bluuebunny/crossref_metadata_2025 huggingface dataset:
Early‐phases [18F]florbetapir and [18F]flutemetamol images as proxies of brain metabolism in the Alzheimer’s disease spectrum
Authors: Boccalini Cecilia , Peretti Débora Elisa , Ribaldi Federica , Stampacchia Sara , Tomczyk Szymon , Rodriguez Cristelle K , Montandon Marie‐Louise , Haller Sven , Giannakopoulos Panteleimon , Frisoni Giovanni B , Perani Daniela , Garibotto Valentina
Published: June 2023

Background

Alzheimer’s disease (AD) neuropathologic changes are β‐amyloid (Aβ) deposition, pathologic tau, and neurodegeneration. Dual‐phase amyloid‐PET might be able to evaluate Aβ deposition and neurodegeneration with a single tracer injection. Early‐frames of amyloid‐PET scans provide a proxy for cerebral perfusion, which has shown good correlations with neural dysfunction measured through metabolic consumption, while the late‐frames depict amyloid distribution. Our study aims to assess the comparability between early frames of amyloid‐PET scans and [18F]fluorodeoxyglucose (FDG) PET in their topography and their ability to discriminate patients in the AD continuum.

Method

166 subjects evaluated at the Geneva Memory Center (Cognitively Unimpaired, CU = 61; Mild Cognitive Impairment, MCI = 73; Dementia = 21) underwent early‐phase amyloid‐PET – using either [18F]florbetapir (eFBP) (n = 95) or [18F]flutemetamol (eFMM) (n = 72) – and FDG PET. Standardized uptake value ratios (SUVR) were extracted within key regions sensitive for AD (metaROI) to evaluate the correlation of eFBP/eFMM and their respective FDG PET scans. To compare the discriminative power of eFBP, eFMM, and FDG SUVR between Aβ‐negative CU and Aβ‐positive impaired patients, receiver operating characteristic analyses and voxel‐wise t‐tests were performed. SPM single‐subject procedure was applied to investigate hypometabolic and hypoperfusion maps and their spatial overlap by means of DICE.

Result

Strong positive correlations were found between eFBP/eFMM and FDG SUVR independently of Aβ status and Aβ radiotracers (r>0.85, p<0.001). Both eFBP and eFMM, and FDG SUVR significantly discriminated AD cognitively impaired patients from CU in the metaROI (AUCFBP = 0.768; AUCFMM = 0.778), with FDG performing slightly better than others (AUCFDG = 0.797). For all tracers, voxel‐wise analyses confirmed reduced signals in regions typically belonging to AD hypometabolic pattern in AD patients when compared to controls. SPM single‐subject analysis revealed different hypometabolism and hypoperfusion patterns with a high spatial concordance, differing between stages (DICE average: AD dementia = 0.91; Aβ‐positive MCI = 0.61).

Conclusion

Distribution of perfusion was comparable to that of metabolism at group level and at single‐subject level. Our findings indicate that eFBP and eFMM imaging provide information closely related to brain regional glucose metabolism supporting their use for individual classification in clinical practice.
Determinants of implementation: Embedding pet robots in nursing homes for dementia care
Authors: Koh Wei Qi , Toomey Elaine , Flynn Aisling , Casey Dympna
Published: June 2023

Background

Pet robots are a type of social robots that have been used to benefit the psychosocial health of people living with dementia, particularly in nursing home settings. Despite the body of literature that have been conducted to evaluate their impacts, research to understand how pet robots can be translated from research into real‐world practice have been largely overlooked. This study seeks to address this knowledge gap by exploring the multilevel barriers and facilitators to implementing two pet robots for dementia care in nursing homes.

Methods

We conducted a descriptive qualitative study, conceptualised and guided using the Consolidated Framework of Implementation Research (CFIR), which consists of 39 constructs within five domains salient to implementation. Maximum variation sampling was used to identify and recruit healthcare professionals and organisational leaders from nursing homes. Individual, semi‐structured interviews were conducted with each participants face‐to‐face or over Zoom. Data was transcribed and analysed using Framework Analysis, supported by the NVivo12 qualitative data management software.

Results

A total of 22 participants from eight nursing homes were included in this study, of which 9 had seen or used a pet robot with residents with dementia. Barriers and facilitators were mapped to constructs from all five CFIR domains: 1) intervention characteristics, 2) outer setting, 3) inner setting, 4) characteristics of individuals and 5) process. Facilitators include the realisticness and familiarity of pet robots, identification of residents’ needs that can be met (or were met) using a pet robot, compatibility with prevailing regulatory guidelines and organisational care process, intrinsic desires to improve residents’ quality of life, and buy‐in from stakeholders. Barriers include a lack of customisability of pet robots to suit residents’ abilities and preferences, doubts about long‐term use, prohibitive costs, lack of external funding, lack of resources and knowledge, infection prevention mandates, and conflicting views on the anthropomorphisation of pet robots.

Discussion

Overall, this study highlights an incongruence between the characteristics of pet robots, organisational considerations (such as available resources), and external contextual factors. These findings have practical utility in informing the development of implementation strategies to guide the translation of pet robots from research into real‐world practice.
Alzheimer’s Disease as an Autoimmune Disease
Authors: Weaver Donald F , Meek Autumn , Reed Mark , Barden Christopher
Published: June 2023

Background

The identification of new exploitable molecular pathogeneses (beyond the conventional amyloid hypothesis) for Alzheimer’s disease (AD) is a continuing neurotherapeutic priority, and has yielded a range of mechanistic proposals including immunopathy, gliopathy, mitochondriopathy, synaptopathy. However, as these new hypotheses emerge, they are often regarded as mutually exclusive and even in competition. Rather than unconditionally rejecting the role of amyloid‐β (Aβ) (or any other proposed mechanism), the need for a broadly‐encompassing model of AD, which harmonizes multiple divergent theories into a single unified explanation emerges as a much‐needed goal.

