bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational progression subtypes of hypometabolism due to Alzheimer’s disease: towards linking antemortem and postmortem diagnoses
Authors: Oxtoby Neil P , Shand Cameron , Bourgeat Pierrick
Published: December 2023

Background

Postmortem diagnosis of Alzheimer’s and related pathologies remains the gold standard. Advanced neuroimaging techniques enable assessment of some pathologies in living subjects, but antemortem signatures are often defined post hoc in postmortem‐defined groups. Here we flip this and estimate data‐driven antemortem signatures of pathology using Subtype and Stage Inference (SuStaIn), then predict postmortem classification. SuStaIn is a machine learning algorithm that jointly estimates subtype clusters of data‐driven disease progression signatures to uniquely unravel spatiotemporal heterogeneity using cross‐sectional neuroimaging data. We evaluate SuStaIn on FDG‐PET scans to produce the first AD subtypes of hypometabolism and explore links with LATE‐NC.

Method

ADNI data was downloaded 06/2022. Model inputs were baseline FDG‐PET SUVR (Desikan‐Killiany parcellation) extracted using FreeSurfer from the N = 1181 (286/791/104 AD/MCI/Ab+CN) available ADNI participants having both T1w MRI and FDG‐PET at baseline. Biomarkers were converted into w‐scores relative to 203 controls (Ab–CN), adjusted for control trends in age and sex using robust linear regression. Postmortem diagnoses (N = 43) of AD/LATE‐NC/mixed were predicted.

Modeling: Hypometabolism subtypes were estimated using SuStaIn. A bespoke “disease signal” approach selected informative biomarkers for w‐score events of interest: 1 (mild), 1.5 (moderate), 3 (severe). Average out‐of‐sample log likelihood (10‐fold cross‐validation) selected the final model (#subtypes, max 5).

Statistical Analysis: Subtype group comparisons of cross‐sectional outcomes and postmortem pathology were performed using common statistical tests.

Result

Figure 1 shows the four subtypes of hypometabolism resulting from our analysis: Typical (limbic+temporal, N = 283: 21/190/72 CN/MCI/AD), Limbic Sparing (N = 261: 19/157/85), Aggressive Typical (early high w‐scores; N = 90: 2/40/48), and Lateral Cortical (N = 62: 1/33/28), with N = 485 (41%) not subtyped. Cognition was worse in the Aggressive Typical/Lateral Cortical subtypes than the Typical/Limbic Sparing (MMSE 25 vs 27; ADAS‐Cog13 19 vs 27) Kruskal‐Wallis test p<10‐3. Figure 2 shows subtyping and staging results (59% subtypeable: N = 696), with AD cases distributed evenly within each subtype and MCI at earlier stages, as expected. Figure 3 is a confusion matrix showing that our model imperfectly predicted postmortem LATE‐NC diagnosis.

Conclusion

Data‐driven antemortem spatiotemporal subtypes of hypometabolism in Alzheimer’s disease were imperfectly predictive of postmortem LATE‐NC/AD classification in a small sample. Validation on larger histopathology samples is necessary to make general conclusions.
Associations of plasma pT205/T205 with Alzheimer’s disease pathology and cognitive function: a comparison with pT217/T217 and pT181/T181
Authors: Janelidze Shorena , Barthélemy Nicolas R. , Stomrud Erik , Bateman Randall J. , Hansson Oskar
Published: December 2023

Background

Alzheimer’s disease (AD) related amyloid (Aβ) and tau pathologies both lead to changes in the cerebrospinal fluid (CSF) levels of phosphorylated tau (p‐tau). However, the extent of these changes appears to vary across different p‐tau variants. Recent evidence has indicated that CSF measures of tau phosphorylation occupancy at T205, pT205/T205, correlated strongly with tau deposition detected by PET and cognitive impairment but were less associated with brain levels of Aβ on PET. Here, we investigated associations of plasma pT205/T205 with tau‐PET and Aβ‐PET as well as cognitive performance in comparisons with two other established plasma p‐tau biomarkers, pT217/T217, and pT181/T181.

Method

This cross‐sectional study included cognitively unimpaired individuals (N = 231) and patients with mild cognitive impairment (N = 106), AD dementia (N = 66) and non‐AD neurodegenerative diseases (N = 18) from the Swedish BioFINDER‐2 study. pT205/T205, pT217/T217, and pT181/T181 were measured in plasma (all participants) and CSF (N = 118) using immunoprecipitation‐coupled mass spectrometry. Tau‐PET, Aβ‐PET and cognitive testing were available in 410, 320 and 406 participants, respectively. Aβ status (A) was defined using either CSF Aβ42/Aβ40 or Aβ‐PET.

Result

We found strong correlations between CSF and plasma levels for all 3 biomarkers (pT205/T205, Pearson r = 0.76; pT217/T217, r = 0.85; pT181/T181, r = 0.67; p<0.001, N = 118) (Figure 1). In A+ individuals (N = 195), associations with tau‐PET (Figure 2) were similar for plasma pT205/T205 (partial Spearman ρ = 0.57, p<0.001) and pT181/T181 (ρ = 0.51, p<0.001) and higher for pT217/T217 (ρ = 0.78, p<0.001). Associations with Aβ‐PET (N = 113) were moderate for plasma pT205/T205 (ρ = 0.38, p<0.001) and pT181/T181 (ρ = 0.36, p<0.001) and stronger for plasma pT217/T217 (ρ = 0.69, p<0.001) (Figure 2). We found similar associations of cognitive performance (based on MMSE, N = 185) with plasma pT205/T205 and pT217/T217 (standardized coefficient β, ‐0.42 and ‐0.46, respectively; p<0.001) whereas associations with pT181/T181 were weaker (β = ‐0.30, p<0.001) (Figure 3). In multivariable models, pT205/T205 (β = ‐0.22, p = 0.015) and pT217/T217 (β = ‐0.39, p<0.001) but not pT181/T181 were independently associated with MMSE. Associations of plasma biomarkers with Aβ‐PET and MMSE were similar in the whole samples but somewhat lower for tau‐PET (Figures 2‐3). A larger dataset will be presented at AAIC.

