bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarker evidence of neurodegeneration in chronic kidney disease, in a general population
Authors: Dittrich Anna , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Zettergren Anna , Simrén Joel , Shams Sara , Machado Alejandra , Westman Eric , Schöll Michael , Skoog Ingmar , Kern Silke
Published: June 2023

Background

Progressive decline in cognition and renal function are both related to ageing. The estimated global prevalence of dementia was 55 million people in 2019, a number expected to increase to 139 million by 2050. Furthermore, chronic kidney disease (CKD) is the second fastest growing cause of death globally. Few studies have examined the link between these conditions. In this study, we examine CKD and estimated glomerular filtration rate (eGFR) in relation to plasma neurofilament light protein (P‐NfL) and volumetric magnetic resonance imaging (MRI) measures of Alzheimer’s disease‐specific and general neurodegeneration.

Method

Using a cross‐sectional design, 744 participants from the Gothenburg H70 Birth cohort 1944 study, conducted in 2014‐2016, underwent MRI examination and blood draws. Plasma NfL concentration was measured using a Single molecule array (Simoa) assay. eGFR was calculated from creatinine and used for CKD diagnosis. CKD was defined as an estimated glomerular filtration rate below 60 mL/min/1.73 m2. Measurements of biomarker evidence of neurodegeneration were compared between participants with and without CKD. Correlations were also performed against eGFR. A logistic regression model adjusting for known risk factors for CKD was performed.

Result

P‐NfL was significantly higher in participants with CKD (p<0.001). No difference was seen in any MRI variables. Only P‐NfL correlated with eGFR (R = ‐0.25, p<0.001), and there was a significant correlation both in participants with and without CKD (R = ‐0.44, p<0.001 and R = ‐0.18, p<0.001 respectively). Furthermore, in a logistic regression model, P‐NfL was a significant predictor of CKD independent of known risk factors including age, sex, education, smoking, hypertension, diabetes, BMI, fasting glucose, LDL‐cholesterol, CRP, and homocysteine (OR (CI); 3.231 (1.743: 5.990), p<0.001).

Conclusion

Our observations suggest that neurodegeneration measured as P‐NfL is a predictor of CKD, independent of hypertension and diabetes. The origin of NfL, and the potential influence on the utilization of P‐NfL as a marker of neurodegeneration in individuals with CKD, should be assessed in future studies.
Unknown treatment effects of donepezil in Alzheimer’s disease: Network analysis of three double‐blind randomized, placebo‐controlled, clinical trials
Authors: Rotstein Anat , Levine Stephen Z , Samara Myrto , Yoshida Kazafumi , Goldberg Yair , Cipriani Andrea , Iwatsubo Takeshi , Leucht Stefan , Furawaka Toshiaki A
Published: June 2023

Background

Psychometric network analysis is an alternative theoretically‐driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer’s disease differently than was previously assumed and consequently detect unknown treatment effects.

Method

Based on individual participant data, extracted from three double‐blind, randomized placebo‐controlled clinical trials, psychometric networks were computed on observed Alzheimer’s Disease Assessment Scale Cognitive Subscale scores at baseline (N = 1,554) and on predicted change scores at 24 weeks of follow‐up for participants who received donepezil (N = 797) or placebo (N = 484).

Result

A novel conceptualization of cognitive impairment in Alzheimer’s disease was displayed through the baseline network, that had 90% (n = 27) positive statistically significant (p<0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change networks. The donepezil change network had more statistically significant (p<0.05) positive associations and a higher global strength (n = 15; S = 1.22; p = 0.03), than the placebo network (n = 8; S = 0.57), suggesting that for those who were treated with donepezil cognition is a more unified construct. Less for those given placebo. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network, suggesting that comprehension of spoken language is most sensitive to pharmaceutical interventions.

Conclusion

Overall, psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer’s disease, points to previously unknown treatment effects and highlights well‐defined aspects that may translate into future treatment targets.
Determining whether sex and zygosity modulates the association between ApoE4 and psychosis in a neuropathologically‐confirmed Alzheimer’s disease cohort
Authors: Fischer Corinne E. , Valcic Mila , Kim Julia , Fornazzari Luis R , Churchill Nathan W , Schweizer Tom A. , Munoz David G.
Published: June 2023

Background

Individuals with the APOE ε4 allele (ApoE4) have an increased risk of developing Alzheimer’s disease (AD) compared to individuals with the more common ε2 or ε3 alleles. Previous work by our group found that female ApoE4 homozygotes with Lewy body (LB) pathology were more likely to experience psychosis compared to female ApoE4 non‐carriers, whereas in males there was no dose‐dependent difference (Kim et al., 2017). The objective of this study was to refine our previous findings by adjusting for covariates (age, education, MMSE scores).

Method

The patient cohort was obtained from the National Alzheimer’s Coordinating Center (NACC). Demographics, APOE genotype, LB pathology, and Neuropsychiatric Inventory (NPI) data was gathered in individuals with neuropathologically‐confirmed AD (n = 1,241). Patients were considered psychotic if they scored positively for delusions and/or hallucinations on the NPI. Two cohorts were extracted, those with LB pathology (LB(+)) and those without (LB(‐)). Within each cohort, patients were classified as E4(‐), E4, or E44 based on the number of APOE ε4 alleles they carried (0, 1, 2, respectively), and stratified by sex. Binary logistic regression was used to predict the relationship between ApoE4 status and sex on presence of psychosis.