Method

We performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic‐molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, new chemical entities were synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small molecule therapeutics.

Result

In response to various stimuli (e.g. infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon ‘self’ neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. Following this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐Alzheimer’s molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD’s complex immunopathic‐proteopathic pathogenesis.

Conclusion

Conceptualizing AD as a brain‐centric autoimmune disease of innate immunity (with Aβ as an immunopeptide), and identifying endogenous regulators of this autoimmunity, represents a novel comprehensive conceptualization approach to AD with therapeutic implications.
ABTEST‐IA: A new reliable tool for the quantification of Aβ40 and Aβ42 in CSF
Authors: Fandos Noelia , Romero Judith , Pascual‐Lucas María , Alcolea Daniel , Castillo Sergio
Published: June 2023

Background

The ratio Aβ42/Aβ40 in cerebrospinal fluid (CSF) is considered one of the most reliable biomarkers of Alzheimer’s Disease. ABtest40‐IA and ABtest42‐IA have been widely used for amyloid‐β (Aβ) quantification in plasma samples. The aim of this study was to validate these tests for the quantification of Aβ40 and Aβ42 in CSF.

Method

Analytical validation of ABtest40‐IA and ABtest42‐IA was accomplished following FDA and EMA reference guidelines. Calibration curves, sensitivity, specificity, accuracy, precision, recovery and dilution linearity were evaluated.

Correlations between ABtest‐IA and an independent fully automated IVD test, (Lumipulse ® G β‐amyloid 1‐40 and 1‐42, Fujirebio), were estimated using 93 CSF samples of PET‐Aβ positive (75%) and PET‐Aβ negative (25%) individuals. Differences in CSF Aβ42/Aβ40 levels between both PET‐Aβ groups were analyzed (Mann Whitney test).

The ability of CSF Aβ42/Aβ40 ratio to discriminate between PET‐Aβ positive and PET‐Aβ negative subjects was evaluated by means of Receiver Operating Characteristic (ROC) curve analysis, considering PET‐Aβ the gold standard.

Result

Calibration curves ranges were set at 43.9 to 500 pg/mL for ABtest40‐IA and 5 to 100 pg/mL for ABtest42‐IA. Intra‐assay, inter‐assay and inter‐lot coefficients of variation were below 5.2% and 7.4% for ABtest40‐IA and ABtest42‐IA respectively. Accuracy evaluation provided mean relative errors of 4.6% and 7.5%.

Spearman correlation coefficients between ABtest‐IA and Lumipulse® were 0.96, 0.95 and 0.93 for Aβ40, Aβ42 and Aβ42/Aβ40 respectively (p values < 0.0001). As expected, Aβ42/Aβ40 ratio levels were significantly lower in the PET‐Aβ positive group (p < 0.0001).

ROC analysis of CSF Aβ42/Aβ40 gave an AUC of 0.85 (95% CI 0.74 to 0.97), very similar to that obtained with Lumipulse®: 0.84 (95% CI 0.72 to 0.98). The overall agreement of PET‐Aβ and ABtest‐IA Aβ42/Aβ40 was 90%, being false positives the majority (78%) of the misclassified subjects. Results are supporting that CSF Aβ42/Aβ40 is an early biomarker of cerebral amyloid deposition.

Conclusion

ABtest40‐IA and ABtest42‐IA were successfully validated as new precise and accurate tools for the quantification of Aβ40 and Aβ42 in CSF samples. ABtest‐IA measures of Aβ42/Aβ40 ratio in CSF identified individuals with brain amyloid deposition with equivalent ability to other test commercially available.
Neurogranin and BACE1 as biomarkers for early detection of Alzheimer’s disease
Authors: Wang Xiao , Priller Josef , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Jessen Frank , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Peters Oliver
Published: June 2023

Background

A major goal on Alzheimer’s disease (AD) is to identify the disease in its earliest stages to provide optimal care for patients as soon as possible. Currently, the initial clinical diagnosis of AD is substantiated by the quantitative analysis of amyloid β (Aβ) peptide and Tau protein (Tau) in the cerebrospinal fluid (CSF). However, when AD becomes manifest in mental disturbances, Aβ and Tau levels have already become static. Thus, the identification of biomarkers within the earliest stages of AD are of utmost interest.

This study aimed to investigate the postsynaptic proteins neurogranin and beta‐secretase 1 (BACE1) for early discrimination in AD spectrum.

Method

We analyzed the data from DELCODE, a multicenter prospective cohort study. CSF levels of neurogranin and BACE1 were measured using ELISA and compared in participants with unimpaired cognition, subjective cognitive decline (SCD), mild cognitive impairment (MCI), mild AD dementia and first‐degree relatives of patients with AD dementia. To explore differences between earlier groups, we further divided SCD into two groups based on Aβ42/pTau181: Aβ42/pTau181‐SCD, Aβ42/pTau181+SCD. Differences between the groups were analyzed with non‐parametric tests. The significance values of group‐wise comparisons were adjusted by Bonferroni correction for multiple tests.

