bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological and methodological factors underlying a continuous amyloid CSF/PET imbalance model and its association with longitudinal cognition
Authors: Mastenbroek Sophie E , Sala Arianna , Gispert Juan Domingo , García David Vállez , Schmidt Mark E , Stephens Andrew W. , Gismondi Rossella , Farrar Gill , Frisoni Giovanni B , Boada Mercè , Ritchie Craig W , Visser Pieter Jelle , Bucci Marco , Hansson Oskar , Barkhof Frederik , Ossenkoppele Rik , Nordberg Agneta K , Rodriguez‐Vieitez Elena , Collij Lyduine E. ,   the AMYPAD consortium
Published: December 2023

Background

Discordance between cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of amyloid‐β (Aβ) occurs in up to 20% of individuals. Generally, Aβ discordance is defined using binary cut‐offs. Given the methodological limitations of this approach, we propose a continuous Aβ CSF/PET imbalance model. We investigated biological and methodological factors underlying discrepancy in these amyloid biomarkers and associations with longitudinal cognition.

Method

We included 383 non‐demented subjects (N
unimpaired = 326, N
mildly‐impaired = 57) from the AMYPAD‐PNHS cohort. Z‐scored CSF Aβ42 and amyloid‐PET (Centiloids [CL]) units were fitted to a hyperbolic regression model by minimizing the Euclidian distance of the observed datapoints to the fitted line. Subject‐specific standardized residuals were derived as a measure of continuous imbalance (Zimbalance), with Zimbalance<0 reflecting greater Aβ abnormality in CSF relative to PET and Zimbalance>0 greater Aβ abnormality in PET relative to CSF (Figure‐1). Linear models adjusted for relevant covariates (Figure‐2) were run between Zimbalance and (1) methodological factors (CSF‐PET interval, CSF kit, PET tracer, and PET injected dose); (2) demographics (age, sex, education, APOE genotype) and CSF p‐tau biomarker; (3) vascular burden (white matter hyperintensities measured as Fazekas scores). Linear mixed models were used to investigate the predictive value of Zimbalance on longitudinal cognition in several domains.

Result

Sample characteristics are shown in Table‐1. Methodological factors were not significantly associated with Zimbalance. Increased CSF p‐tau levels were significantly associated with a higher Zimbalance (i.e. greater Aβ abnormality in PET relative to CSF) (β = 0.06±0.03, p = .033) (Figure‐2). In addition, a lower Zimbalance (i.e. greater Aβ abnormality in CSF relative to PET) was associated with a higher Fazekas score (n = 189, β = ‐0.55±0.26, p = .038) and predictive of faster cognitive decline on a language categorical fluency test (β = ‐0.03±0.02, p = .038) (Figure‐2).

Conclusion

We found that methodological factors did not contribute to a continuous model of Aβ CSF/PET imbalance, suggesting that this imbalance reflects distinct biological profiles. Indeed, continuous CSF/PET imbalance showed differential associations, with greater pathological levels of aggregated Aβ relative to soluble Aβ being related to increased CSF p‐tau levels and excess pathological levels of soluble Aβ relative to aggregated Aβ to increased white matter hyperintensities and steeper cognitive decline.
Apoe ε4 exacerbates age‐dependent decline of cortical microstructural changes in cognitively normal midlife individuals: the PREVENT‐Dementia and ALFA studies
Authors: Mak Elijah , Dounavi Maria‐Eleni , Operto Grégory , Ziukelis Elina T , Jones P Simon , Low Audrey , Swann Peter , Newton Coco , Muniz‐Terrera Graciela , Malhotra Paresh A , Koychev Ivan , Falcon Carles , Mackay Clare , Lawlor Brian , Naci Lorina , Wells Katie , Ritchie Craig W , Ritchie Karen , Su Li , Gispert Juan Domingo , O'Brien John T
Published: December 2023

Background

The APOE ε4 allele is the primary genetic risk factor for the sporadic type of Alzheimer’s disease (AD). However, the mechanisms by which APOE ε4 is associated with neurodegeneration are still poorly understood. Here, we applied the NODDI to characterise the effects of APOE ε4 and its interactions with age and education on cortical microstructure in cognitively normal individuals.

Method

Data from 1954 participants were included from the PREVENT‐Dementia and ALFA (ALzheimer and FAmilies) studies (mean age = 57, 1197 non‐carriers, 757 APOE ε4 carriers). T1 MRIs were processed with FreeSurfer v7.2. The Microstructure Diffusion Toolbox was used to derive Orientation Dispersion Index (ODI) maps from diffusion MRI. Primary analyses were focused on the (a) main effects of APOE ε4, and the (b) interactions of APOE ε4 with age and education on lobar and vertex‐wise ODI and implemented using Permutation Analysis of Linear Models.

Result

APOE ε4 carriers and non‐carriers did not differ in terms of lobar ODI. However, there were APOE ε4 × age interactions in the temporo‐parietal and frontal lobes (TFCE p FWE < 0.05), indicating steeper age‐dependent ODI changes in APOE ε4 (Figure 1). Lobar analyses revealed decreased temporal ODI in APOE ε4 carriers after age = 60 (Figure 2). There was a three‐way interaction of APOE ε4 x age x education; steeper age‐related ODI declines among APOE ε4 carriers with lower years of education (Figure 3, TFCE p FWE < 0.05). There were no significant main effects or interactions of APOE ε4 on cortical thickness.

