bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteome Wide Association Studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson’s disease
Authors: Phillips Bridget , Western Daniel , Wang Lihua , Timsina Jigyasha , Sun Yichen , Gorijala Priyanka , Yang Chengran , Do Anh , Nykanen Niko‐Petteri , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Morris John C , Schindler Suzanne E. , Fagan Anne M. , Puerta Raquel , García‐González Pablo , de Rojas Itziar , Marquié Marta , Boada Mercè , Ruiz Agustin , Perlmutter Joel S. , Ibanez Laura , Perrin Richard J. , Sung Yun Ju , Cruchaga Carlos
Published: December 2023

Background

Leucine‐rich repeat kinase 2 (LRRK2) common gene variants (tagged by rs76904798) are associated with Parkinson’s disease (PD) risk. In a previous study, we found that rs76904798 was associated with CSF GRN levels, but a comprehensive unbiased analysis of associated proteins remains incomplete due to prior focus on cis‐protein quantitative trait loci (pQTL). Using the largest aptamer‐based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals), we performed a trans‐pQTL study to identify proteins associated with the LRRK2 variants and used additional mediation and pathway analyses to better understand downstream effects (Figure 1).

Method

SNP selection using Conditional and Joint Association Analysis (GTCA‐COJO) and PLINK LD r2 scores identified 11 other independently associated SNPs. Fine mapping was performed between each significant aptamer and PD GWAS via proteome‐wide association studies (PWAS) and Mendelian randomization (MR). These aptamers were further analyzed based on PD risk association, brain cell‐type specificity, and gene pathway annotations.

Result

Overall, 26 proteins passed FDR correction and eleven were implicated in PD prior like GRN and GPNMB. PWAS analyses using TWAS/FUSION also indicate 12 proteins were significant and positively associated with PD risk, such as novel proteins C1QTNF1 and SDCBP2, and half were validated by the PPMI data. MR analyses indicate that GRN, GPNMB, HLA‐DQA2, CD68, and LCT are also causal for PD risk (Table 1). Cell‐type enrichment analyses indicate microglia‐specific protein enrichment (Fold change: 7.35, P = 4.91×10−5). Enrichment analyses indicate enrichment for leukocyte activation (GO:0045321, P = 0.002) and microglial cell activation (GO:0001774, P = 0.003) pathways.

Conclusion

Trans‐pQTL can identify novel protein interactions in an unbiased manner. This study linked LRRK2 variants with both PD implicated (GRN, GPNMB) and novel (ITGB2, C1QTNF1) proteins that have support in our PWAS, MR, and PPMI differential protein level analyses. Microglia and lysosome enrichment support the previous observations regarding the importance of microglia and immune system function in the underlying pathobiology of PD (Figure 2). Our results suggest that the CSF concentrations of these proteins (such as GRN, GPNMB, C1QTNF1, and ITGB2) have potential as biomarkers for target engagement and disease progression modification in clinical trials that target LRRK2.
AL002c‐mediated reduction in amyloid β pathology is reflected by changes in plasma Alzheimer’s disease biomarkers in 5XFAD mice
Authors: Burgess Brady , Ibrahim Adiljan , Stansley Branden , Schwabe Tina , Wang Shoutang , Colonna Marco , Tassi Ilaria
Published: December 2023

Background

The R47H variant of the triggering receptor expressed on myeloid cells‐2 (TREM2) gene increases the risk for late‐onset Alzheimer’s disease (LOAD) and reduces TREM2 ligand binding in vitro, suggesting that enhancing TREM2 signaling has therapeutic potential in AD. AL002 is a novel humanized monoclonal Immunoglobulin G1 (IgG1) antibody that targets TREM2 and is currently being tested in a phase 2 trial in patients with early AD. Previously, AL002c, a variant of AL002, reduced filamentous amyloid β (Aβ) plaques and neurite dystrophy and increased inert plaques in a 5XFAD mouse model, while other Aβ pathology measures did not show treatment effects. Total Aβ42/40 ratio in plasma is inversely associated with amyloid burden independent of AD clinical diagnosis2 and is being used as a biomarker in AD clinical trials.3 To further evaluate the impact of AL002c on Aβ pathology, the present study assessed plasma AD biomarkers, including Aβ42/40 ratio, in residual samples from these 5XFAD mice.

Method

Five‐month‐old 5XFAD mice (N = 32, n = 6‐13 per group) expressing either common variant (CV) or R47H variant human TREM2 (hTREM2), but lacking endogenous mouse Trem2, were injected intraperitoneally with 30 mg/kg AL002c or control mouse IgG1 weekly for 12 weeks (Figure 1). Levels of plasma Aβ42, Aβ40, and total tau (t‐tau) were quantified using Simoa® assay (Quanterix).

Result

AL002c‐treated CV‐5XFAD and R47‐5XFAD mice had a higher plasma Aβ42/40 ratio (CV‐5XFAD p <0.001; R47‐5XFAD p<0.05; pooled CV and R47‐5XFAD p < 0.01) and lower plasma t‐tau (CV‐5XFAD p <0.05; R47‐5XFAD p<0.001; pooled CV and R47‐5XFAD p < 0.01) compared with their IgG1‐treated genotype counterparts (Figure 2). No differences were observed between R47H and CV genotypes in plasma Aβ42/40 ratio or t‐tau.