Result

In the LB(+) group, female ApoE4 homozygotes were significantly more likely to experience psychosis compared to female ApoE4 non‐carriers (p = .003). The significant effect remained after adjusting for covariates (p = .027). There was no significant association between ApoE4 and presence of psychosis in males. In the LB(‐) group, there was no significant association between ApoE4 and presence of psychosis in either sex. There was no significant effect in female nor male ApoE4 heterozygotes, with or without LB pathology.

Conclusion

Sex and zygosity modulate the effect of ApoE4 on psychosis in a cohort of neuropathologically‐confirmed AD patients, specifically, that the effect of having 2 ApoE4 alleles on presence of psychosis is limited to female ApoE4 homozygotes with LB pathology. These findings reveal a cohort of AD patients that appear to be particularly vulnerable to developing psychosis.

References: Kim, J., Fischer, C.E., Schweizer, T.A., & Munoz, D.G. (2017). Gender and pathology‐specific effect of Apolipoprotein E genotype on psychosis in Alzheimer’s disease. Current Alzheimer Research, 14(8), 834‐840.
Longitudinal trajectories of dietary quality and cognitive functions in Chinese older adults: The Taiwan Initiative for Geriatric Epidemiological Research (TIGER) cohort study
Authors: Chen Ling‐Wei , Chen Jen‐Hau , Chiou Jeng‐Min , Chen Ta‐Fu , Chen Yen‐Ching
Published: June 2023

Background

Dietary factors influence cognitive functions, but most previous studies were conducted in Western settings and assessed diet only once. Trajectory analysis of diet measured at multiple timepoints can track changes in diet and identify subpopulations requiring more intervention efforts. We thus assessed associations between dietary trajectories and cognitive functions in an understudied Asian elderly population.

Method

The TIGER study involves non‐demented community‐dwelling participants aged ≥65 years recruited between 2011‐2013. Dietary intakes were assessed using a food frequency questionnaire during baseline and 4th‐ and 6th‐year follow‐ups. Modified Alternative Healthy Eating Index (mAHEI) scores (energy‐adjusted using the residual method) were generated at each timepoint to reflect diet quality. Longitudinal trajectories of dietary quality were derived using latent growth mixture modelling. The Montreal Cognitive Assessment—Taiwanese version was used to assess global cognition for outcomes. Cognitive functions (baseline‐normalized z‐scores) of four cognitive domains, i.e., memory, attention, executive function, and verbal fluency, were also assessed. Associations between trajectories of dietary quality and cognitive functions were assessed using linear regressions, adjusting for important covariates including sex, apolipoprotein (APOE) e4 status, baseline age, body mass index (BMI), and depressive symptoms.

Result

Included participants (n = 356) were 54.2% female, had a mean age of 71.6 years, and a mean BMI of 23.8 kg/m2 at baseline. The overall mean mAHEI scores were close to 37 (out of 70 possible) at all three time points. Three trajectories of dietary quality, namely 1) ‘increasing’, 2) ‘decreasing’, and 3) ‘stable‐high’ were identified and deemed optimal considering fit indices and interpretability. Compared with ‘stable‐high’ dietary quality trajectory, the ‘increasing’ trajectory was associated with worse memory performance (adjusted‐β = ‐0.424; 95% CI: ‐0.679, ‐0.169; P = 0.001) whereas the ‘decreasing’ trajectory was associated with worse performance for the verbal fluency domain (adjusted‐β = ‐0.342; 95% CI: ‐0.653, ‐0.030; P = 0.031). No other significant associations were observed.

Conclusion

Maintaining a stable‐high dietary quality trajectory over time is associated with better cognitive functions among Taiwanese older adults. Since there is much room for dietary improvement in this Taiwanese population, interventions to promote and sustain better dietary quality over time can have substantial impacts on their cognitive functions.
Association between olfactory function and cognitive impairment in dementia‐free older adults in Taiwan: A longitudinal cohort study
Authors: Wang Mu‐Cyun , Chen Yen‐Ching , Chiou Jeng‐Min , Chen Ta‐Fu , Chen Jen‐Hau
Published: June 2023

Background

The olfactory impairment could be one of the earliest signs of cognitive impairment. However, limited studies have evaluated olfactory function and cognitive domains in Asian older adults. This study aimed to relate olfaction with global and domain‐specific cognition in Taiwan’s community‐dwelling, non‐demented older adults.

Method

This cohort study is part of the Taiwan Initiative for Geriatric Epidemiological Research, including 310 non‐demented older adults between 2015‐2019 with two repeated measures on cognitive function. Global and domain‐specific (memory, executive function, attention, and language) cognition were assessed by the Taiwanese version of Montreal Cognitive Assessment (MoCA‐T) and a battery of neuropsychological tests, respectively. The Sniffin' Sticks‐Odor Identification Test (SS‐OIT) was utilized to identify impaired olfaction. The generalized linear mixed model was used to examine the association of SS‐OIT with cognitive function over time, after adjustment for age, sex, years of education, apolipoprotein E ε4 status, presence of depression, sleep quality, chronic respiratory diseases, smoking, practice effect and follow‐up time. Subgroup analyses were also conducted.

