bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between self and study partner report on the CFI with regional tau in a multi‐cohort study
Authors: Amariglio Rebecca E. , Jadick Michalina , Robinson Talia L , Klinger Hannah M , Buckley Rachel F. , Marshall Gad A , Vannini Patrizia , Rentz Dorene M. , Johnson Keith A. , Sperling Reisa A.
Published: December 2023

Background

Self‐report of cognitive decline is an early behavioral manifestation of Alzheimer’s disease at the preclinical stage, often thought to precede study partner‐report. Prior work has shown associations between subjective cognitive decline and amyloid, but less is known about tau deposition, particularly once tau has spread to neocortex. Using a multi‐cohort study of cognitively unimpaired individuals, we examined associations between self‐ and study partner‐report, amyloid and regional tau. Specifically, we hypothesized that greater self‐ and study partner‐report of cognitive decline would be observed with tau in the medial temporal lobe (MTL), whereas study partner‐report would be more strongly associated with neocortical (NEO) tau compared to self‐report.

Method

698 cognitively unimpaired individuals (55% elevated‐amyloid, mean age = 72.5, 58% female) came from the A4, LEARN, HABS, and SCD/IADL Studies. All participants underwent Flortaucipir‐PET quantified by SUVr. A MTL tau composite and a NEO tau composite were derived. An internally derived amyloid cut‐off was used for each study. Participants and their study partners completed the Cognitive Function Index (CFI), a 15‐item questionnaire asking about cognitive functioning over the last year. A series of linear regression models using tau (MTL vs. NEO) to predict CFI (self vs. study partner) were conducted, adjusting for age, sex, education, amyloid status and cohort.

Result

We first examined amyloid status and CFI and found elevated‐amyloid was associated with higher self‐report (t = 2.8, p = 0.017), but not study partner‐report (t = 1.5, p = 0.12). Building on this model, greater MTL tau was associated with greater self‐report (t = 3.30, p<0.001) and study partner‐report (t = 3.4, p<0.001), but not amyloid status. Greater NEO tau was associated with greater self‐report (t = 3.2, p = 0.002) and study partner‐report (t = 4.1, p<0.00001), but not amyloid status.

Conclusion

In this multi‐cohort study of cognitively unimpaired individuals, elevated‐amyloid was associated with greater self‐report CFI, but not study partner‐report. When accounting for amyloid status, both MTL and NEO tau were significantly associated with both self and study‐partner report, but effects were numerically stronger for study partner for NEO tau. These findings suggest that CFI report both from the participants and their study partners is valuable at the preclinical stage, but may evolve with increasing tau spread.
Remote, unsupervised measurement of dyadic subjective cognitive change in the Brain Health Registry
Authors: Aaronson Anna , Ashford Miriam T. , Jin Chengshi , Tank Rachana , Camacho Monica R , Fockler Juliet , Flenniken Derek , Truran‐Sacrey Diana , Mackin Scott R , Weiner Michael S. W. , Nosheny Rachel L
Published: December 2023

Background

Early, efficient identification of Alzheimer’s disease (AD) risk is a critical need. Dyadic subjective report from a participant and an informant/study partner (SP) who knows the participant well, may be a reliable and accurate method for assessing AD risk.

Method

The Caregiver and Study Partner Portal within the Brain Health Registry (BHR; an online registry and cohort) is a scalable tool for remotely obtaining dyadic data. All BHR participants are asked to identify a potential SP, who is invited to separately enroll and consent. SPs complete a demographic survey and questionnaires pertaining to cognition, behavioral symptoms, activities of daily living, and the health of the participant. Participants and SPs both complete an online adaptation of the Everyday Cognition Scale (ECog) to assess subjective cognitive change. We analyzed demographic characteristics of the dyads enrolled in BHR and measured correlation between SP and self‐report ECog scores. We used ADNI ECog data to estimate cut points likely to indicate cognitive impairment (1.43 for SP‐report scores and 1.65 for self‐report scores) and determined the number of BHR participants who are possibly impaired based on these cut points.

Result

Out of 93,134 BHR participants, 10,494 (11.3%) have an enrolled study partner (Figure 1). The mean SP‐report ECog score is 1.35±0.50 and mean self‐report ECog score is 1.46±0.47. SP and self‐report ECog scores are correlated (r = 0.47, p < 0.001) (Figure 1). Out of 8,374 participants with available SP‐report ECog scores, 2,194 (26.2%) are possibly impaired. Out of 10,018 participants with available self‐report ECog scores, 2,384 (23.8%) of participants are possibly impaired (Figure 2).