Conclusion

We found novel evidence that APOE ε4 worsened age‐related ODI decreases in brain regions typically associated with atrophy patterns of AD. This finding also suggests that APOE ε4 may hasten the onset age of dementia by accelerating age‐dependent reductions in cortical ODI, although additional studies are needed to verify this hypothesis. These findings were independent of cortical thickness. While conclusions are limited due to the cross‐sectional design, our findings imply that APOE ε4 related changes in ODI may precede macroscopically visible changes in cortical atrophy and may be a more sensitive marker of incipient AD.
Longitudinal change in CSF β‐amyloid1−42 predicts PTSD symptomatology after the COVID‐19 lockdown in cognitively unimpaired older adults
Authors: Palpatzis Eleni , Akinci Muge , Argiris Georgette , Contador Israel , Brugulat‐Serrat Anna , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Carboni Margherita , Minguillón Carolina , Navarro Arcadi , Gispert Juan Domingo , Suarez‐Calvet Marc , Grau‐Rivera Oriol , Sánchez‐Benavides Gonzalo , Arenaza‐Urquijo Eider M
Published: December 2023

Background

Cognitively unimpaired (CU) adults with Alzheimer’s disease (AD) pathologic change may be more vulnerable to developing neuropsychiatric symptoms. We reported an association of higher β‐amyloid (Aβ) and increased anxiety/depression during the COVID‐19 lockdown in CU adults (Akinci et al., 2022). Here, we investigated whether changes in Aβ1−42 predict post‐traumatic stress disorder (PTSD) symptomatology following COVID‐19 lockdown in CU adults at risk for AD.

Method

We included 128 CU participants who underwent lumbar puncture 2.3±0.6 years before and 1.1±0.4 years after the lockdown. The outcome of interest was self‐reported PTSD symptomatology (Impact of Event Scale Revised) measured 1.7±0.1 years after the lockdown. The main predictor was annual rate of change in cerebrospinal fluid (CSF) Aβ1−42 measured with the NeuroToolKit panel of robust prototype assays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Other predictors included sex, age, years of education, stressors during COVID‐19, and anxiety/depression (Hospital Anxiety and Depression Scale, HADS) and perceived stress (Perceived Stress Scale, PSS) measured during lockdown. We performed regression analyses to explore the association between annual rate of change in Aβ1‐42 with PTSD scores adjusting for demographic and stressor variables, and further adjusting for HADS and PSS scores. We then explored the mediating effect of HADS and PSS on the association between change in Aβ1‐42 and PTSD scores.

Result

Participant age ranged from 53−72 and 59% were women (Table 1). Independent of demographic variables and stressors experienced during COVID‐19, the rate of annual change in Aβ1‐42 predicted PTSD scores (p = .008; Table 2). This association attenuated after introducing HADS and PSS scores into the model (p = .066). We found full mediation effects of HADS and PSS scores, explaining 46% and 40% of the effect of annual change in Aβ1‐42 on PTSD scores, respectively (Figure 1).

Conclusion

CU older adults with longitudinal CSF Aβ1−42 increases are more vulnerable to developing PTSD symptomatology after a stressful event, such as the pandemic. Anxiety/depression is one plausible mechanism through which increases in Aβ might exacerbate PTSD symptomatology. The results suggest a window for stress regulation during stressful events to prevent further mental health worsening in people at risk for AD.
Identification of a Novel Mechanism Fostering the Alterations of Brain Energy Metabolism: a Link Between AD and T2DM
Authors: Lanzillotta Chiara , Lanzillotta Simona , Tramutola Antonella , Pagnotta Sara , Domenico Fabio Di , Paul Bindu D , Snyder Solomon , Butterfield D Allan , Perluigi Marzia , Duarte Joao MN , Barone Eugenio
Published: December 2023

Background

Brain insulin resistance (bIR) is associated with mitochondrial stress, failure of energy metabolism, synaptic loss and ultimately neurodegeneration both in Alzheimer’s disease (AD) and Type 2‐Diabetes Mellitus (T2DM). Our group previously demonstrated that loss of BVR‐A is an early event triggering bIR in AD. Hence, we tested the hypothesis that reduced BVR‐A levels link bIR and mitochondrial defects resulting in AD‐like neuropathology in T2DM.

Method

Alterations of insulin signalling, autophagic flux, oxidative stress levels and AD hallmarks were analyzed in the hippocampus of wild‐type and the goto‐kakizaki (GK) model of T2DM rats. Hippocampal mitochondrial function was evaluated by measuring oxygen consumption rate (OCR), mitochondrial complexes, mitochondrial unfolded protein response (UPRmt) and oxidative stress levels. These data were correlated with peripheral metabolic measurements (fasting glucose, insulin and OGTT) and cognitive tasks (spatial memory). To confirm the role of BVR‐A, similar analyses were performed in the hippocampus of WT and BVR‐A KO mice fed a high fat diet (HFD, 60% kcal from fat) for 1, 3 or 8 weeks. Additional mechanistic insights were gained by evaluating mitochondrial function (sea‐horse) and the above‐mentioned intracellular pathways in response to insulin, in neuronal cells lacking BVR‐A.

Result

GK rats displayed a diabetic phenotype and impaired spatial memory. Reduced BVR‐A levels along with IRS1 hyper‐activation and loss of Akt‐mediated inhibition of GSK3ß were observed in the hippocampus, consistent with the regulatory role for BVR‐A. As result, hyperactive GSK3ß accumulated in hippocampal mitochondria fostering their impairment characterized by reduced OCR and activation of UPRmt. Similar alterations in BVR‐A KO mice and in neuronal cells lacking BVR‐A were observed, reinforcing the role for BVR‐A in regulating mitochondrial bioenergetics in response to insulin. HFD regimen promoted worse outcomes in BVR‐A KO mice with respect to WT. Remarkably, gender‐differences were observed whereby female mice show earlier and greater alterations with respect to male mice.

