bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive impairment among sexual and gender minority groups: A scoping review of the literature
Authors: Romanelli Robert
Published: December 2023

Background

Sexual and gender minority (SGM) groups tend to have a higher prevalence of risk factors for cognitive impairment and/or dementia. However, the relationship between sexual orientation and gender identity (SOGI) status and cognitive impairment/dementia is currently unclear. We conducted a scoping review to examine the current state of evidence for this relationship.

Method

A scoping review of the literature was conducted. Five databases (PubMed/Medline, CINAHL, Web of Science, PsycInfo, and Embase) were searched for primary articles published in English to compare incidence or prevalence of cognitive impairment among sexual and gender minority (SMG) groups versus non‐SGM groups. Two reviewers independent screened articles and conducted risk‐of‐bias assessment of eligible articles based on study design, handling of confounding, and measurement of exposure/outcomes.

Result

Fifteen primary studies published from 2007‐2022 were eligible. Most studies (n = 13) were cross‐sectional, with moderate to critical risk of bias. Among eight studies using subjective cognitive impairment (SCI), seven reported a higher prevalence among some SGM groups versus non‐SGM groups. Among seven studies using objective measures of cognitive impairment, three examined prevalence of clinician‐documented diagnosis of dementia, of which two reported a higher prevalence specifically among transgender versus cisgender individuals. Among the other four studies, two reported poorer cognitive performance or memory for SGM versus non‐SGM groups, one reported better performance and another reported no difference in performance. Comparisons across studies are complicated due to inconsistencies in how SOGI status and cognitive impairment were operationalised, as well as the factors used for statistical adjustment; some studies adjusted for putative intermediary factors that potentially drive differences in cognitive impairment.

Conclusion

Whereas most studies have identified a relationship between SOGI status and SCI, evidence is rather mixed with regard to objective measures of impairment. Well‐designed longitudinal, observational studies using objective measures of cognitive impairment are needed, with careful consideration of confounding versus intermediary risk factors.
Clinical profile of Early‐Onset Alzheimer’s disease in Peru: Case Series from a Neurological Care Center
Authors: Castro‐Suarez Sheila , Guevara‐Silva Erik Alberto , Alvarez‐Toledo Kelvin , Caparo‐Zamalloa Cesar , Cornejo‐Olivas Mario , Meza‐Vega Maria
Published: December 2023

Background

Early‐onset Alzheimer’s disease (EOAD) is a rare and devasting form of Alzheimer disease that represents 5.5% of the total number of Alzheimer cases. The clinical presentation is heterogeneous, the amnestic variant is the most frequent, followed by atypical phenotypes including visual (8‐13%), language (7‐9%) and executive/behavioral (2%) variants. Clinical aspects of EOAD in Admixed Latin American population are lacking in the literature.

Method

We reviewed medical records of patients diagnosed as probable EOAD during January‐December 2022. All patients were evaluated by trained neurologists from a dementia outpatient clinic at a tertiary neurologic center in Lima, Peru. Relevant information about neurocognitive, neuropsychiatric, and functional assessments were extracted from medical records with further descriptive analysis. IRB approval from local institution was obtained for this study.

Result

A total of 20 EOAD patients (65% female, age at onset = 55±7.5 years) met the selection criteria. Fourteen cases (70%) were categorized as amnestic variant, 4 cases (20%) of executive/behavioral variant, and 1 case of visual and language variant (5%). The average of education was 10±4.3 years. The delay for diagnosis in this group was from 3 to 5 years. A first‐degree relative with dementia was present in 10% of patients. Clinical and cognitive assessment profile included: MMSE average score was 14.9±4.9 with memory loss and dysexecutive dysfunction predominance for amnestic variant. Based on NPI the most frequent neuropsychiatric symptoms were irritability (62%), depression (53%) and aberrant motor activity (39%) in the group of amnestic variant and irritability (100%), apathy and appetite/eating abnormalities (75%) in executive/behavioral variant. Severity of dementia were assessed by CDR (CDR = 3 for 10.5%, CDR = 2 for 26.3%, CDR = 1 for 57.9% and CDR = 0.5 for 5.3%).

Conclusion

The clinical features of our Peruvian EOAD cohort are mostly consistent with previous reports. There is a significant delay of EOAD diagnosis. The second most frequent variant of EOAD in our series was executive/behavioral variant. Implementing training strategies for clinicians, neurologists, and no‐neurologists, will improve a timely and accurate diagnosis of EOAD. Further prospective and longitudinal studies for EOAD are required to assess disease progression and evolution of symptoms.
Establishing the Trial Ready Registry and Dementia Platform Korea system to advance AD research in Korea
Authors: Kim Haeng Jun , Mook‐Jung Inhee , Kim Ki Woong , Seo Sang Won , Lee Jong‐Min , Jung Sun Jae , Bae Hyunjung , Lee Jihyun ,   TRR Research Group
Published: December 2023

Background

Numerous studies on Alzheimer’s disease (AD) are being undertaken, and there is a plethora of high‐quality clinical data and resources for AD in Korea. However, because the resources and data are not thoroughly standardized, they are challenging to use. The Trial Ready Registry (TRR) and Dementia Platform Korea (DPK) technologies were developed to investigate possible AD therapy targets and biomarkers, as well as to progress the AD research field in Korea by standardizing the dementia dataset in Korea.

Method

To collect human‐derived materials with MCD, we designed the minimum common dataset (MCD), which includes clinical evaluations, cognitive evaluations, magnetic resonance imaging (MRI), Florbetaben (FBB)‐PET, Flutematamol (FMM)‐PET, and blood tests.