Conclusion

These findings demonstrate the feasibility of collecting online, dyad‐report demographic and subjective cognitive change data from a large cohort of participant‐SP dyads. The study failed to recruit an ethnoculturally and educationally diverse cohort of dyads. The positive correlation between self‐ and SP‐report ECog scores suggests dyad concordance in subjective report of change. Future efforts will focus on improving study partner enrollment and BHR task completion, increasing dyad diversity, and investigating the ability of remote dyadic measures to track cognitive decline and clinical progression along the AD continuum.
Alzheimer’s Disease as an Innate Autoimmune Disease Regulated by Tryptophan and Arginine Metabolism
Authors: Meek Autumn , Wang Yanfei , Wu Fan , Reed Mark , Barden Christopher , Weaver Donald F
Published: December 2023

Background

The identification of exploitable molecular pathogeneses for Alzheimer’s (AD) is an ongoing neurotherapeutic priority, yielding a range of different mechanistic proposals including proteopathy, immunopathy, gliopathy, synaptopathy, mitochondriopathy, oxidative stress, and metal dyshomeostasis. Rather than unconditionally accepting/rejecting the role of any one specific disease mechanism, the need for an innovative broadly‐encompassing model of AD, which harmonizes multiple divergent theories into a single unified comprehensive explanation, emerges as a much‐needed milestone on the road to a cure. Characterizing AD as a neurotoxic autoimmune‐inflammatory disorder, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses, may be such a milestone.

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, 981 new chemical entities were designed and synthesized to probe the biochemical pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small molecule therapeutics for AD.

Result

In response to various stimuli (infection, trauma, ischemia, air pollution), 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 such as Aβ. Following this self‐attack, the resulting necrotic 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. Since autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1,137 small molecules normally present in human brain identified tryptophan and arginine metabolism as regulators of brain innate immunity and a source of endogenous anti‐Alzheimer’s molecules capable of modification into therapeutic modulators targeting AD’s complex immunopathic‐proteopathic pathogenesis.

Conclusion

Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.
Electronic Health Record Tools to Facilitate Diagnosis of Cognitive Impairment in Primary Care
Authors: Fitzpatrick Annette L. , Raetz Jaqueline G. , Belza Basia , Park Christina , McKiddy Sarah , Liao Joshua M. , Suchsland Monica Zigman , Singh Angad P. , Olivari Benjamin S. , Gaster Barak
Published: December 2023

With novel biomarkers and treatments for dementia on the horizon, the need to detect cognitive impairment at early stages is urgent. The role of primary care providers (PCPs) in the diagnosis of mild cognitive impairment and dementia is essential in meeting this need. Cognition in Primary Care (CPC) is a quality improvement program developed at the University of Washington (UW), Seattle, which includes a three‐part Continuing Medical Education (CME), clinical workflow, and electronic health record toolset to support PCPs in early diagnosis of mild cognitive impairment and dementia. This program was developed using input from UW providers in primary care practice and elements from the KAER (Kickstart, Assess, Evaluate, Refer) Toolkit developed by the Gerontological Society of America (GSA). Our pragmatic approach involved the development of tools integrated into Epic, the electronic health record system in place at UW, that can be used during a patient visit to guide PCPs through the process of evaluating cognitive function. The toolset includes 1) a list of signs that may trigger the need for a dedicated follow‐up visit to evaluate cognition; 2) a cognitive checklist for related conditions affecting cognition (e.g., potentially harmful medications, depressive symptoms, alcohol use, and obstructive sleep apnea); 3) a structured framework for cognitive evaluation including validated instruments (e.g., MoCA and AD8); 4) referrals to specialty care; 5) billing guidelines; and 6) community resources and materials that patients and care partners can use both pre‐ and post‐diagnosis. We have pilot‐tested these tools in UW primary care clinics and found high utilization both within and outside of targeted clinics indicating a halo effect of usage beyond those who attended the CME training. In this presentation, we will provide detailed descriptions of these Epic tools focusing on clinical application to total patient care. We plan to publish these workflow tools onto the Epic Digital Library to be downloaded and used by other health systems. Future plans include producing on‐demand CME training modules, a post‐diagnosis checklist, and applications for use of these tools in systems outside of Epic.
Isolation of spontaneously‐released brain extracellular vesicles: implications for brain pathology
Authors: Gomes Patrícia A. , Bodo Cristian , Nogueras‐Ortiz Carlos , Samiotaki Martina , Chen Minghao , Soares‐Cunha Carina , Silva Joana , Coimbra Bárbara , Stamatakis George , Santos Liliana , Panayotou George , Tzouanou Foteini , Waites Clarissa , Gatsogiannis Christos , Sousa Nuno , Kapogiannis Dimitrios , Costa‐Silva Bruno , Sotiropoulos Ioannis
Published: December 2023

Background

In the era of Precision Medicine, extracellular vesicles (EVs) exhibit great potential for the theragnostic of brain disorders such as Alzheimer’s disease (AD), a complex disease with no effective treatment and poorly understood risk factors, where pathological heterogeneity and diverse clinical presentations complicate the development of precise patient‐tailored therapies. Thus, the collection and characterization of physiologically relevant EVs, as well as the study of its precipitating/risk factors, are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV preparations with intracellular vesicles.

Method

Based on a multiscale analysis, including cryo‐EM, label‐free proteomics, and ExoView, we hereby present a novel purification method of small EVs (sEVs) based on the spontaneous release of EVs from the brain.

Result

Our advanced EVs analysis demonstrated that our method represents an efficient purification method that captures a small EV‐enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated and under exposure to chronic stress, a clinically‐relevant precipitant of AD. Here we found that the released method monitors the drug‐evoked inhibition or enhancement of sEVs secretion in a very sensitive manner, while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress‐driven brain pathologies.