Conclusion

AL002c‐associated changes in plasma Aβ42/40 and tau were consistent with a concomitant reduction in filamentous plaques and neurite dystrophy.1 These results lend further support to the clinical utility of plasma Aβ42/40 as a marker for the reduction of neurotoxic amyloid plaques in clinical trials with AL002.
CSF proteome profiling reveals a protein panel detecting amyloidosis and progression to dementia in cognitively unimpaired individuals
Authors: del Campo Marta , Quesada Carlos , Vermunt Lisa , Peeters Carel F.W. , Hok‐A‐Hin Yanaika S. , den Braber Anouk , Verberk Inge M.W. , Visser Pieter Jelle , Tijms Betty M. , van der Flier Wiesje M. , Teunissen Charlotte E.
Published: December 2023

Background

Understanding the earliest biochemical changes related to Alzheimer´s disease (AD) pathology is essential for the development of biomarkers and disease‐modifying therapies. Here, we aimed to map the cerebrospinal fluid (CSF) proteomic changes associated with amyloid ß (Aß) pathology in cognitively unimpaired individuals and identify a panel of CSF biomarkers detecting amyloid positivity as well as clinical progression to dementia.

Method

Proximity extension‐based multiplex immunoassays were used to measure 614 proteins in 297 CSF samples from cognitively unimpaired controls with and without amyloid pathology (232 CON/Aβ‐ (age: 68±8; sex: 37% female) and 65 CON/Aβ+ (age: 65±7; sex: 49% female) from the Amsterdam Dementia cohort. A total of 39 cases (13%) progressed to mild cognitive impairment (MCI; n = 19) or dementia (n = 20). An additional cognitively unimpaired control cohort from the EMIF‐twin60+ study (103 CON/Aβ‐ and 19 CON/Aβ+) was used to validate the panel. Data was analysed using nested linear models adjusted for multiple testing and penalized generalized linear modelling.

Result

We identified 110 CSF proteins with different levels in CON/Aβ+ compared to Aβ‐ (q<0.05). Proteins were enriched in processes related to proteolysis, enzyme activation and immunity. Classification modelling revealed a panel of 12‐CSF markers that detect amyloid positivity with high accuracy in both the discovery (AUC: 0.93) and validation (AUC: 0.89) cohorts. This panel also predicted clinical progression to MCI and dementia with high accuracy (AUC: 0.83). Chow´s test analysis revealed a structural change in the relation between a subset of these proteins and CSF Aβ42 before the amyloid positivity threshold.

Conclusion

Overall, this study provides novel pathophysiological leads associated to distinct biological processes in individuals at risk of developing AD‐dementia and provides potential biomarker tools for clinical settings or trials.
A new non‐verbal was developed to differentiate dementia and non‐dementia people and the study was to evaluate its validation
Authors: Huang Guan‐Tsz , Li Kuan‐Ying , Huang Ling‐Chun , Yang Yuan‐Han
Published: December 2023

Background

Dementia, which presents as cognitive decline in one or more cognitive domains affecting function, is increasing globally. Early diagnosis of dementia for general population is important, which needs a screening tool capable of identifying dementia efficiently.

Most cognitive tests for screening dementia are based on verbal administration, which will be influenced by cultural background and language differences, if any.

Developing a screening tool less depended on verbal administration is crucial for these necessities.

Method

Participants aged from 50 to 89 years old were recruited from department of Neurology, Kaohsiung Municipal Ta‐Tung Hospital, Taiwan. Dementia was diagnosed based on clinical diagnosis with referring to cognitive test performance by psychologists by 2011 National Institute on Aging and Alzheimer’s Association (NIA‐AA) criteria for all‐cause dementia .Participants were assessed with Clinical dementia rating (CDR), Cognitive Abilities Screening Instrument (CASI), derived Mini‐Mental State Examination (MMSE) and the non‐verbal cognitive test consisted of visual memory test, digital connection test, clock puzzle, shape color matching and simple card sorting test. These tests were designed to capture cognitive function including visual memory, visuospatial ability, and executive function. Statistical analysis was performed using MedCalc, version 20.14.

Result

In total, 160 demented patients and 81 non‐demented participants were recruited. The performance of the dementia group was worse than that of the control group in all non‐verbal tests. Among these tests, visual memory had the greatest ability to examine dementia with its percentage of recalled visual memory with optimal cut‐off point 70% having a sensitivity 73.38%,specificity 85.19% and area under the curve (AUC) as 0.87. Combining visual memory test, the digital connection test‐1 and the clock puzzle‐1 to discriminate dementia, the AUC was 0.93 and was superior to the AUC of MMSE (AUC = 0.88).

Conclusion

Compared to traditional pencil‐paper tests, non‐verbal tests shown its potentials in screening dementia with fewer language limitation.
Cholinergic deficit induced memory retrieval deficit and hippocampal CaMKII‐alpha deregulation is counteracted by sub‐chronic agmatine treatment in mice
Authors: Ostovan Vahid Reza , Baberi Nahid , Farrokhi Majid Reza , Moezi Leila , Pirsalami Fatema , SoukhakLari Roksana , Moosavi Maryam
Published: December 2023

Background

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disease characterized by brain cholinergic dysfunction. Evidence suggests the impairment of memory retrieval phase in AD. It has been shown that CaMKII‐α expressing neurons are selectively reduced in the hippocampus in AD brains. The present study aimed to investigate the effect of scopolamine on the memory retrieval phase and the hippocampal CaMKII‐α signaling. In addition, the effect of sub‐chronic administration of agmatine against scopolamine induced memory and possible hippocampal CaMKII‐α deregulation was investigated in mice.