Conclusion

Plasma pT205/T205 is a promising novel biomarker that might prove particularly useful when combined with pT217/T217 for monitoring cognitive decline in AD.
Rheumatoid Arthritis, Antirheumatic Drugs and Risk of Dementia: A Registry‐based Study
Authors: Zhu Nanbo , Eriksdotter Maria , Garcia‐Ptacek Sara , Mitra Sumonto , Ajeganova Sofia , Carrero Juan Jesus , Chang Zheng , Xu Hong
Published: December 2023

Background

Systemic inflammation is a shared pathogenesis in dementia and rheumatoid arthritis (RA). It has been postulated that patients with RA are at higher risk of dementia, however, prior studies showed conflicting results. In addition, recent research suggested that biological disease‐modifying antirheumatic drugs (DMARDs) could potentially have a protective effect on dementia.

Method

Using data from the Stockholm CREAtinine Measurements (SCREAM) cohort, we identified all individuals with an incident diagnosis of RA (ICD‐10 codes: M05, M06) during 2008‐2019 in the region of Stockholm. For each individual with RA, 10 age‐ and sex‐matched individuals without RA were randomly selected from the general population as reference individuals. The primary outcome was all‐cause dementia, ascertained via linkage with the Swedish Dementia Registry, clinical diagnoses, or initiation of anti‐dementia drugs. Incidence of dementia was compared between RA patients and reference individuals using Cox proportional hazards models. Subsequently, among patients with RA, we examined the association of initiation of any type of DAMRDs, and specifically initiation of biological DAMRDs, with the risk of dementia using inverse probability weighted Cox models. Socio‐demographics, kidney function, comorbidities, and concurrent use of medications were included as potential confounders.

Result

A total of 8939 patients with RA (median [IQR] age, 63 [51, 73] years; 6237 [69.8%] women) were identified, with a median follow‐up of 5.2 (IQR: 2.5, 8.9) years. Compared with the reference individuals, patients with RA associated with a higher risk of all‐cause dementia (hazard ratio [HR]: 1.18; 95% CI: 1.01, 1.37). Among RA patients, initiation of biological DMARDs was associated with a reduced risk of dementia (HR: 0.34; 95% CI: 0.13, 0.92). However, initiation of any‐type of DMARDs within 3 months was not associated with the risk of dementia (HR: 0.91; 95% CI: 0.71, 1.18).

Conclusion

Patients with RA had a higher risk of developing dementia, and treatment with biological DMARDs might be associated with a decreased risk of dementia. These findings suggest more attention to cognitive function in the clinical management of RA and further investigation on biological DMARDs as a potential therapeutic candidate for dementia.
Diagnosis and care challenges in a patient with early onset familial dementia due to Kufs disease
Authors: Jnanasekharan Arathi , Issac Thomas Gregor , Sivakumar Palanimuthu Thangaraju , Arunachal Gautham
Published: December 2023

Evaluation of early onset dementia comes with a set of unique challenges. The pathway to a specific diagnosis of a rare genetic disorder like adult onset Kufs disease presents additional challenges. Kufs disease is an adult‐onset Neuronal Ceroid Lipofuscinoses which is an inherited lysosomal storage disorder which presents with dementia, myoclonus, epilepsy, extrapyramidal & cerebellar involvements and has an incidence of 1 in 1,000,000 worldwide. We present the case of a 38‐year‐old gentleman who had presented with a six‐year history of progressive cognitive and behavioural symptoms of apathy, attention deficits, recent memory impairment, mutism, dysphagia, social incontinence all leading to significant biopsychosocial dysfunction. Patient had hypothyroidism for 6 years and was on irregular medication. History suggested major neurocognitive disorder in multiple siblings with both parents being cognitively normal. During the initial presentation, he had agitation, poor speech output, irritable affect, soft neurologic signs like Marfanoid habitus, albinotic eyes, hypotonia and high arched palate and no cerebellar signs. Pathway to care was complicated with magico‐religious model of illness accepted by the family members, stigma and fear of ostracization by society. Psychoeducation of the family about medical model and ensuring cooperativeness for evaluation was the initial challenge followed by diagnosis and management of behavioural problems. In addition to the routine dementia workup, CSF study, autoimmune panel and paraneoplastic panel was carried out. Elevated Anti‐TPO suggested possible Hashimoto’s encephalitis. After liaison with neurologist, pulse steroid courses were administered which initially resulted in transient speech improvement and emotional reactivity, but worsening of behavioural symptoms occurred subsequently. Patient required two further admissions during which ECT was administered resulting in significant improvement in aggression and improved fluency of speech, improvement in food intake and selfcare. MRI brain showed mild cerebellar atrophy, hypointense thalami,volume loss in the entire cortex, minimal T2 FLAIR hyperintensities periventricularly.Suspecting familial frontotemporal dementia, genetic counselling and testing was done .It reported positive for a novel splice region deletion variant in CTSF gene of autosomal recessive inheritance suggestive of Kufs disease. Psychoeducation, genetic counselling for other family members, psychosocial and supportive interventions for long‐term care were provided.
The difference in apathy estimates between the patient and caregiver predicts dementia in individuals with amnestic MCI
Authors: Massa Federico , Grisanti Stefano Giuseppe , Chincarini Andrea , Pretta Stefano , Rissotto Roberto , Serrati Carlo , Monacelli Fiammetta , Serafini Gianluca , Calcagno Pietro , Brugnolo Andrea , Pardini Matteo , Nobili Flavio , Girtler Nicola ,   Dementia Disease Management Team# of the IRCCS Ospedale Policlinico San Martino (Genoa, Italy)
Published: December 2023