Result

The TRR‐DPK system is planned to enroll 3,000 participants in MCD exams, blood tests, and brain imaging by 2028. Since 2020, 942 people had been recruited for the system as of December 2022. We collected human‐derived materials such as plasma, serum, DNA, and PBMCs from participants with the purpose of distributing human‐derived materials matched to their brain imaging and clinical data.

Conclusion

We expect that the TRR‐DPK system will improve AD research by giving researchers access to human‐derived materials and a variety of quality‐controlled data.
Multi‐omics approach reveals disturbances in brain phosphatidylcholine metabolism in Alzheimer’s Disease
Authors: Tang Xinyu , Lebrilla Carlito B. , Jin Lee‐Way , Maezawa Izumi , Harvey Danielle J. , Zivkovic Angela M.
Published: December 2023

Background

Lipid dysregulation is implicated in Alzheimer’s disease (AD) pathology, given its involvement in amyloid β processing, myelination, and cell membrane structure. Studies have demonstrated increased phosphatidylcholine (PC) hydrolysis in the brains of AD individuals, but the connections between AD and PC metabolism are not fully understood.

Method

To investigate the alterations in PC metabolism in AD, we analyzed publicly available transcriptomic, metabolomic, and lipidomic data from the ROSMAP study, which included dorsolateral prefrontal cortex (DLPFC) tissue and serum samples. DLPFC and serum samples were classified based on clinical consensus diagnosis of cognitive status at the time of death and the last valid clinical diagnosis, respectively. Concentration differences were determined with a linear model using the Limma R package.

Result

According to the lipidomic results, the concentration of total PC‐containing glycerophospholipid was significantly decreased in AD DLPFC samples (P < 0.05). Specifically, diacyl‐PC and acyl‐alkyl‐PC, the two most abundant subclasses, were significantly decreased in the brains of AD patients (P < 0.05). The concentration of the PC breakdown product, glycerophosphocholine (GPC), was increased in AD patient brains (P‐value < 0.05). However, GPC phosphodiesterase 1 (GPCPD1), the enzyme that further hydrolyzes GPC to free choline, was downregulated and choline abundance was reduced in AD DLPFC samples (P < 0.05). The expression of phosphatidylethanolamine N‐methyltransferase (PEMT), which converts PE to PC, was reduced as was the abundance of PEMT products (PC 18:2/20:4 and PC 18:0/20:4, P < 0.05). These alterations in the brain were not observed in the serum.

Conclusion

These results indicate that PC metabolism is disturbed in the DLPFC of AD patients, with evidence of increased PC breakdown and reduced GPC hydrolysis as well as reduced conversion of PE to PC in AD brains. However, these changes in the brain are not reflected in serum. Further studies are needed to better understand changes in phospholipid metabolism in the brains of AD patients.
Primary etiology and associated medical conditions in Mild Cognitive Impairment Subtypes in the NACC Database
Authors: Elkasaby Mohamed , Appleby Brian , Duffy Charles , Leverenz James B , Malone Joseph , Miller‐Scott Lindsay J , Murphy Tamara B , Ogrocki Paula K. , Pillai Jagan A. , Lerner Alan J.
Published: December 2023

Background

Mild cognitive impairment (MCI) reflects cognitive deficits without significant functional decline in activities of daily living (1). MCI subtypes correspond to phenotypic cognitive impairment patterns in memory, attention, language, executive, and visuospatial compared to age‐adjusted norms: Amnestic single domain (ASD) or multi‐domain (AMD), Nonamnestic single domain (NASD), or Nonamnestic multi‐domain (NAMD). Previous studies have suggested nonamnestic subtypes are more likely to represent non‐AD prodromes, but conclusions have been limited by small sample sizes (1).

Method

Using the National Alzheimer’s Coordinating Center (NACC) database (grant U24 AG072122), we selected all initial Uniform Data Set (UDS) assessments diagnosed as MCI with subtyping. The NACC data was collected from 37 participating Alzheimer’s disease Research Centers. Baseline clinical features, primary etiology and associated medical conditions were collected.

Results

9852 individuals with MCI on baseline UDS visits were analyzed: 45.6% were diagnosed with AD (Table 1). AD was the most common primary etiology in all subtypes, more frequent in amnestic than nonamnestic subtypes (AMD 54.1%; ASD 50.5%; NAMD 20.0%; NASD 18.8%). Overall, 6% were diagnosed with DLB and 3.1% with PD; NAMD and NASD were more frequent than AMD or ASD. The most frequently associated medical conditions were hypercholesterolemia, HTN, depression, anxiety, sleep apnea and diabetes (table 2). The highest percentage of depression and anxiety were in nonamnetsic subtypes. Recent stroke was most frequent in NAMD.

Conclusion

MCI is a heterogeneous disorder, and its classification by subtypes is essential in understanding prodromal stages and neurodegenerative neuropathology. Dementia risk modulation and prevention is linked to identification and treatment of associated medical conditions including frequent neuropsychiatric comorbidity (2).
Recalling Biobank Participants to Clinical Study of Alzheimer’s Disease – FinnGen Pilot Study
Authors: Julkunen Valtteri , Schwarz Claudia , Kalapudas Juho , Hallikainen Merja , Piironen Aino‐Kaisa , Mannermaa Arto , Kujala Hanna , Laitinen Timo , Kosma Veli‐Matti , Paajanen Teemu , Kälviäinen Reetta , Hiltunen Mikko , Herukka Sanna‐Kaisa , Kärkkäinen Sari , Kokkola Tarja , Urjansson Mia , Perola Markus , Palotie Aarno , Runz Heiko , Vuoksimaa Eero ,   FinnGen
Published: December 2023

Background

Population‐based biobanks that comprehensively ascertain health and genetic data hold promise to facilitate identification of Alzheimer’s disease (AD) trial participants. We conducted a pilot study in individuals with mild impairment in cognition or AD to assess the feasibility of recalling biobank participants. We also tested the utility of computer‐ and telephone‐based cognitive assessments as cost‐effective alternatives to in‐person neuropsychological testing and investigated plasma‐based biomarkers.

