed‐attention group got “1 dose” initially and “1 dose” during weeks 8‐16 was evaluated using generalized linear modeling on caregiver‐reported anxiety and burden levels over time.

Results

Both immediate and delayed‐attention groups reported 1) increased respite time, 2) increased respite satisfaction, and 3) felt that they were better caregivers because of respite. At 8 weeks, the immediate group did not change in anxiety while the delayed group worsened (p < 0.001). At 16 weeks, the groups were similar in their anxiety levels. By the 20‐week follow‐up period, when neither group had access to TLC, both groups were worsening in their anxiety. Caregiver burden worsened at 16 weeks for the immediate group.

Conclusion

TLC shows potential as an intervention model to improve respite quality and minimize increases in anxiety and burden over time. Intervention delivery that provides additional features or instructions after the initial orientation may keep participants more engaged and result in better caregiver outcomes over time, compared to providing the full set of online resources all at once.
Correlations between daily activities and the Korean‐Everyday cognition, and the Gottfreis‐Bråne‐Steen scale in the patient complaint with cognitive decline
Authors: Lee Juyoun , Lee Ae Young
Published: December 2023

Background

To get the right diagnosis of dementia, clinicians need a wealth of information from the patient and their caregivers, as well as objective examinations. Some questionnaires may provide sufficient information to be obtained by interviewing. The Everyday Cognition (ECog), and the Gottfreis‐Bråne‐Steen (GBS) scale were developed to measure functional changes in cognitive decline patients through the caregiver’s report. This study aims to evaluate the usefulness of theses scales in the dementia clinic.

Method

The Korean‐ECog (K‐ECog), and GBS scale was answered by 100 caregivers from patients with cognitive decline. Results of neuropsychological tests, and clinical information were collected. Correlation analyses were conducted between K‐ECog, GBS, Korean version of instrumental activities of daily living (K‐IADL), Clinical dementia rating‐sum of boxes (CDR‐SB), global deterioration scale, and other detailed cognitive tests.

Result

This study included 97 patients, including 54 dementia, 34 mild cognitive impairment, and 9 subjective memory impairment. The K‐ECog, and GBS had moderate correlations with K‐IADL, and CDR‐SB. The K‐ECog and GBS had strong correlation each other. And GBS score was effectively differentiated dementia patients from non‐demented patients, respectively.

Conclusion

The two scales, the K‐ECog, and GBS, are well represented cognitive dysfunctions of the daily activities in the patients with cognitive decline, as with the K‐IADL, CDR‐SB. Therefore, these scales can make it easier to understand the patient’s daily cognitive state and diagnose the disease relatively quickly and with little effort.
Global analysis of synapse‐enriched miRNA in Alzheimer’s disease temporal cortex post‐mortem
Authors: Gil Laia Lidón , Núñez‐Llaves Raúl , Perlaza Danna , Cervantes‐González Alba , Tamayo Natalia Valle , Serrano‐Requena Sara , Dolcet Sònia Sirisi , Sánchez‐Aced Érika , Iulita Maria Florencia , Dols‐Icardo Oriol , Lleó Alberto , Pérez‐González Rocío , Belbin Olivia
Published: December 2023

Background

Synapse loss is the major neuropathologic correlate of cognitive impairment in Alzheimer’s disease (AD). MicroRNA (miRNA) regulate synaptic plasticity and play a role in AD pathogenesis and therefore represent potential therapeutic targets. The aim of this study is to determine the role of miRNA‐mediated dysfunction at AD synapses.

Method

We prepared homogenates (H) and synaptosomes (SYN) from frozen post‐mortem temporal cortex tissue from 10 AD (mean age = 77.4±4.2) and 10 non‐pathological controls (CN; mean age = 72.3±5.9). We extracted (mirVana) and quantified miRNA using the TaqManR Advanced miRNA Assay, QuantstudioTM and OpenarrayTM system. Samples were normalized (median Ct). DeltaCt values calculated relative to control hsa‐miR‐16‐5p. We performed linear regression to identify differentially expressed (DE) miRNA across groups, controlling the false discovery rate (FDR) using the Benjamini‐Hochberg method. We considered DE miRNA with fold changes <0.8 or >1.2 (adj.p<0.05) in AD vs CN. We searched two predictive databases (TargetScan and miRDB) for gene targets of the DE miRNA and identified overrepresented target genes using the Panther database (PantherDB.org) after controlling the FDR.