Background

In Alzheimer’s disease, apathy is a common behavioral sign (AD). The Apathy Evaluation Scale (AES) is a measure that investigates caregivers' (CG‐AES) and patients' (PT‐AES) perceptions of apathy, and the discrepancy in their evaluations is a proxy for patients' illness unawareness. We aimed to determine whether apathy and awareness of apathy predict dementia development and timing in a cohort study of individuals with amnesic mild cognitive impairment (aMCI).

Method

We acquired two main indices for analysis from the global AES scores of 110 patients with aMCI and their caregivers: i) ‘Apathy,’ the mean of PT‐AES and CG‐AES, and ii) ‘Discrepancy,’ obtained by subtracting CG‐AES from PT‐AES. Patients were seen every six months for three years, or until they developed dementia. The AES indices and the major demographical/neuropsychological variables were filtered for multicollinearity, and the most robust variables were entered into a logistic regression model and survival analyses (Cox regression, log‐rank test of Kaplan‐Meier curves) to estimate which variables predicted the risk and timing of progression, respectively.

Result

60 patients (54.5%) showed signs of dementia (57 AD) after 6.0‐36.0 months, whereas 28 patients (25.5%) dropped out and 22 patients (20%) were still in an MCI stage. The “Discrepancy” index was a reliable and accurate predictor of the probability of progression (AUC = 0.73) and, after binarization in accordance with a calculated cutoff, of the time to dementia.

Conclusion

A structured assessment of apathy, both by the patient and by the caregiver, can reveal important details about the likelihood and timing of the transition from aMCI to dementia. The difference between the two estimations serves as a reliable predictor of illness unawareness by patients.
Standard resting state electroencephalographic power density computed from posterior bipolar channel characterizes patients with Alzheimer’s disease
Authors: Lizio Roberta , Percio Claudio Del , Lopez Susanna , Tucci Federico , Noce Giuseppe , Güntekin Bahar , Yener Görsev , Babiloni Claudio
Published: December 2023

Background

Abnormalities in cortical sources of resting‐state eyes closed electroencephalographic (rsEEG) rhythms recorded by hospital settings (10‐20 montage) with 19 scalp electrodes characterized Alzheimer’s disease (AD) from preclinical to dementia stages. An intriguing rsEEG application is the monitoring and evaluating of AD progression in large populations with few electrodes in low‐cost devices. Here we assessed whether the above‐mentioned abnormalities could be observed from fewer scalp electrodes in patients with mild cognitive impairment (ADMCI) or dementia (ADD) due to AD.

Method

Clinical and rsEEG data acquired in hospital settings (10‐20 montage) from 88 ADD and 75 ADMCI participants and 70 age‐, education‐, and sex‐matched normal elderly controls (Nold) were available in an Italian‐Turkish archive (PDWAVES Consortium; www.pdwaves.eu). Standard spectral Fast Fourier Transform (FFT) analysis of rsEEG data for individual delta, theta, and alpha frequency bands was computed from 6 monopolar scalp electrodes to derive bipolar C3‐P3, C4‐P4, P3‐O1, and P4‐O2 markers.

Result

The ADMCI and ADD groups showed increased delta/alpha and theta/alpha power density at the C3‐P3, C4‐P4, P3‐O1, and P4‐O2 bipolar channels compared to the Nold group (Figure 1). The best classification accuracy (area under the receiver operating characteristic curve) between the ADD and ADMCI vs Nold individuals was reached using alpha2/theta power density computed at the C3‐P3 bipolar channel (AUROC for ADMCI vs Nold = 81%; AUROC for ADD vs Nold = 90%; Figure 2).

Conclusion

Standard rsEEG power density computed from six posterior bipolar channels characterized AD status from preclinical to dementia stages. These results may pave the way toward diffuse clinical applications in the health monitoring of dementia using low‐cost EEG systems with a strict number of electrodes in lower‐ and middle‐income countries.
Brain and Neural Reserve Mediate Associations Between Lifestyle and Cognition: The Maastricht Study
Authors: De Jong Nathan R. , Jansen Jacobus F.A. , van Boxtel Martin P.J. , Schram Miranda T. , Stehouwer Coen D.A. , van Greevenbroek Marleen M.J. , van der Kallen Carla J.H. , Koster Annemarie , Eussen Simone J.P.M. , de Galan Bastiaan B.E. , Backes Walter H. , Köhler Sebastian
Published: December 2023

Background

Life‐course exposure to risk and protective factors impacts brain macro‐ and micro‐structure, which in turn affects cognition. Brain Age Gap (BAG) directly measures brain reserve by comparing an individual’s neuroimaging‐based predicted age with their calendar age. Higher BAG implies accelerated brain aging and lower brain reserve. In this study, we comprehensively modeled mutual associations between brain risk and protective factors, reserve, and cognition in a large, middle‐aged population using structural equation modelling (SEM).