Result

A total of 530 participants were finally enrolled, including 91 healthy controls, 212 SCD (155 Aβ42/pTau181‐SCD, 57 Aβ42/pTau181+SCD), 114 MCI, 67 AD dementia and 46 first‐degree relatives. The comparisons between different groups showed CSF levels of neurogranin and BACE1 were significantly higher in Aβ42/pTau181+SCD (503.08 ± 202.89 pg /ml and 2406.39 ± 613.89 pg /ml, respectively) than those in Aβ42/pTau181‐SCD (330.94 ± 134.02 pg /ml and 1972.19 ± 561.94 pg /ml, respectively, both P < 0.0001). The AD group showed higher neurogranin levels than all other groups except Aβ42/pTau181+SCD (all P < 0.05). Furthermore, the CSF levels of Neurogranin were correlated with baseline MMSE scores (spearman r = ‐ 0.16, P < 0.001).

Conclusion

This study reveals that neurogranin and BACE1 provide new perspectives for discriminating AD, which may open up possibilities of new therapeutic targets for AD.
Hippocampal BDNF encapsulated cell bio‐delivery improves spontaneous behavioral alternations in the Y‐maze test in AppNL‐G‐F mice.
Authors: Tambaro Simone , Mitra Sumonto , Gera Ruchi , Linderoth Bengt , Wahlberg Lars , Behbahani Homira , Darreh‐Shori Taher , Nilsson Per , Eriksdotter Maria
Published: June 2023

Background

Alzheimer’s disease (AD) is an age‐related disease characterized by synaptic dysfunction, brain inflammation, and neurodegeneration against which there is no effective cure available. Brain‐Derived Neurotrophic Factor (BDNF) is a key molecule involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain permeability. In this study, we used an innovative encapsulated cell biodelivery (ECB) device containing cells capable of locally delivering BDNF to characterize its neuroprotective effects in the novel AD APP‐knock‐in mouse model AppNL‐G‐F.

Method

ECB devices with human ARPE‐19 cells modified to release BDNF were surgically bilaterally implanted in the hippocampus of 3‐month‐old AppNL‐G‐F mice. BDNF effects on AD pathology were evaluated after 1, 2, and 3 months of treatment by immunohistochemical and biochemical analysis. In the 3‐month‐treated groups, exploratory and memory performances were also evaluated using Elevated Plus Maze (EPM) and Y‐maze tests.

Result

The ECB implants were well tolerated with no signs of unwanted side effects or weight loss. A high BDNF staining was detected in most of the brains in the area surrounding the devices at 1‐3 months, but retrieved devices showed variability of BDNF release. Interestingly, three months of BDNF treatment significantly improved AppNL‐G‐F mice´s anxiety behavior in EPM and improved the spontaneous behavioral alternations in the Y‐maze test.

Conclusion

The results of this study are encouraging and support the BDNF device as a promising approach for treating cognitive AD decline. Optimization of the mouse‐sized devices to reduce the variability of BDNF release is needed for future experiments and translated to larger devices for clinical translation.
Effect of alpha‐Synuclein on the binding of [18F]MK‐6240 and [18F]AV‐1451
Authors: Kunach Peter , Moquin Luc , Hopewell Robert , Aliaga Arturo Aliaga , Tissot Cécile , Therriault Joseph , Zimmermann Maria , Kulasek Michal , Soucy Jean‐Paul , Massarweh Gassan , Rosa‐Neto Pedro
Published: June 2023

Background

Binding in alpha‐synuclein containing brain regions have been described for both Flortaucipir ([18F]AV‐1451) and [18F]MK‐6240. Here we assessed whether alpha‐Synuclein constitutes a target for these tau imaging agents.

Method

We used autoradiographic dot blot to validate specific and evaluate off‐target interactions of [18F]MK‐6240 and [18F]AV‐1451 using sarkosyl‐insoluble extracts from PSP, CBD, PiD, and AD cortical tissue which contain fibrillar forms of tau. Tissue concentrations of alpha‐Synuclein are orders of magnitude lower than NFTs leading us to use recombinant alpha‐Synuclein PFFs to evaluate potential off‐target interactions.

Briefly, 1:100 dilutions of each preparation were incubated with 82 fmol of mass in a 30uL total volume. Samples were incubated for 90 minutes at 37°C. Reactions were terminated by pipetting the solution in triplicate onto a glass fiber filter held within a 96‐well dot‐blot aspiration device and the samples were immobilized. Unbound ligand was washed three times with ice cold PBS. The glass fiber filters were transferred to a cassette for exposure to autoradiographic film for 90 minutes and the activity in photostimulated luminescence units per mm2 was calculated using ImageJ software v.1.8.0.

Result

Disintegrations were corrected for decay and normalized to cerebellar extracts for both ligands. [18F]MK‐6240 demonstrated high specificity, binding in AD extracts and AD extracts subject to trypsin treatment. [18F]AV‐1451 demonstrated similar binding in both native and trypsinized AD extracts, while also showing overlapping binding profiles in human alpha‐synuclein PFFs but not in mouse alpha‐synuclein PFFs.