Conclusion

These results suggest that early BVR‐A loss triggers bIR and the hyper‐action of GSK3ß, that, in turn, drives the development of mitochondrial stress in T2DM brain. These alterations accelerate the impairment of energy metabolism and development of AD‐like neuropathology in T2DM.
Validating the clinical utility of AI‐guided tools for early dementia prediction
Authors: Vaghari Delshad , Lee Liz Yuanxi , Burkhart Michael C. , Montagnese Marcella , Zuhlsdorff Katharina , Giorgio Joseph , Chong Eddie , Jagust William J. , Chen Christopher Li‐Hsian , Williams Guy B , Rittman Timothy , Tino Peter , Kourtzi Zoe ,   the Early Detection of Neurodegenerative diseases initiative
Published: December 2023

Background

Recent advances in machine learning highlight the potential of Ai‐guided tools for early dementia prediction with major implications for timely clinical management. Yet, we still lack robust tools for predicting neurocognitive decline early in clinical practice. We have developed a predictive prognostic model based on Generalised Matrix Learning Vector Quantisation (GMLVQ) that combines multimodal biological and cognitive data to predict cognitive decline (Giorgio et al., 2020). Here we test the clinical validity of this model in predicting individualised cognitive trajectories on real‐world memory clinic data.

Method

We trained our model (Fig.1) to classify sMCI (individuals with stable MCI diagnosis within a 3‐year period; n = 290) vs. pMCI (individuals who progressed from MCI to AD within a 3‐year period; n = 120). We tested the model (out‐of‐sample validation) on a) an asymptomatic sample (Berkley Ageing Cohort: BACS, n = 187 healthy controls), b) two clinical samples: National University of Singapore (NUS; AD: n = 32, non‐AD neurodegenerative disease: n = 15, MCI moderate: n = 42, MCI mild: n = 53, Control: n = 27); Quantitative MRI in NHS Memory Clinics; AD: n = 72, MCI: n = 50, Non‐AD: n = 30, Functional/attentional memory symptoms: n = 30, other cognitive disorders: n = 10). We trained and tested the model with baseline structural MRI (medial temporal grey matter density) and cognitive data (following data harmonization across training and test samples). Using a scalar projection method, we generated a prognostic index that indicates distance from the stable prototype and classifies individuals to Clinically Stable vs. Declining (slowly vs. rapidly).

Result

Our trained model on ADNI data classified sMCI vs. pMCI with 79.87% class‐balanced cross‐validated accuracy (sensitivity = 83.33%, specificity = 76.52%). For the clinical NUS and QMIN‐MC samples, most AD patients were classified as rapidly progressive compared to MCI patients that were mostly classified as stable or slowly progressive (Fig.2). In contrast, for the BACS asymptomatic sample most individuals were classified as stable. Survival analysis on the NUS sample— for which longitudinal assessments (up to 6 years) are available— validated the model predictions, showing that patients with higher model‐derived prognostic index decline faster (Fig.3).

Conclusion

Validating our AI‐guided tool for early dementia prediction in real‐world patient data provides evidence for its clinical utility.
Predictors of primary care psychological therapy outcomes for treatment of depression and anxiety in people living with dementia: evidence from national healthcare records in England
Authors: Bell Georgia , Baou Celine El , Saunders Rob , Buckman Joshua , Charlesworth Georgina , Richards Marcus , Fearn Caroline , Brown Barbara , Nurock Shirley , Michael Stuart , Ware Paul , Marchant Natalie L , Aguirre Elisa , Rio Miguel , Cooper Claudia , Pilling Stephen , John Amber , Stott Joshua
Published: December 2023

Background

Primary care psychological therapy services can be effective in reducing symptoms of depression and anxiety in people living with dementia (PLWD) and are recommended in national guidelines (e.g., NICE, UK). However, it is currently unknown which factors are associated with better psychological therapy outcomes in PLWD.

Method

National linked healthcare records (IAPT, HES, MHSD, HES‐ONS mortality data) were used to identify 1,522 PLWD who attended psychological therapy services across England. Associations between various factors (dementia‐specific and non‐dementia specific) and therapy outcomes on widely used anxiety (GAD7) and depression (PHQ9) measures (reliable improvement, recovery, deterioration, dropout) were explored.

Result

People with FTD were more likely to experience a deterioration in depression or anxiety symptoms compared to people with vascular dementia (OR = 2.98, 95%CI[1.08,8.22], p = .03) and people with Alzheimer’s disease (OR = 2.95, 95%CI[1.15,7.55], p = .03). Age at dementia diagnosis did not predict any therapy outcomes after controlling for sociodemographic and clinical factors. Greater depression severity (recovery: OR = .95, 95%CI[.92,.98], p<.001; deterioration: OR = 1.73, 95%CI[1.04,2.90], p = .04), lower anxiety severity (improvement: OR = 1.06, 95%CI[1.03,1.09], p<.001; deterioration: OR = .89, 95%CI[.84,.94], p<.001; dropout: OR = 1.06, 95%CI[1.02,1.11], p = .01), lower work and social functioning (improvement: OR = .98, 95%CI[.96,.99], p = .002; recovery: OR = .98, 95%CI[.96.99], p = .002; dropout: OR = 1.03, 95%CI[1.01,1.05], p = .01), psychotropic medication use (improvement: OR = .62, 95%CI[.46,.84], p = .002; recovery: OR = .67, 95%CI[.51,.90], p = .01; deterioration: OR = 1.73, 95%CI[1.04,2.90], p = .04), being working age (improvement: OR = 2.11, 95%ci[1.10, 4.04], p = .02; recovery: OR = 2.03, 95%CI[1.10,3.73], p = .02), and fewer therapy sessions (improvement: OR = 1.10, 95%CI[1.06,1.14], p<.001; recovery: OR = 1.12, 95%CI[1.09,1.16], p<.001) were all associated with worse psychological therapy outcomes in PLWD.