Methods

Cognitive test scores, lifestyle, and 3T MRI data for n = 4881 participants (mean age(±SD) = 59.2(±8.6), 50.1% male) were available from The Maastricht Study, a population‐based cohort study with extensive phenotyping. Whole brain volumes (gray matter (GM), cerebrospinal fluid (CSF), white matter hyperintensity (WMH)), cerebral microbleeds (CMB), and structural white matter connectivity were calculated. Lifestyle factors were combined into the Lifestyle for BRAin health (LIBRA) weighted sum score, with higher score indicating greater dementia risk (Figure 1). Cognition was calculated by averaging z‐scores across three cognitive domains (executive function and attention, memory, information processing speed). BAG was calculated by comparing calendar age to predictions from a neuroimaging‐based multivariable regression model. Paths between LIBRA, BAG and cognitive function were tested using linear regression and SEM, adjusting for confounders. LIBRA was split into tertiles for SEM analysis.

Results

CSF, GM, WMH and CMB best predicted BAG (R2 = 0.455, RMSE = 6.44). In regression analysis higher LIBRA scores (greater dementia risk) were associated with higher BAG (standardized regression coefficient ß = 0.127, p<0.001), lower connectivity (ß = ‐0.071, p = 0.002) and worse cognition (ßlinear = ‐0.044, p = 0.017, ßquadratic = ‐0.047, p = 0.018). Higher BAG was associated with lower connectivity (ß = ‐0.418, p<0.001) and worse cognition (ß = ‐0.165, p<0.001). Lower connectivity was associated with worse cognition (ß = 0.086, p<0.001). In mediation analysis (Figure 2), 21% of the total differences between the highest and lowest LIBRA tertile on cognition was mediated by BAG (ßindirect = ‐0.019, p<0.001; ßtotal = ‐0.092, p<0.001), and an additional 4.1% was mediated via connectivity (ßindirect = ‐0.003, p<0.001; ßtotal = ‐0.073, p<0.001).

Conclusion

Associations between health‐ and lifestyle‐based risk/protective factors (LIBRA) and cognition is partially explained by maintenance of brain reserve (BAG) and neural reserve (connectivity). Lifestyle interventions promoting brain and neural reserve may help maintain cognitive function into older age.
Associations of adherence to a dietary index based on the EAT–Lancet reference diet with cognition, brain volumes, and ecological sustainability parameters: Results from the Rhineland Study
Authors: Tavares Juliana F. , Conzen Christina‐Alexandra , Estrada Santiago , Etteldorf Rika , Landstra Elvire Nadieh , Boenniger Meta M. , Nöthlings Ute , Breteler Monique M.B.
Published: December 2023

Background

Food systems play a major role in both human and planetary health. In 2019, the EAT‐Lancet Commission proposed a universal, healthy reference diet, intending to improve environmental sustainability and prevent non‐communicable diseases (Willet et al, 2019). Adherence to the EAT‐Lancet reference diet (ELR‐diet) has been previously associated with lower cardiometabolic diseases and mortality risk (Knuppel et al, 2019; Stubbendorff et al, 2022). However, the effects of the ELR‐diet on brain‐related outcomes remain largely unexplored. Therefore, we quantified the ELR‐diet adherence and its associations with cognitive function, brain structures and ecological sustainability parameters in a population‐based German cohort.

Methods

Our study population consisted of Rhineland Study participants with complete dietary assessment at baseline. We used a semi‐quantitative food frequency questionnaire to estimate ELR‐diet adherence through a 14‐item composite index, based on the EAT‐Lancet Commission recommendations. Diet‐related greenhouse‐gas emissions (GHGEs) and land use (LU) were calculated on the basis of each participant’s total food intake, expressed as kgCO2 equivalents and m2×year, respectively. Cognitive performance was measured in multiple domains (processing speed, executive function, working and episodic verbal memory). These domains were summarized using z‐score averaging, producing a global cognitive function and a total memory score (n = 7017, age 56.2±13.4 years). Brain volumetric measures (total brain, white and grey matter, cortex and hippocampus) were obtained from available T1‐MRI scans (n = 5184, age 55.9±13.4 years) using Freesurfer. We quantified the relationship between ELR‐diet adherence and the outcomes using multivariate linear models adjusted for age, sex, education and BMI.

Results

Higher ELR‐diet adherence (per SD increase) was associated with better global cognitive performance (ß = 0.02, 95%CI = 0.01; 0.03), and executive function (ß = 0.03, 95%CI = 0.01; 0.04), episodic verbal memory (ß = 0.04, 95%CI = 0.02; 0.06) and total memory (ß = 0.02, 95%CI = 0.01; 0.03) domains. Moreover, the ELR‐diet was inversely associated with GHGEs (ß = ‐0.28, 95%CI = ‐0.30; ‐0.25) and LU (ß = ‐0.38, 95%CI = ‐0.41; ‐0.34). No associations between the ELR‐diet and brain volumes were observed.

Conclusion

Our study shows that adherence to the ELR‐diet is associated with favorable cognitive performance and reduced environmental impact, but not with brain volumetric measures. These findings support the potential health and environmental benefits of the EAT–Lancet Commission recommendations.
Plasma pTau‐217 and NfL concentrations across diagnoses in an unselected memory clinic cohort
Authors: Rousset Rebecca Z. , Verberk Inge M.W. , Lemstra Afina W. , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , Jeromin Andreas , den Braber Anouk , van Harten Argonde C. , Teunissen Charlotte E.
Published: December 2023

Background

Alzheimer’s Disease (AD) plasma biomarkers have been proposed for amyloid positivity identification and for differentiating between diagnoses. Phosphorylated Tau‐217 (pTau‐217) has demonstrated good predictive ability for AD vs healthy controls. Neurofilament Light chain (NfL) differentiates between Frontotemporal Dementia (FTD) and other dementia. These factors have not be extensively tested in real‐world cohorts. The aim of this study was to investigate how pTau‐217 and NfL concentrations differ across clinical diagnoses in an unselected, real‐world memory clinic cohort.