Method

Adult male NMRI mice were administered with agmatine at the doses of 5, 10, 20, 30 and 40 mg/kg/i.p. or saline for 11 days. Acquisition and retrieval tests of passive avoidance task were performed on days 10 and 11, respectively (30 Min following agmatine treatment). Scopolamine (1 mg/kg/i.p.) was administered once, 30 Min before retrieval test. Upon completion of the behavioral tasks, the hippocampi were isolated for western blot analysis to detect the phosphorylated and total levels of CaMKII‐α and beta actin proteins.

Result

The results showed that scopolamine induced memory retrieval deficit and decreased the phosphorylated level of hippocampal CaMKII‐α. Sub‐chronic agmatine treatment at the dose of 40 mg/kg prevented scopolamine induced memory retrieval deficit and restored the level of hippocampal phosphorylated CaMKII‐α.

Conclusion

This study suggests that hippocampal CaMKII‐α might play a role in scopolamine induced amnesia and sub‐chronic agmatine prevents the impairing effect of scopolamine on the retrieval phase of memory and the phosphorylation of hippocampal CaMKII‐α protein.
Slowly progressive Right Temporal Variant of Frontotemporal Dementia with ALS2 mutation: A case report
Authors: Fernandez Paulo Eduardo Lahoz , Cordeiro Anna Beatriz Perdigão , Bertolucci Paulo Henrique Ferreira
Published: December 2023

Background

Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder characterized by behavioral and personality changes. Findings show variation in the disease progression. Some patients show a rapid progression over a few years, and others show little or no changes over a decade (1) Mutations in the amyotrophic lateral sclerosis 2 (ALS2) gene cause autosomal recessive motor neuron diseases, including juvenile‐onset amyotrophic lateral sclerosis (JALS), and other associated disorders. (2) We present a rare case.

Method

We describe the clinical and imaging features of a man who presented a rare case of Slowly progressive Right Temporal Variant of Frontotemporal Dementia with ALS2 mutation.

Result

A 63‐year‐old man presented a 10‐year history of insidious and slowly progressive behavioral changes. He showed reduced emotional responsiveness, with no concern since his wife had received a diagnosis of a malignancy. He followed with disinhibition, and impulsive actions such as excessive shopping with no payment, overspending, and socially inappropriate behavior. He also had a compulsive/ritualized behavior with stereotyped speech, and counting repeatedly steps. His medical family history was unremarkable. The neuropsychological evaluation showed impairment of executive functioning, MMSE 27/30. Neurological examination was normal. Brain MRI frontotemporal atrophy with a marked asymmetry in the right temporal lobe in sagittal, axial, and coronal sequences. CSF biomarkers showed elevated t‐tau with no other changes, and the genetic test showed an ALS2 heterozygous mutation., also counting repeatedly steps.

Conclusion

The presence of the C9ORF72 mutation has been shown in slowly progressive FTD, however, other mutations such as ALS2 have not yet been reported with the following phenotype, as in this case (3)

References:

1. Hornberger M, Shelley BP, Kipps CM, Piguet O, Hodges JR. Can progressive and non‐progressive behavioural variant frontotemporal dementia be distinguished at presentation? J Neurol Neurosurg Psychiatry. 2009 Jun 1;80(6):591‐3.

2. Sheerin UM, Schneider SA, Carr L, Deuschl G, Hopfner F, Stamelou M, et al. ALS2 mutations. Neurology. 2014 Mar 25;82(12):1065‐7.

3. Khan BK, Yokoyama JS, Takada LT, Sha SJ, Rutherford NJ, Fong JC, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J Neurol Neurosurg Psychiatry. 2012 Apr;83(4):358‐64.
Speech changes in neurodegenerative diseases relate to clinical outcomes
Authors: Gumus Melisa , Koo Morgan , Bhan Aparna , Robin Jessica , Black Sandra E.
Published: December 2023

Background

The detection and characterization of speech changes may help in the identification of neurodegenerative diseases and have the potential to help with patient characterization and monitoring. Yet, there is limited research validating the presence of speech changes across different types of neurodegenerative disease. We report on the relationships between speech and other clinical assessments in the individuals with different dementia diagnoses and in comparison to healthy older adults.

Method

We analyzed speech recordings from 109 patients (52F, 57M; Age = 72.63± 8.61) who were diagnosed with various neurodegenerative diseases, including Alzheimer’s disease, Frontotemporal Dementia, and Vascular Cognitive Impairment, in a cognitive neurology memory clinic. Speech recordings of an open‐ended picture description task were processed using the Winterlight speech analysis platform which generates >500 acoustic and linguistic features. We investigated the linear relationship between the speech features and clinical assessments including the Mini Mental State Examination (MMSE), Western Aphasia Battery (WAB), and Mattis Dementia Rating Scale while controlling for age, sex and years of education. Speech features that were significantly associated with clinical measures were then included in group comparisons with healthy older adults (N = 74, ∼39F; Age = 61.31±7.29).

Result

Speech features including lexical and syntactic features were significantly correlated with clinical assessments in patients, across diagnoses. Lower MMSE scores were associated with the use of more familiar nouns (β = ‐1.60, p<.001). Similarly, increased impairment as assessed by the WAB was correlated with the use of higher frequency nouns (β = ‐0.01, p<.001). Patients used significantly more nouns (z = 6.25, p<.001) and shorter words (z = 8.33, p<.001) than the healthy older adults. Their speech duration was also significantly shorter (z = 7.98, p<.001) and they paused more (z = 5.19, p<.001).