Conclusion

Predictors of psychological therapy outcomes in PLWD were largely in line with those identified for a general population above and beyond dementia‐specific factors. Additional support and adaptations, such as more therapy sessions and regular clinical reviews, may be required to improve therapy outcomes in PLWD, particularly in those who are younger and have more severe depression.
5‐HT1A Receptor Agonist, SUVN‐N9503012 for the Treatment of Dementia and Associated Neuropsychiatric Disorders
Authors: Abraham Renny , Petlu Surendra , Thentu Jagadeesh Babu , Grandhi Venkata Ramalingayya , Raya Anji Reddy , Ganuga Narender , Medapati Rajesh Babu , Subramanian Ramkumar , Rasheed Mohammed Abdul , Nirogi Ramakrishna
Published: December 2023

Background

Dementia such as Alzheimer’s disease (AD) dementia is a growing unmet medical condition which involves a gradual decline in cognition and function. Few therapeutic options are available for the treatment of dementia of this type with limited efficacy.

Methods

SUVN‐N9503012 was characterized for its in‐vitro affinity towards 5‐hydroxytryptamine 1A (5‐HT1A) receptors using radioligand binding and functional assays. Its pharmacokinetic properties were evaluated both in rodents and dogs. The procognitive efficacy of SUVN‐N9503012 was evaluated in combination with the current standard of care (SOC), donepezil. As dementia is a co‐morbid with depression and aggression, SUVN‐N9503012 was evaluated for its potential in treating depression and agitation/aggression like behaviors.

Results

From in‐vitro assays, SUVN‐N9503012 was found to be a potent and selective agonist at 5‐HT1A receptors. SUVN‐N9503012 is orally bioavailable in rats and dogs and showed adequate brain penetration in rats. SUVN‐N9503012 potentiated the procognitive effects of donepezil in rat object recognition task. SUVN‐N9503012 was also found to have antidepressant like activity in rat as well as in mice in a forced swim test. SUVN‐N9503012 was found to have anti‐aggressive like activity in a mice resident‐intruder task.

Conclusion

From the efficacy studies carried out in combination with donepezil, we conclude that SUVN‐N9503012 has procognitive like activity in animal models of learning and memory. Apart from its procognitive like effects, SUVN‐N9503012 exhibited both anti‐depressant and anti‐aggressive like properties as well.
Defining tau pathology and neurodegeneration by dual‐phase 18F‐Flortaucipir PET as diagnostic and prognostic biomarkers in a memory clinic setting
Authors: Boccalini Cecilia , Mathoux Gregory , Peretti Débora Elisa , Ribaldi Federica , Scheffler Max , Perani Daniela , Frisoni Giovanni B , Garibotto Valentina
Published: December 2023

Background

18F‐Flortaucipir‐PET allows visualization of tau deposits (T) representing a powerful diagnostic and prognostic tool for Alzheimer’s disease (AD). Dual‐phase 18F‐Flortaucipir‐PET can also evaluate neurodegeneration (N) through the early‐phase images. We aim to assess the diagnostic and prognostic power of visual and semi‐quantitative T assessment and the potential added value of early‐phase images.

Method

We included 245 subjects from the Geneva Memory Clinic who underwent 18F‐Flortaucipir‐PET (157 with a dual‐phase protocol). Amyloid (Aβ) status was available for 207 subjects and clinical follow‐up for 135. T positivity and a Braak staging estimate were evaluated visually and semi‐quantitatively by standardized uptake value ratio (SUVr) in AD‐related regions. N status was semi‐quantitatively defined using early‐phase images as a summary metric in the AD meta‐ROI region. Receiver Operating Characteristic (ROC) analyses were applied to compare T and N discriminative power. Linear mixed‐effects models tested the prognostic values of T alone and T combined with N (T/N profiles).

Result

The mean age of the participants was 70.49±9.13 years, 52.2% were females and 55.7% were Aβ+. 53.4% of subjects had Mild Cognitive Impairment (MCI), 19.8% had dementia and 26.7% were cognitively unimpaired. All T‐assessment modalities significantly discriminated Aβ+ MCI and demented subjects from others (AUC>0.80), Aβ+ from Aβ‐ subjects (AUC>0.85), and cognitive decliners from stable individuals at follow‐up (AUC>0.79). The discriminative power of N, assessed by early‐phase images, was lower compared to T, with AUC ranging from 0.63 in discriminating Aβ+ MCI and demented subjects from others to 0.71 for discriminating Aβ+ T+ from Aβ‐ T‐ subjects. Linear mixed‐effect models showed that T+ individuals presented a significantly faster cognitive decline than the T‐ group (p<0.001) as well as T+/N+ and T+/N‐ compared to T‐/N‐ group (p<0.001), independently from T classification methods.