Conclusion

[18F]AV‐1451 binds to recombinant human alpha‐Synuclein PFFs as it does to native AD‐tau PHFs. Future experiments should assess patient derived alpha‐Synuclein aggregates as a potential off target binding to [18F]AV‐1451.
Relation of different CSF biosignatures to clinical phenotypes in a memory clinic cohort
Authors: Alanko Vilma , Mravinacová Sára , Kivipelto Miia , Månberg Anna , Nilsson Peter , Sandebring‐Matton Anna
Published: June 2023

Background

The heterogeneity of a multifactorial disease like Alzheimer’s disease (AD) cannot be captured solely with ATN biomarkers. Previous research has identified mixed neuropathologies as well as subtypes discovered by brain scans and cerebrospinal fluid (CSF) proteomics in AD cohorts. Still, we need a better understanding of how clinical characteristics distribute between subgroups of AD. Additionally, various approaches determining subgroups need to be evaluated. AD, which falls under the umbrella term dementia, could in fact also be considered an umbrella itself with distinct subgroups.

Method

Altogether 288 CSF samples from patients from the Karolinska University Hospital memory clinic in Solna, Sweden, were analysed. Patients in the cohort were diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and different dementias, mainly AD. Using an antibody‐based suspension bead array, levels of 75 proteins were measured. Clustering analysis methods were used to identify subgroups.

Result

The assessed panel reveals differences in patterns of protein levels within diagnostic groups and by applying clustering analyses subgroups across the dementia spectrum can be identified. Furthermore, Gene Ontology search implies differences in plausible underlying disease mechanisms between the distinct subgroups. It is of interest to explore to what extent, e.g., cardiovascular conditions or psychological burden are represented in the subgroups.

Conclusion

Identifying subgroups within different diagnostic groups may prove to be crucial for finding the most suitable prevention and treatment options, particularly when disease modifying drugs are developed and tested.
Perceived usefulness of a shared journal feature to support coordination and communication across dementia care networks
Authors: Linden Anna , Jolliff Anna , Werner Nicole , Elliott Christian , Zuraw Matthew
Published: June 2023

Background

Care partners (family and friends) for people living with Alzheimer’s Disease and related dementias (ADRD) often provide care within a care network of both informal (e.g. family, friends) and formal (e.g. home aides, respite care) supports. Care networks can improve care but are often associated with increased communication and coordination demands. Technology interventions have potential to support care networks, but evidence is limited. This study explored care network use of a shared communication platform to identify care partner’s perceptions of the platform’s usefulness.

Method

This study used data from a feasibility trial for CareVirtue, a web application designed to support care partners in storing and sharing information with members of their network. Fifty‐one care networks comprised of a primary care partner and other network members (N = 61) in California and Wisconsin used CareVirtue for 60 days and completed a post‐trial semi‐structured interview. This analysis focused on CareVirtue’s journal feature, which allows users to share daily experiences through written posts published to a newsfeed that care network members can view and comment on. We exported the text of these journal entries and conducted team‐based content analysis. We performed a thematic analysis on interview transcripts to identify themes related to the journal’s usefulness.

Result

In total 2,535 journal entries from 51 primary care partners (75% female, mean age = 60 years old, 55% children of care recipient, 40% spouses) and their care network were analyzed.

Journal entries: We identified four categories of communication and coordination activities: 1) information acquisition in which care network members sought updates; 2) information sharing including tracking behaviors, symptoms, and daily activities; 3) strategy development in which care network members used two‐way communication to co‐create care solutions; and 4) feedback including affirmation, empathy, gratitude, confirmation, and information exchange.

Interviews: We identified three journal usefulness themes: individual level usefulness including tracking information and therapeutic benefits; network level usefulness including facilitating collaboration; and relational usefulness including increased situational awareness and feeling seen as a care partner.

Conclusion

The CareVirtue journal facilitated communication across the care network and also enabled self‐exploration, heightened awareness, and collaborative strategy development among the care network.
A systematic review of the neuroanatomical correlates and predictors of psychosis in Alzheimer’s disease
Authors: Scarfo Sara , Grigoriadou Loulouda , Marsella Antonella M.A. , Moshfeghi Yashar , McGeown William J
Published: June 2023

Background

Psychotic symptoms (delusions or hallucinations) are a particularly prevalent form of neuropsychiatric symptom in people with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). Notably, their presence has been associated with an aggravation of the clinical picture of AD, with features including more rapid cognitive and functional decline, increased distress for the individuals and their caregivers (resulting in a higher rate of hospitalisation), and increased mortality. A growing number of studies detailing the relationship between neuroanatomy and these symptoms have been published in the last three decades in an attempt to clarify the underlying mechanisms. The aim of this systematic review is to capture all of the studies on AD that report links between psychotic symptoms and neuroanatomy, and to synthesise and evaluate these. Differences in the neuroimaging techniques employed, psychosis assessment tools, and brain areas investigated, as well as the sample size of the studies and disease stage of the patients, are likely to produce heterogeneous results, and these factors will be investigated during the review process.

Method

The protocol for this systematic review has been pre‐registered using the Open Science Foundation (DOI 10.17605/OSF.IO/TG8XP). Searches were performed using the databases PubMed, Web of Science and PsycInfo. These were followed by screening titles and abstracts and then full texts. These steps were performed by two independent reviewers, and recorded in a PRISMA flowchart. Inclusion of the studies was determined according to the following eligibility criteria: studies were either cross‐sectional or longitudinal to investigate the brain regions/networks that predict the future manifestation of psychotic symptoms; they contained samples of people with AD and/or MCI; they had a focus on delusions and/or hallucinations; they were limited to publications in English and peer‐reviewed publications; they had no restriction on publication date.

Result

Data extraction on full texts is currently underway. Once extraction is complete, data will be synthesised through summary tables and narrative descriptions.