Result

Better olfactory identification ability (i.e., increased SS‐OIT score) was associated with better performance of global cognition (MoCA‐T: β = 0.14, 95% confidence interval = 0.05‐0.24), memory (logical memory ‐ immediate and delayed theme and free recall: β = 0.06 to 0.09), executive function (trail making test‐A: β = 0.05 for baseline, ‐0.03 for interaction with follow‐up years), and verbal fluency (β = 0.08). Anosmia (SS‐OIT score ≦8) was associated with impaired memory [the lowest tertile (T1) vs. higher tertiles (T2+T3), adjusted odds ratio (aOR): 2.40 to 3.06], and verbal fluency (T1 vs. T2+T3, aOR = 2.39). After stratified analyses, the associations above remained significant in apolipoprotein E ε4 non‐carriers (MoCA‐T: β = 0.19; memory: β = 0.08 to 0.11; verbal fluency: β = 0.08), older adults without respiratory diseases (MoCA‐T: β = 0.14; memory: β = 0.06 to 0.10; verbal fluency: β = 0.10), and older adults without depression (MoCA‐T: β = 0.14; memory: β = 0.06 to 0.09; trail making test‐A: β = 0.04 for baseline, ‐0.02 for interaction with follow‐up years; verbal fluency: β = 0.09).

Conclusion

Impaired olfactory identification is associated with poor global or domain‐specific cognition in non‐demented older adults. Further research is required to validate our findings and clarify the underlying mechanism between anosmia and cognitive impairment.
Patterns of disruption of white matter integrity in mild cognitive impairment and Alzheimer’s disease with and without vascular comorbidities
Authors: Konwar Srijan
Published: June 2023

Background

Alzheimer’s disease (AD) has been primarily been considered a grey matter disease. Recent studies, however, indicate the presence of white matter abnormalities in AD. This study’s aim was to investigate the patterns of white matter disruption in people with mild cognitive impairment (MCI) and AD dementia with vascular comorbidities (obesity, diabetes and hypertension).

Method

Diffusion Tensor Imaging (DTI) was used to appraise white matter integrity using diffusion indices such as axial diffusivity (AxD) and mean diffusivity (MD). Participants were stratified according to presence or absence of vascular comorbidities and group status (controls n = 13, MCI n = 13 and AD n = 13). The vascular comorbidities were binarized into High Risk (either one or more vascular risks) or Low Risk (no vascular risks). Each pathological group was compared to Low‐Risk controls who served as the reference sample. Both groups were matched by age. For each of the group comparisons, there were 13 participants for each condition with the exception of the Low‐Risk AD group comparison where there were only 7 participants for both conditions. Between group differences in diffusion indices were measured using voxel‐wise whole brain approach using tract based spatial statistics (TBSS). A non‐parametric unpaired T‐Test was conducted between each group and the reference sample while controlling for location (site of recruitment), total intracranial volume and years of education.

Result

The results indicate that vascular comorbidity primarily affects the right projection fibres, forceps major, posterior areas of the corpus callosum such as the splenium as well as right fornix/stria terminalis. In the absence of comorbidities, in MCI and AD white matter is compromised in commissural fibres such as genu and body of the corpus callosum along with forceps minor.

Conclusion

These results suggest that microstructural differences are more visible than macrostructural changes in AD. The results suggests that late myelinating fibres are more prone to damage to both neurodegeneration and vascular risks. In addition, the splenium of the corpus callosum is affected at a more severe stage in AD but is also affected by the presence of vascular risks.
White matter hyperintensities in strategic tracts for cognitive impairment: A multicenter lesion‐symptom mapping study in 3525 memory clinic patients
Authors: Coenen Mirthe , Biesbroek J. Matthijs ,   Meta VCI Map consortium
Published: June 2023

Background

White matter hyperintensities (WMH) due to small vessel disease (SVD) are associated with dementia risk. Previous studies suggest that the cognitive impact of WMH depends on location. However, these studies were potentially limited by moderate brain lesion coverage. We aimed to identify strategic WMH locations for cognitive impairment in memory clinic patients by performing a large‐scaled multicenter study providing unprecedented lesion coverage.

Method

Individual patient neuropsychological and MRI data from eleven memory clinic cohorts were harmonized. Voxel based lesion symptom mapping‐ (VLSM) and region of interest (ROI) based analyses were performed to identify strategic WMH locations for four cognitive domains (attention and executive functioning, information processing speed, verbal memory, and language). A strategic WMH score was calculated based on quartiles of WMH volumes in the strategic white matter tracts and was related to cognition using Lasso regression, accounting for multicollinearity, and multivariable linear mixed models.

Result

The combined sample consisted of 3525 patients (age: 71.6 ± 9.0 years; 49.9% female) (Table 1). The WMH prevalence maps are shown in Figure 1. In the merged study sample, 63.0% of the supratentorial white matter was affected by WMH in ≥5 patients and could be included in the VLSM analysis. In the VLSM analysis, statistically significant voxels were found for each of the four cognitive domains, after correction for total WMH volume and multiple testing. These voxels were mostly located in the left and right anterior thalamic radiation and the forceps major. Independent ROI based analysis confirmed these strategic tracts and additionally identified the left inferior fronto‐occipital fasciculus as significant tract (Table 2). The strategic WMH score was significantly associated with lower performance on attention & executive functioning (B‐0.146; p<0.001), information processing speed (B‐0.090, p = 0.023), language (B‐0.124, p = 0.003), and verbal memory (B‐0.128, p<0.001), independent of total WMH volume, age, sex, education, brain parenchymal fraction, and study site.

