bluuebunny/crossref_metadata_2025 huggingface dataset:
Higher glucose parameters at baseline are related to hippocampal volume decline after a 2‐year multidomain lifestyle intervention to prevent cognitive decline in people at risk of developing Alzheimer’s disease: Exploratory results from the FINGER study
Authors: Lorenzo Thais , Solomon Alina , Ngandu Tiia , Lehtisalo Jenni , Gispert Juan Domingo , Torre Rafael , Kivipelto Miia
Published: December 2023

Background

Lifestyle interventions for preventing cognitive decline have provided promising results in older at‐risk individuals. Two modifiable risk factors are insulin resistance and diabetes mellitus, since they’ve been associated with higher risk of cognitive decline. However, it remains unclear if healthy individuals with higher normal glucose levels are free from suffering the negative effect of pathological glucose values on brain and cognition. The Oral Glucose Tolerance Test (OGTT) is a sensitive measurement for non‐detected glucose metabolism disorders and might be related with changes in brain structure and cognition. In this study we hypothesised that changes in glucose parameters will be associated with brain structural changes.

Method

1.259 participants of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) were included [Table 1]. A sample of 132 participants had brain MRI scans, and 47 also underwent PiB‐PET and FDG‐PET scans. Global GMv, hippocampal volumes, WMHv and cortical thickness measurements were analysed to assess the association between brain structural changes and glucose homeostasis. AD‐signature composites were also calculated from FDG‐PET and PiB‐PET scans data for the analysis. SPSS was used for linear regression models.

Results

Baseline AUC‐OGTT, 120min‐OGTT and fasting glucose were negatively associated (p<0.05) with 2‐year change in hippocampal volume [Table 2]. A negative association was also found between baseline AUC and change in FDG‐PET‐AD‐composite (p = 0.028). Three negative associations were additionally found at baseline between AUC‐OGTT and cortical thickness (p = 0.015), fasting glucose and total GMv (p = 0.015), and HbA1c and FDG‐PET‐AD‐composite (p = 0.033) [Table 3]. Interestingly, a positive association was found in a smaller sample (n = 38) between the TyG index and change in PiB‐PET‐AD‐composite (0.014). No associations were found between glucose parameters and the remaining imaging data.

Conclusion

In a sample of participants at risk for dementia, baseline higher measures of peripheral glucose metabolism such as AUC‐OGTT and 120min‐OGTT glucose were related to greater decline in hippocampal volume, irrespective of the randomisation group and after considering abnormal glucose metabolism. These results suggest that glucose homeostasis might have an impact on brain structure in participants with higher normal glucose parameters measurements.
Early Results of a Pilot Program Providing Virtual Support to Family Caregivers of People with Alzheimer’s Disease to Reduce Their Stress and the Risk of Complications for Their Loved Ones
Authors: Laird Rosemary D.
Published: December 2023

Background

The Florida Department of Elder Affairs and Navigating Aging Needs, LLC (NAN) have formed a public‐private partnership providing virtual support to family caregivers of people with Alzheimer’s disease living at home. The program targets patients with high‐level daily care needs and with increased risk for future decline and need for costly Medicaid‐supported care.

Objectives

To reduce stress for family caregivers and reduce risk of complications for their loved ones with Alzheimer’s disease.

Methods

Family caregivers who qualify for state assistance were offered a 12‐month support program. Support included regular meetings (Zoom or phone) with a personal licensed social worker. The initial assessment included 80 questions on the AD patient’s medical, emotional, social, and legal/financial well‐being and the validated battery of 12 questions comprising the Zarit Burden Scale. Following the assessment, the social worker provided the family caregiver with a personal plan that identified areas of risk that “need attention” or “may need attention,” along with resources to address identified needs. For the following three months, the social worker met with the family caregiver regularly to help resolve areas identified as high risk and discuss other relevant issues as they arose. After three months of guidance and support, the social worker conducted a re‐assessment with the family caregiver.

Results

Data are available for the first hundred family caregivers participating in the pilot for three months. Initial results demonstrate a positive impact on AD patients’ medical, emotional, legal/financial outcomes including hospitalizations, falls, depression, anxiety, advanced directives, and financial planning. Early results also show reduced Zarit Burden Scale scores for family caregivers.

Conclusion

Providing virtual support to family caregivers of people with Alzheimer’s disease shows early signs of reducing the caregivers’ stress and the risk of complications for their loved ones. The Florida Department of Elder Affairs and NAN continue to evaluate the program’s impact on family caregivers, people with AD, and the cost of supporting this complex population.
Tau accumulation within the default mode network as a predictor of longitudinal clinical decline in atypical Alzheimer’s disease
Authors: Howe Inola , Eckbo Ryan , Wong Bonnie , Quimby Megan , Hochberg Daisy , McGinnis Scott M. , Touroutoglou Alexandra , Putcha Deepti , Dickerson Brad C. , Katsumi Yuta
Published: December 2023

Background

Identifying individuals with symptomatic Alzheimer’s disease (AD) at greater risk of steeper cognitive decline would allow professionals and loved‐ones to make better‐informed medical, support, and life‐planning decisions. In typical AD, the magnitude of cerebral tau accumulation in vivo predicts clinical deterioration. Despite its promise, the utility of tau PET in predicting cognitive decline in individuals with atypical clinical presentations of AD remains unclear. We examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline across atypical AD syndromes.