Result

Of the 751 miRNA included on the Openarray, we detected 411 in H and 432 in SYN, with 89% overlap between AD and CN in SYN. To enrich our analyses for miRNA that are predominantly present at the synapse, we took forward only the 47 miRNA with >1.2‐foldchange (adj.p<0.2) in SYN vs H in either AD or CN. miR‐132‐3p and miR‐132‐5p were under‐expressed (0.17‐fold, p = 0.001 and 0.35‐fold, p = 0.006, respectively) and miR‐181a‐3p was over‐expressed (2.13‐fold, p = 0.04) in AD compared to CN SYN. The 594 gene targets of upregulated synaptic miRNA (miR‐181a‐3p) were overrepresented in pathways regulating synaptic function and mitochondrial bioenergetics and integrity. The 474 and 1230 targets of downregulated synaptic miRNA (miR‐132‐3p and miR‐132‐5p, respectively) were overrepresented in the same pathways as well as pathways related to interleukin production, tau pathology, Abeta production, apoptotic signalling and oxidative stress.

Conclusion

Three synapse‐specific miRNA are differentially expressed at AD synapses and target genes involved in core AD‐related processes, thus making them promising therapeutic targets. Future studies will seek to validate these findings and determine the specificity for AD over other neurodegenerative diseases.
Two‐stage diffusion model deriving FDG‐PET from T1 Weighted Magnetic Resonance Images for diagnosis of Alzheimer’s disease
Authors: CHEN Ke , Hosseini Akram A. , Weng Ying , Dening Tom , Zuo Guokun
Published: December 2023

Background

Alzheimer’s Disease (AD) is a neurodegenerative disease which is characterized by cognitive and functional impairment, and defined by triad of Amyloid status, Tau pathology, and Neuroimaging marker of neurodegeneration or neuronal injury. An early diagnosis of AD can be challenging and it can be detected earlier in brain functional imaging than brain structural imaging.

Method

We develop a pipeline for synthesizing FDG‐PET/MRI from source MRI‐T1‐Weighted (MRI‐T1W) images based on denoising diffusion mechanism [1]. The pipeline includes a forward pass which encodes the source MRI‐T1WI images to gaussian noise space, and a backward pass which generates the corresponding FDG‐PET from the derived noises with repeated denoising steps. Furthermore, to validate the effectiveness of the synthesized FDG‐PET images, we also develop multiple types of classifiers and the experiments for both single input of MRI‐T1WI and joint input of MRI‐T1WI and synthesized FDG‐PET.

Result

The experiments are performed on 1036 of FDG‐PET/MRI pairs (286,474, 276 for Cognitive Normal, Mild Cognitive Impaiement and Alzheimer’s Disease each) are obtained from ADNI [2] datasets and display the promising results with low Mean Absolute Error (MAE) and high Structural Similarity Index Measure (SSIM) for the two stage diffusion denoising based FDG‐PET synthesis pipeline. The results for the additional classification experiments also show that in most cases the joint input enhances the classifiers' performance in accuracy and F1‐score. The results also indicate that the synthesized FDG‐PET images are not only visually similar to the ground truth images, but also improve the performance of machine learning based AD diagnosis.

Conclusion

This work provides support for the notion that machine learning‐derived image analysis may be a useful approach to improving the diagnosis of AD.

Reference:

[1] Ho, J., Jain, A., & Abbeel, P. (2020). Denoising diffusion probabilistic models. Advances in Neural Information Processing Systems, 33, 6840‐6851.

[2] Petersen, R., Aisen, P. S., Beckett, L. A., Donohue, M. C., Gamst, A. C., Harvey, D. J., … & Toga, A. W. (2010). Alzheimer’s disease neuroimaging initiative (ADNI). Neurology, 74(3), 201‐209.
Association of white matter hyperintensity burden and cognitive performance in young‐aged, middle‐aged and old‐aged participants: Results of the population‐based 1000BRAINS study
Authors: Jokisch Martha , Schramm Sara , Jockwitz Christiane , Caspers Svenja , Jöckel Karl‐Heinz , Erbel Raimund , Weimar Christian , Hermann Dirk , Gronewold Janine ,   the Heinz Nixdorf Recall Study Investigative Group
Published: December 2023

Background

Some individuals seem less susceptible to the effect of high white matter hyperintensity (WMH) load on cognition reflecting differences in individual cognitive reserve (CR). Little is known about young‐ or middle‐aged participants. The aim of the present study was to examine (1) the effect of WMH on global cognition in three different age groups and (2) if education (as proxy for CR) moderates this association.