Methods

We utilized FinnGen, a large population‐based biobank study of up to 500,000 participants representing almost 10% of the Finnish population. Single‐center cross‐sectional study included individuals with ICD‐10 codes for AD (G30) and mild cognitive disorder (MCD; F06.7). Dementia screening instruments were in‐person Mini‐Mental State Examination (MMSE) and telephone interview for dementia (TELE). Episodic memory was assessed with three trial word list tasks in three formats; in‐person, with web‐based tool and with the modified Telephone Interview for Cognitive Status including three learning trials. Each of these yielded immediate and delayed free recall measures. Blood samples were collected to determine plasma‐based biomarkers: amyloid beta (Aβ)1‐40 to Aβ1‐42 ratio, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and phosphorylated‐tau181 (pTau‐181).

Results

A total of 78% (110/140) of a pre‐specified FinnGen sub‐cohort were successfully reached. Of those, 39% (43/110) were willing to participate and 19% (N = 27, mean age = 72y, 13 women) completed the study. FinnGen and hospital records largely matched. For 8/12, MCD was due to other reasons than early AD. MMSE and TELE correlated .818 (p< .001). Immediate and delayed recall measures correlated across three formats: from .584 to .679 (p’s<.003) and from .250 to .424 (p’s: .031 ‐ .218), respectively. AD group had higher levels of GFAP (p = .002) and pTau‐181 (p = .020). TELE was negatively correlated with GFAP (p = .011), NfL (p = .001) and pTau‐181 (p = .006). Moreover, p‐Tau181 had negative correlations with episodic memory measures (all r’s< ‐.202) with telephone‐administered immediate recall reaching statistical significance (r = ‐.394, p = .042).

Conclusions

Informative, customized clinical recall studies from FinnGen are feasible. Remote testing is a cost‐effective approach in recall studies. Next phase of our study aims to invite cognitively unimpaired FinnGen participants for screening of high AD risk individuals.
Comparison of delay correction methods to estimate 18F‐florbetaben kinetics in the brain using an image derived input function on total‐body EXPLORER PET
Authors: Bhattarai Anjan , Holy Emily Nicole , Li Elizabeth , Wang Yiran , Spencer Benjamin A. , Wang Guobao , Decarli Charles , Fan Audrey
Published: December 2023

Background

Absolute quantification of β‐amyloid binding from 18F‐florbetaben PET requires compartment kinetic modeling and an input function. This study uses non‐invasive Image Derived Input functions (IDIFs), derived using a new total‐body EXPLORER PET/CT scanner (Spencer et al., 2021). For accurate kinetic modelling, it is imperative to correct for time delay from the IDIF location to tracer arrival to the tissue of interest. The standard approach of Joint Estimation (JE) fits for delay time in tandem with other kinetic parameters and is computationally extensive (Feng et al., 2021). This study investigates the utility of Leading Edge (LE) ‐a novel and computationally efficient pulse timing method to estimate delay (Li et al., 2021) compared to JE in estimating 18F‐florbetaben kinetics in the brain grey matter regions, known to be vulnerable in Alzheimer’s Disease (AD).

Method

The study cohort included 14 individuals (9 cognitively unimpaired, 2 MCI, and 3AD; age = 66‐86 years) of the UC Davis Alzheimer’s Disease Research Center. Dynamic total‐body 18F‐florbetaben PET images were acquired for 110min using the uEXPLORER, and reconstructed (resolution = 2.344 mm isotropic voxels, framing protocol:30×2s, 12×10s, 7×60s, 20×300s).

The dynamic brain‐cropped images were motion corrected (Jenkinson et al., 2002), and linearly registered to individual subject’s T1W (Jenkinson & Smith, 2001). Individual T1W were segmented using DKT atlas to obtain cerebral grey matter ROIs (Desikan et al., 2006). Dynamic time activity curves for each ROI were fit to the two‐tissue compartmental model, using a subject‐specific IDIF (population metabolite‐corrected) derived from the descending aorta (Figure1). Kinetic parameters were estimated and compared between JE and LE methods.

Result

Strong associations were observed between JE and LE estimated 18F‐florbetaben kinetic parameters, including vb(r = 0.84, p<0.001), K1(r = 1, p<0.001), k2(r = 0.9, p<0.001), k3(r = 0.93, p<0.001), and k4(r = 0.86, p<0.001), in all the brain regions (Figure2). Quantitative kinetic results averaged across the selected grey matter regions (N = 11) are reported in Figure3.

Conclusion

This study demonstrated the utility of IDIF extracted from total‐body dynamic PET to estimate 18F‐florbetaben tracer kinetics in the brain grey matter regions. Furthermore, the results show that LE can be an efficient surrogate for JE based approach in grey matter focused PET kinetic modelling of 18F‐florbetaben.
Pain experience in immigrants living with dementia in residential aged care homes: A study from an Australian dementia behavior support service
Authors: Atee Mustafa , Morris Thomas , Whiting Daniel , Chejor Pelden , Cain Trish , Laging Bridget , Porock Davina
Published: December 2023

Background

Untreated pain in aged care residents living with dementia has been linked to delirium, hospitalizations, inappropriate pharmacotherapy, disrupted activities of daily living, and reduced quality of life. Pain experiences and expressions are subjective and to a large extent culturally driven. As dementia advances, older immigrants living with dementia may revert to their culture and language of origin and may experience pain differently. Further, there is limited studies on the pain experience of immigrant residents living with dementia. This study aims to describe the pain experience in immigrants living with dementia in Australian residential aged care homes (RACHs).