Conclusion

Overall, this method will contribute to the characterization of the biomarker profile of physiologically relevant brain‐derived sEVs in brain function and pathology.
Downregulating functional hyperactivity in APOE ε4 carriers: an important avenue for early‐life risk reduction
Authors: Lancaster Claire L , Dowell Nicholas , Bakker Arnold , Hinds Chris , Nwaubani Prince , Bird Chris , Tabet Naji , Rusted Jennifer M
Published: December 2023

Background

Hyperactivity in the brain regions supporting episodic memory (the hippocampus and default mode network) drives the accumulation of Alzheimer’s Disease (AD) neuropathology and the resulting cascade of brain network disruption. Pharmacologically reducing hippocampal hyperactivity using the anti‐seizure medication Levetiracetam improves memory in individuals with prodromal AD. Carriers of an APOE e4 genetic risk variant show patterns of brain hyperactivity from youth. This study tests if Levetiracetam can prophylactically manage hippocampal hyperactivity in mid‐age APOE e4 carriers, and if such a reduction is associated with improved cognitive performance.

Method

Fifty cognitively healthy adults (aged 45‐65 years), differentiated by APOE genotype (25 e4 carriers, 25 e33 carriers), are participating in a double‐blind, placebo‐controlled trial of Levetiracetam (125mg bidaily for two‐weeks). Analyses will primarily focus on change in task‐related and resting functional magnetic resonance imaging (fMRI) brain blood‐oxygen‐level‐dependent response (BOLD) following Levetiracetam. In addition, the everyday cognitive effects of this manipulation will be evaluated, including on daily smartphone‐based measures of memory and attention.

Result

To date, 43 participants are enrolled in the 8‐week intervention (23 of whom have completed). Adverse events relating to the study drug have been minimal; only one participant has withdrawn in response to experiencing side‐effects. APOE genotype and treatment order (Levetiracetam, placebo) will be unblinded at the end of data collection (anticipated April 2023).

Conclusion

Conclusions from this work will help expose routes to AD risk reduction, and the potential for repurposing an existing treatment for mid‐age individuals at elevated genetic risk for future dementia. This research will motivate longer‐term clinical trials for risk reduction strategies across the lifespan.
Cardiovascular risk factors and their relationship to age of onset of Alzheimer’s disease in people with Down syndrome
Authors: Pape Sarah
Published: December 2023

Background

People with Down syndrome (DS) are at ultra‐high risk of developing Alzheimer’s dementia (AD). This is primarily due to the triplication of amyloid precursor protein on chromosome 21. Despite common genetic drivers there are large variations in the age of AD onset. In sporadic AD poor cardiovascular health has been associated with increased risk of AD. It has not been established whether the same risks apply to people with DS.

Method

Large population‐based cohort study utilising data from UK‐based primary care electronic health records. Measurements of nine cardiovascular parameters were used to analyse patterns across adulthood. These were systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), body mass index (BMI), total cholesterol, high and low density lipoproteins, triglycerides, and glycated haemoglobin (HbA1c). Survival curves were fitted with hazard ratios (HR) and crude incident rates calculated using cardiovascular parameters measured between age 25‐34 years as predictor variables and incidence of dementia as the outcome. Age, sex, level of intellectual disability, history of congenital heart disease (CHD), cardiovascular disease, hypothyroidism and diabetes were included as covariates.

Result

6,424 adults with DS were identified, matched to 23,143 controls. Low PP (<40mmHg), HR 1.45; low DBP (<62mmHg), HR 1.77, and low SBP (<100mmHg), HR 1.83 increased risk of dementia incidence. High SBP (>140mmHg), HR 2.04 increased risk but few people had high values. Raised BMI >25kg/m2 increased incidence dementia risk (HR 1.63). The risk was the same whether someone was overweight or obese. Hypothyroidism, history of CHD, male sex were significant contributors in the models. There was a cumulative effect of risk. People with 1 or 2 risk factors had HRs of 3.15 compared to those with zero risks, whilst people with 3 or more cardiovascular risk factors had HRs of 5.69.

Conclusion

Cardiovascular health in earlier adulthood affects age of AD onset in people with DS. Cardiovascular multi‐morbidity was associated with increased incidence dementia risk suggesting that risks interact in a cumulative fashion. Reducing the number of risks by actively screening and managing medical co‐morbidities in people with DS may therefore help delay the onset of AD. Multi‐domain interventions may be particularly important.
Comparative evaluation of FDA‐approved drugs for managing the symptoms of AD
Authors: Ozsahin Ilker , Onakpojeruo Efe Precious , Uzun Berna , Ozsahin Dilber Uzun , Butler Tracy A
Published: December 2023

Background

AD is a neurodegenerative disorder characterized by the gradual deterioration of mental abilities over time. According to estimates, 5.8 million Americans age 65 and older currently have AD dementia, and by the year 2050, that number is projected to reach 13.8 million. There is currently no cure for AD but medications have been shown to help some people manage the disease’s symptoms. Although there are disease modifying drugs target the amyloids such as Aducanumab and Lecanemab, high costs (around $30,000/year) and severe side effects make them unfavorable for many patients suffering from AD. However, prescribing the appropriate drug considering many factors affecting the decision‐making such as cost of the drug, safety of drug, and patient’s medical history might be a relatively challenging task for a physician and time‐consuming for patients in case the first prescribed drug is not tolerated or worsens the symptoms. Therefore, there is an urgent requirement for better tools to aid in prescribing the most appropriate drug.