Conclusion

Speech changes representing decreased speech, with simpler vocabularies and syntax, were detectable in patients with different neurodegenerative diseases and correlated with clinical outcomes. These same speech patterns differed in patients with neurodegenerative disease compared to healthy older adults. Speech has the potential to be a sensitive measure for detecting cognitive impairments across various neurodegenerative diseases.
A case‐series comparison of semantic control in the logopenic variant primary progressive aphasia and Alzheimer’s disease
Authors: Henderson Shalom K , Rowe James B. , Ralph Matthew A Lambon
Published: December 2023

Background

Semantic cognition requires both semantic representation (conceptual knowledge), and semantic control (the ability to shape and manipulate information for a particular context/task) (Lambon Ralph, Jefferies, Patterson, & Rogers, 2017). Prior investigations have contrasted the semantic representation loss in semantic dementia with semantic control deficits in post‐stroke semantic aphasia (SA) (Jefferies & Lambon Ralph, 2006; Thompson et al., 2022). The logopenic variant of primary progressive aphasia (lvPPA) has neuroanatomical commonalities with SA, including damage centred on the left temporoparietal and inferior frontal regions, and neuropsychological commonalities including executive and language impairments. Accordingly, we investigated whether lvPPA impairs semantic control.

Method

We compared 12 individuals with lvPPA, 9 with typical amnestic Alzheimer’s disease (AD), and 12 age‐matched healthy controls on a battery of verbal and non‐verbal semantic, language, memory and executive functioning tests.

Result

The lvPPA patients spanned multiple levels of performance across the different tests and showed the characteristic features of a semantic control deficit: (i) They showed impairments in tests that require greater semantic demand (e.g., semantic association knowledge test more than straightforward word‐picture matching); (ii) only lvPPA patients showed strong correlations between semantic and executive tests; (iii) an effect of item familiarity was not found in lvPPA patients; and (iv) both lvPPA and AD patients benefited from phonemic cueing on the Boston Naming Test.

Conclusion

LvPPA patients’ performance on semantic tests is similar to that of previously reported SA, suggesting an impairment of semantic control. Imaging analysis is underway and will be available at the AAIC conference.

References:

Jefferies, E., & Lambon Ralph, M. A. (2006). Semantic impairment in stroke aphasia versus semantic dementia: a case‐series comparison. Brain, 129(Pt 8), 2132‐2147. https://doi.org/10.1093/brain/awl153

Lambon Ralph, M. A., Jefferies, E., Patterson, K., & Rogers, T. T. (2017). The neural and computational bases of semantic cognition. Nat Rev Neurosci, 18(1), 42‐55. https://doi.org/10.1038/nrn.2016.150

Thompson, H. E., Noonan, K. A., Halai, A. D., Hoffman, P., Stampacchia, S., Hallam, G., . . . Jefferies, E. (2022). Damage to temporoparietal cortex is sufficient for impaired semantic control. Cortex, 156, 71‐85. https://doi.org/10.1016/j.cortex.2022.05.022
Subjective cognitive impairment and biomarkers of Alzheimer’s disease
Authors: Zullo Leonardo , Fenix Brice , Rabl Miriam , Clark Christopher , Popp Julius
Published: December 2023

Background

Subjective cognitive impairment (SCI) is common in older adults. It may represent the earliest clinical manifestation of cognitive decline and Alzheimer’s disease (AD).

Objectives

1) to evaluate associations between SCI and cerebrospinal fluid (CSF) biomarkers of AD; 2) to identify specific single questions or question combinations that are related to the presence of cerebral AD pathology; 3) to evaluate whether using SCI related scores or specific questions combined with other clinical features and biomarkers may improve prediction of cognitive decline.

Method

We conducted a longitudinal study in 164 non‐demented subjects participating on a biomarker study in a memory clinic setting, aged 53 to 88 years, with CDR scores of 0 (N = 84) and 0.5 (N = 80). SCI was assessed using the Cognitive Complaint Interview (CCI, Thomas‐Antérion et al., 2006), a validated 10 items questionnaire. Accordingly, SCI is defined as present when the subject answers “yes” to 3 or more items; and/or to item 5, and/or to items A, 4, 5, 7, 8. All participants underwent comprehensive neuropsychological evaluations and CSF biomarkers analysis. “Amyloid positivity" and “AD pathology” were defined according to the CSF Aβ1‐42 levels and pTau181/Aβ1‐42 ratio, respectively. Logistic regressions were used to address the associations of interest.

Results

Participants with SCI had significantly lower Aβ1‐42 and higher Tau and pTau181 levels compared to those without SCI. SCI was associated with amyloid positivity while CCI total score and the question A (reporting changes in memory) were associated with both amyloid positivity and AD pathology in the whole cohort. When performing analysis separately in the CDR = 0 and CDR = 0.5 subgroups the associations remained significant in the CDR = 0.5 group. Only question 6 (difficulties in finding words) was associated with AD pathology in the CDR = 0 group. Results on the prediction of cognitive decline at follow‐up visits will be presented at the conference.

