bluuebunny/crossref_metadata_2025 huggingface dataset:
Functionality and socio‐demographic factors in chilean’s community‐dwelling elderly with subjective cognitive complaints . The GERO Cohort
Authors: Loyola Walter Sepúlveda , Lillo Patricia , Zitko Pedro , Cerda Mauricio , Villagra Roque , Parrao Teresa , Gomez Rodrigo , Barría Silvia , Demanet Michele , Amieva Helene , Thumala Daniela , Henriquez Fernando , Slachevsky Andrea
Published: December 2023

Background

Subjective cognitive complaints (SCCs), defined as cognitive concerns of people who may or may not have deficits in objective, is considered a predictor for cognitive and functional decline and incident to dementia risk of progression to dementia. SCC is a heterogeneous condition associated. Most of the studies have been carried out in populations other than those of Latin America. The objective of this study was to analyze the socio‐demographic and functional profile in SCC elderly with and without cognitive impairment.

Method

The GERO cohort is a prospective cohort study of community‐dwelling elderly with SCC, without dementia, aged 70 or older living in Santiago, Chile. Participants were identified by a household census and information on demographics, biomedical, psychosocial, neuropsychological, neuropsychiatric, and motor function were collected by means of questionnaires and evaluations. Montreal Cognitive Assessment (MOCA) was used to compare individuals with and without cognitive impairment (MOCA score ≤ 21 and > 21 respectively). Functionality was measured with the Pfeffer Functional Activities Questionnaire (FAQ) and Technology Activities of Daily Living Questionnaire (T‐ADLQ) that yield a global score and score by domain of activities of daily living (ADL), i.e basic (BADL), instrumental (IADL), and advanced ADL (a‐ADL).

Result

From May 2017 to December 2020, a total of 17,759 households were successfully approached, identifying 2,533 eligible subjects, of which 299 individuals were included. After evaluation, 7 individuals were excluded for different reasons and 291 individuals were analyzed, female 80% (n = 243). The age of the individuals was 76.8 ± 5 years old, 60% of the participants were older than 75 years old. Participants with cognitive impairment compared to those without it were older (p = 0.003), with lower education years (p = <0.001), lower income (p = 0.036), lower MMSE score (p = <0.001), decline in a‐ADL (p = 0.006) and with more hypertension prevalence (p = 0.009)

Conclusion

Few other studies addressed cognitive complaint and functionality decline in recruited elderly at home. Older adults with cognitive impairments are characterized by less years of education, income, poor functionality and more comorbidities. Future multidimensional and prospective analysis of this cohort could bring more information about this association.
Genetic variants underlying the neuro‐anatomical signatures of hypertension measured on structural MRI
Authors: Govindarajan Sindhuja Tirumalai , Mamourian Elizabeth , Cui Yuhan , Wen Junhao , Erus Guray , Abdulkadir Ahmed , Melhem Randa , Bryan R Nick , Shou Haochang , Wolk David A. , Nasrallah Ilya M. , Davatzikos Christos
Published: December 2023

Background

Hypertension (HTN) is associated with gray matter (GM) atrophy and increased white matter hyperintensity (WMH) burden, increasing their susceptibility to Alzheimer’s disease and related dementias. We developed a machine learning based model to quantify spatial patterns of abnormality recognizing HTN‐related brain changes (SPARE‐HTN) from structural magnetic resonance images (sMRI). We performed a genome wide association study (GWAS) to identify the genetic variants and associated biological traits that underlie the “expression” of HTN‐related brain changes, i.e., the individualized SPARE‐HTN index.

Method

SPARE‐HTN model was trained on the large multi‐study iSTAGING dataset, with regional GM volumes from T1‐weighted images and lobar WMH volumes from T2‐weighted FLAIR images used as imaging features. GWAS was carried out in a subset of N = 7490 (46% Female, Age = 65.5±7 years) hypertensive participants from UK‐Biobank. A GWAS of SPARE‐HTN scores was run using linear regression with Plink, correcting for the top 40 genetic principal components, age, sex, and intracranial volume. Significant SNPs were identified and mapped to functional genes using the Functional Mapping and Annotation (FUMA) platform; and candidate SNPs were mapped to the GWAS catalog.