Conclusion

Our results show a similar diagnostic and prognostic power of visual and semi‐quantitative T evaluation of 18F‐Flortaucipir‐PET, proving its high potential for clinical applicability. The N status assessment with early‐phase images did not improve the prediction of cognitive decline. Its usefulness for differential diagnosis by the topographical information provided should be investigated.
Risk factors of young‐onset dementia: a UK Biobank study
Authors: Hendriks Stevie , Ranson Janice M , Peetoom Kirsten , Tai Xin You , Lourida Ilianna , de Vugt Marjolein , Llewellyn David J , Köhler Sebastian
Published: December 2023

Background

While age is the main risk factor for developing dementia, in young‐onset dementia (YOD) symptoms can already start before the age of 65 years. Genetic factors figure more prominent in the onset of YOD than late‐onset dementia but still only account for 5‐10% of the clinical YOD cases. It is therefore important to understand how modifiable risk factors, such as lifestyle or cardiovascular factors, and their interactions with genetic factors are associated with risk for YOD. The aim of this study was to examine a comprehensive set of factors and their association with the incidence of YOD.

Method

We used data from individuals aged under 65 years (n = 356,052) in the UK Biobank, a prospective population‐based cohort, to investigate risk factors related to YOD. Incidence of dementia was determined from hospital and death records. Potential risk factors were identified from systematic reviews on late‐onset dementia and YOD, including socio‐demographic, genetic, lifestyle, environmental, blood markers, cardiometabolic, psychiatric and other factors. These were analyzed in multivariable Cox proportional hazards regression.

Result

During 2,891,409 person‐years of follow‐up, 485 cases of YOD were reported. Incidence rates for women increased from 1.88/100,000 person‐years in age 40‐44 to 53.38/100,000 person‐years in age 60‐64. In men incidence rates increased from 5.41/100,000 person‐years in age 45‐49, to 79.54/100,000 person‐years in age 60‐64. A total of 38 variables were analyzed. In univariable analyses, 30 factors were associated with YOD, of which 15 were significantly associated with the incidence of YOD in multivariable analyses. These variables included lower formal education, lower socioeconomic status, carrying the apolipoprotein ε4 allele, no alcohol use, alcohol intoxication, social isolation, vitamin D deficiency, high c‐reactive protein levels, lower handgrip strength (i.e., higher physical frailty), hearing impairment, orthostatic hypotension, stroke, diabetes, heart disease and depression.

Conclusion

This study found potentially modifiable risk factors for YOD. While further exploration of these risk factors is necessary to validate our findings and identify potential underlying mechanisms, addressing these modifiable factors may prove effective in mitigating the risk of developing YOD.
Effects of a short‐term Mediterranean diet on mental health, cognition and cerebral blood flow in UK adults: MediMood study protocol
Authors: Esgunoglu Latife , Liaquat Marrium , Gillings Rachel , Lazar Alpar , Brooks Jon , Penny William , Hornberger Michael , Jennings Amy , Minihane Anne‐Marie
Published: December 2023

Background

Dementias and mental health disorders (i.e. depression, anxiety) are significant public health challenges. Chronic consumption of a Mediterranean diet (MD) has been associated with lower incident dementia, improved cognitive performance, and reduced brain atrophy. Yet, short‐term studies and randomised clinical trials (RCT) are lacking. Our systematic review of RCTs showed that in only four available studies, a MD can improve attention, alertness and contentment in up to 10 days (1). In a controlled efficacy study with all foods provided, we aim to explore postprandial, 24‐h and 5 days impacts of a MD and a Western diet (WD) on mood, anxiety and cognition, cerebral blood flow as assessed by MRI.

Method

MediMood is an efficacy crossover RCT. Individuals (n = 25) over 18 years with mild to moderate anxiety and/or depression will complete a 5‐day MD and a 5‐day WD intervention with a 4‐week wash‐out period, with foods, meal plans and instructions provided. Biological samples (blood, urine, faeces) will be collected. The primary outcomes are mood and anxiety assessed using Bond‐Lader and POMS questionnaires. Secondary outcomes include cognitive outcomes assessed through computerised neuropsychology tests, brain perfusion assessed by MRI, select cardiometabolic and inflammatory biomarkers, ketones, brain‐derived neurotrophic factor, several hormones (e.g. serotonin, dopamine), gut microbiome speciation, sleep quality and behaviour change. The assessment time points during each arm are baseline (day 1 morning), postprandial (post day 1 lunch), 24‐h (day 2 morning) and day 6 morning.

Result

NA

Conclusion

This will be the first well‐controlled RCT examining the acute and short‐term impacts of a MD and a WD on mental health and cognition in a targeted risk group. MediMood considers interfaces between sleep quality and the gut‐brain axis as modifiable determinants of mental health. We expect the findings to provide novel insights in efficacy of a MD on daily and short‐term well‐being in those with existing mild‐moderate mental health difficulties and to provide an initial mechanistic understanding of any observed benefits.

Funding:

Medical Research Council (MRC, UK), NuBrain Consortium (MR/T001852/1); Turkish Government personal PhD scholarship

References:

1. Esgunoglu L, Jennings A, Connole ES et al. (2021) Br J Nutr
Effectiveness of a multicomponent lifestyle intervention against cognitive decline and dementia in an at‐risk‐population in Germany – Preliminary results of the cluster‐randomized AgeWell.de‐trial
Authors: Zülke Andrea , Pabst Alexander , Luppa Melanie , Czock David , Haefeli Walter E. , Wiese Birgitt , Hoffmann Wolfgang , Frese Thomas , Gensichen Jochen , König Hans‐Helmut , Kaduszkiewicz Hanna , Thyrian Jochen René , Riedel‐Heller Steffi G.
Published: December 2023

Background

Mounting evidence suggests that dementia can be prevented. Targeting several risk factors simultaneously constitutes a promising strategy for preserving cognitive function. The AgeWell.de‐study was a cluster‐randomized trial applying a multi‐domain intervention to preserve cognitive function in older adults at risk for dementia in Germany.