Conclusion

This systematic review intends to provide a comprehensive summary and synthesis of the brain regions and networks that are associated with psychosis and will capture key elements of the studies that are likely to impact their findings.
Pathologic TDP43 Associated Tri‐Glial Dysfunction in Amnestic and Non‐amnestic Clinical Dementia Syndromes: A Multiplexed Immunofluorescence Study
Authors: Lilek Jaclyn N , Ajroud Kaouther , Spencer Callen , Matos Arleen , Liu Xueyan , Bonakdarpour Borna , Mesulam M.‐Marsel , Bambakadis Eva , Shapiro Rachel , Feldman Alexander , Castellani Rudolph J , McCord Matthew , Jamshidi Pouya , Gefen Tamar , Weintraub Sandra , Flanagan Margaret E ,   Mesulam Center for Cognitive Neurology & Alzheimer’s Disease
Published: June 2023

Background

Alzheimer’s disease (AD) is a substantial cause of death and disability. In addition to the plaques and tangles classically observed in AD, other co‐existing brain lesions also contribute to the development of cognitive impairment, such as pathologic trans‐active response DNA‐binding protein 43 (pTDP43). TDP43 is ubiquitously expressed in the brain and mechanistic studies suggest potential roles for TDP43 in maintaining normal physiologic conditions in glia (astrocytes, microglia, oligodendrocytes) (Bulgiani, 2022). Effective glial functioning and signaling are crucial to maintaining functional connectivity and pTDP43 is strongly associated with lower cognitive performance (Flanagan, 2018). However, pTDP43’s role in tri‐glial dysfunction remains unclear. We hypothesize that nuclear astrocytic TDP43 loss alters astrocyte‐to‐microglial signaling, and results in tri‐glial dysfunction. Here we examine glial pTDP43 subtypes in amnestic and non‐amnestic clinical dementia syndromes with matched AD pathology.

Method

Paraffin embedded autopsy samples (hippocampus and middle frontal cortex) were stained using multiplexed immunofluorescence (Pu.1: microglia, GLUL: astrocytes, total TDP43), and imaged. Indica Labs Halo software was used to perform quantitative analyses on whole slide images. Cases were matched for AD pathology (low and high) (Montine, 2012). Students’ t‐tests were performed to compare cell counts between groups. Kolmogorov–Smirnov test was performed to check approximate normality before applying t‐test and all measurements passed it. Clinical phenotypes (AD dementia vs. behavioral variant frontotemporal dementia (bvFTD)) and pTDP43 status were compared (n = 50). Spatial localization plots, NSInC colocalization indices, and Box plot comparisons were used to assess the impact of glial pTDP43 on the microenvironment.

Result

Hippocampal astrocyte counts are lowest in the AD dementia setting with the highest AD pathology burden, and presence of co‐existing pTDP43. Cases with high AD pathology had lower astrocyte counts when co‐existing pTDP43 was present when comparing both AD dementia with pTDP43 vs. AD dementia without pTDP43 (p = 0.03), and AD dementia with pTDP43 vs. bvFTD without pTDP43 (p = 0.05).

Conclusion

Contradictory to studies showing increased GFAP in mutant TDP43 mice (Yan, 2014), the lowest astrocyte counts were found in individuals with AD dementia, highest burden of AD pathology, and presence of pTDP43. Results support the role of astroglial heterogeneity contributing to white matter dysfunction via selective vulnerability.
Levels of insulin pathway proteins in persons with concomitant Alzheimer’s disease dementia and type 2 diabetes mellitus
Authors: Grigoli Marina Mantellatto , de Oliveira Danielle dos Santos Maia Salheb , Manzine Patricia Regina , Cominetti Marcia Regina
Published: June 2023

Background

Alzheimer’s disease (AD) is a gradual and progressive neurodegenerative disease characterized by predominant cortical atrophy in the medial temporal lobe. Since the results of the Rotterdam study in 1992, it has been known that type 2 diabetes mellitus (T2DM) increases the risk of dementia. Persons with T2DM have structural brain changes and cognitive impairment, with a high risk of developing AD. These data suggest that insulin may play a key role in brain activity and memory formation. The objective of this study was to verify if there are alterations in the levels of proteins of the insulin pathway in cognitively healthy individuals, with AD, with T2DM and with the concomitant presence of AD and T2DM.

Method

The study was approved by the UFSCar’s ethics committee (CAAE: 31634720.9.0000.5504) and recruited participants aged 60 years or older. The AD diagnosis was obtained using the criteria of the National Institute Aging Alzheimer’s Association (NIA/AA). T2DM was defined as self‐reported use of oral antidiabetic drugs. Specific inclusion and exclusion criteria and cognitive assessment of the MMSE and CDR were applied to all participants. Plasma was collected by venepuncture and protein levels of ISNR, IRS1, Akt1, PI3KCD, MAPK1, MAPK8, PTP1B and IDE (Life‐Span Biosciences) were analysed using ELISA (Enzyme Enzyme‐Linked Immunosorbent Assay).

Result

Several proteins of the insulin pathway were found to be significantly different among patients with AD, T2DM and AD+T2DM, compared with healthy controls (figure 1), reinforcing the strong correlation between T2DM and AD. Main alterations were found for INSR, IRS1, Akt1, PIK3, MAPK, PTP1b and IDE among healthy participants and those with AD+T2DM.