Method

Fifty‐seven A/T/N‐positive patients (mean age = 64.13 ± 7.72; 24M/33F) with atypical syndromes of AD (19 Posterior Cortical Atrophy, 16 logopenic variant of Primary Progressive Aphasia, 16 dysexecutive AD, five early‐onset AD with single‐domain impairment, and one Corticobasal Syndrome) and 24 amyloid‐negative control participants were included in this study. All participants underwent 18F‐Flortaucipir (FTP) PET, amyloid PET, and structural MRI scans at baseline. The rate of clinical decline was quantified as the annualized change in Clinical Dementia Rating Sum‐of‐Boxes scores (CDR‐SB) at baseline and follow‐up visits (mean time interval = 1.24 ± 0.34 years). General linear model analyses were performed to examine the pattern of baseline cortical tau deposition in atypical AD patients and its relationship with the rate of clinical decline.

Result

Compared with amyloid‐negative controls, atypical AD patients showed prominent FTP uptake in posterior cortical regions at baseline, including bilateral posterior cingulate cortex/precuneus and lateral temporo‐parietal cortices, which canonically constitute the posterior default mode network (DMN). A brain‐behavior regression analysis revealed widespread regions within the DMN where the magnitude of baseline FTP uptake predicted the rate of change in CDR‐SB, with anterior DMN regions (medial prefrontal and anterior temporal cortices) most strongly predicting clinical decline.

Conclusion

Greater baseline tau accumulation in the anterior DMN, possibly suggesting more extensive tau spread in this network, predicts faster clinical decline in atypical AD. This may serve as an imaging biomarker to guide prognostication for patients with atypical AD and their families and to inform the design of clinical trials, including potentially recruiting multiple clinical phenotypes of AD into a single trial.
Association of Traumatic Brain Injury, Mild Cognitive Impairment and Dementia in the Framingham Heart Study
Authors: Durape Shruti , Joshi Prajakta S. , Burton Rebecca , Chien‐Young Kurtis , Price Eden , Yhang Eukyung , Liu Yulin , Ang Ting Fang Alvin , Devine Sherral A. , Gurnani Ashita S , Katz Douglas I , Tripodis Yorghos , Alosco Michael L , Dams‐O'Connor Kristen , Au Rhoda , Mez Jesse B.
Published: December 2023

Background

Research on the relationship between traumatic brain injury (TBI), Alzheimer’s disease (AD) and related dementias is inconsistent. Population based studies have been limited by their characterization of TBI, dementia or both.

Design/Methods

The Framingham Heart Study (FHS) is a population‐based cohort study which recruited its original cohort between 1948‐1950, and its offspring cohort between 1971‐1975. Information on TBIs was collected across the lifespan by comprehensive review of medical records, FHS health history updates and exams and self‐report. TBI occurrence and severity were operationalized using modified American Congress of Rehabilitation Medicine and Veterans Affairs/Department of Defense criteria respectively. Mild cognitive impairment (MCI), dementia, and AD dementia consensus diagnoses were operationalized using modified Petersen criteria, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, and National Institute of Neurological and Communicative Diseases and Stroke/AD and Related Disorders Association criteria respectively. Participants with history of TBI were matched to those without TBI for age and sex, with a 1:3 ratio. Participants with prevalent MCI or dementia were excluded.

Results

1,676 participants with TBI (cognitively normal at time of TBI) and 5,260 age‐ and sex‐matched participants without TBI were followed for 357,483 person‐years. 336 (20.05%), 267 (15.93%) and 177 (10.56%) of those with TBI developed MCI, all‐cause dementia and AD dementia respectively compared with 728 (13.84%), 536 (10.19%) and 440 (8.37%) participants without TBI. For mild TBI, hazard ratios (HRs) for MCI, all‐cause dementia and AD dementia were 1.56 (95%CI 1.16–2.11), 1.30 (95%CI 0.91–1.87), and 0.99 (95%CI 0.64–1.54) respectively. For moderate‐to‐severe TBI, HRs for MCI, all‐cause dementia and AD dementia were 3.95 (95%CI 1.25–12.45), 5.13 (95%CI 1.09‐24.19), and 7.42 (95%CI 0.87–63.55) respectively.

Conclusion

In these cohorts comprehensively assessed for TBI and dementia‐related outcomes and followed for more than a decade after TBI, there were small to moderate sized associations of mild TBI and large associations of moderate‐severe TBI with MCI and all‐cause dementia. Association between mild TBI and dementia may be driven by non‐AD etiologies.
Relationship of Atrophy and Tau Imaging Subtypes in Prodromal and Clinical AD
Authors: Risacher Shannon L , Deardorff Rachael , Saykin Andrew J.
Published: December 2023

Background

Amyloid‐positive MCI and AD participants show heterogeneity in patterns of atrophy and tau‐deposition. We sought to directly compare the previously‐defined subtypes (hippocampal sparing (HpSp), limbic predominate (LP), typical AD (tAD), and minimal atrophy) derived from [18F]flortaucipir PET (T) and structural MRI (N) in the context of positive amyloid (A). In addition, we examined assessed associations between demographic factors and subtype group for atrophy or tau.

Methods

243 amyloid‐positive participants from ADNI with MRI and tau PET scans at the same visit were included (160 MCI, 83 AD). Brain volumes were extracted using Freesurfer version 6 and tau PET SUVR values were extracted using standard techniques. Hippocampal to cortical ratios for grey matter volume and tau SUVR were calculated as previously described (Risacher et al. 2017 Neurology). Minimal pathology subjects showed similar levels of atrophy relative to cognitive normal participants. Relationships between atrophy‐ and tau‐based subtypes, as well as their relationship to sex and race/ethnicity were assessed using a Chi‐square test. An ANOVA model was used to compare age and education between atrophy‐ and tau‐based subtypes.