Method

We included 418 consecutive patients from the Amsterdam Dementia Cohort. Patients were split among 12 diagnoses, including SCD, Mild Cognitive Impairment (MCI), probable AD, Dementia with Lewy Bodies (DLB) and FTD (Table 1). pTau‐217 was measured using the novel AlzPath assay, while NfL was measured using the Quanterix Simoa assay. were used to classify patients as high or low for pTau‐217 and NfL levels. The pTau‐217 cutoff (0.58 pg/mL) was the Youden index cutoff derived from the present data, based on amyloid‐positive AD vs amyloid‐negative SCD diagnosis (n = 57), using amyloid status derived from cerebrospinal fluid or Amyloid positron emission tomography for classification. (18.2 pg/mL) was chosen based on the sample’s median age (64 years) and taking the value associated with the 90th percentile of normal NfL levels (NfL interface for physicians (shinyapps.io)).

Result

pTau‐217 levels were highest in patients with AD and Primary Progressive Aphasia (PPA), and lowest in those with Vascular Dementia (VaD) and other neurological diagnosis (Figure 1). NfL levels were highest in patients with VaD and FTD, and lowest in SCD and psychiatric diagnoses. The cutoffs highlighted similar trends, with higher proportions patients with elevated pTau‐217 levels observed in possible and probable AD, MCI, and DLB. Higher proportions of patients with high NfL levels were observed in FTD, PPA, VaD, and possible AD (Figure 2).

Conclusion

pTau‐217 concentrations vary as expected across the different diagnoses, with highest concentrations in AD pathology diagnostic groups. The elevated levels observed in DLB and PPA could be due to underlying AD co‐pathology. Following previous results, NfL concentrations were highest in FTD and lowest in psychiatry and SCD.
Predicting progression to Alzheimer’s disease dementia using cognitive measures: findings from the Essex Memory Clinic
Authors: Whitfield Tim , Macdougall Amy , Schott Jonathan M , Frost Chris , Walker Zuzana
Published: December 2023

Background

Timely diagnosis of Alzheimer’s disease (AD) is important for patients, carers and healthcare systems. It is therefore imperative to identify measures with the greatest power to predict future AD dementia. In contrast to research settings, expensive biomarkers are not always available in memory clinics. It is therefore vital to identify predictive measures which can be used in ordinary clinical settings.

Method

This study utilized clinical assessment data from 328 patients assessed in the Essex Memory Clinic between 2002 and 2019. Only patients with a diagnosis of subjective cognitive decline (SCD) or mild cognitive impairment (MCI) at baseline and a minimum of two follow‐up visits were included in analyses. Lasso logistic regression (using AD at visit 3 as the outcome) and Lasso Cox proportional hazards models (using time to AD at visit 3 and beyond as outcome) were fitted in two stages. The first stage included baseline cognitive scores only, while the second stage also included change scores for these measures (derived by subtracting scores at baseline from those at the first follow‐up visit).

Result

In the first stage models, lower Mini‐Mental State Examination (MMSE) and Logical Memory Test (LMT) delayed recall scores, and longer Trail‐Making Test part A (TMT‐A) time were associated with greater odds (logistic regression) and hazards (Cox proportional hazards) of progression to AD. In addition, in the Cox model (only), lower baseline Cambridge Cognitive Examination‐Revised (CAMCOG‐R) score was associated with greater hazard of AD. In the second stage models, worsening CAMCOG‐R and LMT (delayed recall) scores were independently associated with both the odds/hazards of AD.

Conclusion

In this memory clinic cohort, the cognitive scores most predictive of progression to AD were the delayed LMT, TMT‐A, CAMCOG‐R and MMSE. These results are in‐keeping with earlier work conducted in research cohorts. The inclusion of cognitive change scores over one year follow‐up improved predictive accuracy versus baseline scores alone.
Association between the COVID‐19 restrictions, educational level and depression with the Subjective Memory Complaints in aging people from Latin American countries
Authors: Rivera‐Fernandez Claudia , Soto‐Añari Marcio F. , Lopez Norman , Ramos‐Henderson Miguel , Guinea Sara Fernández
Published: December 2023

Background

The subjective memory complaints (SMC) are associated with an increased risk of Alzheimer´s disease. Its prevalence has linked to emotional status, demographics factors and family neuropsychiatric history (Rabin et al, 2017). In addition, some recent studies have associated it with the restrictions during the pandemic of COVID‐19 (Prommas et al, 2022). Our objective was to analyze these factors with SMC in Latin‐American older people during the lockdown of COVID‐19.

Method

A cross‐sectional study was developed in 10 Latin‐American countries: Argentina, Bolivia, Chile, Colombia, Ecuador, Guatemala, Mexico, Peru, Dominican Republic and Venezuela. We evaluated 5245 older adults (66.14% women y 33.86% men). The mean age was 69. 6 (SD = 7.28) and the years of schooling was 11 (SD = 5.85). All participants completed the short version of the Yesavage Geriatric Depression Scale, the functional scale AD8 (Alzheimer’s Disease 8) and completed ah‐doc questionnaire about family neuropsychiatry history, demographics and clinical factors. The SMC was tested with the item: ¿Do you think that are you experiencing more forgetfulness than people of your same age? We performed binary logistic regression considering SMC as dependent variable and demographics, family neuropsychiatry history and emotional status as predictors.