Conclusion

This large multicenter study provides strong evidence that the cognitive impact of WMH in memory clinic patients depends on location and identified four significant white matter tracts. With further refinement, WMH location might become a useful diagnostic biomarker for SVD‐related cognitive impairment.
System dynamics model on the interplay between social health and dementia
Authors: Lenart‐Bugla Marta
Published: June 2023

Background

Dementia, as a multi‐factorial condition with complex underlying mechanisms, demands a comprehensive approach of prevention and treatment, especially, focused on psychosocial interventions. This work is aimed at presenting a system dynamics (SD) model on the role of social health in the trajectory from cognitive health to dementia.

Method

We used a staged approach for building a SD model, presenting SH‐cognition bidirectional relationship, based on (1) systematic literature review on factors related to cognitive decline, (2) Group Model Building sessions with interdisciplinary experts, (3) iterative way of integrating results from epidemiological, multi‐national cohort studies, (4) ongoing revisions of SH concept via structured discussions between experts. This knowledge synthesis was harmonized and transformed into a causal pathway model in Kumu program (https://kumu.io/).

Result

The SD model presents maps on three levels: health domains, concepts with dimensions, markers. The last is a representation of interaction and feedback mechanisms between social health and cognition through three pathways: Physiological, psychological, and health‐behavioral, and through, so called ‘cognitive reserve & brain reserve’. Each marker is described with definitions and level of evidence (from expert’s knowledge to systematic review). The outcome shows that multiple SH factors contribute to cognitive decline and dementia (e.g. loneliness, being single), being risk factors, and other serve as protective factors (e.g. high social frequency, social support). In return, presence of dementia symptoms influences SH, f.ex. making the individual more dependent on social network, or being less satisfied with social ties.

Conclusion

The SD model elucidates dynamic and complex relationships between dementia and SH, which might serve a role of a reserve in the context of changed roles in social life of an individual with dementia. This novel representation will be translated into key elements and targets for recommendations for interventions, both for prevention and for improved dementia care.
White matter lesions predominantly located in deep white matter represent embolic etiology rather than small vessel disease
Authors: Jung Young Hee H
Published: June 2023

Background

Individuals with cerebral small vessel disease (CSVD) usually have both periventricular and deep white matter hyperintensities (dpWMH). However, we often encounter individuals whose WMH lesions are mainly located in the corticomedullary or deep white matter with minimal periventricular WMHs (dWMH). We aimed to determine if the dWMH pattern could be attributed to embolic etiologies.

Methods

We retrospectively recruited participants who had undergone comprehensive dementia evaluation, agitated saline contrast echocardiography, and brain MRI. The participants were classified into two groups according to WMH distributions, the dWMH (WMHs in deep and corticomedullary area, with minimal periventricular WMHs) and the dpWMH (mainly periventricular WMHs with or without deep WMHs) groups. We hypothesized that dWMH is more likely associated with embolism, whereas dpWMH with CSVD. We compared the clinical characteristics, WMH distributions, and the positive rate of agitated saline study between the two groups.

Results

Of the 90 participants, 27 fulfilled the dWMH criteria and 12 met the dpWMH criteria. The dWMH group was younger (62.2±7.5 vs 78.9±7.3, p<0.001), and had a lower prevalence of hypertension (29.6% vs. 75%, p = 0.008), DM (3.7% vs. 25%, p = 0.043), and hyperlipidemia (33.3% vs. 83.3%, p = 0.043) than the dpWMH group. Regarding deep white matter lesions, the number of small lesions (<3 mm) was higher in the dWMH (10.9±9.7) than the dpWMH (3.1±6.4) group (p = 0.008), and WMHs were predominantly distributed in border‐zones of major cerebral arteries and corticomedullary areas.

Most importantly, the positive rate of agitated saline was higher in the dWMH than the dpWMH group (81.5% vs. 33.3%, p = 0.003).

Conclusions

The dWMH group with younger age, fewer cardiovascular risk factors showed more border‐zone distributions, and higher positivity of agitated saline test than dpWMH group, indicating that WMH distributions mainly in the corticomedullary or deep area with minimal periventricular WMH lesions suggest embolic etiologies.
CenTauRz: A standardized quantification of tau PET scans
Authors: Dore Vincent , Bullich Santiago , Bohorquez Sandra Sanabria , Leuzy Antoine , Shimada Hitoshi , Rowe Christopher C. , Bourgeat Pierrick , Lopresti Brian J. , Huang Kun , Krishnadas Natasha , Fripp Jurgen , Takado Yuhei , Stephens Andrew W. , Weimer Robby , Higuchi Makoto , Hansson Oskar , Villemagne Victor L
Published: June 2023

Background

Over the past decade, several PET tracers were developed to visualise and quantify tau pathology in vivo. However, all these tracers have distinct off‐target binding, different dynamic ranges and likely different levels of non‐specific binding resulting in large variability in semiquantification. We propose to standardise the sampling and the quantification across all available tau tracers.

Method

549 participants underwent tau scans with either 18F‐FTP (Cognitively Unimpaired (CU) = 54/AD = 14), 18F‐MK6240 (CU = 186/AD = 89), 18F‐PI2620 (CU = 17/AD = 21), 18F‐PM‐PBB3 (CU = 30/AD = 28), 18F‐GTP1 (CU = 7/AD = 38) or 18F‐RO948 (CU = 35/AD = 30). All CU individuals were Aβ‐ and all AD were Aβ+. The tau scans were spatially normalized using CapAIBL and the cerebellar cortex was used as reference region. We constructed a “universal” tau mask from the intersection of all the specific tau tracer masks, after subtracting AD from CU. All tau PET studies were sampled with a Mesial Temporal (MTL) and a Meta Temporal (MetaT) composites constrained by the universal mask. For each tracer and in composite, the mean and standard deviation of the Aβ‐ CU SUVR for each tau tracer were used to generate z‐scores (CenTauRz).