Results

A significant association between tau‐based and atrophy‐based subtypes was observed, driven by consistency in minimal atrophy, HpSp, and tAD groupsp = 0.024). In addition, differences by sex and race/ethnicity were also observed for atrophy but not tau subtypes with non‐Hispanic Whites most likely to be either minimal atrophy or tAD, while African Americans were more likely to be HpSp. Finally, significant differences in age and education were observed across the atrophy subtypes, with the HpSp group being younger and less educated, while the LP were older and more educated.

Conclusions

Overall, we observed consistency between atrophy‐based and tau‐based subtypes, especially minimal pathology, tAD, and HpSp forms. Interesting associations between demographics and atrophy but not tau subtypes were also observed. Future studies in larger and more diverse samples are needed. These results underscore the importance of examining heterogeneity in amyloid‐positive MCI and AD across multiple modalities to better understand patterns of A/T/N pathophysiology that may have implications for risk of progression and personalized therapeutic strategies.
Synapse dysfunction and astrocyte reactivity are associated independently of amyloid‐β and tau pathologies
Authors: Rohden Francieli , Bellaver Bruna , Ferreira Pamela C.L. , Aguzzoli Cristiano Schaffer , Lussier Firoza Z , Soares Carolina , Povala Guilherme , Ferrari‐Souza João Pedro , Zalzale Hussein , Leffa Douglas Teixeira , Abbas Sarah , Cabrera Arlec , Lemaire Peter Charles , Tissot Cécile , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Rahmouni Nesrine , Benedet Andrea Lessa , Cohen Annie , Lopez Oscar L. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Souza Diogo O. , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A.
Published: December 2023

Background

Biomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.

Method

Cerebrospinal fluid (CSF) biomarkers were measured in participants of the McGill TRIAD cohort. 75 individuals (>50 years old, 44 cognitively unimpaired (CU), and 31 with cognitive impairment (CI)), had available Aβ and tau‐PET. We measured CSF GFAP and synaptic markers (growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptotagmin 1 (SYT1), presynaptic protein synaptosomal‐associated protein 25 (SNAP‐25)). Linear regressions adjusted for age, sex, clinical diagnosis, and Aβ/tau‐PET were used to test the associations between astrocyte reactivity and synaptic function.

Result

Demographic information is shown in Table 1. We found an association between CSF GFAP and presynaptic markers (GAP‐43: p<0.0001, β = 0.1076; SYT1: p<0.0001, β = 0.0024; SNAP‐25 long: p<0.0001, β = 0.0008) as well as postsynaptic markers (Ng: p<0.05, β = 0.0066) independently of Aβ and tau burden (Figure 1).

Conclusion

Our biomarker results support experimental literature suggesting that astrocyte reactivity plays a role in downstream synaptic dysfunction independent of the brain levels of Aβ and tau tangles pathologies. This supports in vitro literature suggesting that therapeutic interventions targeting astrocyte reactivity can contribute to halting AD progression.
Baseline Amyloid and Tau Deposition Predict Distinct Patterns of Longitudinal White Matter Degeneration: A Diffusion MRI Investigation
Authors: Blujus Jenna K , Oh Hwamee
Published: December 2023

Background

Neuritic plaques with fibrillar beta‐amyloid (Aβ) peptides and tau‐protein neurofibrillary tangles are hallmark features of Alzheimer’s disease (AD) pathology. While concomitant differences in white matter (WM) integrity were found in association with Aβ deposition or tau pathology, a unique effect of each pathology on WM integrity remains unknown. In this study, we examined the unique effects of AD pathologies on WM integrity both cross‐sectionally and longitudinally.

Method

A total of 334 participants (188 cognitively normal (CN), 114 mild cognitive impairment, and 32 AD) was selected from the ADNI database, based on the availability of two timepoints of diffusion MRI (dMRI) data, and baseline amyloid and tau PET data. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA) and annualized FA change maps were created to measure voxel‐wise WM change over time. Baseline global amyloid SUVR values were converted to a centiloid scale. Baseline tau SUVRs were evaluated by Braak staging (I‐entorhinal, II‐hippocampal, III/IV‐limbic, V/VI‐neocortex). The associations between AD pathologies and cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age and sex.

Result

Cross‐sectionally, baseline tau burden in Braak stages I, III/IV, and V/VI related to lower WM integrity, independent of Aβ, while there was no association between baseline Aβ and WM integrity, independent of tau. Longitudinally, limbic and neocortical tau at baseline uniquely predicted WM integrity loss across widespread regions, including left superior longitudinal fasciculus and the body and splenium of corpus callosum. Moreover, baseline Aβ burden significantly related to WM integrity loss across widespread regions, only when entorhinal and hippocampal tau was controlled for. Similar, but weaker, patterns of the associations between baseline AD pathology and longitudinal WM integrity loss were also found only within CN group.

Conclusion

These findings suggest distinctive associations between AD pathology and WM degeneration such that Aß exerts widespread deleterious effects on WM integrity primarily early in AD pathophysiology, whereas, once spreading to the neocortex, tau burden drives WM neurodegeneration. The distinctive downstream pathways associated with each AD pathology may underlie differential cognitive profiles across the disease stages.
Developing a brief, accurate and adaptive version of the Boston Naming Test based on high‐fidelity estimates of item properties
Authors: Giauque Thomas A. , Shaughnessy Lynn , Lin George , Smith Maurice , Press Daniel Z.
Published: December 2023

Background

Current naming tests such as the Boston Naming Test (BNT) and the Multilingual Naming Test have demonstrated significant clinical utility in detecting naming deficits in mild cognitive impairment (MCI), assisting with differential diagnosis among neurodegenerative disorders, and measuring disease progression in AD. However, the tests are time‐consuming due to their large number of items, and pen‐and‐paper administration. A computerized, adaptive naming test could increase the accuracy and speed of assessment, enhance usability, and minimize cross‐cultural testing disparities.