Methods

In this regard, we propose using fuzzy Preference Ranking Organization Method for Enrichment of Evaluations (PROMETHEE), a multi‐criteria decision‐making (MCDM) method, to compare, evaluate, and rank the FDA‐approved drugs for managing AD symptoms. Drugs used in this study include Donepezil [Aricept], Rivastigmine [Exelon], Galantamine [Razadyne], Memantine [Namenda], and Memantine + Donepezil [Namzaric] with the following criteria: cost, safety of drug, tolerability, interaction with other drugs, response to cognitive impairment, symptoms management rate, and side effect. To the best of our knowledge, any decision‐making methodologies have not been proposed for use in identifying the most appropriate drugs for AD patients.

Result

Results showed that [Namzaric] came first in the ranking, and followed by [Aricept], [Namenda], and [Razadyne] while [Exelon] ranked as the least favorable drug.

Conclusion

MCDM methods can be used as a decision‐aid system for evaluating AD drugs and this study can be extended including more criteria and new drugs as they become available.
Clusters of dementia risk factors are distinctively associated with socioeconomic factors
Authors: Delgado Carolina , Martin Consuelo San , Vergara Rodrigo , Rivero Juan JOSE Mariman
Published: December 2023

Background

For effective dementia prevention, the understanding of the local population’s risk profile and its socioeconomic associations is mandatory. Our aim is to explore if there are clusters of dementia risk factors in Chilean adults and if they are associated with different socioeconomic variables.

Method

Dementia‐free subjects ≥45 years old, from the 2016‐2017 Chilean National Health Survey, were analyzed stratified by sex and age (midlife/ later life), searching for profiles of association of 6 variables that had been related with dementia risk (years of education, systolic blood pressure, body mass index (BMI), alcohol consumption, physical activity, and depressive symptoms).

Result

We found 3 clusters that shared similar risk factors in each sex/age group (Figure 1 Women, Figure 2 Men). There was a cluster with high systolic blood pressure (HSBP) generally associated with high BMI in all sex/age groups; A cluster with depressive symptoms, and a physically inactive cluster in ¾ of sex/age groups. In men later life, in addition there was a cluster with excessive alcohol consumption and in women midlife a low risk profile. The cluster with HSBP alone or with high BMI, had lower years of education and lower family income than the other clusters. In contrast, the physically inactive and the low risk clusters had higher levels of education, while the depressive cluster had variable association with educational levels. The HSBP and the depressive clusters had a high proportion of multimorbidity, with a very high burden of risk factors for dementia.

Conclusion

The clusters of health conditions related with dementia risk in Chilean adults that are distinctively associated with socioeconomic variables.
ALZHEIMER’S DEMENTIA EARLY DIAGNOSIS, CHARACTERIZATION, PROGNOSIS AND TREATMENT DECISION VIA A SOFTWARE‐AS‐MEDICAL DEVICE WITH AN ARTIFICIAL INTELLIGENT AGENT
Authors: Battista Petronilla , Nemni Raffaello , Vitali Paolo , Alì Marco , Zanardo Moreno , Salvatore Christian , Sirabian Graziella , Capelli Dario , Bet Luciano , Callus Edward , Bertoldo Enrico Giuseppe , Fiolo Valentina , Minafra Brigida , Fundarò Cira , Scotti Giuseppe , Sardanelli Francesco , Papa Sergio , Castiglioni Isabella
Published: December 2023

Background

TRACE4AD (DeepTrace Technologies s.r.l, Italy) is a machine learning‐based software‐as‐medical device able to predict the conversion to Alzheimer’s disease (AD) dementia of subjects at risk within 24‐months exploiting automatic processing of T1‐weighted MPRAGE brain MRI study and neuropsychological tests. TRACE4AD provides a report with the predicted individual risk of conversion to AD dementia, specific cognitive deficits, and suggestions supporting neurologists in diagnosis and characterization, prognosis, and decision‐making. We tested TRACE4AD in the clinical setting in its ability, at baseline, to: a) predict amnestic Mild Cognitive Impairment (MCI) conversion to AD dementia within 24‐months; b) characterize cognitive deficits; c) support neurologists' decision‐making.

Method

We retrospectively included 92 subjects (mean age 73.12±7.6, 46% female): 32 patients from two Italian centers where TRACE4AD was implemented after user training; and 60 subjects from the ADNI dataset. All patients had a brain MPRAGE study at baseline, 77/92 patients (83.7%) also performed a neuropsychological assessment at baseline, 75/92 patients (81.5%) had a stable clinical diagnosis at 24‐month. TRACE4AD extracted the gray matter map from MPRAGE and used it (combined with cognitive measures when available) to make inferences. Reference standards were: a) the neurologist’s clinical diagnosis at 24‐months, b) the neuropsychological assessment at the baseline, c) the agreement with the neuro exam and intervention decision time and type defined by neurologists at the baseline.