Result

SPARE‐HTN was associated with regional atrophy most prominent in perisylvian and temporal cortex and increased WMH volumes, particularly in frontal white matter. SPARE‐HTN scores showed better discriminative power between normal and stage 1 participants (Cohen’s‐d effect size, d = 0.2) and stage 2 (d = 0.71) hypertensive participants when compared to total WMH volume (d = 0.04 and 0.38, respectively). GWAS identified N = 321 independently significant SNPs, of which a subset N = 46 candidate SNPs were mapped to 6 genes (ICA1L, CARF, WDR12, NBEAL1, KRT8P15, CYP20A1) in Chromosome 2 (Figure 2). These genes were previously reported to be associated with several cardiovascular conditions including coronary artery disease and stroke, and with increased WM damage on sMRI and diffusion MRI (Figure 3).

Conclusion

The individualized imaging marker, SPARE‐HTN, was associated with genes relevant to HTN with traits including cardiovascular conditions and higher prevalence of WMH, and was more sensitive to HTN than total WMH volume. SPARE‐HTN is a useful tool to characterize HTN‐related brain changes and monitor treatment effects at an individual level.
Relationship between baseline levels of subjective cognitive concern and physical, cognitive and social activity in the U.S. POINTER Study
Authors: Sachs Bonnie C. , Baker Laura D , Caudle Brad A , Farias Sarah Tomaszewski , Katula Jeffrey A. , Lee Athene KW , Lovato Laura , Snyder Heather M , Thro Amber Adkins , Papp Kathryn V. ,   The U.S. POINTER Neuropsychology Team and the larger U.S. POINTER Study Group
Published: December 2023

Background

There has been little investigation into the relationship between physical, cognitive, and social activity and subjective concern about cognition (SCD) in the absence of objective cognitive decline. This concern about subjective change is an important concept in the field of Alzheimer’s disease as it independently confers risk for developing MCI/AD. However, the exact relationship between SCD and engagement in positive daily activities is poorly understood. This project examines the relationship between SCD and self‐reported engagement in these activities.

Method

U.S. POINTER is a phase 3, multicenter, 2‐year randomized controlled trial of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Participants completed myriad measures at baseline, including the Cognitive Function Inventory (CFI) assessing subjective cognitive decline, and the Community Healthy Activities Model Program for Seniors (CHAMPS) which assesses self‐reported engagement in social, cognitive, and physical activities over the past 4 weeks.

Results

Baseline study characteristics of the current sample (N = 1823) are: Mean age = 68.2y (5.2), 73.5% female, 29.8% with less than 18+ years education, and 29.3% from underrepresented groups (URG). In separate multivariate linear models, CFI was associated with weekly caloric expenditure in exercise (p< .001) and cognitive activity (p <.001), such that CFI scores were higher for participants with lower exercise‐related caloric expenditure and lower cognitive activity levels. Higher CFI scores also tended to predict social activity levels (p = .06). The inverse relationship between CFI and all three variables is significant in women (p = .04; .0001; .05, respectively) but not in men, and the CFI‐cognitive activity relationship is significant for URG (p = .005) but not White participants.

Conclusion

In sum, SCD and engagement in physical, cognitive, and social activities are inversely related to varying degrees, such that individuals who report lower levels of engagement in these activities report more subjective cognitive concerns. However, different patterns emerged for some subgroups. Additional modeling is needed to demonstrate the directionality of the relationships between these activities and CFI, and the relationship with demographic variables of interest.
Automated Analysis of REM Sleep without Atonia in the Lewy Body Disease Spectrum
Authors: Strainis Emma P. , Jagielski Jack T. , LeClair‐Visonneau Laurene , Przybelski Scott A. , Feemster John C , McCarter Stuart J , Carvalho Diego Z. , Silber Michael H , Vemuri Prashanthi , Jack Clifford R. , Miyagawa Toji , Forsberg Leah K. , Fields Julie A. , Savica Rodolfo , Graff‐Radford Jonathan , Jones David T. , Botha Hugo , Ramanan Vijay K , Knopman David S. , Graff‐Radford Neill R , Ferman Tanis J , Petersen Ronald C. , Lowe Val J. , Boeve Brad F. , Kantarci Kejal , Dredla Brynn , Louis Erik K St
Published: December 2023

Background

Quantitative rapid eye movement (REM) sleep without atonia (RSWA) recorded during polysomnography (PSG) represents loss of normal REM sleep atonia. RSWA is the neurophysiologic signature of REM sleep behavior disorder (RBD). Visually scored RSWA is a candidate biomarker for synucleinopathies. However, visual RSWA scoring requires expert scoring, limiting widespread application. We comparatively analyzed RSWA in DLB and iRBD using the automated Ferri REM Atonia Index (RAI).