Method

Current naming tests that produce accurate results over a range of naming abilities are lengthy, because they must both include items that densely cover the large range of potential abilities. In contrast, an adaptive test can be more efficient, by quickly zeroing in on a narrow range and then concentrating test questions only in the vicinity of the participant’s underlying ability. This maximizes efficiency in terms of information obtained per item, by tailoring the test to avoid items that would, based on previous responses, be either too easy or too difficult for the current participant.

Result

We show via a series of probabilistic simulations that the precision of item property estimates would limit effectiveness of adaptive strategies previously attempted (Fergadiotis et al., 2015). In fact, we find that the mismatch between the true properties of items and existing estimates, due to the broad confidence regions of these estimates (Embretson & Reise, 2000) considerably reduces achievable accuracy. We are therefore in the process of delineating item properties with considerably higher fidelity than those currently available in order to achieve the efficiency improvement that adaptive testing can in principle deliver, analyzing the results of individual item responses from over a 1000 BNT administrations from participants distributed across a range of ability levels. We will test the ability of adaptively‐chosen 12‐item subsets of the BNT to estimate the full scores from our clinics via simulation and implement a new ipad‐based adaptive tool, prospectively testing its accuracy in predicting the BNT score and its ability to identify MCI and AD.

Conclusion

The development of a computerized, adaptive, naming test may allow considerable time savings while maintaining accuracy.
Hi‐C analysis in frontal cortex using local ancestry identifies ancestry‐specific chromatin 3D interactions
Authors: Wang Liyong , Xu Wanying , Liu Xiaoxiao , Rajabli Farid , Celis Katrina , Lu Leina , Gearing Marla , Bennett David A. A , Flanagan Margaret E , Weintraub Sandra , Geula Changiz , Schuck Theresa , Scott William K. , Dykxhoorn Derek M. , Griswold Anthony J. , Pericak‐Vance Margaret A. , Young Juan I. , Jin Fulai , Vance Jeffery M.
Published: December 2023

Background

Genetic risk for Alzheimer Disease (AD) varies across populations with different ancestry. Three‐dimensional (3D) genome architecture regulates gene transcription. Genome‐wide Hi‐C analyses have revealed dynamic 3D genome changes during development and disease progression. The variation of 3D genome architecture on different ancestral background, however, has not been extensively studied, especially at high‐resolution level. Recently, we developed the DeepLoop pipeline enabling robust high‐resolution analysis. We applied DeepLoop to characterize 3D genome architecture in frontal cortex from African American (AA) and European (EU) donors while considering local ancestry (LA) in admixed samples.

Methods

Hi‐C libraries were constructed and ∼500 million of paired‐end reads were obtained in 8 samples (4 AA and 4EU) that were sex‐matched and homozygous for APOEε4. We partitioned Hi‐C data into compartment A (open and transcriptionally active chromatin) and compartment B (compacted and transcriptionally silenced chromatin). In total, 6206 compartment bins across the genome were compared at a 500kb resolution. DeepLoop was used to call chromatin loop (often represents promoter‐enhancer interaction) at a 5kb‐resolution. LA was calculated using RFMix with SNP‐array data and a reference panel from 1000 Genomes for EU, African (AF) and Amerindian (AI) ancestry.

Results

Most of the A and B compartments were consistent among individuals with only <5% of them switched between AA and EU individuals. The EU samples have slightly (107 bins) more transcriptionally active bins than the AA samples. While many of homozygous LA blocks displayed same chromatin loop pattern between and within ancestries, we did observe ancestry‐specific loop as well as differences between individuals of the same ancestry. Importantly, the presence of heterozygous LA (African/EU) at some loci displayed a composite loop pattern that was present in the same region of homozygous LA of African or EU ancestry.

Conclusion

The 3D genome architecture can be variable between different ancestral backgrounds as well as between individuals of the same LA. We hypothesize that admixture of LA can create novel or demolish chromatin interactions observed in the homozygous LA. These data emphasize the importance of LA in identifying the causal loci contributing to AD in admixed population such as AF and Hispanic/Latino.
Combining plasma p‐tau231 and glial fibrillary acidic protein produces higher discriminative accuracy for amyloid positivity than other blood‐based biomarker combinations
Authors: Bolton Corey J , Khan Omair A. , Liu Dandan , Houston Michelle L , Pechman Kimberly R. , Gifford Katherine A. , Hohman Timothy J. , Blennow Kaj , Zetterberg Henrik , Jefferson Angela L.
Published: December 2023

Background

Plasma phosphorylated tau (p‐tau)231 is an emerging blood‐based biomarker that has shown great promise for early identification of individuals at risk of Alzheimer’s disease (AD). However, it is unclear if this biomarker is sufficient as a standalone test or if diagnostic classification improves when simultaneously considering other plasma biomarkers. We investigated various plasma biomarkers, individually and in combination, in relation to cerebrospinal fluid (CSF) amyloid positivity.