Methods

A sample of residents who were referred to Dementia Support Australia (DSA, a national behavior support service) for the period 01/06/2018‐30/06/2022 was eligible to be included in the study. Pain was assessed using PainChek®, a validated point‐of‐care medical device for non‐verbal adults living with dementia. PainChek® consists of six domains: Face (9 items), Voice (9 items), Movement (7 items), Behavior (7 items), Activity (4 items) and Body (6 items). The sum of domain scores produces a final score that match the following pain levels: 0‐6 (no pain), 7‐11 (mild pain), 12‐15 (moderate pain) and 16‐42 (severe pain). Immigration status was defined as country or place of birth reported other than Australia.

Results

The eligible sample [n = 8607, 84.5 (7.0) y, 55.4% female, Alzheimer’s disease = 37.8%, vascular dementia = 12.9%, mixed dementia = 9.5%] had 4411 pain assessments completed, with an average total pain score of 9.4 (5.1). The prevalence of pain was 68.4% in the sample, with over one‐third of episodes represent mild pain (36.0%), and almost one‐third in moderate‐severe pain (20.1% and 12.2%, respectively). Among other factors, pain was the primary contributing factor (60.1%) in causing neuropsychiatric symptoms of dementia, such as agitation/aggression and depression. Top five countries of birth for DSA referrals were England, Italy, Greece, Scotland, and Germany.

Conclusion

Pain is a prevalent clinical problem in immigrants living with dementia in Australian RACHs, who were seeking external behavior support for their neuropsychiatric symptoms.
Social relationship factors, cognitive activity engagement and cognitive decline across 25 years in the Maastricht Ageing Study.
Authors: Duffner Lukas , Deckers Kay , van Boxtel Martin P.J. , de Vugt Marjolein , Köhler Sebastian
Published: December 2023

Background

Social relationship factors and cognitive activity engagement have been suggested as protective for cognitive decline and dementia. However, relatively few studies have addressed the risk for reverse causation with extended follow‐up periods. This study therefore aimed at examining associations between those factors and cognitive decline across up to 25 years.

Method

We used data of 1,823 participants of the Maastricht Ageing study, who received baseline measurements of social relationship factors (social network size, social activity engagement and loneliness) and cognitive activity engagement (e.g. hours per week spent with reading books) from 1993 to 1995. Associations with baseline levels and change in memory, processing speed and executive functioning until the fifth Wave of follow‐up (2019 to 2022) were assessed using linear‐mixed models, controlling for age, sex, education, and a summary score of ten risk and protective factors for cognitive decline and dementia (the LIfestyle for BRAinhealth/LIBRA score).

Result

Mean age at baseline was 51.1 years (SD = 16.4) and 49.9% of participants were female. Participants were followed up for 17.3 years on average (SD = 9.1). At baseline, more frequent social activity engagement was positively associated with processing speed (p<.001). Moreover, larger social network size (p = .023), and more frequent cognitive activity engagement (p = .037) were associated with better executive functioning. Longitudinal analyses showed that people with smaller social network size (p<.001) and higher levels of loneliness had a steeper decline in processing speed from baseline to the 25‐year follow‐up (p = .020). People with higher levels of loneliness additionally showed a steeper decline in memory (p = .006).

Conclusion

Social relationship factors were associated with cognitive function and decline across 25 years in a sample representative of the general Dutch adult population. Our findings support their role as potential targets for the maintenance of optimal cognitive functioning.
Cerebral microbleeds and amyloid pathology
Authors: Oomens Julie Elisabeth , Jansen Willemijn J. , Freeze Whitney M. , Maserejian Nancy Nairi , Verhey Frans R.J. , Vos Stephanie J. B. , Visser Pieter Jelle ,   the Amyloid Biomarker Study group
Published: December 2023

Background

Cerebral microbleeds (CMBs) are common in the elderly population and are associated with cognitive decline. The aim of the current study was to examine the association between CMBs and cerebral amyloid pathology in cognitively unimpaired (CU) and cognitively impaired (CI) individuals included in the Amyloid Biomarker Study.

Method

We included 2550 CU and 1002 CI participants from 12 cohorts of the Amyloid Biomarker Study. Presence of amyloid pathology was determined based on Aß42 levels in CSF (n = 2873) or amyloid‐PET (n = 679) using data‐driven or center‐specific cutoffs. CMBs were assessed on in vivo MRI and were classified as present (≥1) or absent. The association of amyloid pathology with CMBs and its dependency on age, sex, APOE‐e4 carriership and hypertension was assessed using generalized‐estimating‐equations.

Result

Thirty‐seven percent of participants were amyloid positive, 38% were APOE‐e4 carrier, 54% were female, 30% had hypertension and 17% had CMBs (20% of the amyloid positive and 16% of the amyloid negative group, respectively). The mean age was 66.7 years (SD9.2). In CU participants, there was no association between amyloid pathology and CMBs. In CI individuals, CMB prevalence was associated with amyloid pathology depending on age (p = 0.044). At younger ages (<75 years), CMBs were more common in amyloid positive rather than amyloid negative participants while at older ages, amyloid negative participants had CMBs more often. However, the interaction between amyloid status and age became insignificant when hypertension was considered. CMB prevalence was associated with amyloid pathology depending on hypertension (p = 0.006). In CI participants without hypertension, CMBs were more common in those that were amyloid positive rather than amyloid negative. In CI participants with hypertension, there was no significant difference in CMB prevalence between the amyloid positive and negative groups (Figure 1). Sex and APOE‐e4 status did not affect the observed associations between amyloid pathology and CMBs in participants with CI.