Result

TRACE4AD accurately predicted conversion to AD dementia in 93.3% of patients based on the MRI, and in 96.6% based on MRI and cognitive measures. Cognitive deficits were found in agreement with the neuropsychological assessment for all patients except one who presented with major depression. We found disagreement between the neurologist’s decision at baseline and the tool in only two patients, defined with normal cognition by the neurologist and predicted at high risk of AD dementia conversion by the tool. TRACE4AD supported neurologists' decision by 12 months in 15/17 patients for the prompt decision at baseline.

Conclusion

TRACE4AD is promising, safe, and effective in supporting neurologists in the clinical practice of MCI across different centers.
Cerebrovascular features of Alzheimer’s disease in adults with Down syndrome
Authors: Brickman Adam M. , Lao Patrick J. , Edwards Natalie C. , Rizvi Batool , Wilcock Donna M. , Gutierrez Jose , Head Elizabeth
Published: December 2023

Background

Cerebrovascular disease contributes to clinical onset and course of Alzheimer’s disease (AD) but it is unclear if it is related directly to AD pathogenesis. In late onset AD, MRI markers of small vessel cerebrovascular disease relate to AD diagnosis, genetic risk for AD, and severity of AD symptoms, but it is not possible to determine whether these associations reflect comorbidity due to risk factor exposure or whether they represent a core feature of AD. We have been studying cerebrovascular features of Alzheimer’s disease in adults with Down syndrome, who are at genetic risk for developing AD but have very low prevalence of classical vascular risk factors.

Method

In the context of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS), a US‐based multisite observational study of the clinical, biomarker, and pathological features of AD in adults with Down syndrome, our laboratory has analyzed high‐resolution, harmonized MRI scans for markers of cerebrovascular disease, including white matter hyperintensities (WMH), enlarged perivascular spaces, microbleeds, and infarcts, in adults with Down syndrome across the adult lifespan. We tested the association of these markers with age, AD‐related clinical diagnoses, proteomic profiles of vascular function and inflammation, and AD‐related biofluidic biomarker concentrations.

Result

Our studies show that MRI‐derived markers of cerebrovascular disease are prevalent in adults with Down syndrome and increase in severity across AD‐associated clinical diagnoses. Age analyses suggest that there is an inflection of these markers at around age 40, when other pathological features also begin to emerge. Proteomic correlates of these cerebrovascular disease markers suggest an association with inflammatory processes in presymptomatic and neurodegenerative processes in symptomatic adults with Down syndrome. Finally, markers of cerebrovascular disease are particularly associated with plasma phosphorylated tau concentrations in adults with Down syndrome.

Conclusion

Our work shows that MRI‐derived markers of cerebrovascular disease are prevalent, related to AD symptoms, temporally track with AD pathology, relate to inflammation and neurodegeneration markers, and associate with markers of tau pathology. Without the confound of exposure to peripheral vascular risk factors, these observations suggest that cerebrovascular disease represents a “core feature” of AD that contributes both to symptoms and to disease pathogenesis.
APOE ε4 is associated with reduced myelin and thus faster rate of tau PET accumulation
Authors: Rubinski Anna , Zheng Lukai , Dewenter Anna , Franzmeier Nicolai , Stephenson Henry G. , Deming Yuetiva , Bendlin Barbara B , Ewers Michael
Published: December 2023

Background

Myelin is the cholesterol‐rich layer ensheathing axons in the white matter (WM). The APOE ε4 allele has been associated with both reduced cholesterol transport to myelin layers in mice and with faster tau progression in individuals with AD. Here we asked the questions whether 1) APOE ε4 is associated with lower myelin and 2) any myelin decreases mediate the association between APOE ε4 and the rate of tau‐PET accumulation in Aβ+ individuals. To assess myelin, we repurposed florbetapir‐PET tracer binding, previously shown to be sensitive to myelin binding protein in the WM (Stankow et al. Annals Neurol 2011).

Method

We included 43 Aβ‐ cognitively normal (CN, global florbetapir SUVR < 1.11) and AD‐spectrum participants (56 CN Aβ+, 32 MCI Aβ+, and 20 AD Aβ+) from ADNI. To extract individual myelin levels, we averaged each participant’s florbetapir SUVR within individual T1‐MRI based WM masks (global myelin) or 58 fiber‐tracts generated from multishell DTI (fiber‐tract myelin). To control for a putative influence by grey‐matter florbetapir levels, we adjusted the individual WM‐florbetapir SUVRs for grey‐matter florbetapir SUVR via linear regression analysis and computed z‐scores of the adjusted WM‐florbetapir SUVRs across all participants (Moscoso et al. EJNNMI, 2022). For tau‐PET, flortaucipir SUVRs were extracted in Braak‐stage GM ROIs or in the tracts’ cortical projection zones, and mixed effect linear regression was used to estimate the rate of regional flortaucipir change.