Method

Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 155, 72±6 years, 33% female) underwent fasting lumbar puncture and blood draw. CSF β‐amyloid42 (Aβ42) and β‐amyloid40 (Ab40) and plasma p‐tau231, glial fibrillary acidic protein (GFAP), Aβ42, Aβ40, and neurofilament light chain (NfL) were analyzed in batch. The Aβ42/40 ratio was used for all analyses and CSF amyloid positivity was defined as Aβ42/40 ratio <0.072. Logistic regression models related each biomarker to amyloid positivity, adjusting for age, sex, race/ethnicity, apolipoprotein E‐ε4 status, and cognitive status. Subsequent models included p‐tau231 as the predictor in a base model with other biomarkers being added individually and then in combination with other biomarkers to the base model. Models were compared using likelihood ratio test (LRTest) and Akaike Information Criterion (AIC) values.

Result

In single predictor models, p‐tau231 (C‐index = 0.87, p = 0.005) and GFAP (C‐index = 0.87, p = 0.01) were associated with amyloid positivity, while other biomarkers were not (p‐values>0.35). In models including p‐tau231 and various biomarker combinations, p‐tau231 remained significant in each model (p‐values<0.02). In comparison to the base model with p‐tau231 only, models adding GFAP (AIC = 143.8, LRTest p = 0.008), GFAP and NfL (AIC = 145.5, LRTest p = 0.02), and GFAP and Aβ42/40 (AIC = 145.8, LRTest p = 0.03) improved prediction of amyloid positivity. The model including plasma p‐tau231 and GFAP was the best fitting model (C‐index = 0.89).

Conclusion

In this sample of community‐dwelling older adults free of clinical dementia, we found plasma p‐tau231 and GFAP were associated with amyloid positivity. Models including both p‐tau231 and GFAP performed best, and adding additional plasma biomarkers to this combination did not produce a better fitting model. Taken together, these findings highlight the utility of plasma p‐tau231 for screening for amyloid status and suggest that including plasma GFAP will improve discriminative accuracy.
Elevated cerebrospinal fluid chitinase‐3 protein like‐1 (YKL‐40) is associated with decreased glucose metabolism in amyloid‐positive participants.
Authors: Page Frederick A , Crook Harry , Edison Paul
Published: December 2023

Background

The diverse role played by astrocytes in neurodegeneration remains elusive. Astrocytes elicit a substantial impact on the fluorodeoxyglucose (FDG)‐positron emission tomography (PET) signal, an imaging modality that is used as a surrogate marker for neuronal loss. The association between astrocyte activation and FDG‐PET uptake has been evaluated with astrocyte‐targeting PET. Measuring reactive astrocytosis with fluid biomarkers may be a simpler and affordable way of studying astrocytes and their association with FDG‐PET. The cerebrospinal fluid (CSF) biomarker chitinase‐3 protein like‐1 (YKL‐40), a marker of reactive astrocytosis is elevated in the CSF of AD patients, although its role is unclear. Here, we examined the relationship between CSF YKL‐40 and PET imaging markers across the AD continuum.

Method

421 participants, including 89 patients with AD, 234 patients with mild cognitive impairment (MCI), and 98 cognitively normal control (CN) participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database based on the availability of coinciding amyloid (Aβ)‐PET, FDG‐PET and structural magnetic resonance imaging (MRI), and CSF YKL‐40. The relationships between CSF YKL‐40 and PET imaging markers were explored using both a region of interest (ROI) and a voxel‐wise approach.

Result

AD patients demonstrated elevated CSF YKL‐40 compared to CN (p<0.001) and MCI (p<0.001) participants. CSF YKL‐40 was also significantly elevated in Aβ positive participants (p<0.001). ROI analysis revealed negative associations between CSF YKL‐40 and FDG‐PET uptake throughout the cortex in Aβ positive participants but limited to the cingulate cortex in Aβ negative participants. At a voxel‐level, Aβ‐PET uptake was positively associated with CSF YKL‐40 in Aβ positive participants. Meanwhile, a negative association was observed between CSF YKL‐40 and FDG‐PET across the brain in Aβ positive participants, a relationship lost in Aβ negative participants.

Conclusion

CSF YKL‐40 levels likely become elevated as AD progresses due to gradual amyloid deposition. Contrary to previous findings, reactive astrocytosis, as measured here with CSF YKL‐40, was associated with a reduction in glucose metabolism in amyloid positive participants, possibly due to the damaged caused to neurons by the AD pathology.
Passive non‐wearable technology for real‐time detection of COVID‐19 infection in people living with dementia
Authors: Kolanko Magdalena A. , Soreq Eyal , Lai Helen , Purnell Matthew , Walsh Chloe , Whitethread Nicole , Sharp David J
Published: December 2023

Background

People with dementia (PLWD) are disproportionately affected by COVID‐19, as they are at a greater risk of becoming infected (1), and have an increased risk of disease‐related morbidity and mortality (2,3). The clinical presentation of COVID‐19 in PLWD is often asymptomatic or atypical, reducing early recognition of symptoms and timely treatment (4). Continuous monitoring of physiological parameters such as heart rate and respiratory rate using digital health technologies holds promise for early disease detection. Recent studies demonstrated that consumer wearable devices such as smartwatches can identify COVID‐19 by capturing subtle intra‐individual changes in physiological parameters (5‐11). However, the use of wearable devices in PLWD is significantly limited due to the lack of acceptance and poor compliance (11‐14). Here we present the first non‐contact monitoring technology using an under‐mattress pressure‐sensor mat to detect and predict COVID‐19 infection in PLWD.

Method

We used contactless Withings Sleep Analyser (WSA) to continuously monitor the night‐time physiology of 120 PLWD enrolled in the CR&T MINDER cohort study. A total of 38 positive COVID‐19 cases were reported since late 2021. Based on the minute‐to‐minute time series extracted from the WSA, average nocturnal heart and respiratory rates were calculated. We examined whether physiological deviations from a person’s baseline were detected in retrospect around the time of the reported illness.