Result

1291 (24.61%) of participants manifest SMC, with higher prevalence in Peru and Colombia (x2 = 70.37, p<.001). The family history of depression (OR 1.43, p = .022) and dementia (OR 1.34, p = .038), higher scores of depression (OR 1.37, p<.001) and more age (OR 1.01, p = .028); increase the risk of SMC. On the other hand, having more years of schooling (OR 0.95, p<.001) and more days in confinement (OR = .99, p = .001) seem to reduce the risk of SMC.

Conclusion

The emotional status and the family history of neuropsychiatry disorders, are more associated with SMC. In the opposite way, more years of schooling and more days in quarantine reduced the risk of SMC. We suggest to follow‐up the sample and use wider instruments related to memory complaints and other cognitive domains.
Memory markers in preclinical Alzheimer’s disease
Authors: Seo Eun Hyun , Yoon Hyung‐Jun , Lee Kun Ho
Published: December 2023

Background

Episodic memory impairment is a widely known core clinical symptom of Alzheimer’s disease (AD). However, it is still uncertain if it is possible to detect meaningful signs or changes in memory in the preclinical stage of AD due to their within‐normal‐range performance. In the current study, we investigated both verbal and visuospatial memory as markers to track the disease progression in the preclinical AD.

Method

We selected cognitively normal (CN) participants from the Gwangju Alzheimer’s Disease and Related Dementia Cohort in Korea. We included a group of CN individuals who showed a significant amyloid‐beta (aß) deposition, defined by amyloid PET, at baseline and completed at least two follow‐up evaluations. In the final analysis, we included 130 individuals in the preclinical stage of AD. Episodic memory measures were delayed recall scores from the Rey Complex Figure Test (RCFT_delayed) and Seoul Verbal Learning test (SVLT_delayed). We performed logistic regression analysis with stepwise selection to examine associations between memory tests and progression.

Result

The mean follow‐up month was 36.21. Twenty‐one (16.2%) participants were converted to MCI (n = 19) or AD dementia (n = 2), while the rest stayed as CN. When both RCFT_delayed and SVLT_delayed at baseline were entered in the logistic regression model, only the RCFT_delayed was significantly associated with the progression (OR = 0.288; 95% CI, 0.138‐0.602; p = 0.001). When change scores were added to the model, RCFT_delayed at baseline (OR = 0.223; 95% CI, 0.101‐0.496; p < 0.001), RCFT_delayed change score (OR = 0.470; 95% CI, 0.258‐0.857; p = 0.014), and SVLT_delayed change score (OR = 0.523; 95% CI, 0.290‐0.942; p = 0.031), were significant.

Conclusion

Our results suggest that visuospatial, not verbal, memory measures may play an important role in sensitively detecting the relevant sign of future progression in asymptomatic individuals. In terms of verbal memory, the longitudinal decline was associated with progression. Our study suggests that the inclusion of a visuospatial memory test and repeated evaluation can help to detect the earliest decline in the preclinical stages of AD.
Longitudinal retinal microvascular changes in preclinical Alzheimer’s disease
Authors: Curro‐Tafili Katie R. , Bouwman Femke H. , den Braber Anouk , Verbraak Frank D. , van Nispen Ruth , van de Kreeke Aleid , van de Giessen Elsmarieke , Tan H. Stevie
Published: December 2023

Background

The retina has become an area of increasing interest as a potential biomarker for neurodegeneration, as it is easily accessible and patient friendly. Previous studies have shown changes in the vasculature of the retina in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in a cross sectional design. In this study we explore longitudinal retinal microvascular changes in amyloid beta positive (AB +) participants compared with amyloid beta negative (AB‐) participants.

Method

We analysed data from 159 cognitively normal participants (mean age 70.6 SD ± 5.91, 55% females) for changes in four microvascular parameters at baseline and 2 year follow up. (mean time between visits 2.2 years ± 0.23 SD) (Table 1) Amyloid status was obtained from positron emission tomography scans (PET) performed in both 2015 and 2019. The Cirrus 5000 Optical Coherence Tomography Angiography (OCT‐A) was used to obtain baseline and follow up measurements of the optic nerve head (ONH) and macula.

Result

In total, data from 123 AB‐ participants and 37 AB+ participants were included in the analysis. AB (+) participants were further divided into converters (AB‐+,n = 19) and those positive on both PET scans. (AB ++, n = 18) A decrease in vessel density (VD) of the ONH in AB++ participants was demonstrated over time, (p = 0.04) however no change over time was found for VD in the macula inner and outer ring or foveal avascular zone (FAZ). (Figure 2) The VD was found to be consistently higher amongst AB++ participants in the macula inner and outer rings (p<0.05) and the FAZ area was higher in AB‐+ participants. (p<0.05)

Conclusion

This study showed change in VD over time for the ONH region in participants who have been AB + for 4 years or longer. These participants further demonstrated a higher VD in the macula inner and outer rings compared to AB—and AB‐+ participants. Additional longitudinal studies where amyloid status is present for longer periods of time amongst cognitively healthy participants should be undertaken to see if these OCTA microvascular changes could be used as a biomarker in preclinical AD.
Feasibility Study for Longitudinal Retinal Imaging in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) Trial
Authors: Rissman Robert A , Ngolab Jennifer , Donohue Michael C. , Belsha Alison , Salazar Jennifer , Cohen Paula , Jaiswal Sandhya , Tan Veasna , Aggarwal Neelum T. , Alber Jessica , Johnson Ken , Jicha Gregory A , van Dyck Christopher H , Lah James J. , Salloway Stephen , Rafii Michael S , Aisen Paul S. S , Sperling Reisa A.
Published: December 2023

Background

Alterations to the retina manifest in patients diagnosed with neurodegenerative diseases such as Alzheimer’s disease (AD). Retinal imaging techniques open the possibility for non‐invasive evaluation of AD pathology. Clinically AD diagnosed patients exhibit retinal spots that may be amyloid deposits. Few studies monitoring preclinical individuals exist, limiting the assessment of the feasibility of retinal imaging as a biomarker for early‐stage AD risk detection.