Result

Higher APOE ε4 score was associated with both lower WM‐florbetapir z‐score (β = ‐0.329, p<0.001) and faster tau‐PET increase in Braak stage 3+4 ROIs (β = 0.224, p = 0.01) in Aβ+ participants (Fig. 1A&B). Using bootstrapped mediation analysis, we found that the WM‐florbetapir z‐score mediated the effect of APOE dosage on the rate of tau‐PET accumulation in Braak 3+4 (b = 2´10‐4 [95% CI: 2´10‐5, 3´10‐4], p = 0.02, Fig 1C). At the fiber‐tract level, APOE ε4 dosage exacerbated the association between decreased fiber‐tract florbetapir and faster tau‐PET increase in the tracts’ projection zones (p<0.001).

Conclusion

APOE ε4 may contribute to the accumulation of tau pathology in a myelin dependent manner. Myelin impairment is treatable by several known drugs and therefore an attractive therapeutic target in AD.
White matter changes in the cholinergic system in Alzheimer’s disease and dementia with Lewy bodies
Authors: Schumacher Julia , Ray Nicola , Hamilton Calum Alexander , Bergamino Maurizio , Donaghy Paul C , Firbank Michael J , Watson Rosie , Roberts Gemma , Allan Louise M , Barnett Nicola , O'Brien John T , Thomas Alan J , Taylor John‐Paul
Published: December 2023

Background

The early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD.

Methods

NBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data.

Results

Free water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls).

Conclusion

Our cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations.
Longitudinal white matter integrity alterations as a function of Preclinical Alzheimer’s Pathology: findings from the EPAD non‐demented cohort
Authors: Lorenzini Luigi , Tranfa Mario , Ingala Silvia , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Chetelat Gael , Ewers Michael , Payoux Pierre , Martinez‐Lage Pablo , Ritchie Craig W , Gispert Juan Domingo , Brunetti Arturo , Mutsaerts Henk‐Jan , Wink Alle Meije , Barkhof Frederik
Published: December 2023

Background

Cross‐sectional diffusion tensor imaging (DTI) studies report white matter (WM) microstructural alterations, mainly involving fornix and corpus callosum (CC), in symptomatic stages of Alzheimer’s Disease (AD). Exploring these changes longitudinally in relation to preclinical and prodromal AD pathology is essential to track disease progression.

We investigated trajectories of WM alterations in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort and their relationship with AD biomarkers.

Method

EPAD inclusion criteria were age>50 years and Clinical Dementia Rating≤0.5. We selected participants with baseline CSF samples, and longitudinal DTI scans. After defining AT groups(Ingala et al. 2021), A‐T+ participants were excluded (final N = 283).

MRI acquisition and preprocessing was previously described(Lorenzini et al. 2022). We extracted fractional anisotropy (FA) in 14 regions(Mori et al. 2005) from DTI as a marker of WM integrity. Site harmonization of MRI‐derived data was performed with ComBat toolbox(Fortin et al. 2018).

Age‐ and sex‐corrected linear mixed models with random intercepts on participants were used to estimate time‐effect on MRI‐derived phenotypes, and their interaction with AT status. Results were corrected for multiple testing.

Result

At baseline, A+T‐ participants showed lower FA in body/columns (ß = ‐0.04, p<0.01) and crus of fornix (ß = ‐0.01, p = 0.04), and in splenium (ß = ‐0.007, p = 0.04) and body of CC (ß = ‐0.01, p = 0.03) compared to A‐T‐. In the whole group, FA decreased over time in splenium (ß = ‐0.003, p<0.01), body (ß = ‐0.002, p<0.01) and genu of CC (ß = ‐0.009, p<0.01), body/columns (ß = ‐0.004, p<0.01) and crus of fornix (ß = ‐0.005, p<0.01), and inferior longitudinal fasciculus (ß = ‐0.007, p<0.01). Compared to A‐T‐, A+T+ participants showed steeper FA reduction in superior (Interaction:ß = ‐0.004, p = 0.03) and anterior corona radiata (Interaction:ß = ‐0.006, p = 0.02).

Conclusion

Our results suggest that WM integrity in key AD regions may degenerate early in the AD continuum, showing greater impairment over short‐time intervals in individuals with higher AD‐specific pathological burden.
Transition in the cognitive continuum from normal cognition to dementia: the interplay of lifelong cognitive reserve with brain aging and genetic predisposition
Authors: Li Yuanjing , Dekhtyar Serhiy , Grande Giulia , Kalpouzos Grégoria , Laukka Erika J , Fratiglioni Laura , Qiu Chengxuan
Published: December 2023

Background

Higher cognitive reserve (CR) has been associated with lower risks of cognitive decline and dementia. In this study, we sought to investigate associations of lifelong CR capacity with transitions of cognitive phenotypes in older adults, while accounting for age, sex, APOE genotype, and pathological load of brain aging.

Method

This population‐based Swedish National study on Aging and Care‐Kungsholmen included 2631 participants (age≥60 years, 61.4% female) free of dementia at baseline (2001‐2004); among them 517 had brain MRI. At baseline, lifelong CR capacity was assessed by integrating early‐life education, midlife occupational complexity, later‐life social network and leisure activity. The load of pathological brain aging was assessed using volumes of grey matter (GM), white matter, hippocampus, and white matter hyperintensity, and count of perivascular space and lacunes. Cognitive impairment no dementia (CIND) and dementia were defined at baseline and across up to 15 years until 2016‐2019. Data were analyzed using the Markov multi‐state model.