Result

Out of the 38 individuals who tested positive for COVID‐19 during the study (Fig.1), 25 had sleep data available around the time of their positive test. Of these 25 cases, 24 (96%) had abnormally high respiratory rate (Fig.2a), and 22 also had abnormally high heart rates (Fig.2b) within the 2‐week period preceding the COVID‐19 diagnosis. Our anomaly detection algorithm, which flags deviations in heart and respiratory rates above a certain threshold, correctly identified all 24 cases of abnormal physiology associated with COVID‐19 infection.

Conclusion

Passive monitoring of night‐time physiology using non‐invasive and non‐wearable technology allows early identification of changes in an individual’s baseline physiology, which can be used for real‐time detection of respiratory infections, including COVID‐19 in vulnerable groups of patients. Such technology could help healthcare providers to proactively identify and treat infections early, potentially improving patient outcomes.
Cognitive Reserve and Age‐Related Decline in Cognitive and Gait Domains: Results from the LonGenity Study
Authors: Blumen Helena M , Jayakody Shanika Oshadi , Emmeline Ayers , Barzilai Nir , Milman Sofiya , Weiss Erica , Verghese Joe
Published: December 2023

Background

Individuals with high cognitive reserve (CR) can adapt to dementia‐related brain changes and delay the onset of cognitive impairment and dementia. High CR is accumulated from frequent participation in cognitive, physical, and social activities. Whether high CR protects against age‐related cognitive and gait decline, however, is not well‐understood. We have shown that high CR is associated with a slower rate of age‐related cognitive decline, but not gait speed decline. Here, we examined associations between cognitive, physical, and social CR proxies and age‐related decline in different cognitive (processing speed, memory, and executive function) and gait (pace, rhythm, and variability) domains.

Method

Up to 12 years of cognitive and gait data from 1,079 older (75.4±6.7 years; 56.0% women) LonGenity study participants were examined. Three cognitive domains – processing speed (trails A, digit‐symbol substitution), memory (free recall, logical memory) executive function (trails B‐A, digit span) – and three gait domains – pace (gait speed, step length), rhythm (step time, swing time) and variability (step‐time variability, step‐length variability) – were derived with principal components analyses. Cognitive (years of education), physical (blocks walked daily; weekly physical activity), and social (working/volunteering, living with someone) CR proxies were obtained from self‐report at baseline. Linear mixed‐effects models were adjusted for sex, parental longevity, baseline cognitive impairment, and comorbidities.

Result

Higher CR when assessed with any CR proxy (except weekly physical activity) slowed the rate of decline in processing speed. Higher weekly physical activity and more years of education slowed the rate of decline in executive function. Higher number of blocks walked daily slowed the rate of decline in memory. No CR proxies were associated with pace and variability gait domains. Higher social CR when assessed with working/volunteering, however, slowed the rate of increases (worsening) in rhythm.

Conclusion

These findings suggest that CR is associated with age‐related decline in several cognitive domains (processing speed, memory, and executive function) and select gait domains (rhythm) – yet the protective effects of cognitive, physical, and social CR on cognitive and gait domain decline are not uniform. Future research is needed to confirm these initial observations and develop interventions for domain‐specific decline in cognition and gait.
Differentiation of frontotemporal dementia subtypes using neuroimaging‐based multi‐type parallel feature embedding
Authors: Ma Da , Stocks Jane K , Lockhart Samuel N. , Craft Suzanne , Rosen Howard J. , Gurcan Metin Nafi , Popuri Karteek , Beg Mirza Faisal , Wang Lei
Published: December 2023

Background

Frontotemporal dementia (FTD) represents a collection of neurocognitive syndromes with frontotemporal lobar degeneration (FTLD) neuropathology, and is associated with significant clinical, pathological, and genetic heterogeneity. We trained a deep neural network (DNN) classifier to differentiate behavioral‐variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and non‐fluent variant (nfvPPA) patients using MRI scans drawn from two multi‐site neuroimaging consortiums.

Methods

BvFTD (N = 173), nfvPPA (N = 63), and svPPA (N = 41) patients with T1‐MRI were extracted from the FTLD Neuroimaging Initiative (FTLDNI) and the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) databases. MRI data were preprocessed with FreeSurfer, with cortical thickness, cortical volume, and subcortical volumes extracted. Cortical measures were parcellated into 360 patches (i.e., ROIs) according to the HCP‐MMP1 atlas. Both the patch‐based cortical thickness and volume features were harmonized to control confounding effects of sex, age, total intracranial volume (TIV), cohort, and scanner. Multi‐type features were parallelly fed into a multi‐layer‐perceptron (MLP)‐based classifier. Weighted cross‐entropy loss function was used to account for unbalanced sample sizes across FTD subtypes. 10‐fold nested cross‐validation was used to evaluate the robustness of the classification model, with data split into 80/10/10 of training/validation/test data sets.

Results

Visual evaluation z‐scores of cortical features among FTLDNI and ALLFTD groups revealed site‐specific differences significantly reduced by feature harmonization, especially for volume (Figure 1). The balanced accuracy of the ensembled DNN classifier of each FTD subtype on test sets across all ten folds reached 0.76 ± 0.09 for bvFTD, 0.79 ± 0.07 for nfvPPA, and 0.88 ± 0.07 for svPPA (Figure 2). Figure 3 shows confusion matrices for classification performance in the test set across ten cross‐validation folds.