Result

Using a threshold of 2 CenTauRz in the MetaT regions, all tracers highly discriminated Aβ+ AD from Aβ‐ CU (ACC = [0.94‐1], sens = [0.84‐1], spec = [0.96‐1]) with mean CenTauRz for the different AD cohorts ranging from 8 to 14. Lower accuracy was observed in the MTL (ACC = [0.78‐1]) due to lower sensitivity in some cohorts [0.65‐1] however, the specificity was similar to that in the MetaT composite (spec = [0.94,1]).

Conclusion

All tracers exhibited comparably high discriminative power to separate Aβ+ AD from Aβ‐ CU, where AD Aβ+ displayed a consistent range of CenTauRz across tracers. However, there were some differences between cohorts. For example, different PET scanners, with different sensitivities were used. For some cohorts, scans were selected as extreme representative cases, while for others the scans were more representative of clinical settings, with AD patients at early stages (with low or negative tau scans) or with suspected hippocampal sparing subtype that likely explains the lower accuracy in the MTL for some cohorts. Further studies with larger cohorts to validate the universal mask and CenTauRz scale are ongoing.
Elevated CSF GAP43 is driven by tau aggregation rather than β‐amyloid and neurodegeneration in Alzheimer’s disease
Authors: Lan Guoyu , Cai Yue , Li Anqi , Liu Zhen , Guo Tengfei
Published: June 2023

Background

Cerebrospinal fluid (CSF) pre‐synaptic protein growth‐associated protein 43 (GAP43) appears to be closely linked to neurodegeneration and cognitive decline in Alzheimer’s disease (AD). However, it is not well characterized about the associations of CSF GAP43 with β‐amyloid (Aβ), tau, neurodegeneration and cognitive decline.

Method

We identified 790 Alzheimer’s Disease Neuroimaging Initiative participants with concurrent CSF GAP43, Aβ PET, CSF p‐Tau181, residual hippocampal volume (rHCV), 18F‐fluorodeoxyglucose (FDG) PET and cognitive assessments within one year. Among of them, 340 individuals had longitudinal CSF GAP43 measurements. We compared baseline and longitudinal changes of CSF GAP43 among different biological stages defined by Aβ PET (A), CSF p‐Tau181 (T) and rHCV (N) in addition to their associations with Aβ PET, CSF p‐Tau181, rHCV, FDG PET and cognition cross‐sectionally and longitudinally, controlling for age, sex, APOE‐ε4 status and diagnosis.

Result

Among different A/T and A/T/N profiles, we found all CSF p‐Tau181‐positive individuals had significant higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases regardless of Aβ deposition and hippocampal atrophy (Figure 1). Furthermore, increased CSF p‐Tau181 rather than Aβ PET was related to higher baseline CSF GAP43 and faster rates of CSF GAP43 increases regardless of A/T profiles (Figure 2). In the subgroups of individuals with longitudinal MRI, FDG PET and cognition data, we found that higher CSF GAP43 concentrations (n = 377) and faster rates of GAP43 increases (n = 240) were associated with faster hippocampal atrophy, hypometabolism and cognitive decline (Figure 3).

Conclusion

These findings imply that tau aggregation rather than Aβ pathology is driving pre‐synaptic loss measured by CSF GAP43, which subsequently contributes to hippocampal atrophy and hypometabolism, resulting in cognitive decline in AD. Altogether, CSF GAP43 may be considered for an extra biomarker beyond A/T/N biomarkers, which can provide new insights into underlying AD pathogenesis prior to neurodegeneration.
Alteration of metabolic profile during the progression of Alzheimer’s disease
Authors: Yu Wuhan , Li Xuebing , Yu Weihua , Lü Yang
Published: June 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that threatens the population health of older adults. However, the mechanisms of how altered metabolism involves AD pathology are poorly understood. This study intends to provide novel insights into the role of metabolic alteration in the pathology and identify potential metabolic biomarkers for AD diagnosis

Method

The Gas chromatography‐mass spectrometry (GC‐MS) was used to measure the concentrations of serum metabolites in a cohort of subjects with AD (n = 88) and cognitively normal control (CN) (n = 85). The patients were classified as very mild (n = 25), mild (n = 27), moderate (n = 25), and severe (n = 11). Serum metabolic profiles were analyzed by multivariate (principal component analysis) and univariate approaches (t‐tests, false discovery, receiver operating characteristic curves, and correlation analysis). The artificial neural network model (ANN) was applied to identify potential biomarkers of AD. Biofunctional enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes.

Result

The results revealed considerable separation between the AD and CN patients. Edetic acid, (S)‐3,4‐Dihydroxybutyric acid, and arachidonic acid were identified as potential AD diagnostic biomarkers using an ANN model. And the classification model could predict the risk for AD with high accuracy (AUC = 0.93). The most significant changes in the metabolite’s composition occur during the very mild to the mild stage. The metabolic enrichment analysis revealed that carbohydrate metabolism deficiency and disturbance of amino acids, fatty acids, and lipids metabolism are involved in AD progression. Especially, pathway analysis highlighted that l−glutamate participated in four crucial nervous system pathways (including GABAergic synapse, glutamatergic synapse, retrograde endocannabinoid signaling and synaptic vesicle cycle).