Method

Individuals with a Cardiovascular Risk Factors, Aging and Dementia (CAIDE) dementia risk score ≥ 9 points aged 60‐77 years were recruited. According to randomization of their general practitioner (GP) practice, patients received either a multi‐domain intervention (optimization of nutrition and medication, physical, social and cognitive activity, cardiovascular risk management, intervention in case of depressive symptoms and/or grief) or general health advice and GP treatment as usual over 24 months. Primary outcome was global cognitive performance, assessed using a composite score based on z‐scores of domain‐specific neuropsychological tests.

Result

Of 1,030 participants at baseline (intervention/control: n = 487/543), n = 819 (intervention/control: n = 378/441) completed the follow‐up assessment. Intervention and control group did not differ regarding global cognitive performance (β = 0·010, 95% CI: ‐0·085; 0·105) at follow‐up. However, post‐hoc analyses revealed beneficial effects for social cognition (β = 0·132, 95% CI: 0·012; 0·252) and health‐related quality of life (β = 0·194, 95% CI: 0·065; 0·323). The intervention improved global cognitive performance (β = 0·221, 95% CI: 0·015; 0·428), social cognition (β = 0·259, 95% CI: 0·024; 0·494) and health‐related quality of life (β = 0·421; 95% CI: 0·114; 0·728) in participants with low education, and reduced depressive symptoms in highly educated participants (β = ‐0·431; 95% CI: ‐0·781; ‐0·082). Younger participants benefitted from the intervention regarding social cognition (β = 0·174, 95% CI: 0·010; 0·337) and health‐related quality of life (β = 0·405, 95% CI: 0·241; 0·570).

Conclusion

No effect of the multi‐domain intervention on global cognitive performance was found for the overall sample. The intervention benefitted global cognitive functioning in individuals with low education and social cognition and health‐related quality of life across the sample. Further benefits regarding specific subgroups point towards the usefulness of tailored interventions.
the impacts of language decoding and literacy of adults in the cognition of elderly people and its occupational engagement
Authors: Santos Tomaz Kelle Luisa , Maciel Francisca Izabel Pereira , Resende Elisa de Paula França , Zacarias Ana Paula , Assenção Joanna , Ribeiro Norton Grey , Grinberg Lea T , Rincon Luciana Paula , Friedlander Clarisse , Victor João , Lourandes Rocha Aida , Ruppert Emma Patrice , Caramelli Paulo
Published: December 2023

Background

Brazil has a population of 11 million illiterate individuals. This percentage among Brazilians over 60 equals 18%. In view of this, researchers from the Colleges of Medicine and Education from Federal University of Minas Gerais, Brazil, created Alfabetização e Memória (PROAME) – a project that investigates the relations of late literacy with adults’ psychosocial health. The analysis carried out associated the variables of mental and social health to the literacy process, taking into account memory and language aspects.

Method

This study evaluated 130 illiterate adults living in the city of Belo Horizonte, Brazil. 108 participants fitted all criteria and agreed to undergo this survey. There were 31 men (28,4%) and 78 women (71,5%); their average age was 58,5 (±9,6). Regarding race, 91% were black/brown (83,4%), 11 were white (10,1%) and 1 was indigenous (0,1%). 80 of those participants completed all clinical evaluations, interviews and pedagogical diagnoses before and after our intervention through a period of 7 months. The goal was to qualitatively analyze the participants’ discourse, focusing on evidence of the improvement of their autonomy. This was done by associating aspects from occupational engagement to the so‐called social literacy, which consist in the practical application of reading and writing on previously illiterate adults.

Result

The average age of the participants who completed the evaluations was 58,9 (±9,1), and 64 of them were women (80,0%). Both the interviews (made before and after our intervention) and the pedagogic report of 15 random individuals were analyzed. The results show progress in: their engagement in meaningful activities of daily life; their autonomy, sociability and self esteem; their use of technological applications; their occupational repertoire and their reading and writing abilities.

Conclusion

A pedagogical intervention made up by specific reading and writing activities, carried out with illiterate adults during 6 months, resulted in benefits for the participants. However, in face of the high illiteracy levels in Brazil, it is necessary a broader engagement in developing studies and literacy programs for adults as political, educational and health goals. By raising the literacy levels, we expect to guarantee the rights of marginalized individuals in Brazilian society.
New mitochondrial DNA methylation profiling method confirms epigenetic marker in the brain
Authors: Smith Adam R. , Soanes Darren , Moore Karen , Jeffries Aaron , Lunnon Katie
Published: December 2023

Background

There is growing evidence for the role of DNA methylation in regulating the transcription of mitochondrial genes. This is particularly important in neurodegenerative disorders characterised by mitochondrial dysfunction, including Alzheimer’s disease. However, current methods to create genome‐wide, high‐resolution analysis of the mitochondrial DNA methylome are challenging and lack control standards.

Method

Here, we present a new methodological approach to interrogate the mitochondrial DNA methylome at single base resolution using Oxford Nanopore technology and the creation of independent controls. Firstly, we isolate enriched mtDNA from SH‐SY5Y cell lines and post‐mortem brain tissue and use long‐range PCR (LR‐PCR) to generate 0%, 50% and 100% methylation controls. These controls were then validated using pyrosequencing and then run on the Oxford Nanopore (OXNP) long read sequencer. Finally, we used data generated by our controls to train existing methylation calling packages to better call mtDNA methylation in a post‐mortem human brain sample.

Result

We present a new and effective method of profiling mtDNA methylation on native DNA. Using this approach, we show that mitochondrial DNA methylation is relatively low but conserved, with peaks in DNA methylation >5% at several sites.