Result

During the mean 10.7 years of follow‐up, 9.0% had incident dementia (95%CI: 7.8%–10.3%). Among people free of CIND at baseline (n = 2023), 27.4% had incident CIND during follow‐up (25.3%–29.6%). Higher lifelong CR capacity (mean value of composite CR score = 0.2; range: ‐4.2‐3.6) was associated with a lower risk of direct transitions from non‐dementia (normal or CIND) to dementia (multivariable‐adjusted HR = 0.84; 95% CI 0.73–0.95) and from normal cognition to CIND (0.79; 0.73–0.85), but not with the direct transitions from normal cognition to dementia (0.86; 0.72–1.03), from CIND to dementia (0.93; 0.76–1.14), or from CIND to normal cognition (1.15; 0.98–1.35). Higher lifelong CR capacity was associated with a lower risk of direct transition from normal cognition to dementia in people with APOE‐ε4 and those with high GM volume (2nd‐4th quartiles), but not in those without APOE‐ε4 or with low GM volume (1st quartile) (P‐for‐interaction<0.05). There was no statistical interaction of CR with age, sex, or other brain MRI markers on cognitive transitions.

Conclusion

Higher lifelong CR capacity may benefit late‐life cognitive status by reducing the risk of cognitive deterioration to dementia, especially in people with genetic predisposition or with low neurodegenerative load.
Eye movements during the judgment of line orientation test in patients with Alzheimer’s disease and amnestic mild cognitive impairment
Authors: Akkoyun Müge , Koçoğlu Koray , Boz Hatice Eraslan , Tüfekci Işıl Yağmur , Ekin Merve , Akdal Gülden
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by early impairment of memory. However, recent studies have revealed early abnormalities in other cognitive functions, such as visuospatial functions, the ability to process visual information, and visuospatial attention. The Judgment of Line Orientation (JLO) is a neuropsychological test commonly used to measure visuoperceptual and visuospatial abilities. Eye movements are a practical method for assessing cognitive processes during visual tasks. This study aimed to investigate eye movement patterns during the JLO test in AD and amnestic mild cognitive impairment (aMCI).

Method

The study sample consisted of 16 patients with AD (mean age 72.2±7.9 years), 34 patients with aMCI (mean age 70.3±6.5 years), and 37 HC (mean age 67.7±6.7 years). Eye movements during the 30‐item Benton JLO test were recorded with the EyeLink 1000 Plus. Fixation duration (FD), the response time (RT), and the total number of correct and incorrect responses were calculated.

Result

The mean of JLO scores was significantly lower in aMCI and AD than in HCs (p<0.001). In the correct responses, Patients with AD had a statistically significantly less FD on the test lines compared HCs (p = 0.019). Moreover, FD on the reference lines of correct responses was significantly decreased in AD (p = 0.006) and aMCI (p = 0.016) compared to HCs. In the incorrect responses, FD on the test lines was significantly increased in aMCI (p = 0.009) and AD (p = 0.008) compared to the HCs. The FD on the reference lines of the incorrect responses was increased in AD (p = 0.021) and aMCI (p = 0.013) groups compared to HCs. Additionally, AD (p = 0.001) and aMCI (p = 0.004) groups showed significantly increased RT in incorrect responses compared to HCs.

Conclusion

This study showed that the AD and aMCI groups looked at visual stimuli with less fixation duration than HCs. The patient groups looked at the target for a longer time in incorrectly answered trials and had a delay in making decisions. The findings may indicate difficulties in visual‐spatial processing and visual‐attention deficit in these patient groups and provide insight into the underlying cognitive processes involved in visual perception in AD and MCI.
Cognitive Reserve proxies for individuals with intellectual disabilities: a Scoping Review
Authors: La Face Annalisa , Pucci Veronica , Mondini Sara , Gasteiger‐Klicpera Barbara
Published: December 2023

Background

Dementia in people with Intellectual Disability (ID) has a prevalence three times greater (Strydom et al., 2007) and with an earlier onset (Dodd et al., 2015) than in the general population. Despite the fact that virtually all adults with ID display neuropathology consistent with dementia by the age of 40, many of them never show the clinical symptoms (Strydom et al., 2009): there is no linear link between degree of brain damage and severity of the symptomatology (Arvio & Bjelogrlic‐Laakso, 2021). This discrepancy could be attributed to a difference in Cognitive Reserve (CR, Stern, 2009). However, CR has never been systematically studied specifically in relation to ID. To fill this gap, we aimed to identify potential indicators (“proxies”) of CR specifically relevant for people with ID to be included in future instruments. Indeed, activities potentially promoting and enhancing CR in people with ID may not overlap with those considered by the instruments for the general population (see CRIq, Nucci et al., 2012).

Method

A Scoping Review was conducted in PubMed and Scopus. N = 1239 potentially relevant papers were identified, 104 papers were assessed for eligibility and 17 studies matched our inclusion criteria.