Conclusion

Serum metabolomic analysis demonstrated that the metabolic alterations had already arisen at the very mild stages of dementia. Disrupt energy metabolism may be the core of the vicious cycle in AD, resulting in a wide range of metabolic disorders, including abnormal glucose metabolism, TCA cycle impairments, amino acids, fatty acids, and lipids dysregulation. Furthermore, a metabolic diagnostic model of AD was constructed using ANN, which could robustly differentiate AD patients from CN. Our study identified new markers for AD diagnosis and highlighted the roles of metabolic changes on the progression of AD.
Locus Coeruleus hypopigmentation in frontotemporal lobar degeneration and its relation to cerebrovascular injury biomarkers
Authors: Taheri Saeid
Published: June 2023

Background

Increasing evidence suggests that degeneration of Locus Coeruleus (LC) neurons is a common feature of various neurodegenerative diseases. Including patients neuropathologically diagnosed with frontotemporal lobar degeneration (FTLD). Based on the histopathological patterns FTLD has been categorized into three distinct subtypes; FTLD with tau immunoreactivity inclusion (FTLD‐tau), FTLD with TDP‐43 (transactive response DNA‐binding protein 43 kDa) immunoreactivity inclusion (FTLD‐TDP), and FTLD with other than tau and TDP‐43 immunoreactivity inclusion (FTLD‐Others). However, the significance of LC degeneration as a marker of the FTLD subtypes has not been fully explored. The purpose of this study was to investigate if the graded LC hypopigmentation can be used as a biomarker to separate distinct subtypes of FTLD.

Method

The sample included 63 participants from the National Alzheimer’s Coordinating Center’s (NACC) data sets who had ante mortem neuropathological and CSF data. LC pigmentation was graded as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The relationship between LC gross anatomy (hypopigmentation) and CSF A‐beta and Tau levels was explored. Also, the relationship between LC hypopigmentation and FTLD type was investigated. Moreover, markers of cerebrovascular diseases, including infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy, were investigated for their correlation with LC hypopigmentation.

Result

The hypopigmentation of LC is highly correlated with FTLD‐tau, then with a lower degree with FTLD‐TDP and less correlated with FTLD‐Other. Both LC and Substantia Nigra damage was correlated with CSF tau. We did not find statistically significant correlations between FTLD and cerebrovascular disease markers.

Conclusion

Ante mortem LC hypopigmentation could be used as a biomarker to differentiate underlying FTLD‐tauopathies from clinically similar FTLD‐TDP proteinopathies.
Lifestyle and pharmacological interventions in South America: Potential barriers for recruitment, implementation, and effectiveness
Authors: de Oliveira Fabricio Ferreira , Smith Marilia Arruda Cardoso , Naffah‐Mazzacoratti Maria da Graça , Bertolucci Paulo Henrique Ferreira
Published: June 2023

Background

The study of vascular cognitive impairment and dementia (VCID) risk factors must be reproduced in every community so that disparities may be addressed. In South America, diverse levels of education, mixed ethnicity, genetic and cultural heterogeneity, and the burden of cerebrovascular risk are important features to be investigated for proper interventions.

Methods

Observational and interventional VCID studies from South America will be discussed so that issues concerning potential barriers for participant recruitment and research effectiveness may be addressed.

Results

Few South American institutions have studied risk factors for VCID. Older people suffer the effects of restrictions to female education that occurred a century ago. Cross‐sectional studies demonstrated that APOE‐ε4 carrier status predisposes to physical inactivity and has smaller effects over dementia onset than in studies from the Northern Hemisphere, possibly due to ethnical disparities, while the burden of combined cerebrovascular risk factors (and smoking in particular) in this regard is high. Foreigners living in Brazil had later dementia onset, unexplained by common genetic variants. While prevalent in almost half of the older population, and associated with earlier dementia onset particularly in women, depression could be a risk factor or a prodromal symptom. Late life prospective studies verified that cerebrovascular risk factors such as arterial hypertension, hypercholesterolemia and a higher coronary heart disease risk, or increased creatinine clearance for women only, may be neuroprotective against cognitive and functional decline, probably due to enhanced cerebral perfusion. Lifetime sanitary conditions and increasing late life body mass index may protect against frailty, while education is neuroprotective for women and APOE‐ε4 carriers (though associated with faster cognitive decline in some cohorts). Longitudinal pharmacogenetic studies demonstrated that potential benefits of cerebrovascular metabolism modulators such as angiotensin‐converting enzyme inhibitors and lipophilic statins depend upon epistatic interactions among specific genetic variants. Caregiver awareness of the need to control cerebrovascular risk is beneficial for patients.

Conclusions

Genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes interact on mechanisms of neurodegeneration. Adherence to lifestyle and pharmacological interventions in South America is highly dependent upon proper funding, public support, harmonization efforts, institutional expertise and leadership, and caregiver education. (Supported by FAPESP grant #2015/10109‐5)
Amyloid‐β and tau imaging in chronic traumatic brain injury
Authors: Hicks Amelia J , Ponsford Jennie L , Spitz Gershon , Dore Vincent , Krishnadas Natasha , Roberts Caroline , Rowe Christopher C.
Published: June 2023

Background

Amyloid‐β and tau are the pathological hallmarks of Alzheimer’s disease. There is evidence of elevated amyloid‐β and tau immediately following moderate to severe traumatic brain injury (TBI). This suggests TBI may initiate pathological processes that lead to Alzheimer’s disease. It is not clear whether amyloid‐β and tau remain elevated in the chronic post‐injury period. To address this issue, we assessed amyloid‐β and tau burden in long‐term TBI survivors (≥ 10 years post injury) and healthy controls using PET imaging.