Conclusion

We have annotated patterns of DNA methylation at single base resolution across the mitochondrial genome in human brain, using our new laboratory pipeline and Oxford Nanopore technology to profile native DNA. Looking to the future this method could be utilized to further investigate the role of mitochondrial epigenetic mechanisms in neurodegenerative disorders, such as Alzheimer’s disease.
Functional connectome‐based prediction of individual clinical and cognitive scores in midlife population with risk of dementia
Authors: Cao Bolin , Deng Feng , Qi Qing , Muniz‐Terrera Graciela , Malhotra Paresh A , Koychev Ivan , Ritchie Karen , O'Brien John T , Ritchie Craig W , Lawlor Brian , Naci Lorina
Published: December 2023

Background

It is well acknowledged that Alzheimer’s Disease (AD) neuropathology start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. Resting‐state functional connectivity (FC) is increasingly used to understand early brain changes in Alzheimer’s disease (AD) (Sperling, 2011; van den Heuvel & Sporns, 2019). We asked whether risk for late‐life dementia impacts functional connectivity in cognitively healthy middle‐aged individuals.

Method

Functional Magnetic Resonance Imaging and detailed neuropsychological assessments were obtained for 585 (207/378 female/male) cognitively healthy individuals, aged 40‐59 years (mean = 50.9), from the PREVENT‐Dementia study. Dementia risk was calculated with the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score. A novel connectome‐based predictive method called NBS‐Predict was used to investigate the association between FC and CAIDE score and its role in cognition.

Result

FC significantly predicted CAIDE scores across the whole cohort (r = 0.207, p < 0.001). FC within and between the cingulo‐opercular network (CON) and sensorimotor network (SMN), as well as between CON and fronto‐parietal network (FPN), and between SMN with default mode network (DMN), and FPN contributed the most (Figure 1). Furthermore, we found that, in the high dementia risk group (CAIDE > 6) only, FC, mainly in DMN‐SMN and DMN‐CON (Figure 2), significantly predicted multisensory processing cognitive score (r = 0.114, p<0.05).

Conclusion

Our results show that FC can be used to detect early brain changes associated with risk of future dementia in cognitively healthy individuals. This method has implications of the early detection of dementia in preclinical populations.
Ameliorative effects of Aqueous Fruit Pulp Extracts of Adansonia digitata on the Hippocampus of Aluminium Chloride‐treated Adult Wistar Rats
Authors: Suleiman Sadiya , Musa Sunday Abraham , Adebisi Samuel , Oderinde Gbenga Peter
Published: December 2023

Background

This study evaluated the effects of aqueous extract of Adansonia digitata fruit pulp (AEAD) on the hippocampus of Aluminium chloride Alzheimer model Wistar rats.

Method

Thirty Wistar rats (110‐150g) were randomly divided into six groups (n = 5). The animals in Group 1 were administered 2ml/kg distilled water. Group 2 were administered 100mg/kg AlCl3. Groups 3 were administered 595mg/kg ascorbic acid. Group 4 and 5 were administered 100mg/kg AlCl3 + 500mg/kg AEAD and 100mg/kg AlCl3 + 1500mg/kg AEAD respectively. Group 6 were administered 100mg/kg AlCl3 + 595mg/kg ascorbic acid. Once daily, for four consecutive weeks, behavioral tests for spatial memory using the Morris water maze test were carried out. Experimentation lasted for 28 days after which the animals were humanely sacrificed.

Result

Animals treated with A. digitata and Ascorbic acid following Aluminium exposure showed significant decrease (11.67±1.74) in the time taken for the experimental rats to locate the escape platform. The result of the oxidative stress study showed a significant increase Malondialdehyde concentration and decrease in Superoxide dismutase (SOD) and reduced glutathione (GSH) in groups exposed to aluminium chloride, however, treatment with A. digitata and Ascorbic acid following Aluminium exposure did not show any significant difference when compared to the control group. Histopathological studies revealed degenerating pyramidal cells, Karyolysis, Pkynosis, were observed in the hippocampus of the aluminium treated group. Treatment with Adansonia digitata and Ascorbic acid ameliorated the changes observed in groups exposed to aluminium. The histoarchitecture of the aqueous extracts treated groups were preserved, particularly the 1500mg/kg doses.

Conclusion

A. digitata fruit pulp possess vital antioxidant properties that could ameliorate the toxic effects of aluminium on the Hippocampus of adult Wistar rats and as such could be used as a treatment of aluminium toxicity.
Race/ethnic disparities in mis‐identification of dementia in Medicare claims
Authors: Zhu Carolyn W , Gu Yian , Cosentino Stephanie , Hernandez Michelle , Stern Yaakov
Published: December 2023

Background

Studies have shown that mis‐identification of dementia in Medicare claims is quite common. We extend the literature by examining potential race/ethnic disparities in mis‐identification of dementia in Medicare claims in a diverse cohort of older adults who underwent careful clinical assessment.

Method

Participants were enrolled the Washington Heights‐Inwood Columbia Aging Project (WHICAP), a multiethnic, population‐based, prospective study of cognitive aging in which dementia status is assessed using a rigorous clinical protocol. The current study included 1,178 participants clinically diagnosed with dementia and 3,048 never diagnosed with dementia. ICD‐9‐CM diagnosis codes in all available Medicare claims (1999‐2019) were compared to clinical dementia diagnosis, and categorized into 3 mutually exclusive groups: (1) congruent identification, (2) over‐identification (no clinical dementia, claims‐identified dementia), and (3) under‐identification (clinical dementia, no claims‐identified dementia) during the study period. Race (White, African American/Black, Other) and ethnicity (Hispanic/Latinx, non‐Hispanic/Latinx) were self‐reported. Multinomial logistic regression model was used to examine the relationship between race/ethnicity and congruency of dementia identification after controlling for clinical (cognition, function, comorbidities) and demographic characteristics (age, sex, education), and inpatient and outpatient utilization. Estimated average marginal effects are reported.