Conclusion

We developed a deep‐learning‐based framework to classify three FTD subtypes: bvFTD, nfvPPA, and svPPA. The combination of feature harmonization and parallel multi‐type feature embedding framework showed promising differentiation power. This work can be used to recognize at‐risk populations for early and precise diagnosis, to aid intervention planning. Future studies will compare classification based on different input features and use visualization methods to identify the most discriminative regions and explore their clinical relevance.
A modified Mediterranean‐ketogenic diet favorably modulates the metabolic profiles of mild cognitively impaired individuals
Authors: Batra Richa , Huynh Kevin , Schweickart Annalise , Neth Bryan J. , Arnold Matthias , Kastenmuller Gabi , Meikle Peter J , Craft Suzanne , Krumsiek Jan , Kaddurah‐Daouk Rima F.
Published: December 2023

Background

Impaired glucose utilization is central to the pathogenesis of Alzheimer’s disease. In a hypometabolic state, the brain depends on alternative sources of energy, including amino acids, fatty acids, and ketone bodies (KBs). As KBs can cross the blood‐brain barrier, it is considered that a ketogenic diet could augment the high energetic demand of the central nervous system (CNS). A ketogenic diet is already a part of clinical care in epilepsy a CNS disorder. However, the holistic benefits of this diet for Alzheimer’s remain to be determined.

Methods

A randomized crossover pilot trial was conducted where participants consumed either the Modified Mediterranean‐Ketogenic Diet (MMKD) or the American Heart Association Diet (AHAD) for 6 weeks, followed by a 6‐week washout, after which the respective other diet was consumed for 6 weeks. The cohort included both mild cognitively impaired (MCI) and cognitively normal (CN) individuals. Serum and cerebrospinal fluid (CSF) samples of these individuals were profiled using two metabolic platforms: MS‐based and NMR‐based metabolomics. Diet‐related changes in levels of metabolites were determined using linear‐mixed effect models with age and sex as confounders.

Results

We identified post‐diet changes in the two diet groups (AHAD and MMKD), two cognitive groups (MCI and CN), and two fluids (serum and CSF). AHAD was associated with a decrease in serum levels of only a single metabolite, glutamine. MMKD led to widespread lipidomic and metabolic changes in the serum of mild cognitively impaired individuals. Remarkably, MMKD was associated with the reversal of AD‐related metabolic alterations identified in large cohorts like ADNI, AIBL, ROS/MAP, and signature for incident dementia in large epidemiological studies. The post‐MMKD changes include correcting metabolic dysregulation in branched‐chain amino acids, triglycerides, and plasmalogens a class of lipids implicated in membrane structure and function. Peripheral‐central metabolic correlations will be shared.

Conclusion

Our findings highlight the potential of dietary interventions, specifically the MMKD, in improving the cognitive and metabolic state of individuals with MCI. Further investigation is needed to capture the entirety of MMKD‐related modulation in metabolic profiles and the resulting benefit for AD.
A novel role for APP in neural circuit function
Authors: Harris Samuel S , Rajani Rikesh , Zuenkler Jana , Ellingford Robert , Yang Mengke , Lee Byung Il , Hyman Bradley T. , Müller Ulrike , Busche Marc Aurel
Published: December 2023

Background

Despite the importance of the amyloid‐precursor protein (APP) to Alzheimer’s Disease pathophysiology and therapy, and notable pan‐cellular and synaptic abundance, the physiological function of APP and its homologues remains to be fully elucidated in‐vivo. Here, we interrogated how the APP family regulates neuronal cell function and long‐range neural circuit dynamics in the intact brain.

Method

APPflox/flox/APLP2flox /flox/APLP1−/− mice were crossed with NexCre mice expressing Cre prenatally from ∼E12.5 in postmitotic neuronal precursor cells of the cortex and hippocampus, producing a conditional triple knockout model (cTKO) of the APP family in excitatory forebrain neurons that is associated with pronounced behavioral deficits (Steubler et al., 2021, EMBO Journal). Neuronal function at the single cell/unit and circuit‐level was characterised using in‐vivo two‐photon and mesoscopic calcium imaging, and bilateral Neuropixels recordings in awake and anesthetised mice.

Result

cTKO mice exhibited pronounced suppression in spike timing variability and dynamic excitability in visual cortex and hippocampus CA1 relative to controls, with a marked inter‐hemispheric decoherence of oscillatory activity (including low‐frequency and sleep‐associated slow waves) and dysfunctional intrahemispheric propagation of neuronal activity. Further, cTKO mice also displayed behavioural abnormalities in open field tests relative to controls which was linked to functional deficits. High‐resolution synaptic imaging revealed a significant reduction in the number of synapses containing the NMDA receptor subunit GluN1 in cTKO mice versus controls, with partial NMDA receptor agonism (d‐cycloserine, 30mg/kg, i.p.) ameliorating cellular and circuit‐level impairments as well as behavioral impairments.

Conclusion

These findings provide novel in‐vivo evidence for an essential role of APP in regulating synaptic function via an effect on NMDA receptors, that elucidate the physiological role of this preeminent protein family and have important implications for disease and therapy.
Socioeconomic variation in modifiable risk factors for dementia
Authors: Bothongo Phazha LK , Waters Sheena , Chandra Avinash , Uchegbu Ijeoma , Jeraldo Rosario Isabel Espinoza , Anjum Rifah , Byford Michelle , Livingston Gill , Mukadam Naheed , Marshall Charles R
Published: December 2023

Background

Most studies on modifiable risk factors for dementia are in relatively affluent populations, but dementia risk is higher among those who are more materially deprived. We aimed to consider whether this is accounted for by potentially modifiable risk factors, and compare the overall population attributable fraction (PAF) in the least and most socioeconomically deprived participants within the UK Biobank (UKB).