Method

We quantitatively analyzed the RAI in 12 DLB and 20 iRBD patients, compared to 20 controls using Hypnolab Software for Sleep Analysis (SWS Soft, Inc, Colognola ai Colli, Italy). PSG data were converted to European Data Format (.EDF), and the submentalis surface electromyogram (EMG) signal was notch‐filtered at 60 Hertz and rectified. Automatically calculated RAI scores were comparatively analyzed across groups (DLB, iRBD, controls) using Kruskal Wallis H tests for group comparisons, and regression analyses determined relationships between diagnosis, age, and sex. Logistic regression ROC determined optimal RAI for distinguishing iRBD from DLB. When interpreting RAI, lower values represent greater amounts of RSWA, and higher values represent more normal REM atonia.

Result

Mean age was older in DLB than in iRBD or controls (72.6 vs. 68.7 vs. 66.5 years). All 12 DLB participants were men, the iRBD group had 18 men and 2 women, and controls were comprised of 16 men and 4 women. Mean RAI was lowest in DLB (0.46), intermediate in iRBD (0.71) and highest in controls (0.96), indicating a gradient in RSWA amounts from DLB patients (highest) to controls (lowest) (Figure). Regression demonstrated diagnosis independently predicted RAI, controlling for age and sex (adjusted R2 = 0.49, p = 0.0001). The RAI that optimally distinguished iRBD from DLB was 0.46 (specificity 85%, sensitivity 58%, AUC = 0.75).

Conclusion

The RAI demonstrated a clear gradient throughout the Lewy body spectrum; highest (indicating lowest RSWA amounts) in controls, intermediate in iRBD, and lowest (indicating greatest RSWA) in DLB. The RAI is a promising, time efficient and broadly applicable candidate biomarker for DLB and iRBD. Automated quantitative RSWA could be a valuable tool for deep phenotyping throughout the Lewy body disease spectrum.
Community support service use and Black family caregiver mental health outcomes
Authors: Johnson Florence U , Robinson‐Lane Sheria G , Veliz Philip
Published: December 2023

Background

Family and friends provide 83% of dementia patients’ essential personal care needs without compensation or training. More than 11 million Americans provided care in 2020, totaling an estimated 15.3 billion hours of assistance valued at nearly $250 billion. The stress associated with caring for a person living with dementia (PLWD) can significantly affect the caregiver’s physical and mental health. Caregiver stress is a significant problem that proportionately affects Black family caregivers. Adult day programs, support groups, help‐seeking, respite, and dementia training can assist Black family caregivers in avoiding stress‐related mental health issues. CSS aids caregivers in keeping PLWD safe at home and postponing or avoiding institutionalization. This study examines how CSS affects Black family caregivers' mental health.

Method

The secondary analysis of data from the National Health and Aging Trends Study (NHATS) Round 5 and the National Study of Caregiving (NSOC) Rd II, 2015, n = 2,204 caregivers. The dementia classification (those with probable or possible dementia) caregivers was n = 1,027. Descriptive statistics and logistic regression analyses evaluated caregiver stress (based on the relationship and interaction with the PLWD) and the use of CSS.

Result

Findings indicated that most caregivers were females (66%) between 55 to 65+ years old. Analysis of the stress measures derived from questions about the caregiver’s relation with the PLWD suggests that overall, the caregivers enjoy spending time with the PLWD (96%). Stress measures did not indicate that caregivers experienced much stress. Black caregivers received less dementia training than their White counterparts: 13% vs. 29%. A small percentage of caregivers attended support groups (5% and less).

Conclusion

The results of this secondary data analysis do not distinguish Black and White family caregiver stress or their use of support services to address stress. The reason is not apparent, but it may be that the most vulnerable groups did not participate in the NHATS/NSOC research, which may account for these results. Qualitative research is required to explore Black caregivers’ stress and support utilization perspectives deeply.
Vascular risk factors are a major contributor to cognitive impairment and degenerative dementia in India
Authors: Kumar S Sandeep , Mekala Shailaja , Somaraj Aparna , Thanissery Nithin , Arshad Faheem , Ramakrishnan Subasree , Kaul Subhash , Alladi Suvarna
Published: December 2023

Background

The burden of vascular contribution to cognitive impairment and dementia is high in low and middle‐income countries (LMIC) like India. It is crucial to determine burden of vascular contribution to dementia in India, to develop effective preventive and treatment strategies. The aim of the study was to determine the prevalence of vascular risk factors across the spectrum of cognitive impairment and dementia in a large dementia cohort in South India.

Method

Patients with cognitive impairment and dementia from the dementia registries of two University referral hospitals in South India were included. All patients underwent clinical, cognitive and imaging study and standard criteria were used to diagnose MCI, AD, FTD, VaD and mixed dementia. Vascular risk factor profile was determined in patients, and the presence of hypertension, diabetes, cardiac disease, stroke, smoking and chronic alcoholism were noted.