Method

We compared extent and distribution of retinal fluorescent spots and cerebral amyloid in clinically normal individuals who screened positive for high amyloid levels through positron emission tomography (PET) from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) as well as a companion cohort of individuals who exhibited low levels of amyloid PET in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. We quantified the number of curcumin‐positive fluorescent retinal spots from participants from both studies to determine retinal amyloid deposition at baseline.

Result

Participants from the A4 trial exhibited a greater number of retinal spots compared to those from the LEARN study. We report a positive correlation between retinal spots and brain amyloid, as measured by the standardized uptake value ratio (SUVr).

Conclusion

The results of this study support the use of retinal fundus imaging for and assessing relationships with brain amyloid PET SUVr. Further work is needed to determine the nature of retinal spots and their relationship with actual amyloid plaques cross‐sectionally and longitudinally.
Elective Surgery in People with Dementia in Northern Ireland
Authors: O'Hara Leeanne , Zafeiridi Evi , Passmore Anthony Peter , Cunningham Emma L , McGuinness Bernadette
Published: December 2023

Background

Elective care is defined as care that is planned in advance for those that require a procedure or treatment for an existing condition. Elective surgery aims to improve the physical or psychological quality of life for a patient and may extend the life of an individual. Evidence has shown that surgery in people with dementia (PwD) carry even more risk than those in the general ageing population particularly in terms of post‐operative complications and mortality rates. Whilst thousands of elective surgeries take place every year, it is unclear how many of these are conducted on PwD. This study explores the types and rates of elective surgery in PwD in Northern Ireland and the contributing factors to patient referral for elective surgery.

Method

Data was accessed through the Honest Broker Service (NI) and was retrospectively analysed. Dementia was defined in people who received one or more dementia medications (as outlined in the British National Formulary (BNF)) or when dementia was identified as a primary or secondary cause of death. Elective surgeries were identified by elective surgery referrals (Patient Administration System) (dementia cohort: n = 26,780; control: n = 24,056).

Result

Overall, significantly less PwD were referred for an elective surgery compared to controls. Within the PwD group those who had higher odds to undergo an elective surgery were male, of younger age, lived in rural areas, did not transition to a care home, and were married instead of single or widowed. PwD were less likely to have an elective surgery if they received antipsychotics, but they were more likely to have a surgery if they received lipid lowering drugs, antihypertensives, hypnotics and anxiolytics, antidepressants, or antiarrhythmics. The most common surgeries from both PwD and controls were surgeries for lens, bladder and skin. Having an elective surgery was associated with lower odds of death for PwD and controls compared to people who did not undergo a surgery.

Conclusion

This paper can inform health policy through insight into factors contributing to the rate and types of elective surgery referrals for PwD to ensure PwD are afforded the same care when it comes to elective surgery compared with the general population.
Validation of genetic stratification for risk of Alzheimer’s disease using UK Biobank
Authors: Escott‐Price Valentina
Published: December 2023

UK Biobank is a very large cohort (N = 364,195) with a sufficient number of Alzheimer’s disease (AD) participants (N = 2,431) for statistical analyses. Many participants are only now reaching the age where they are at risk of developing AD and the number of AD cases is expected to grow. We have generated polygenic risk scores (PRS) in the UK Biobank data, using both standard and Bayesian approaches. These risk scores have been computed across all available SNPs (genome‐wide) and for biologically defined gene‐sets (microglia regions (Gosselin et al 2017, Science) based on GWAS signatures and transcriptomic data (Tansey et al 2018, Genome Medicine), synapse (Koopmans et al 2019, Neuron), and genome‐wide significant genes (Andrews et al 2020, Lancet Neurology)). The APOE index SNPs had prediction accuracy (AUC) of 68.6% and PRS excluding APOE region had AUC = 53.4%. The microglia gene‐set had an AUC of 59.1%, the synapse gene‐set AUC = 59.4%, and the set of genome‐wide significant genes (Andrews et al 2020, Lancet Neurology) AUC = 53.2%, increasing to 70.5%, 69.8% and 70.2%, respectively, when APOE was accounted for separately. The UK Biobank data is enriched with late onset AD cases who develop AD at a younger age compared to average age at AD onset since the cohort is, in general, younger than most AD case/control studies. Therefore, PRS including APOE have the best prediction accuracy, since APOE is associated with younger onset (Liu et al 2013, Nature Review Neurology). Gene‐sets explain a large proportion of prediction accuracy using fewer SNPs (3% and 7% SNPs for microglia and synapse gene‐sets, respectively). Enrichment of other AD related genes will be possible to observe as the UK Biobank cohort increases in age, and more individuals are diagnosed with AD.
Discovery of causal relations of risk factors using Mendelian randomisation and genetic colocalization with UK Biobank data
Authors: Dehghan Abbas , Tzoulaki Ioanna , Elliott Paul
Published: December 2023