Conclusion

CMB prevalence is associated with amyloid pathology and this association is dependent on hypertension. Knowledge on the background prevalence of CMBs considering AD biomarker and vascular risk factor status is needed to inform clinical trial design and safety evaluation of AD therapies.
A composite endpoint using version 3 of the Alzheimers’ Disease Research Centers’ neuropsychological test battery
Authors: Chan Kwun Chuen Gary , Saykin Andrew J. , Barnes Lisa L. , Kukull Walter A. , Dodge Hiroko H
Published: December 2023

Background

Version 3 of the Uniform Data Set (UDS) has been collected by the National Alzheimer’s Coordinating Center (NACC) since 2015, which contains neuropsychological test scores on multiple domains. However, its potential utility as prevention trial outcomes needs to be examined, in comparison with other previously validated outcomes.

Method

The analytical sample was extracted from the December 2022 data freeze from NACC, which includes baseline and follow‐up visits from participants who were cognitively normal during initial visits. Standardized z‐scores for each cognitive domain (attention/working memory, episodic memory, semantic memory/language, executive function, visuospatial function) were calculated. Linear mixed effects models with random intercepts and slopes were used for studying longitudinal changes comparing participants who progressed to MCI or AD (decline subgroup) and those who remained cognitively normal for up to 4 years of follow‐up (stable subgroup), controlling for baseline age, sex, race, education and APOE‐e4 carrier status. We then constructed an approximate effect size weighted average of domain‐specific scores as a global composite measure, obtain effect size estimates using the mini‐mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the composite measure as outcomes, and perform sample size calculations using the following assumptions: a significance level of 5%, 80% power, an equal proportion randomized in a hypothesized intervention and a placebo control arms, in which the intervention group has a 10% to 30% reduction of progression to MCI during the study period, each participant has a baseline visit and up to four annual follow‐up visits, a dropout rate of 10% per year.

Result

The estimated difference of the annualized rate of change in z‐scores between the decline and stable subgroups ranged from 0.028 (attention) to 0.105 (executive function) standardized units for the domain‐specific scores, and 0.068 standard deviation units for the composite score. The composite score requires a smaller sample size for detecting the same level of reduction in progression compared to MoCA and MMSE.

Conclusion

Using a global composite score of UDS version 3 neuropsychological tests as a prevention trial outcome would result in about 30‐50% reduction of sample size needed compared to MMSE and MoCA.
Facilitating Clinical Use of the Amsterdam Instrumental Activities of Daily Living Questionnaire: Normative Data and Diagnostic Cutoff Values
Authors: Postema Merel C. , Dubbelman Mark A. , Verrijp Merike , Visser Leonie N.C. , Visser Pieter Jelle , Zwan Marissa D. , van der Flier Wiesje M. , Sikkes Sietske A.M.
Published: December 2023

Background

The Amsterdam Instrumental Activities of Daily Living Questionnaire(A‐IADL‐Q) measures impairments in everyday functioning in the context of dementia. To facilitate interpretation and clinical implementation of the A‐IADL‐Q, we aimed to generate demographically‐adjusted norm scores and a clinical cutoff value.

Method

Cross‐sectional data were used from Dutch Brain Research Registry(N = 1,064; mean (M) age = 62±11year; 69.5% female) European Medial Information Framework‐Alzheimer’s Disease(EMIF‐AD) 90+ (N = 63; Mage = 92±2year; 52.4% female), and European Prevention of Alzheimer’s Dementia Longitudinal Cohort Study(EPAD‐LCS)(N = 300; Mage = 62±7year; 71.7% female)(Table 1). Norm scores were generated using a I) linear regression model approach; and II) Box‐Cox Power Exponential(BCPE) model approach (the latter falling within the generalized model for location shape and size(GAMLSS) framework). For both methods, different combinations of the variables age, sex and education were tested (including polynomial age and age*education interaction) and the best model was selected based on the lowest Aikake Information Criteria(AIC) value. Next, diagnostic contrast was generated using an independent memory clinic sample (the Amsterdam Dementia Cohort(ADC)(N = 2,123, Mage = 64±8year, 46.1% female)(Table 1), including people with dementia (both Alzheimer’s Disease(AD) and non‐AD). The optimal cut‐off value for cognitively healthy versus dementia was determined, and corresponding diagnostic accuracy was calculated using area under the receiver operating curves(AUC‐ROC). This optimal cutoff was then applied to different diagnostic contrasts, including mild cognitive impairment(MCI) and subjective cognitive decline(SCD).

Result

The best suitable normative model was the linear regression model, including cubic polynomial for age, education, and age*education interaction. This model was considered superior to the best BCPE model, which had infinitely large residuals due to bad model fit. The optimal cutoff to distinguish normal functioning from dementia, based on bootstrap average estimates of the Youden Index, was 1.82 standard deviation(SD) below the population mean, resulting in an AUC of 0.97[95%CI 0.98‐0.98]). Normative data are made publicly available in an online tool(Fig.1).

Conclusion

We established demographically adjusted norm scores for the A‐IADL‐Q using a large representative sample, and provided an optimal cutoff value for cognitively healthy versus dementia, with outstanding accuracy. Our results, captured in the online tool, can help clinicians to interpret A‐IADL‐Q scores more easily by allowing comparison of functioning against a reference population.
Dementia and Dental health among attendees at a Geriatric outpatient clinic in Nigeria
Authors: Majekodunmi Mofoluwake , Elugbadebo Olufisayo Oluyinka
Published: December 2023

Background

There is a relationship between cognitive function and dental health as cognitive impairment may lead to poor tooth brushing activities as well as poor dental care and use of medications.