Method

Using a cross‐sectional design, we recruited individuals following a single moderate to severe TBI at least 10 years previously from an inpatient rehabilitation program. A demographically similar healthy control group was recruited from the community. PET data were acquired using 18F‐NAV4694 (amyloid‐β) and 18F‐MK6240 (tau) tracers. PET scans were classified as positive or negative using visual assessment. Amyloid‐β deposition was quantified using the Centiloid scale. Tau deposition was quantified using the standardized uptake value ratio (SUVR) in four key composite regions of interest (ROI). We examined PET data in relation to time since injury and age at injury. PET data were analysed in a series of regression analyses controlling for age and sex.

Result

The sample comprised 87 individuals with TBI (71.3% male; M = 57.53 years, SD = 11.53) and 59 controls (59% male; M = 60.34 years, SD = 11.97). Our results showed that individuals with TBI were not more likely than controls to have a positive amyloid‐β or tau scan based on visual assessment. Individuals with TBI did not have significantly higher 18F‐NAV4694 Centiloid values or 18F‐MK6240 tau SUVRs in any ROI. No associations were identified for amyloid‐β or tau burden with time since injury or age at injury.

Conclusion

A single moderate to severe TBI was not associated with higher burden of amyloid‐β or tau pathologies in the chronic period following injury relative to healthy controls. Amyloid‐β and tau burden did not show a significant increase with years since injury. Likewise, we found no evidence that amyloid‐β and tau burden were greater for those who were older at the time of their injury.
Antibiotics: Treatment for Alzheimer’s diseases
Authors: Chandolia Priyanka , Agrawal Mohit
Published: June 2023

Background

Alzheimer’s is a specific neurodegenerative disease that accounts for 60‐80% of overall dementia cases. This is the most common type of dementia arises from the deposition of beta‐amyloid plaques and neurofibrillary tangles, in the hippocampal region and the entorhinal cortex tends to cause neuronal death. Currently, available drugs can provide symptomatic relief in patients associated with AD. Recently, it has been reported that antibiotics can exert a variety of biological actions that are independent of their anti‐microbial activity, including anti‐inflammatory, anti‐excitotoxic, anti‐apoptotic, and antioxidant activities.

Method

A number of antibiotics are used in the preclinical and clinical studies of Alzheimer’s disease. Among all antibiotics β‐lactam antibiotics and tetracyclines are well reported to reach CSF concentration, targeting Alzheimer’s disease. These two classes well suggest their neuroprotective role in various neurodegenerative disorders. β‐lactam antibiotics (penicillins and cephalosporins) has been demonstrated as protectors against near excitotoxicity. Ceftriaxone posses good BBB penetration thus used for various neurodegenerative disorders and shows the improvement in learning and cognitive functions when studied in transgenic models of AD.

Result

The combination of two well known pharmacokinetically safer antibiotics to synergize their individual effects and develop a newer approach concerning the treatment of AD.

Conclusion

Furthermore, there is a need to develop the neuroprotective mechanisms in the treatment of Alzheimer’s disease.
Preliminary data on micro errors as a sensitive measure of everyday functioning in older adults
Authors: Holmqvist Sophia L. , Mckniff Moira , Pinsky Emma , Mis Rachel , Simone Stephanie M. , Tassoni Molly , Hackett Katherine , Lloyd Nicole , Giovannetti Tania
Published: June 2023

Background

Mild difficulties with daily tasks are associated with cognitive abilities and future cognitive decline but are difficult to measure objectively. Performance‐based tests with high task demands (e.g., multitasking, prospective memory) have been fruitful in capturing mild functional difficulties, however measuring certain aspects like overt errors or completion time often shows floor effects and thereby fail to discriminate between individuals with subtle functional decline. We propose a different approach that involves coding micro‐error defined as inefficient but not overtly erroneous actions (e.g., mis‐reaching toward the wrong object) during relatively simple, performance‐based tests, such as the Naturalistic Action Test (NAT). We present preliminary findings on the validity of micro‐errors as sensitive measures of cognition in participants with healthy cognition, mild cognitive impairment (MCI), and mild dementia.

Method

27 older adults (Healthy, MCI, Dementia) completed the NAT, which requires participants to make a breakfast and a lunch using objects presented on a table. Standard cognitive tests (memory, language, etc.) were administered. NAT scores reflecting micro‐errors, total steps accomplished, and completion time were examined across participant groups and included in correlation analyses.

Result

Worse performance on the NAT was associated with disease severity (micro errors Mean (SD) ‐ Healthy: M = 3.05 (.79); MCI: M = 8.80 (1.28); Dem: M = 9.33 (4.84); completion time(sec) ‐ Healthy: M = 211.84 (10.70); MCI: M = 352.00 (110.50); Dem: M = 363.00 (36.67); total steps accomplished‐ Healthy: M = 32.79 (0.12); MCI: M = 31.80 (0.73); Dem: M = 30.67 (2.33)). Among those with healthy cognition and MCI, greater micro errors were associated with lower accomplishment scores (r = ‐.422, p = .040) and longer completion times (r = .388, p = .061). Micro‐errors, but not accomplishment scores or completion time, were significantly associated with cognitive tests, who made more micro‐errors obtained a lower overall cognitive composite (r = ‐.434, p = .034) and a lower memory score (r = ‐.438, p = .032).