Result

The study included 1,520 White, 1,333 African American/Black, and 1,373 participants of other races. 1,985 participants self‐identified as Hispanic, 2,241 non‐Hispanic. Among participants clinically diagnosed with dementia, the proportion who were accurately identified with dementia in Medicare claims were 83.2%, 77.8%, and 73.2% in White, African American/Black, and other races, respectively; 75.9% and 79.7% in Hispanics and non‐Hispanics, respectively. Among participants clinically diagnosed without dementia, the proportion of participants who were accurately identified without dementia in Medicare claims were: 86.1%, 87.3%, and 82.3% in White, African American/Black, and other races, respectively; 82.4% and 87.5% in Hispanics and non‐Hispanics, respectively. After controlling for participant characteristics, multinomial logistics regression results show the probability of over‐identification with dementia was 2.2% higher for African American/Black participants than White (p = 0.05) and 2.7% higher for Hispanic participants than non‐Hispanics (p = 0.03). Differences in under‐identification by race/ethnicity were no longer statistically significant.

Conclusion

African American/Black and Hispanic participants were more likely to be over‐identified with dementia in Medicare claims.
The shortened version of a web‐based cognitive test tool, cCOG, retains good accuracy in detecting mild cognitive impairment and dementia
Authors: Landen Sophie M. , Gils Aniek M. , Handgraaf Dédé , Hasselbalch Steen G. , Mecocci Patrizia , Soininen Hilkka , Tolonen Antti , Lötjönen Jyrki , Paajanen Teemu , Lemstra Afina W. , Flier Wiesje M. , Sikkes Sietske A.M. , Rhodius‐ Meester Hanneke F.M.
Published: December 2023

Background

cCOG, a web‐based cognitive test tool, has been shown to detect mild cognitive impairment (MCI) and dementia accurately. However, the test now takes approximately 25 minutes to complete, which could be burdensome for patients, especially with cognitive impairment. We assumed that shortening certain subtasks leads to a decrease in total test duration and therefore increases the user‐friendliness of cCOG. In this study, we examined whether shortening these subtasks influences the discriminative value of cCOG.

Method

From the PredictND and Amsterdam Dementia Cohort (ADC) cohort, we included cCOG results of 424 participants (n = 234 cognitively normal (CN), n = 84 MCI, n = 106 dementia) who were on average 70±9 years and 54% were female. cCOG consists of five subtasks: episodic memory learning, reaction time, modified trail‐making A and B and episodic memory recall. Scores for all subtasks except episodic memory recall were abbreviated into shorter versions, e.g. by cutting the number of items/trials. A global cognitive score (GCS) was computed using a linear regression model based on scores of all subtasks for both the original as the short version. To investigate the diagnostic accuracy of both versions, we calculated pairwise area under the curve (AUC) comparisons for differentiating MCI and dementia from CN.

Result

Shortening of subtasks led to an average decrease of 4.7 minutes of the total test time (20.1%) for the PredictND cohort (n = 314), with even 5.7 minutes decrease in the dementia group (Figure 1). The accuracy of the GCS based on the short version for differentiating MCI from CN was lower than based on the original version though still considered excellent (AUC = 0.87 [0.83‐0.92] original; AUC = 0.86 [0.81‐0.90] short; Figure 2). For differentiating dementia from CN, the short version performed comparable to the original version (AUC = 0.93 [0.89‐0.96] original; AUC = 0.92 [0.88‐0.96] short; Figure 3).

Conclusion

Shortening subtasks decreased the test duration of cCOG with approximately 5 minutes, while the diagnostic accuracy was preserved. An additional pilot study is needed to test the effect of shortening subtasks on episodic memory recall and global cognitive score. Further development of a user‐friendly and accurate web‐based cognitive test tool is crucial to keep dementia care accessible and affordable.
Examining widowhood duration with depression and cognitive impairment among older women using nationally representative Longitudinal Aging Study in India
Authors: Muhammad T. , Zanwar Preeti Pushpalata , Srivastava Shobhit
Published: December 2023

Background

Losing loved ones is considered one of the most stressful events in life. With the increase in life expectancy globally over the past century, widowhood has become an older women’s issue. The study aimed to examine the association of widowhood duration with depression and cognitive function among older women in India.

Method

We used the nationally representative Longitudinal Aging Study in India baseline wave, conducted during 2017‐18. Sample comprised of 16,075 older women ages 60 years and above. We conducted descriptive statistics, bivariate analysis and multivariable logistic regression to examine the association of widowhood duration with depression and cognitive impairment.

Result

Nearly 25% of the older women who suffered from cognitive impairment were widowed for more than 10 years whereas, about 14% of older women who suffered from depression were widowed for at least four years. Older women who were widowed for more than 10 years were 43% significantly more likely to suffer from cognitive impairment in reference to older women who were currently married [adjusted odds ratio (AOR): 1.43, confidence interval (CI): 1.27‐1.61]. Older women who were widowed for at least four years were two times significantly more likely to suffer from depressive symptoms compared to older women who were currently married [AOR: 2.01, CI: 1.66‐2.42].

Conclusion

The findings highlight that widowed older Indian women are disadvantaged with respect to the duration of bereavement that leads to worse mental health both in the short and long terms. It suggests that women who are struggling to adjust to such transitions may be particularly at risk for adverse mental health outcomes.