Method

A cross sectional study was carried out on three hundred patients attending a geriatric clinic in Nigeria. The diagnosis of dementia was made using ICD 10 diagnostic criteria. Dental health was assessed using a dental chart that shows the number of teeth present and absent in the four quadrants of the mouth.

Result

Blessed Dementia Rating Scale (BDRS) and Instrumental Activities of Daily Living (IADL) showed statistical significant association with tooth loss. BDRS (p = 0.001), IADL (p = 0.007). There was positive correlation between tooth loss and BDRS. Pearson correlation = 0.19, p = 0.001. The mean number of tooth loss was significantly higher in patients with dementia compared to those without cognitive impairment.

Conclusion

The finding of higher tooth loss among people with dementia may support the evidence of ascending infection leading to inflammation in the brain might be responsible.
Personalised activity cards, goal‐directed daily (physical) activity and rest‐activity rhythm in institutionalised persons living with dementia
Authors: Wolf Evelien , Sikkes Sietske A.M. , Milders Maarten V. , Drent Madeleine , Scherder Erik J.A.
Published: December 2023

Background

(Physical) inactivity and disturbances in the rest‐activity rhythm (e.g. more daytime sleeping and more night‐time restlessness) are common in institutionalised persons living with dementia (iPwD). Both are associated with worse quality of life (QoL), which underlines the need for non‐pharmacological interventions. The purpose of this study was to examine if the implementation of personalised activity cards (PACs) could enhance the amount of time spent on goal‐directed daily (physical) activities and improve the rest‐activity rhythm in iPwD.

Method

This prospective longitudinal quasi‐experimental multicentre study was conducted on 11 wards in 8 nursing homes in the Netherlands. The intervention consisted of PACs, a structured method for offering personalised activities based on input from (professional) caregivers. The PACs were implemented on 5 wards. The other 6 wards received care as usual (control group). Intervention compliance was checked every two weeks with an online survey. Outcome variables included minutes spent on goal‐directed daily (physical) activity as measured with an adjusted version of the Physical Activity Survey in Long‐Term Care (PAS‐LTC; observations by researchers), and rest‐activity rhythm was assessed using Actiwatch activity monitors. Outcomes were assessed at baseline (T0), and after 12‐15 weeks (T1).

Result

We analysed the data of 84 iPwD; intervention group: n = 35, control group: n = 49 (Table 1). Intention‐to‐treat mixed model analyses showed no significant interaction effects of the intervention (group × time) on goal‐directed daily (physical) activity and rest‐activity rhythm variables (Table 2). One ward in the intervention group did not implement the PACs. The four wards that did implement the PACs reported diverging percentages of the execution of planned activities, even as low as 33.5% (range 33.5‐74.2%). The most reported reason for not executing activities on the PACs was that employees were too busy.

Conclusion

Contrary to our expectations, implementing PACs did not show any effect on goal‐directed daily (physical) activity in iPwD. The lack of improvement in activity level might be an explanation for the lack of improvement in rest‐activity rhythm. These findings support previous research that it can be difficult to implement new methods in the nursing home environment, and underline the importance of more implementation research
The effect of local versus remote Beta‐Amyloid on functional connectivity mediated Tau‐Spread in Alzheimer’s Disease
Authors: Wanger Fabian , Steward Anna , Biel Davina , Dewenter Anna , Roemer Sebastian Niclas , Ewers Michael , Dehsarvi Amir , Franzmeier Nicolai
Published: December 2023

Background

In Alzheimer’s disease (AD), Amyloid‐beta deposition (Ab) is associated with tau spreading from epicenters to connected regions. Yet, Ab and tau accumulate in strikingly different patterns, and it is unclear how Abdrives tau spreading. We envision two mechanisms, i.e. i) that cortical Ab exerts remote effects and “pulls” tau out of connected epicenters or ii) that tau is pushed out of epicenters, once Ab has reached the tau epicenters (Fig.1A). We tested both mechanisms in AD spectrum patients and determined the predominant mechanism by which Ab drives tau spreading.

Methods

We included 313 ADNI participants (n = 110 CN Ab‐, n = 98 CN‐Ab+, n = 70 MCI Ab+, n = 35 Dementia Ab+), with baseline amyloid‐ and longitudinal tau‐PET, based on which we calculated tau‐PET rates of change (ROC) for 200 cortical ROIs (Schaefer‐atlas; Fig.2). Using the same atlas, a resting‐state fMRI‐connectivity template was obtained in 42 healthy controls. For each subject, we determined tau epicenters as 5% of ROIs with highest baseline tau‐PET and assessed epicenter connectivity. Using ROI‐wise regression, we tested whether faster tau‐PET increase was explained by the simultaneous occurrence of i) higher tau‐PET in the epicenter, ii) stronger connectivity to the tau epicenter and iii) higher Ab in the target region (i.e. pull‐effect) or the tau epicenter (i.e. push‐effect). Lastly, we assessed ROI‐wise main effects of local Ab vs. Ab in the tau epicenter on tau‐PET changes, to determine which mechanism predominates.

Results

Higher tau and Ab in the epicenter explained faster tau‐PET increase in connected temporo‐parietal and frontal regions (Ab‐push‐effect, Fig.1B). In contrast, Ab‐pull‐effects were found also for late‐Braak regions (Fig.1C). Congruently, we found that Ab push effects dominated over Ab‐pull effects in temporo‐parietal brain regions, whereas Ab‐pull effects dominated in late‐Braak regions (Fig.1D‐F). Lastly, patients in which Ab and tau converged locally showed fastest subsequent tau accumulation (Fig.3).