Conclusion

Subtle errors and inefficient actions (micro‐errors) during highly familiar everyday tasks are valid indicators of cognitive difficulties in older adults without dementia. Micro‐errors may be more sensitive than time to completion and task accomplishment and may be obtained from 5‐10 minutes of task performance. Micro‐errors have potential to identify risk of decline and as sensitive functional outcomes in clinical trials.
Determinants of cognitive and brain resilience to tau pathology: A longitudinal analysis
Authors: Bocancea Diana I. , Svenningsson Anna L , van Loenhoud Anna C. , Groot Colin , Barkhof Frederik , Strandberg Olof , Smith Ruben , Pontecorvo Michael J. , Rabinovici Gil D. , van der Flier Wiesje M. , Hansson Oskar , Ossenkoppele Rik
Published: June 2023

Background

Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease (AD) spectrum are insufficiently understood. Longitudinal data is necessary for revealing which factors contribute to maintaining cognition (cognitive resilience, CR) or preserving brain structure (brain resilience, BR) despite elevated tau, and for clarifying whether these factors provide a baseline advantage and/or moderate rates of brain structural and cognitive change. We therefore investigated whether age, sex, education, APOE‐e4 status, intracranial volume (ICV) and cortical thickness (in CR analysis) moderate the association between baseline tau load and subsequent changes in cognition and cortical thickness.

Methods

The study included 341 amyloid‐β‐positive individuals from a multi‐cohort dataset (BioFINDER‐1/AVID/ADNI/UCSF), diagnosed with MCI or AD dementia at the time of the baseline [18F]flortaucipir tau‐PET scan, who had longitudinal cognitive assessments (CR sample). A subset (n = 133) additionally underwent longitudinal structural MRI (BR sample). We used (separate) linear mixed‐effect models with MMSE as outcome to investigate the association of key baseline variables‐of‐interest (age, sex, APOE‐e4 status, education, ICV and global cortical thickness) with cognitive decline in the presence of tau (covaried for cohort). A three‐way interaction between time, tau and the predictor‐of‐interest was initially assessed. In the absence of a moderation effect, we subsequently assessed models including only the two‐way interaction between each predictor and time. These analyses were repeated with global cortical thinning as an outcome variable.

Results

Characteristics of the CR sample and BR sub‐sample are described in Table‐1. Models revealed that younger age (βInteraction = ‐0.18, p<0.01), higher education (βInteraction = ‐0.62, p<0.001), larger ICV (βInteraction = ‐8.12, p<0.01) and greater cortical thickness (βInteraction = ‐9.9, p<0.05) were related to higher CR, as these factors moderated the relationship between tau pathology and decline in MMSE (Figure‐1,2). No predictor moderated tau effects on cortical thinning nor explained additional variance (Table‐2).

Conclusion

This study indicates that tau pathology affects cognitive decline differently across age, education, ICV and cortical thickness levels. Understanding moderators of prospective cognitive decline and cortical thinning related to tau pathology, as well as their complex interactions, may be relevant for improving prognosis and clinical trial design in AD.
The relationship between traumatic brain injury and the neuropathology of dementia
Authors: McCann Heather , Halliday Glenda M , Shepherd Claire E
Published: June 2023

Background

Clinical studies indicate that traumatic brain injury (TBI) is linked to an increased risk of dementia during life. However, studies involving neuropathologically‐confirmed cases have shown conflicting results. This study was aimed at assessing a large brain bank cohort to identify any association between TBI and the presence of pathologies underlying the most commonly found dementias, Alzheimer’s disease (AD) and Lewy body disease (LBD).

Method

636 cases were assessed for this study (average age 76.2). Cases with a history of TBI were identified using donor records held at the Sydney Brain Bank. We use the term "TBI” to include a single or multiple TBIs, as well as repetitive mild neurotrauma that may be subconcussive (N = 109). Amyloid plaque and alpha synuclein pathologies were identified by immunohistochemistry. Neurofibrillary tangles were identified using modified Bielschowsky silver staining. Pathology was assessed according to current neuropathological diagnostic criteria. Multivariate regression statistics were used to assess the effect of TBI, age and gender on amyloid plaque (A score), neurofibrillary tangles (B score) and Lewy pathology stages. Multinomial logistic regression was used to examine the effect of TBI on pathological diagnosis.

Results

TBI was not significantly associated with increased amyloid (p = 0.05) or Lewy pathology stages (p = 0.65), however the odds of having a higher neurofibrillary tangle stage increased by 75% in the TBI group (p = 0.009)(Figure 1). Gender was not a significant predictor of amyloid (p = 0.29), neurofibrillary tangle (p = 0.89) or Lewy pathology (p = 0.15). Not unexpectedly, age was a significant predictor of AD pathologies, including amyloid (p = <0.0000001) and neurofibrillary tangle (p = 0.00002) stages, although age was not a significant driver of Lewy body pathology (p = 0.1). There was no association between TBI and overall diagnosis of AD neuropathologic change or LBD (p = 0.12).

Conclusions

In this elderly neurodegenerative cohort, age remains a risk factor for AD, but not LBD pathology. Gender did not have a significant association with these pathologies in this cohort. TBI did not increase the risk of AD but did increase the frequency of neurofibrillary tangles, suggesting that abnormal tau protein accumulation following TBI is an important long‐term consequence that may contribute to poor brain aging and future neurodegeneration.