Result

We consider as proxies of CR all lifestyle factors and life experiences proven in past studies to be positively correlated with the cognitive performance or with the everyday functioning of adults with ID, even if not explicitly labeled as proxies of CR. Some proxies found are partly overlapping with the ones used to quantify CR in the general population: Education, Occupation, Leisure and Physical activity. Yet, others are uniquely suitable for the population with ID: Type of schooling, Parental educational level, Environmental stimulation and Living place. Those should be incorporated within the instruments developed and validated in the future to assess the CR of people with ID.

Conclusion

This Review is the first step toward the development of the first instrument to measure CR in people with ID. The hope is that it will be integrated among the instruments routine used in the clinical practice and assure people with ID an early and accurate diagnosis of dementia.
Which intrinsic and extrinsic factors predict decline of activities of daily living in dementia?
Authors: Puthusseryppady Vaisakh , Bregola Allan , Camino Julieta , Backhouse Tamara , Mioshi Eneida
Published: December 2023

Background

Various intrinsic and extrinsic dementia factors have been suggested to contribute separately to disability in people with dementia (PwD). Objective: To investigate if the combination of specific intrinsic and extrinsic factors at baseline can predict longitudinal declines in activities of daily living (ADL) performance of PwD at 12‐month follow‐up

Method

141 community‐dwelling PwD‐carer dyads were assessed on their global cognition (ACE‐III), apathy (CBI‐R), carer management styles (DMSS), medical comorbidities (CCI), and ADL performance (DAD) at baseline, and for a subset of participants (n = 53), at 12‐month follow‐up. Multiple linear regression models were run to assess: 1) the relationships between PwD’s DAD scores and the remaining variables at baseline and 2) whether these variables’ scores at baseline can predict longitudinal change in the PwD’s DAD scores.

Result

At baseline, having lower ACE‐III (β = 0.379, p<0.001), higher CBI‐R (β = −0.287, p<0.001), higher DMSS criticism (β = −0.409, p = 0.003), lower DMSS encouragement (β = 0.387, p = 0.006), and higher CCI scores (β = −2.660, p = 0.008) were significantly associated with having lower DAD scores. The PwD’s DAD scores significantly declined from baseline to follow‐up (p<0.001, d = 1.15), however this change could not be predicted by the baseline scores of any of the independent variables. This change was instead predicted by declines in the PwD’s ACE‐III scores from baseline to follow‐up (β = 1.021, p = 0.001).

Conclusion

In our limited sample, cognitive changes seem to be the main factor underlying longitudinal decline in ADL performance for PwD. Carer management styles appear relevant in predicting current ADL performance but not in predicting longitudinal ADL decline.
DEPRESCRIBING IN OLDER POLY‐TREATED PATIENTS AFFECTED WITH DEMENTIA: A SHARED EXPERIENCE BETWEEN UNIVERSITY AND TERRITORY
Authors: Gareri Pietro , Gallelli Luca , Palleria Caterina , Gareri Ilaria , De Sarro Giovambattista
Published: December 2023

Introduction

The present study aimed to assess geriatric poly‐treated patients of the Center for Cognitive Disorders and Dementia of Catanzaro Lido, in collaboration with the School of Pharmacology, University of Catanzaro, Faculty of Medicine. We used the Beers, and STOPP & START criteria for assessing poly‐treatment and deprescribing in the population under investigation.

Patients and Methods

In the time range between October 2021 and September 2022, we randomly assessed 205 patients, 114 outpatients, and 91 home care patients.The primary outcomes were: 1) deprescribing inappropriate drugs through the Beers and STOPP & START criteria;2) assessing duplicate drugs, and the risk of iatrogenic damage due to drug‐drug and drug‐disease interactions.

Results

69 men and 136 women, mean age of 82.7±7.4 years old, were studied. Of these, 91 patients were home care patients and 114 were outpatients. The average of the drugs used in the sample was 9.4 drugs/patient; after the first visit and the consequent deprescribing process, the average dropped to 8.7 drugs/patient (p = 0.04). Potentially inappropriate drugs were overall 74(36.1%). Of these, long half‐life benzodiazepines (8.8%), non‐steroidal anti‐inflammatory drugs in chronic use (> 15 days) (3.4%), tricyclic antidepressants (3.4%), first‐generation antihistamines (1.4%), anticholinergics (11.7%), ticlopidine (1.4%), prokinetics in chronic use (1.4%), digoxin at dosage > 0.125 mg (1.4%), amiodarone (0.97), a‐lytics (1.9%). The so‐called “duplicate” drugs were overall 26 (12.7%). 10 potentially dangerous prescriptions were found for interactions (4.8%).

Discussion and conclusions

Applying the Beers and STOPP&START criteria can improve the use of drugs in the poly‐treated patient. We underline the importance of checking all the drugs taken periodically, discontinuing drugs with the lowest benefit/harm ratio and the lowest probability of adverse reactions due to withdrawal. Currently, there are no guidelines to properly address the management complexities of the older patient. Computer tools and properly trained teams (doctors, nurses, pharmacists) could identify, treat and prevent possible drug interactions.