Conclusion

Ab exerts local and remote effects on tau spreading, yet local convergence of Ab and tau in the epicenter may predominantly drive tau spreading. Thus, local convergence of Ab and tau is a key event in AD that gives rise to accelerated tau spreading, previously referred to as cataustrophy.
Artificial neural network application to characterize patients with Alzheimer ’s disease and Mild Cognitive Impairment from Cognitive Normal.
Authors: Cheung Eva YW , Mak Henry , Chiu Patrick Ka‐Chun , Shea Yat Fung , Chau Anson CM , Kwan Joseph SK
Published: December 2023

Background

This study aimed to build an artificial neural network model to differentiate patients with various diagnosis, including Alzheimer’s disease (AD), mild cognitive impairment (MCI) from cognitive normal (CN) using structural MRI images.

Methods

MRI T1 image of 580 participants (97 AD, 291 MCI and 192 CN) were downloaded from ADNI, which is a publicly available database. The MPRAGE T1W MRI were pre‐processed by SPM software, including re‐orientation, segmentation and normalized to the whole brain mask template. 3D slicer software with pyradiomics extension were employed to extract the 107 radiomics features within the brain. Also, 45 brain regional volumes were segmented and calculated using Freesurfer. The AD, MCI and CN groups were divided into a training group and a validation group based on 70:30 ratio. Ten‐fold cross validation were performed to minimize the chance of overfitting. Three feed forward neural network model were built using the neural network toolbox of MATLAB, with one model using 107 radiomics alone (R model), one with 45 brain regional volumes (V Model) and the last one with both radiomics and volumes features (R+V model).

Results

The receiver operating characteristics (ROC) curves showed that the V model and the R+V model achieved excellent accuracy, with 96.6% and 94.8% respectively. The area under the curve (AUC) was 99.6% and 97.9% respectively.

Conclusion

The neural network model can accurately differentiate AD, MCI from HC. The application is practical and can be fully automatic, which can be used for dementia screening.
Sleep problems predict decline in attention over time in older adults with essential tremor
Authors: Tsapanou Angeliki , Ghanem Ali , Nguyen Neil , Chapman Silvia , Dargie Samantha A. , Huey Edward D. , Louis Elan D. , Cosentino Stephanie
Published: December 2023

Background

There is growing evidence that patients with Essential Tremor (ET) are at higher risk for Mild Cognitive Impairment (MCI) and dementia than controls. ET is a quite heterogeneous disorder, including not only motor symptoms, but sleep deficits as some of its non‐motor characteristics. The aim of the current research was to investigate the extent to which sleep problems predict cognitive change over time in patients with ET.

Method

Two hundred and one patients enrolled in a longitudinal, observational study of cognitive function in ET (COGNET) were included in the current analyses. Sleep was examined used the Pittsburg Sleep Quality Index (PSQI). Five cognitive domains were extracted from an extensive neuropsychological assessment: memory, executive function, attention, language, and visuo‐spatial ability. Generalized estimated equations were used to examine the association between sleep problems at baseline and cognitive changes over four‐intervals follow‐up spanning of 4 years.

Result

Our sample was mostly women (60%), with 78 mean years of age, and 16 mean education years. Habitual sleep efficiency (dividing the amount of time spent asleep divided by the total amount of time in bed) was significantly associated with attention performance longitudinally, so that poorer efficiency was associated with more rapid decline in attentional abilities over the years. No other sleep problem was associated with change in any cognitive domain.

Conclusion

People with ET have increased chance for decline in attentional abilities when having sleep problems and more specifically, less habitual sleep efficiency. Early detection of, and intervention for, difficulty with sleep efficiency may protect against aspects of cognitive decline in people with ET.
The effect of basal forebrain atrophy on the rate of cognitive decline in older adults without dementia
Authors: Xia Ying , Maruff Paul , Dore Vincent , Bourgeat Pierrick , Villemagne Victor L , Rowe Christopher C , Coulson Elizabeth J , Fripp Jurgen
Published: December 2023

Background

In early Alzheimer’s disease, degeneration of the cholinergic basal forebrain (BF) system correlates with amyloid‐β (Aβ) burden and contributes to cognitive decline, particularly in the domains of memory and attention processing. However, the nature of these interrelationships remains unclear. This study investigated the effects of Aβ and BF atrophy on cognitive decline of memory and attention in older individuals without dementia.

Method

The BF volumes were quantified from MRIs of 577 participants (73.3 ± 6.3 years old, 55.1% female) from the Australian Imaging, Biomarker and Lifestyle (AIBL) study, including 495 cognitive unimpaired (CU) individuals and 82 with mild cognitive impairment. Aβ‐PET assessment was completed at baseline, and Aβ+ was determined using Centiloid > 20. The cognitive decline in memory and attention was assessed using the relevant AIBL composite scores, over 6.0 ± 3.1 years (up to 13 years). BF z‐scores were calculated using the mean and standard deviation of BF volumes in the CU Aβ‐ group, and z‐scores < ‐1 was classified as BF atrophy (BF+). Participants were then grouped according to the Aβ status and presence of BF atrophy (Table 1). Linear mixed‐effects models assessed differences in rates of cognitive decline in memory and attention across different classification groups. Magnitudes of differences in slopes of decline were expressed using Cohen’s d.

Result

In Aβ‐ individuals, BF atrophy was associated with faster rates of cognitive decline in both memory and attention, with medium effect sizes (Table 2 and Figure 1). In re‐analyses restricted to Aβ+ subjects, BF atrophy remained related to memory decline (p = 0.035, d = 0.33) but not to decline in attention. Compared to Aβ‐ subjects without BF atrophy, both Aβ+ groups had faster decline in both domains, with large effect sizes (all d > 0.8).