Many risk factors, disease traits and comorbidities have been associated with Alzheimer Disease (AD). However, given the long subclinical development of the disease it is difficult to establish temporal order or to rule out shared aetiologies in observational research. Novel analytical molecular epidemiology approaches can be used in AD to investigate potential causality. Mendelian randomisation analysis is an approach where genetic instruments are used as a proxy for the exposure and allow us to investigate the causality of the associations in an observational setting. By selecting genetic instruments MR can be extended to proxy a drug target which allows to mimic the effect of medications targeting that particular gene. Colocalization is another method that tests whether a single genetic variant is driving the association of a shared gene for two traits or disorders. The availability of large‐scale data in UK Biobank including genome‐wide association data (GWAS) and whole genome sequencing (WGS) with a range of questionnaire data, physical measurements, proteomics and other biological measurements and clinical phenotypes has the potential to develop new knowledge on AD aetiology using these new approaches. For example, we were able to study the association between features from MRI brain imaging with AD through the MR approach and show associations between genetically predicted brain iron accumulation in different brain areas with AD risk. In another approach, we were able to study pleiotropic genetic variants that affect both cardiovascular traits and AD and through colocalization identify genes that are likely to be causal for both diseases. Using the wealth of phenotypic data in UK Biobank we were able to further explore the effect of these genes across the phenome and exposome. Further molecular data is expected to be released in UK biobank including proteomics and enhance the study of molecular fingerprints of AD and to extrapolate this knowledge to medications that target them and to elucidate underlying disease pathways.
Alzheimer’s Disease genetic risk factor APoE 4 impact auditory processing in young adults
Authors: Ducos Emma Marie Madeleine , Schneefeld Felix , Igloi Kinga , Arnal Luc H.
Published: December 2023

Background

Recent studies have suggested that prodromal stages of Alzheimer’s Disease (AD) are accompanied with central auditory system dysfunction, which may be used as early indicators of disease onset and progression. In AD patients of 60 years old and more and in APOE4 carriers, atypical patterns of oscillatory entrainment to repetitive sound transients have been reported and suggested as potential neuromarkers of AD. Whether such alterations of auditory functions relate to genetic risk factor of AD (APOE4) at an early age (<30) is unknown.

Method

We used EEG recordings to measure auditory responses to repetitive sounds (1 second click trains presented at various frequencies (10‐250Hz) in 32 young neurotypical participants). To test whether auditory responsivity is affected by AD risk factor, we compared auditory brain responses from 17 APOE3 (age mean = 21.6, sd = 1.8) and 17 APOE4 carriers (age mean = 23.6, sd = 4.9).

Result

Comparing the magnitude of auditory event related potentials (ERP) we observed that APOE4 carriers exhibit slightly attenuated P2 and P3 ERP responses as well as delayed N1 and P2 ERP responses compared to APOE3 carriers. Focusing on Auditory Steady State Response (ASSR) power across frequencies (10‐90Hz), we observed that APOE3 carriers exhibit reliably larger neural entrainment than APOE4 carriers (Cohens’ d = 0.8, ‘large’ effect size). This difference was sustained across the peristimulus time course and did vary across stimulus frequencies.

Conclusion

Overall, these results suggest that central auditory differences can be detected very early in at‐risk populations. Studying these signals could help identify early AD pathology and provide an entry point for therapeutic interventions against neurodegeneration.
Comparison between self‐ and informant‐rated versions of the Mild behavioral impairment checklist in patients with mild cognitive impairment
Authors: Matuskova Veronika , Krejci Monika , Horakova Hana , Ismail Zahinoor , Laczó Jan , Hort Jakub , Vyhnalek Martin
Published: December 2023

Background

Mild behavioral impairment (MBI) describes de novo emergent and persistent neuropsychiatric symptoms in older individuals. MBI is common in individuals with mild cognitive impairment (MCI), but self‐endorsed symptoms may not align with reports from informants. In this study, we explore the consistency between self‐ and informant‐rated versions of the Mild behavioral impairment checklist (MBI‐C), which is used to assess MBI.

Method

We included 68 individuals with MCI (MMSE 26.59±2.55) who underwent neurological, extensive neuropsychological examination and brain MRI within the Czech Brain Aging Study and had no history of prior psychiatric disorder. Both participants and their close informants completed The Czech version of the MBI‐C (MBI‐C self and MBI‐C informant, respectively). The consistency and differences between the MBI‐C self and informant total and domain scores (i.e. motivation, affect, impulse dyscontrol, social inappropriateness and psychotic symptoms), and the presence of MBI based on a cut‐off of ≥7, were examined using Wilcoxon signed‐rank test, the binomial test and Spearman´s rank correlation. Further, we explored the association between the informant‐self score difference with the MMSE as a measure of global cognition.

Result

There was no difference between MBI‐C self and informant total score (both median ratings were 5.0). Among the domain scores, we observed a difference between self and informant ratings in the impulse dyscontrol (Z = ‐2.97, p = 0.003), but not in any other score. Disagreements on the presence of MBI were observed in 19 participants (28%), but both patients and informants were equally likely to disagree on the MBI presence vs. absence. We observed weak to modest correlations between MBI‐C self and informant total and domain scores (rS = 0.34‐0.53, ps<0.01). The informant‐self score difference in MBI‐C impulse dyscontrol was negatively associated with the MMSE (rS = ‐0.39, p = 0.001).

Conclusion

Patients with MCI and their informants were not consistent regarding the presence of MBI, but among those who disagreed, neither informants nor patients were more likely to report MBI. The informants reported more severe impulse dyscontrol symptoms compared to the patients with MCI themselves and this difference was negatively associated with lower MMSE. The observed inconsistencies provide implications for clinical and research settings.