Conclusion

The peripheral alterations found in the levels of insulin pathway proteins confirm the possible relationship between T2DM and AD and reinforce the importance of the insulin signalling pathways, as they can play a fundamental role in AD. The clinical impact of this study is related to a new approach that could be used in the treatment of this type of dementia, also observing the metabolic and inflammatory states of the patients, in addition to contributing to a better understanding of the biology of the disease itself.
Association of Apolipoprotein E ε4 with Tau and Amyloid‐β PET in a memory clinic cohort
Authors: Peretti Débora Elisa , Ribaldi Federica , Stampacchia Sara , Tomczyk Szymon , Blouin Jean‐Louis , Wyss‐Dominguez Carine , Abramowicz Marc , Frisoni Giovanni B , Garibotto Valentina
Published: June 2023

Background

The Apolipoprotein E ε4 (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease (AD). Previous studies have found a link between ApoE4 genotype and tau (T) deposition in the medial temporal lobe (MTL). However, further studies disentangling the influence of genotype on tau deposition and amyloid (A) are still needed. The aim of this study was to assess tau and amyloid deposition depending on subject genotype in a memory clinic cohort.

Method

89 subjects from the Geneva Memory Center underwent amyloid and tau PET imaging, and ApoE genotyping (ApoE2 carriers, ApoE3 homozygotes, ApoE4 carriers). The remaining subjects were classified as ApoE3. Amyloid uptake has been calculated as centiloid values and tau uptake as standardized uptake value ratio (SUVR), normalized to cerebellar uptake. Positivity for each biomarker was based on thresholds published by previous studies. Correlation between amyloid centiloid and tau SUVR in general and by genotype was calculated. ANOVA with Tuckey correction for multiple comparisons was used to assess differences between tau or amyloid PET uptake across different genotypes.

Result

85% of the A+T+ subjects were carriers of the ApoE4 gene. The association between neocortical amyloid and MTL tau stratified by genotype showed that these measures are correlated in ApoE4 carriers (r = 0.52, p = 0.001). The correlation was not significant in non‐carriers. MTL tau SUVR was higher in ApoE4 carriers and significantly different when compared to non‐carriers. Furthermore, tau SUVR from lateral and superior temporal lobes were also significantly different in ApoE4 carriers vs. non‐carriers even when not considering the centiloid value, showing an amyloid‐independent association between tau SUVR and genotype is not limited to the MTL. Centiloid values showed similar differences when comparing ApoE4 carriers with non‐carriers.

Conclusion

ApoE4 gene carriers present a significant increase of both tau and amyloid load with respect to non‐carriers. Furthermore, increased tau deposition independent from amyloid load is not limited to the MTL, with the entire temporal lobe showing higher tau pathology in ApoE4 carriers.
Continuous wave 670nm LED light therapy improves short‐ and long‐term object recognition, locomotion, and reduces phosphorylated tau burden in 3xTgAD mice
Authors: Johnson Kevin J , Johnson Kathia M , Taglialatela Giulio , Micci Maria‐Adelaide
Published: June 2023

Background

Photobiomodulation (PBM) therapy uses 620‐1100nm red to near‐infrared light to modulate biological processes including neuroinflammation, amyloid and tau oligomerization, and apoptosis. We have shown that 670nm light therapy reduces synaptic vulnerability to amyloid‐β oligomers in wild‐type (WT) mice and reduces tau oligomerization in mouse models of tauopathy. Here we sought to determine if 670nm light therapy could rescue cognitive and motor dysfunction and reduce tau hyperphosphorylation in 14‐to‐18‐month‐old 3xTgAD mice.

Method

14‐to‐18‐month‐old 3xTgAD mice were treated with continuous‐wave 670nm LED light applied directly to the head for 90s per day, 5 days per week for 4 weeks. 3xTgAD sham and WT controls were held under the LED device with the light turned off for the same amount of time. During the fourth week of treatment, spontaneous locomotor behavior was measured by placing animals in an empty chamber for 10 minutes using ANY‐maze software to track mobility data. Animals were then tested for working memory in the Y maze spontaneous alternation task and short‐and long‐term memory in the novel object recognition task. At the completion of behavioral testing on treatment day 20, brains were collected for western blot analysis of total tau and phospho‐tau (pTau).

Result

Light‐treated 3xTgAD mice showed increased distance traveled compared to sham (17.43 ± 3.46 vs. 9.97 ± 3.03, one‐way ANOVA p = 0.03), and decreased immobile episodes (4.50 ± 1.92 vs 10.00 ± 1.83, one‐way ANOVA p = 0.02) in the spontaneous locomotor activity test. Light‐treated animals also showed significant object recognition at 2 hours (DI 32.75 ± 7.71, one sample t‐test p<0.001) and 24 hours (DI 44.14 ± 15.73, one sample t‐test p = 0.001) post‐training. Light treatment also reduced the ratio of hippocampal pTau/Tau in 3xTg AD mice as compared to sham (0.11 ± 0.05 vs. 0.32 ± 0.13, one‐way ANOVA p = 0.04).

Conclusion

Here we show rescue of locomotor behavior and cognitive dysfunction, and reduction of Tau phosphorylation in the hippocampus of 3xTgAD mice using a non‐invasive transcranial treatment with 670nm LED light. Our data suggest that treatment with 670nm red light could significantly improve cognitive function in AD patients and reduce hyperphosphorylation of tau thus possibly preventing further neurodegeneration.
Using the Integrated Cognitive Assessment (ICA) to improve the efficiency of primary care referrals to memory services
Authors: Kalafatis Chris , Shore Judith , Modarres Mohammad Hadi , Apostolou Panos , Tabet Naji , Khaligh‐Razavi Seyed‐Mahdi
Published: June 2023

Background

Existing primary care cognitive assessment tools are crude or time‐consuming screening instruments which can only detect cognitive impairment when it is well established, impacting carers and patient quality‐of‐life.