Conclusion

In dementia‐free subjects from this memory clinic cohort SCI‐related scores and single questions indicate amyloid positivity and the presence of AD pathology depending on the absence/presence of mild cognitive impairment. Further studies are needed to evaluate the diagnostic and prognostic utility of cognitive complains in memory clinic patients.
Exploration of the tumorigenic, metabolic, and cognitive consequences of tau protein removal
Authors: Erichsen Jennifer M. , Garbarino Valentina R. , Rodriguez Anna , Lee Jillian K. , Shayne Justin C. , Orr Timothy C. , Orr Miranda E.
Published: December 2023

Background

Tau accumulation causes tauopathies and drives cellular senescence, which can lead to inflammation, neurodegeneration, and cognitive impairment. The association between intracellular tau deposition and pathogenesis has prompted therapeutic strategies that reduce tau expression. However, tau is also critical in microtubule stabilization, synaptic plasticity, and maintaining DNA integrity. We investigated the impact of tau removal on brain cell senescence and associated neurocognitive behaviors in aged tau knockout (Mapt0/0) and wild type control (Mapt+/+) mice. We also assessed physical, metabolic, histological, and biochemical outcomes in Mapt0/0 and Mapt+/+ mice and in response to high fat diet (HFD), a stressor that drives DNA damage.

Method

20‐month‐old female Mapt0/0 and Mapt+/+ mice were subjected to the Elevated Plus Maze to assess anxiety‐like behavior. Mice were then fed control (CTL) or HFD (60% kcal fat) for 9 weeks. Behavioral and physical measures were then assessed, and brain tissue was further analyzed via gene expression, biochemistry, and histological assays.

Result

Tau knockout and HFD, separately and additively, caused weight gain and insulin resistance. Removing tau primed cells to proliferate, as Mapt0/0 mice had increased body size, organ size, and tumor burden compared to Mapt+/+. We observed no difference in senescence between genotypes on CTL diet. The HFD increased senescence only in Mapt+/+ mice, whereas Mapt0/0 mice displayed increased tumor burden. Mapt0/0 mice displayed anxiety‐ and depressive‐like behaviors on both diets. Transcriptomic and protein expression data revealed that several molecules responded similarly to tau removal and HFD exposure, but Mapt+/+ and Mapt0/0 mice responded differently to HFD. Genotype differences in DNA damage and cell cycle dysregulation were also observed.

Conclusion

Mapt0/0 mice did not accumulate senescent cells but demonstrated anxiety‐like behaviors in the presence of elevated DNA damage; thus tau knockout may drive neuropsychiatric phenotypes which can be dissociated from obesity and senescence. Mapt0/0 mice also developed tumors, suggesting that tau plays a critical role in cell fate decisions, including senescence versus cancer. Overall, we found that tau removal prevents senescent cell accumulation with the tradeoff of tumorigenic, metabolic, and cognitive consequences. We caution against removing tau until a better understanding of its physiological roles are defined.
BAG3 regulates RAB35 mediates the Endosomal Sorting Complexes Required for Transport/Endolysosome pathway and Tau clearance
Authors: Lin Heng , Tang Maoping , Ji Changyi , Girardi Peter , Cvetojevic Gregor , Chen Daniel , Koren Shon , Johnson Gail VW
Published: December 2023

Background

Declining proteostasis with aging contributes to increased susceptibility to neurodegenerative diseases, including Alzheimer’s disease (AD). Emerging studies implicate impairment of the endosome‐lysosome pathway as a significant factor in the pathogenesis of these diseases. Our lab was the first to demonstrate that BAG3 regulates phosphorylated tau clearance. However, we did not fully define how BAG3 regulates endogenous tau proteostasis, especially in the early stages of disease progression.

Methods

Mass spectrometric analyses were performed to identify neuronal BAG3 interactors. Multiple biochemical assays were used to investigate the BAG3‐HSP70‐TBC1D10B‐Rab35‐Hrs regulatory networks. Live‐cell imaging was used to study the dynamic of endosomal pathway. Immunohistochemistry and immunoblotting were performed in human AD brains and BAG3 overexpressed P301S tau transgenic mice.

Results

The primary group of neuronal BAG3 interactors identified are involved in the endocytic pathway. Among them were key regulators of small GTPases, such as the Rab35 GTPase activating protein, TBC1D10B. We demonstrated that a BAG3‐HSP70‐TBC1D10B complex attenuates the ability of TBC1D10B to inactivate Rab35. Thus, BAG3 interacts with TBC1D10B to support the activation of Rab35 and recruitment of Hrs, initiating ESCRT‐mediated endosomal tau clearance. Further,TBC1D10B shows significantly less co‐localization with BAG3 in AD brains than in age‐matched controls. Overexpression of BAG3 in P301S tau transgenic mice increased the co‐localization of phospho‐tau with the ESCRT III protein CHMP2B and reduced the levels of the mutant human tau.

Conclusion

We identified a novel BAG3‐TBC1D10B‐Rab35 regulatory axis that modulates ESCRT‐dependent protein degradation machinery and tau clearance. Dysregulation of BAG3 could contribute to the pathogenesis of AD.
Brain metabolism during delirium
Authors: Caplan Gideon A
Published: December 2023

Background

Altered cerebral glucose metabolism manifested by increased cerebrospinal fluid (CSF) lactate and decreased neuron specific enolase during delirium has been found in CSF analyses in multiple settings, although without change in CSF or blood glucose. These changes correlate with markers of delirium severity and outcomes of delirium.

However, patients with delirium are acutely unwell in hospital and have multiple comorbidities. The contribution of acute illness and dementia have not been excluded.