Method

We included 707 healthy participants (18‐85 years) without evidence of cardiovascular/neurological disease (young‐aged: 18‐44 years (Ø33.5±6.7): n = 108; middle‐aged: 45‐65 years (Ø57.9±5.5): n = 341; old‐aged: >65 years (Ø72.0±4.1): n = 258) from the population‐based 1000BRAINS study. An extensive cognitive assessment was conducted. The sum of all cognitive domain z‐scores defined the global score. Education was classified according to the International Standard Classification of Education as total years of formal education, combining school and vocational training. Magnetic resonance imaging (MRI) was carried out on a 3‐Tesla‐MR‐scanner (Tim‐TRIO, Siemens Medical Systems, Erlangen, Germany). WMH volume was determined using the Brain‐Intensity‐Abnormality‐Classification‐Algorithm. The associations of global cognition as outcome with WMH volume (in cm3) as predictor were analyzed using linear models (PROCESS v4.1 macro for SPPS) stratified by age group resulting in regression coefficient b with 95% confidence intervals (CI; adjusted for age, sex, depression, diabetes mellitus). To examine moderation effects of education, all models contained an interaction term (WMH x education).

Result

Higher WMH volume was associated with lower global cognition in middle‐aged participants (b:‐0.27 (‐0.52 to ‐0.03, all reported results are fully adjusted). This effect was moderated by education (interaction term: b:‐0.07 (‐0.014 to ‐0.01)). In the young‐aged group, the association between WMH load and cognition was ‐1.27 (‐3.30 to 0.77). No association was found in the old‐aged group (b: ‐0.03 (‐0.20 to 0.14)).

Conclusion

Higher WMH load was associated with lower cognitive performance only in middle‐aged participants and was moderated to a small degree by education. Overall, the influence of WMH on global cognition in our cohort of healthy participants seems limited. Future analyses will focus on specific cognitive domains that might be more vulnerable to higher WMH load and will examine participants with certain cardiovascular risk profile.
Association of creatine kinase with cognition, neuroimaging, and Alzheimer’s pathology
Authors: Wang Yu‐tong , Gao Pei‐yang
Published: December 2023

Background

Creatine kinase (CK) and its related metabolites are known to imply cardiovascular system disease, whereas the cardiovascular metabolic state is associated with the state of cognitive well‐being of the brain. However, the extent to which CK levels is related with cognitive impairment has not been revealed.

Method

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were used for this study. We first investigated the intergroup difference of participants demographic, cognitive status, Alzheimer’s disease (AD) diagnosis, and cerebrospinal fluid (CSF) AD pathology biomarkers. Next, we conducted to use liner regression model to examine the association of CK with CSF AD pathology biomarkers, cognition, and brain structure. Last, mediation analyses were utilized to explore whether the association between CK and cognition were mediated by CSF AD pathology biomarkers.

Result

A total of 1,607 participants (mean age were 73.82±7.23 and 55.76% were male) from the ADNI database were involved in this cross‐sectional study. We found a significant difference through age, gender, AD diagnosis, and cognitive status subgroups in intergroup difference analysis (P<0.05). Meanwhile, significant association of lower level of CK with decreased level of β‐amyloid1‐42 (Aβ; β = 0.069, P = 0.040) and increased level of phosphorylated tau (P‐tau; β = ‐0.084, P = 0.007), and total‐tau (T‐tau; β = ‐0.071, P = 0.021), respectively. Liner regression analysis also indicated that the lower level of CK was associated with worse cognition (Mini‐Mental State Examination: β = 0.059, P = 0.021; Alzheimer’s Disease Assessment Scale: β = ‐0.065, P = 0.012), however not to brain structure. Moreover, mediation analysis identified CSF AD pathology biomarkers mediated the association between level of CK and cognition.

Conclusion

Our findings offered detailed proof to advise that the lower level of CK was significantly associated with poor cognition and it might be mediated by CSF AD pathology biomarkers. For future research, it is necessary to identify the precise reason and process by which changed levels of CK impact cognition.
Analytical and clinical validation of a progranulin ELISA in the FTD disease spectrum
Authors: Meda Francisco , Simrén Joel , Archetti Silvana , Cantoni Valentina , Andreasson Ulf , Blennow Kaj , Borroni Barbara , Kvartsberg Hlin , Zetterberg Henrik
Published: December 2023

Background

The granulin gene (GRN) encodes for the glycoprotein progranulin (PGRN) which is involved in lysosomal function and homeostasis. Heterozygous mutations in this gene lead to PGRN haploinsufficiency and are usually associated with genetic frontotemporal dementia (FTD) (Holler et al., 2017). FTD is a diverse neurodegenerative disease with distinct phenotypes. It is considered the second most common form of early onset dementia, after Alzheimer’s disease (AD), and is characterized by protein aggregation, neurodegeneration and lysosomal dysfunction (Greaves et al., 2019). In this study, we aimed to perform analytical and clinical validation of a commercial progranulin kit (Adipogen Life Sciences) for clinical use.