We initiated the Accelerating Dementia Pathway Technologies (ADePT) study to develop a real‐world evidence basis to support the adoption of the Integrated Cognitive Assessment (ICA), a 5 minute computerised cognitive test that employs artificial intelligence to improve its accuracy, as an inexpensive screening tool for the detection of cognitive impairment and improving the efficiency of the dementia care pathway.

Method

Patients referred to memory clinics from primary care General Practitioners (GPs) were recruited. Participants completed the ICA either at home or in the clinic along with medical history and usability questionnaires. The GP referral and ICA outcome were compared with the specialist diagnosis obtained at the memory clinic.

The clinical outcomes as well as costing data were used as part of an economic analysis to assess the potential health economic benefits of the use of the ICA in the dementia diagnosis pathway in the United Kingdom.

Result

87 participants referred to memory clinics were recruited who completed all assessments (40 dementia, 19 mild cognitive impairment, 12 inconclusive, 5 healthy, 3 non‐dementia conditions). From these patients the ICA was able to identify cognitive impairment with a sensitivity of ∼90%.

The results of the health economics model, utilising real world data collected from the ADePT study estimates that if the ICA were introduced in a primary care setting then it could result in a cost saving to the health and social care system of approximately £147 per patient over a lifetime horizon (∼£44m of direct costs to the health care system) or £283 per patient if introduced into a secondary care setting.

Conclusion

The results from this study demonstrate the potential of the ICA as a screening tool to support accurate referrals from primary care settings to memory clinics. The introduction of disease modifying treatments for Alzheimer’s and dementia will further improve the case for earlier detection of the condition and therefore increase the cost‐effectiveness of more accurate screening using tests such as the ICA tool.
Neuropsychiatric inventory questionnaire scores are predictive of dementia progression
Authors: Rao Sumedha R , Housini Mohammad , Royall Donald R. , Palmer Raymond F. , Barber Robert
Published: June 2023

Background

In ageing adults, the most common form of dementia is Alzheimer’s disease (AD). AD pathogenesis involves the accumulation of beta‐amyloid (Aβ) protein aggregation in plaques and tau proteins in neurofibrillary tangles that are associated with a decreased number of synapses in the brain, altered neuronal function and cell death via neurotoxicity, as well as learning and memory deficits. Clinically, the presence and severity of neuropsychiatric symptoms that AD patients present with can be reliably measured by the Neuropsychiatric Inventory Questionnaire (NPIQ). This study aims to explore the association between baseline mental health and the severity of AD progression.

Method

To measure baseline mental health, NPIQ scores were used while the change in deq was used to represent the severity of AD progression within the TARCC cohort. deq is a homolog of d, a reliable latent dementia proxy that represents cognitive correlates of functional status and is specific for distinguishing cases with AD from other dementia‐related presentations. Most crucially, the deq homolog has been adjusted for equivalence across ethnicities. Using stratified analysis and structured equation models, the association between baseline mental health and change in was investigated.

Result

The first model exploring NPIQ and the change in deq was only adjusted for baseline deq; it showed NPIQ explaining 19% of the variance in delta deq and was statistically significant at p = 0.016 for Non‐Hispanic Whites. With the second model, age, sex, and education were adjusted for in addition to baseline deq. NPIQ was shown to explain 25% of the variance in delta deq while being statistically significant at p = 0.037 for Non‐Hispanic Whites. This model was replicated in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort; NPIQ was shown to be predictive for delta deq at p = 0.013.

Conclusion

In Non‐Hispanic Whites, worse baseline mental health has been shown to predict increased severity and progression of AD. This makes it a clinical therapeutic target with the possible benefit of impacting the course of AD in patients. The fascinating interplay between mental health and its relationship to Alzheimer’s disease should be studied further with an additional focus on ethnicity.
Brain insulin resistance and Alzheimer’s molecular changes induced by Western diet
Authors: Domańska Justyna Marta , Mietelska‐Porowska Anna , Want Andrew , Wieckowska‐Gacek Angelika , Wojda Urszula
Published: June 2023

Background

Western diet (WD) is a type of nourishment based on ultra‐processed foods, rich in simple sugars and saturated fats. Long‐term consumption of WD may lead to disruption of insulin signaling and development of insulin resistance. It is supposed that insulin resistance is a probable risk factors for Alzheimer’s disease (AD). The aim of this study was to verify this hypothesis in wild type mice by checking the WD effect on initiation and propagation of main neuropathological AD features such as amyloid‐β (Aβ) plaques and neurofibrillary tangles, which start from the entorhinal cortex in the temporal area, and progresses to the hippocampus, resulting in the loss of memory and cognition.

Method

Males of wild type C57BL/6J mice were fed WD diet or standard diet (SD; CTR). Mice experimental groups (WD and CTR) were divided into age subgroups 4‐, 8‐, 12‐ and 16‐month‐old. In the first step, the WD‐diet dependent insulin signaling was analyzed, and the levels of the insulin pathway components: p‐IRS‐1(Ser616), p‐Akt(473), p‐GSK‐3β(Ser9) in the entorhinal cortex and hippocampus were assessed. To analyze further whether WD‐derived impairments in insulin signaling may induce neuropathological AD features, p‐Tau(Thr231) and APP/Aβ were analyzed by immunoblotting and immunofluorescence of mouse brain tissue sections from entorhinal cortex and the hippocampus.