Result

Of a total 1811 patients with cognitive impairment, 180 (9.9%) patients were diagnosed to have MCI, 517 (28.5%) AD, 205 (11.3%) FTD, 844 (46.6%) had VaD & 64 (3.5%) had mixed dementia. Overall, hypertension was the most prevalent vascular risk factor (62.7%) followed by stroke (46.6%). 35.5% of patients had diabetes mellitus(DM), 15.2% had chronic alcoholism, 14.4% were smokers and 14.2% had history of cardiac disorders.Hypertension was most commonly encountered in patients with AD (76.4%), followed by mixed Dementia (68.75%), VaD (63.4%), MCI (44.4%) and FTD (39.5%).DM was present in a high proportion of all subtypes of cognitive impairment and dementia (24.4% to 46.8%). The proportion of patients with stroke was highest in VaD (82.1%), but was also associated with one‐fourth of patients with AD and 15% of patients with mixed dementia. Frequency of smoking, chronic alcoholism and cardiac disease was highest in mixed dementia and VaD.

Conclusion

Our results demonstrate that a large burden of vascular risk factors exist in all forms of cognitive impairment and dementia in the Indian context. Hypertension and diabetes were found to be commonly associated with neurodegenerative dementia, in addition to vascular and mixed dementia. This large burden of vascular contribution represents needs and an opportunity to implement strategies to reduce burden of dementia in India and other LMICs
Psychometric properties and diagnostic utility of the Technology‐Activities of Daily Living Questionnaire (T‐ADLQ) for illiteracy in Lima, Peru
Authors: Custodio Nilton , Henriquez Fernando , Montesinos Rosa , Delgado Carolina , Malaga Marco , Chambergo‐Michilot Diego , Slachevsky Andrea
Published: December 2023

Background

Functional decline (FD) is defined as the deterioration of the ability to perform activities of daily living (ADLs). This FD is a critical dimension that allows determining the threshold between dementia disorders and previous stages of cognitive impairment. ADLs include activities that are divided into three main dimensions: basic (BADL), instrumental (IADL), and advanced (AADL). The Technology‐Activities of Daily Living Questionnaire (T‐ADLQ) (1) assesses these different ADL dimensions. To date, the dimensions of ADLs have not been assessed in the continuum ranging from healthy controls (HC), amnestic mild cognitive impairment (a‐MCI), to Alzheimer’s disease dementia (ADD) in the illiterate population. The study aimed is to validate the T‐ADLQ and evaluate FD across the three dimensions of ADL in healthy and cognitively impaired illiterate adults >50 years.

Method

A cross‐sectional study of illiterate subjects in Peru. Inclusion criteria: men and women over 50 years of age; with less than one whole year of formal education and unable to read and write and grouped into 1 of 3 cognitive categories: healthy controls (HC) (n = 64), a‐MCI (n = 60), and early ADD (n = 63). Neuropsychological measures included the RUDAS, MMSE, and IFS. FD was assessed with the FAQ and the T‐ADLQ. The latter questionnaire, assessed by informants, evaluated the different dimensions of ADLs.

Result

The results on the global FD (T‐ADLQ total score) and the three ADL dimensions differed significantly among the three groups (Table 1). The T‐ADLQ total score correlated significantly with the FAQ (Table 2) and had high internal consistency (Cronbach’s alpha = 0.966). In addition, the T‐ADLQ total correlated significantly with instruments of global cognition and executive functions (Table 2). Finally, receiver operating characteristic (ROC) analyses, through the calculation of the area under the curve (AUC), showed that the total T‐ADLQ and the different dimensions discriminated better between HC vs. ADD and HC vs. a‐MCI but not between a‐MCI and ADD (Table 3).

Conclusion

The total T‐ADLQ scale and its three dimensions have good psychometric properties (validity and reliability) and excellent diagnostic utility. This result demonstrates that the T‐ADLQ is a good instrument to evaluate FD in illiterate populations.
The immune cytokine granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) is an effective treatment for both Alzheimer’s disease and the viral diseases caused by West Nile Virus and SARS‐CoV‐2 infection, indicating that inflammation and viral infection may be partners and therapeutic co‐targets in many brain disorders
Authors: Potter Huntington , Boyd Timothy D. , Woodcock Jonathan H , Sillau Stefan H , Ahmed Md. Mahiuddin , Wang Athena Ching‐Jung , Chial Heidi J , Coughlan Christina M , Kendall Lon V. , Bosco‐Lauth Angela , Markham Neil , Stonedahl Sarah , Fong Derek , Clarke Penny , Tyler Kenneth L.
Published: December 2023