Method

We studied two groups of acutely unwell older people in hospital after excluding underlying dementia by history and the Informant Questionnaire on Cognitive Decline in the Elderly. The first group had delirium and the second group had no delirium. All patients underwent a 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) scan in hospital while unwell, and during delirium for the first group. Confounders on FDG‐PET such as structural brain lesions and medications that affect brain metabolism were excluded.

Then we also compared the delirium FDG‐PET scans to a group with Alzheimer’s dementia.

Result

Patients with delirium demonstrated a unique, novel pattern of brain hypometabolism that reflected symptoms of delirium. The affected areas included: bilateral thalami; right posterior cingulate cortex (PCC); right superior frontal, right infero‐lateral anterior temporal and left superior parietal cortices. The areas highly negatively correlated with delirium severity scores (Spearman’s rank correlation coefficients between ρ = ‐0.39 and ‐0.71; p values from 0.089 to 0.001) and performance on a range of relevant neuropsychological tests, for example thalami and Trail Making Test B (Spearman’s ρ = ‐0.52; p = 0.028). Direct comparison to AD scans significant thalamic hypometabolism (p<0.01) in delirium, but the PCC was not different.

Conclusion

In patients with acute illness but without dementia, delirium is accompanied by regional cerebral hypometabolism in a distribution that is not consistent with any known pattern of dementia. While there is some overlap with AD, thalamic hypometabolism is atypical of AD and consistent with the clinical features of delirium.

References

Nitchingham AR, Pereira JV‐B, Wegner EA, Oxenham V, Close J Caplan GA. Regional cerebral hypometabolism on 18F‐FDG PET/CT scan in delirium is independent of acute illness and dementia. Alzheimers & Dementia 2022; 1‐10.
Delirium Following Elective Arthroplasty Predicts Mild Cognitive Impairment (MCI) and Dementia Eight Years Later However This Is Not Independent of Pre‐Operative Neurodegenerative Biomarkers And Cognition
Authors: Sweeney Aoife , Passmore Anthony Peter , Beverland David , McGuinness Bernadette , McAuley Daniel F , O'Brien Seamus , Heslegrave Amanda , Schott Jonathan M , Zetterberg Henrik , Veleva Elena , Laban Rhiannon , Cunningham Emma L
Published: December 2023

Background

In 2012‐2014, an observational cohort study of postoperative delirium (POD) in an elective arthroplasty population recruited 315 individuals aged over 65 without a diagnosis of dementia. This follow‐up study aims to determine what effect POD has on cognitive function eight years later.

Method

Preoperatively, participants underwent cognitive assessments and sampling of blood and cerebrospinal fluid (CSF) which were analysed for amyloid‐beta (Aβ)40, Aβ42, glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and interleukin (IL)‐6.

In 2021, n = 172 of n = 264 surviving participants completed virtual cognitive assessments and agreed to have their medical records reviewed. For those who had died (n = 50), death certificates were obtained to determine if the participant died with a diagnosis of dementia. Univariate analyses and binary logistic regression were undertaken to investigate factors associated with mild cognitive impairment (MCI)/dementia in this cohort at eight years (Table 1). In cases when MCI or dementia was suspected, an expert consensus panel reviewed medical notes, cognitive test scores and informant reports to determine if a participant had MCI or dementia.

Result

Of the n = 222 participants, n = 30 had POD in 2012‐2014 and n = 22 had developed dementia or MCI. On univariate analyses, those who developed MCI/dementia at eight years were significantly older at the time of surgery (p = .02), had greater preoperative functional impairment (p = .02), and depression (p = .03) and performed worse on a number of cognitive tasks pre‐operatively (p<.05). Rates of POD were significantly greater in those who subsequently developed MCI/dementia (p = .03). In those who developed MCI/dementia, preoperative plasma and CSF measures of Aβ42 were significantly lower (p<.01), while CSF neurofilament light (NFL) and plasma IL‐6, GFAP and NFL were significantly higher (p<.05). On multivariate analyses, CSF Aβ42 (p = .02) and preoperative phonemic fluency (p = .01) remained significant predictors of MCI/dementia, while POD did not (Table 1).

Conclusion

This study did not find an independent association between delirium following elective arthroplasty and the development of MCI/dementia eight years later. The results of our study indicate preoperative CSF Aβ42 and cognitive function predict longer‐term outcomes and that the association between delirium and subsequent MCI and dementia is not independent of these factors.
A Study of Factors Influencing Quality of Life among Community Dwelling Elderly in Korean Urban Community
Authors: Lee Kyoung Hwan
Published: December 2023

Background

We examined the factors influencing quality of life among community dwelling elderly in Busan city.

Method

The subjects of this research were 160 community‐dwelling elderly people without dementia and major depressive disorder. Korean version of World Health Organization Quality of Life assessment instrument‐Abbreviated form (WHOQOL‐BREF), Korean version of Short Geriatric Depression Scale (SGDS‐K) and Korean version of MiniMental State Examination (K‐MMSE) were administered for each subject. Low quality of life was defined as below 60 points of WHOQOL‐BREF.

Result

The high quality of life group showed higher score of MMSE, lower score of GDS‐K, higher educational level and married status. About a third of the subjects complained about low quality of life. In the low quality of life group, there were significant associations between quality of life and SGDS‐K (p<0.001), but there was no association with education (p = 0.708), marital status (p = 0.410), and K‐MMSE (p = 0.683).