Conclusion

These findings indicate that the effects of Aβ and BF atrophy are additive in terms of their influence on the rate of decline in memory. However, BF atrophy influences the rate of decline in attention only in the absence of abnormal Aβ burden.
Rapid, scalable assay of amylin‐β amyloid co‐aggregation in brain tissue and blood
Authors: Kotiya Deepak , Leibold Noah S , Verma Nirmal , Jicha Gregory , Goldstein Larry B , Despa Florin
Published: December 2023

Background

Islet amyloid polypeptide (amylin) secreted from the pancreas crosses the blood brain barrier into the brain parenchyma and interacts with Alzheimer’s disease (AD) associated cerebral β‐amyloid (Aβ) plaques, which are found in both sporadic and early‐onset familial AD. Immunoprecipitated amylin from human AD brain tissue analyzed by Western blot using an anti‐Aβ antibody detects Aβ immunoreactivity, which indicates that the amylin and Aβ peptides aggregate in the brains of humans with AD, forming amylin‐Aβ hetero‐oligomers that are sodium dodecyl sulfate (SDS)‐soluble. We report the development of an ELISA to detect amylin‐Aβ hetero‐oligomers in brain tissue and blood.

Method

The amylin‐Aβ ELISA relies on a monoclonal anti‐Aβ middomain antibody (detection) and a polyclonal anti‐amylin antibody (capture) designed to recognize an epitope that is distinct from the high affinity amylin‐Aβ binding sites. We screened temporal cortex homogenates obtained from 13 cognitively unaffected (CU) humans and 47 persons with sporadic AD (sAD) for amylin‐Aβ hetero‐oligomers. Individuals were of similar age (sAD, 85.65 ± 7.04 years vs. CU, 87.22 ± 7.30 years; p = 0.482). Brain tissue amylin and Aβ concentrations were measured using conventional ELISAs. Amylin‐Aβ oligomer levels were also measured in whole blood lysates from APP/PS1 rats and APP/PS1 rats expressing amyloid forming amylin in the pancreas (APP/PS1/HIP rats; all rats age‐matched, 16‐months).

Result

The brains of most AD patients had detectable amylin‐Aβ hetero‐oligomer concentrations, whereas about half of those CU had brain tissue amylin‐Aβ hetero‐oligomers below the detection limit (0.02 ng/mg total protein; one‐way ANOVA, P < 0.0001). Amylin‐Aβ hetero‐oligomers were more common in brains with frequent neuritic plaques (CERAD C). Higher brain tissue amylin‐Aβ hetero‐oligomer levels were associated with greater brain tissue amylin concentrations (r = 0.38; P < 0.05). There was no correlation between cerebral amylin‐Aβ hetero‐oligomer accumulation and age in the analysis of samples from sAD and CU groups (r = ‐0.22; P > 0.05). Levels of amylin‐Aβ hetero‐oligomers in whole blood lysates obtained from APP/PS1/HIP rats were higher than those from APP/PS1 littermates (P < 0.05).

Conclusion

Studies are needed to determine the extent to which amylin‐Aβ hetero‐oligomerization can be detected in human blood.
Analysis of blood and cerebrospinal fluid flows in preclinical AD. Preliminary results from ALFA+ cohort
Authors: Falcon Carles , Mansilla‐Usero Celia , Morante‐Alberti Carla , Blennow Kaj , Zetterberg Henrik , Kollmorgen Gwendlyn , Carboni Margherita , Grau‐Rivera Oriol , Minguillon Carolina , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

Background

Intracranial cerebrospinal fluid (CSF) motion is driven by the wave pressure associated with arterial blood flow into the skull (Figure 1). Since one of the roles of CSF is the clearance of neural waste, it was investigated the relationship between blood and CSF flow parameters (as measured by magnetic resonance imaging [MRI]) and CSF Ab42/40 and ptau‐181 levels in the preclinical stages of Alzheimer’s disease (AD).

Method

Three hundred sixty‐five subjects from the ALFA+ cohort underwent two MRI phase‐encoded velocity sequences (30 frames per cardiac cycle) to measure (1) blood flow in carotids below carotid bifurcation and (2) CSF flow through foramen magnum. The scanner’s Q‐flow tool was used to quantify stroke volume (volume per cardiac cycle), percent of vessel’s area increase and flow velocity increase, as a proxy for vessel elasticity and flow pulsatility, respectively. Associations between flow parameters and age, CSF Ab42/40 and ptau‐181 concentrations were sought, correcting for sex, age and time between lumbar puncture and MRI (P<0.05).

Result

One hundred thirty‐two subjects were excluded because the scanning session was not completed, showed missing or outlier values or did not pass quality control (artifacts or unbalanced outwards‐inwards CSF flow measures), resulting in a final sample size of 233 participants (mean age [SD]: 60.8±4.5 years; male: n = 73 [31.3%]). Figure 2 shows the plots with the most significant relationships between flow parameters, CSF biomarkers, CSF volume and age. It was observed that a higher stroke volume in CSF flow was associated with lower Ab42/40 and higher ptau‐181 concentrations in CSF.

Conclusion

These results indicate that, despite the role of CSF in waste clearance, the accumulation of amyloid and tau in the brain might be neither caused nor enhanced by a global deficit in CSF circulation. We hypothesize that a higher volume of CSF associated with age and high ptau‐181 levels and/or the loss of parenchyma elasticity might reduce the global intracranial compressibility, resulting in an enhanced response to pressure increase due to blood flow into the skull, which could explain the observed increase in CSF flow associated with the early stages of AD.