Method

Analytical validation was carried out by testing assay precision, selectivity, measurement range, dilution linearity, interferences and sample stability using de‐identified plasma samples according to previously described procedures (Andreasson et al., 2015). For clinical validation, PGRN levels were measured in plasma from 32 cognitively healthy individuals, 52 confirmed GRN mutation carriers (GRN+ symptomatic, n = 31; GRN+ pre‐symptomatic, n = 21), 25 C9orf72 mutation carriers (C9orf72+ symptomatic, n = 20; C9orf72+ pre‐symptomatic, n = 5) and 216 patients with different neurodegenerative diseases (AD n = 64; behavioral variant FTD n = 64, primary progressive aphasia n = 46, corticobasal syndrome n = 24, progressive supranuclear palsy n = 18) of which 70 were confirmed as non‐mutation carriers.

Result

Among the analytical validation parameters, assay precision indicated an inter‐plate coefficient of variance <7%, selectivity with an average value of 96% spike recovery, measurement range 6.25‐400 ng/mL and linearity range from 1:50 to 1:200 dilution. Hemolysis did not interfere with progranulin measurement and progranulin levels were resistant to freeze/thaw cycles and storage at different temperatures. For the clinical validation, this assay is capable of distinguishing GRN mutation carriers from controls and non‐GRN mutation carriers with very good sensitivity and specificity and established cut‐off at 51 ng/mL (97%, 98%, respectively).

Conclusion

In this study, we demonstrate robust analytical and diagnostic performance of this commercial progranulin kit for implementation in clinical routine. This allows a straightforward screening of patients to identify individuals who are GRN mutation carriers and thus, likely improve clinical management. This assay might also be used to evaluate the effect of novel PGRN‐targeting drugs and therapies.
Alzheimer’s disease biomarker‐related phospho‐tau 181 signals localize to demyelinated axons of parvalbumin‐positive GABAergic interneurons in App knock‐in mouse
Authors: Hirota Yu , Sakakibara Yasufumi , Takei Kimi , Nishijima Risa , Iijima Koichi M. , Sekiya Michiko
Published: December 2023

Background

Tau proteins phosphorylated at Thr181 (p‐tau 181) in cerebrospinal fluid and blood is a sensitive biomarker for Alzheimer’s disease (AD). An increase in p‐tau 181 level well correlates with Aβ pathology and precedes neurofibrillary tangle formation in the early stage of AD, though the relationship between p‐tau 181 and Aβ‐mediated pathology is less well understood. We have recently reported that p‐tau 181 signals are detected in the axonal structures and represent axonal abnormality around Aβ plaques in the cortex of App knock‐in mouse model of Aβ amyloidosis (AppNLGF
mice). However, from which neuronal subtype(s) these p‐tau 181‐positive axons are originated remains elusive. In this study, we aimed to determine which neuronal subtype(s) express p‐tau 181 in the axons.

Method

To investigate the localization of p‐tau 181 signals in the brains of aged (24‐month‐old) AppNLGF
and wild‐type mice, we prepared frozen brain sections and co‐immunostained with antibodies against p‐tau 181 and myeline basic protein (MBP), the glutamatergic neuronal vesicle marker vesicular glutamate transporter 1 (VGLUT1), the GABAergic neuronal vesicle marker vesicular GABA transporter (VGAT), the inhibitory neuron marker parvalbumin, the cholinergic neuronal vesicle marker vesicular acetylcholine transporter (VAChT), or the noradrenergic neuronal vesicle marker norepinephrine transporter (NET).

Result

Histochemical analyses revealed that p‐tau 181 signals were not overlapped with axons of unmyelinated cholinergic nor noradrenergic neurons, but well colocalized with myelinated axons of parvalbumin‐positive GABAergic interneurons, but not of glutamatergic neurons. Interestingly, the density of unmyelinated axons was significantly decreased in AppNLGF
mice, while that of glutamatergic, GABAergic or p‐tau 181‐positive axons was less affected. Instead, myelin sheaths surrounding p‐tau 181‐positive axons were significantly reduced in AppNLGF
mice.

Conclusion

This study suggests that p‐tau 181 signals may represent axonal abnormality of parvalbumin‐positive GABAergic interneurons with disrupted myelin sheaths in brains of mouse model of Aβ pathology.