Conclusion

Depressive disorders including minor depressive disorder and subsyndromal depression, might play a role in the quality of life rather than cognitive impairments in community‐dwelling elderly people. Therefore, the treatments for the depressive mood should be considered in dealing with low quality of life.
Measurement of amyloid beta in nasal secretions as a potential biomarker for Alzheimer’s disease
Authors: Choi Seong Hye , Lee Sang‐Myung , Cho Won Woo , Cho Sungbo , Minn Yang‐Ki
Published: December 2023

Background

We investigated the level of amyloid beta (Aβ) in nasal secretions of patients with Alzheimer’s disease using multichannel impedance analyzer (ToAD) and electrical‐immunosorbent assay (El‐ISA), and determined the predictive value of Aβ in nasal secretions for AD diagnosis.

Method

Nasal secretions were obtained from 84 participants with probable AD dementia (ADD), 83 with amnestic mild cognitive impairment (MCI), 22 with cognitive decline associated with other neurological disorders (OND), and 62 cognitively unimpaired (CU) participants. Aβ oligomers in nasal secretions were analyzed using ToAD / El‐ISA analytical systems. Capture antibodies in El‐ISA kits specifically capture Aβ oligomer in nasal secretion, and then detection probes for El‐ISA method bind with amyloid beta oligomer sequentially. Finally, unbound free detection probes in solution was electrochemically measured by ToAD analyzer for quantifying Aβ oligomers. Because this analytical method is based on the back‐titration, the change of electrical signal is inversely proportional with the concentration of detectable Aβ oligomers. Electrical signals finally expressed to Cantis AD Index (CAI, 0∼99) which normalized by standards for system calibration.

Result

The CAI was higher in the probable ADD group than in the CU group (p < 0.05). The accuracy of the CAI was fair in separating into the probable ADD and CU groups (AUC of the ROC curve = 0.665, 95% CI = 0.572‐0.758, SE = 0.047, p = 0.001). The accuracy of the CAI was fair in separating into the participants with positive amyloid PET scan and those with negative amyloid PET scan (area under curve [AUC] of the receiver operating characteristic [ROC] curve = 0.697, 95% confidence interval [CI] = 0.629‐0.766, SE = 0.035, p < 0.001). The CAI has a negative correlation with Mini‐Mental State Examination score and positive correlations with Clinical Dementia Rating scale‐Sum of Boxes and amyloid PET centiloid scale scores.

Conclusion

These results demonstrate that the level of Aβ in nasal secretions increases in AD and the detection of Aβ in nasal secretions using ToAD / El‐ISA analytical systems may be possible in predicting ADD.
Clinical appications of EEG/MEG in AD: diagnosis, prognosis and treatment monitoring
Authors: Gouw Alida A
Published: December 2023

Background

Electroencephalography (EEG) and magnetoencephalography (MEG) capture neuronal functioning directly, thereby providing an objective intermediate marker between pathological changes and cognitive symptoms in neurodegenerative diseases. Both techniques are highly suitable as tools in the context of memory clinics and their use for treatment monitoring is increasingly recognized.

Method

We will highlight recent developments important for the use of EEG / MEG as diagnostic and prognostic markers in dementia and as outcome measures in Alzheimer’s disease (AD) trials.

Result

In memory clinics, both visual and quantitative EEG / MEG are being used as supportive evidence in diagnostic challenges, especially when other pathology specific –likely more invasive‐ biomarkers are not available. Increasing numbers of papers using artificial intelligence to differentiate a specific dementia type from cognitively healthy subjects report fair to excellent accuracies that are especially high for dementia with Lewy Bodies (DLB). Multi‐class classification between six memory clinic diagnoses resulted in MEG‐based diagnostic profiles describing the probability estimates of each class. These diagnostic profiles provide an informative and intuitive tool for clinical use. In pre‐clinical stages of AD spectral changes are predictive of future cognitive decline, and in the mild cognitive impairment stage it differentiates between progression into dementia due to AD or DLB. As EEG / MEG are found to be sensitive to longitudinal changes, there is increasing interest in the use of EEG as outcome measures in clinical trials. Both spectral and functional connectivity measures showed a treatment effect in phase 2 pharmacological studies in early AD, giving objective support for (subtle) clinical effects of the drug on trial. The pursuit of discovering even more sensitive, robust and complementary measures lead to novel neurophysiological markers reflecting functional connectivity, signal variability and neuronal hyperexcitability.

Conclusion

EEG / MEG provide diagnostic and prognostic information applicable in memory clinics. The use of sensitive conventional and novel markers in (pharmacological) trials can support clinical treatment effects and have potential to reduce the size of trials.
Interneuron hyperexcitability in an APP/PS1 mouse model of Alzheimer’s disease
Authors: Hijazi Sara , van Heusden Fran C , Diachenko Marina , Nejat Mazyar Abdollahi , Smit August B. , Linkenkaer‐Hansen Klaus , van Kesteren Ronald E.
Published: December 2023

Background

Neuronal hyperexcitability is commonly observed in Alzheimer’s disease (AD) patients and in mouse models of AD. What is not clear yet is whether hyperexcitability occurs in all neurons or whether certain types of neurons are selectively vulnerable towards developing a hyperexcitable phenotype.

Method

Electrophysiological recordings were performed in hippocampal slices from APP/PS1 mice to measure intrinsic and network properties of excitatory pyramidal neurons and of inhibitory parvalbumin (PV)‐positive interneurons. Cell type‐specific chemogenetic interventions were used to selectively reverse the hyperexcitable phenotype of these neurons. The outcome of these interventions was measured using hippocampal slice physiology, local field potential (LFP) recordings and behavioral assessment.