Method

The UKB is a cohort study with 502,656 volunteer participants registered between 2006‐2010, aged 40‐60 years at baseline, and followed for up to 16.8 years. Material deprivation was quantified using the Townsend Deprivation Index grouped into quintiles, with higher scores meaning higher deprivation. We assessed interactions between Townsend quintiles (using least deprived as reference), and each modifiable risk factor. To estimate the PAFs of 12 modifiable risk factors (diabetes, hypertension, depression, hearing loss, obesity, traumatic brain injury, less education, social isolation, physical inactivity, air pollution, and smoking), we first estimated hazard ratios (HRs) (adjusted for age, gender, and ethnicity) stratified by Townsend. HRs were then converted to relative risk for PAF calculation.

Results

6,624 incident cases of dementia developed in 1.6%(95%CI = 1.5‐1.7)(n = 11679/10369) of participants in the most deprived group, compared to 1.2%(95%CI = 1.1‐1.3)(n = 1174/98074) in the least deprived group. The mean age at dementia diagnosis were 72.7 years(SD,6.3){in most deprived}, and 73.8 years(SD,5.1){in least deprived}. The combined PAF(95%CI) for dementia was 40.3%(40.0‐40.6){most deprived}, versus 27.2%(27.0‐27.5){least deprived}. The most deprived, compared to the least deprived, had higher PAFs for: (a)Midlife hypertension: 7.7%(7.6‐7.9) vs 4.1%(3.9‐4.2); (b)Less education: 5.8%(5.6‐5.9) vs 3.4%(3.2‐3.6); (c)Diabetes: 4.4%(4.3‐4.6) vs 3.1%(3.0‐3.2); (d)Physical inactivity: 3.5%(3.4‐3.6) vs 0.7%(0.6‐0.7);) (e)Social isolation: 3.4%(3.3‐3.5) vs 1.0%(1.0‐1.1); (f)Midlife obesity: 2.1%(2.0‐2.2) vs 1.2%(1.2‐1.3); and (g)Smoking 1.8%(1.7‐1.9) vs 0.5%(0.5‐0.6). Air pollution had a PAF of 1.8%(1.7‐1.9) in the least deprived, and 0.0% in the most deprived. The remaining risk factor PAFs did not differ between the most and least deprived.

Conclusions

In this volunteer cohort, which is relatively wealthy, a higher proportion of dementia cases were attributable to major modifiable risk factors in more socioeconomically disadvantaged participants. Targeted interventions particularly addressing midlife hypertension, education, physical activity and social isolation might mitigate known inequalities in dementia risk according to socioeconomic status.
CSF total tau is more closely associated with synaptic dysfunction than overt neurodegeneration
Authors: Soares Carolina , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Aguzzoli Cristiano Schaffer , Ferrari‐Souza João Pedro , Zalzale Hussein , Lussier Firoza Z , Rohden Francieli , Abbas Sarah , Lemaire Peter Charles , Leffa Douglas Teixeira , Cabrera Arlec , Therriault Joseph , Benedet Andrea Lessa , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Vermeiren Marie , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Cohen Annie , Lopez Oscar L. , Tudorascu Dana , Klunk William E , Villemagne Victor L , Soucy Jean‐Paul , Gauthier Serge , Souza Diogo O. , Karikari Thomas K , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Zimmer Eduardo R , Pascoal Tharick A.
Published: December 2023

Background

CSF total tau (t‐tau) is postulated as a marker of neuronal degeneration in the ATN criteria. Here, we hypothesize that CSF t‐tau is more closely related to synaptic loss than over neurodegeneration.

Method

We evaluated 128 older individuals (75 CU,33 MCI,20 AD) in the TRIAD cohort (McGill, Canada) with CSF t‐tau, SNAP25long and Neurofilament Light (NfL), Amyloid‐beta (Aβ) positron emission tomography and magnetic resonance imaging, and clinical assessments. We used increased SNAP25long as an index of synaptic dysfunction (S+) and reduced hippocampal volume as neurodegeneration (N+). S and N positivity were determined using a cutoff anchored in young CU individuals. Linear regression models were used to test the association between CSF t‐tau, SNAP25long and NfL levels and hippocampal volume, adjusted for age, sex, and cognitive status. ANCOVA was employed to inspect CSF t‐tau levels across the groups 1) S‐N‐; 2) S+N‐; 3) S‐N+; 4) S+N+, adjusted for age, sex, cognitive status, and Aβ burden.

Result

We found that a model with the addition of SNAP25long to the covariates explained 65% of the variance (p‐value<0.0001) of CSF t‐tau. Alternatively, hippocampal volume (R2 = 0.2187; p‐value<0.0001) and NfL (R2 = 0.3671; p‐value<0.0001) alone or in combination explained less than 40% of the variance of CSF t‐tau (R2 = 0.3597; p‐value<0.0001) (Figure 1). Interestingly, we observed an increase of CSF t‐tau in the S+N‐ group but not in the S‐N+, further supporting that CSF t‐tau is abnormal in the presence of synaptic dysfunction rather than neurodegeneration. Additionally, Loess regression lines confirm a larger magnitude of change of synaptic dysfunction as a function of t‐tau, compared with neurodegeneration (Figure 3).

Conclusion

Our results suggest that CSF t‐tau may reflect synaptic loss rather than neuronal degeneration. This has implications for the interpretability of results obtained with CSF t‐tau in biomarker studies.