Result

Entorhinal cortex proved to be more sensitive to WD‐dependent insulin impairments than the hippocampus: immunoblotting analysis of mouse entorhinal cortex brain lysates revealed an increase in p‐IRS‐1(Ser616) levels, indicating the development of insulin resistance under WD diet. Moreover, a change in the localization of p‐Tau(Thr231) in cellular compartments from fibers to nerve cell bodies indicated a progressive tauopathy. In addition, we also observed an age‐dependent decrease in APP protein levels correlating with the appearance of Aβ peptides in the cytoplasm of neurons under the WD diet.

Conclusion

Obtained results suggest that the WD diet, by inducing abnormalities in insulin signaling in the brain, promotes the development of AD, and may be consider as a significant modifiable risk factor for AD, additional to the genetic risk factors.
Prediction of sleep quality scores using dynamic functional network connectivity of young adults: A reproducibility analysis
Authors: Sendi Mohammad S.E. , Dini Hossein , Zendehrouh Elaheh , Salat David H , Calhoun Vince D
Published: June 2023

Background

Dynamic functional network connectivity (dFNC) estimated from resting‐state functional magnetic resonance imaging (rs‐fMRI) is a potentially powerful approach to investigate human behavior and cognition. However, previous studies barely investigate the reproducibility of dFNC features links with cognition. This study aims to examine whether the data collected in four different sessions reproduce the same results using the sleep scores by applying a dFNC method to resting‐state fMRI (rs‐fMRI) data from the Human Connectome Project (HCP) Young Adult.

Method

We used the Pittsburgh Sleep Quality Index (PSQI) scores and four sessions of rs‐fMRI (15 minutes each) from 833 young adults (age between 22 to 37yrs). We calculated the dFNC for each participant using a fully automated Neuromark independent component analysis and a sliding window technique to estimate dFNCs. A k‐means clustering approach partitioned dFNCs into two group‐level distinct states and subject‐level state vectors. Next, we estimated dFNC features from each individual’s state vector and dFNCs. Finally, we trained a 10‐fold support vector regression model to predict the sleep scores based on the dFNC features. We applied all the procedures mentioned above to all four sessions separately.

Result

We found dFNC features can successfully predict each participant’s night sleep time. The correlation between the actual score and the predicted one was R = 0.0853 (p = 0.0182) for session1, R = 0.0696 (p = 0.0485) for session2, R = 0.0764 (p = 0.0393) for session2, and r = 0.0788 (p = 0.0285) for session4. The dFNC features for none of four sessions could predict other sleep scores.

Conclusion

We showed that the dFNC feature could predict the amount of sleep during the night in the HCP Young Adult population. Additionally, we showed the prediction result replicates across all four rs‐fMRI sessions. Future studies are needed to explore the reproducibility of the result within the age range of the HCP dataset.
Microbiome‐associated metabolic determinants of neurodegeneration and cognitive resilience
Authors: Matz Lisa M , Shah Nisarg S. , Urban Randall J , Kayed Rakez , Buffington Shelly A
Published: June 2023

Background

Type 2 diabetes (T2D) is a common antecedent of pathological neurodegeneration and accompanying dementia, including Alzheimer’s Disease (AD); however, the mechanistic link between metabolic and neurodegenerative disorders remains unresolved (1‐3). Study of a small cohort of dementia patients revealed divergent gut microbiota composition, increased gut permeability, and inflammation, implicating a microbial determinant in neuroimmune dysregulation (4), an emerging player in neurodegeneration (5). Notably, the microbiome is a source of neuroprotective metabolites (6), highlighting the need to elucidate the role of the microbiome and realize the potential for its therapeutic modulation in AD. We recently began a clinical trial focusing on individuals of Mexican descent living in Southern Texas, a population with increased prevalence of co‐morbid T2D and early onset AD (7‐8), with the working hypothesis that diet‐driven shifts in gut microbiome composition contribute to T2D and AD pathophysiology in this population (9‐11).

Method

We will perform metagenomic 16S rRNA gene amplicon sequencing and compare within (alpha) and between (beta) sample diversity as well as quantitative phylogenetic and taxonomic comparisons. Using 3xTg‐AD and hTau mouse models, we will determine the impact of microbial depletion via broad spectrum antibiotics on AD pathology and cognitive function. Data will be analyzed separately for each sex using nested t‐tests, nested one‐way ANOVA, or a mixed effects model to account for litter effects.

Result

Data resulting from our preclinical animal and clinical human studies will inform future experiments in which we will transplant fecal microbiota samples derived from T2D versus non‐diabetic human subjects into microbially‐depleted, “humanized” AD mice. We will then perform metabolomic, molecular, electrophysiological, and behavioral analyses to determine the impact(s) of T2D gut microbiota on host AD‐like pathology and behavioral phenotypes.

Conclusion

Characterizing gut microbiome signatures of T2D individuals of Mexican descent living in Southern Texas could identify key actors among “disease state” microbiota which may exacerbate or accelerate neurodegenerative disorders, as well as gut microbiota present in healthy controls lost in the T2D population which contribute to molecular mechanisms of cognitive resilience. Consequently, our approach may lead to novel immunotherapeutic approaches to target or limit neuroinflammation in AD.