Result

The intrinsic excitability of hippocampal PV interneurons was significantly higher in APP/PS1 mice at 3‐4 months of age whereas pyramidal neurons were not affected at this age. Increased excitability of PV interneurons coincided with impaired learning and memory in the Morris water maze. Reducing the activity of PV neurons using chemogenetics resulted in a complete and long‐lasting rescue of PV cell excitability, network properties and learning and memory. LFP recordings revealed changes in oscillatory power and excitation/inhibition balance that could be related to early PV cell hyperexcitability and may translate to novel EEG biomarkers to detect AD at an early stage in humans.

Conclusion

Hyperexcitability of hippocampal PV interneurons is an early cellular phenotype in APP/PS1 mice that is causally related to neuronal network and memory impairments, whereas pyramidal cells only become hyperexcitable at later disease stages. These findings are relevant for AD as they may help to identify neuronal activity markers that are specific for early disease stages as well as cell type‐specific ion channels or receptors that can be targeted to treat AD in its earliest stage.
Determinants of successful cognitive aging over 15 years: a population‐based study
Authors: Ekström Ingrid , Josefsson Maria , Bäckman Lars , Laukka Erika J
Published: December 2023

Background

Although aging is related to loss in cognitive function, some individuals maintain high levels of cognitive performance also in late life. However, studies mapping longitudinal cognitive trajectories are scarce and little is known about the factors that may promote successful cognitive aging (SCA). We sought to identify predictors of SCA, based on latent profiles derived from interindividual differences in rate of change across several cognitive domains.

Method

We followed 1,966 individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC‐K) over 15 years (mean baseline age = 71.6 years; 62.9% female). Participants were free from dementia at baseline and had undergone at least two cognitive assessments during follow‐up. Cognition was assessed with a comprehensive battery, including tests of semantic memory, episodic recall and recognition, letter and verbal fluency, and executive function. We estimated level and change within each of the cognitive domains with linear mixed effect models, based on which we classified participants into successful, normal, or decline groups. These groups were used to derive profiles of overall cognitive change trajectories, through latent class analysis. We then investigated demographic, health, lifestyle, and genetic predictors of profile membership.

Result

We obtained three latent cognitive profiles. 31.6% of the sample was classified as successful, 50.6% as normal, and 17.8% as decliner. In multi‐adjusted multinomial logistic regression analysis, membership in the successful profile was predicted by female sex, higher education, and a faster walking speed (ps < 0.003). Current smoking, feelings of loneliness, and carrying the Apolipoprotein ԑ4‐allele were associated with a lower likelihood of being classified as successful (ps < 0.037). Higher age, diagnosis of diabetes or depression, and being an ԑ4‐carrier increased the likelihood of being classified into the decline profile (ps < 0.026).

Conclusion

We identified several demographic, lifestyle, health, and genetic factors of SCA. Of note, these factors were different from those that predicted accelerated cognitive decline. Although some cognitive loss may be an inevitable part of aging, our results suggest certain modifiable factors (i.e. smoking and quality of social interactions) to be related to maintained cognitive function in older age.
Accelerated brain ageing in participants with higher cerebrovascular lesion load across aging, cognitive impairment, and mixed presentation
Authors: Beheshti Iman , Potvin Olivier , Dadar Mahsa , Duchesne Simon
Published: December 2023

Background

We aimed to investigate the association between cortical brain age and white matter hyperintensities (WMH) in diverse forms of clinically‐defined vascular conditions. Our hypothesis was that a higher WMH burden would be associated with higher cortical brain age in all clinical subtypes.

Method

We used standardized MRI data obtained from participants in the COMPASS‐ND cohort of the CCNA. We used a standard linear support vector regression algorithm to estimate brain age, matching chronological age to cortical anatomical measurements obtained with the FreeSurfer toolbox on T1‐weighted MRI, sex, and intracranial volume. We calculated brain‐PAD (i.e., predicted brain age minus real age) and applied bias adjustment to remove age‐dependency in the estimates. A validated automated technique utilizing T2‐weighted and fluid attenuated inversion recovery MRIs was used to compute WMH loads.

Result

Participants included 107 CIE, 240 mild cognitive impairment (MCI), 115 vascular‐MCI (V‐MCI), 81 probable Alzheimer’s disease (AD), and 50 V‐AD. There was a significant difference in brain‐PAD [ F (4,599) = 56, P < 0.001, ANCOVA test] among groups, whilst adjusting for sex and chronological age. All four categories of patients exhibited a significantly higher mean brain‐PAD than CIE (P < 0.001), with the AD cohort having the highest brain‐PAD. There was a significant difference in WMH loads [ F (4,586) = 48, P < 0.001, ANCOVA test] between groups, whilst adjusting for sex and age. All cohorts showed a positive correlation between brain‐PAD and WMH, indicating accelerated ageing in people with higher WMHs. We observed moderate and significant correlations between brain‐PAD and WMH loads for V‐MCI (r = 0.34, P < 0.001) and V‐AD (r = 0.36, P = 0.001) but weaker, while significant correlations in CIE (r = 0.20, P = 0.035) and AD cohorts (r = 0.24, P = 0.025).

Conclusion

We observed a positive and significant link between brain‐PAD and WMH in all categories. This finding indicates on the importance of treatment and prevention strategies for vascular risk factors, which might be able to slow down the progression of cerebrovascular lesions and delay the effect on cortical thickness.