Background

GM‐CSF has been considered a potential therapeutic target in many disorders associated with inflammation because it is upregulated and upregulates other inflammatory molecules such as IL‐1, IL‐6, and TNF‐a. However, its ability to increase the number and activation of phagocytic cells in the periphery and brain suggested to us that its upregulation in rheumatoid arthritis (RA) might underlie the finding that RA protects against another inflammatory disorder, Alzheimer’s disease (AD) by aiding phagocytosis of amyloid deposits. Treatment of mouse models of AD with GM‐CSF reverses amyloid deposition and normalizes cognition. A double‐blind placebo‐controlled phase II trial showed that three weeks of treatment with human recombinant GM‐CSF (sargramostim) in mild‐to‐moderate AD participants led to improved cognition (MMSE) and blood biomarkers of amyloid, Tau, and neurodegeneration (A+T+N). GM‐CSF/sargramostim treatment is also efficacious in humans and/or animal models with other inflammation‐associated diseases/disorders (Parkinson’s disease, Down syndrome, chemo‐brain, and normal aging).

Method

Based on findings that innate immunity and microglia underlie viral control, we investigated GM‐CSF in a mouse model of West Nile Virus encephalopathy and a mouse model of SARS‐CoV‐2/COVID‐19. C57BL/6 mice were infected by footpad injection of 1,000 pfu of WNV (TX2002‐HC strain). ACE2 receptor Tg mice were infected with 4,000 pfu of SARS‐CoV‐2 by nasal instillation. Mice were treated IP daily with 5 mg of recombinant GM‐CSF starting the day after infection and analyzed for pathology, morbidity, and mortality at death or at sacrifice at 2 weeks. The SARS‐CoV2‐infected mice were also analyzed for viral titers in brain and lung.

Result

GM‐CSF treatment improved survival in both the WNV and SARS‐CoV‐2 models. SARS‐CoV‐2 viral titers in affected tissues, including brain, were greatly reduced by GM‐CSF treatment.

Conclusion

By activating both the innate and adaptive immune systems, GM‐CSF may be an effective therapy for viral diseases and may protect against viral re‐infection more effectively than antiviral drugs or monoclonal antibodies, a serious concern during the COVID‐19 pandemic. These results also challenge the belief that inflammation in these disorders contributes essentially to the disease. It is possible that the anti‐viral activity of GM‐CSF may also underlie some of its efficacy in AD.
Physical activity reduces the socioeconomic disparity in dementia risk: A UK Biobank cohort study
Authors: Song Suhang , Sun Yitang , Zhang Yuchen , Ye Kaixiong , Shen Ye , Gu Yian
Published: December 2023

Background

Greater socioeconomic deprivation (SED) has been shown to be associated with a higher risk of dementia. There is an urgent need to investigate whether modifiable lifestyle factors, such as physical activity (PA), can help address the SED disparity in dementia. The current study aims to examine whether PA moderates the association between SED and dementia risk.

Method

Data were obtained from UK Biobank, a nationwide cohort study with over half a million participants recruited during 2006‐2010. We excluded those diagnosed with dementia at baseline. SED was represented by the Townsend deprivation index (TDI) at recruitment, with a higher TDI score indicating a higher degree of deprivation. PA was assessed by an International Physical Activity Questionnaire, and participants were classified into low, moderate, and high PA groups according to their total amount of PA measured by metabolic equivalents. Dementia was defined from self‐reported verbal interviews, hospital episode records, and death register data. Cox proportional hazard models were used to examine the association of TDI and PA with dementia risk, adjusting for baseline age, sex, ethnicity, self‐reported overall health, and assessment centers.

Result

This study included 399,270 participants (209,358 [52.44%] females, and 363,116 [90.94%] Whites) aged 38‐73 years (mean = 56.32, standard deviation [SD] = 8.12), with a mean follow‐up period of 12.95 years (SD = 1.85). When categorized by TDI tertile, those in the high‐deprivation group (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.24‐1.56, p<0.001) had an elevated risk of dementia, relative to the participants in the low‐deprivation group. Greater PA attenuated the association between TDI and dementia risk (HR[moderate‐PA*TDI] = 0.96, 95% CI = 0.93‐0.99, p = 0.021; HR[high‐PA*TDI] = 0.97, 95% CI = 0.93‐1.00, p = 0.080). In the low PA group, the high TDI group faced 1.46 times (95% CI = 1.13‐1.89, p = 0.004) higher risk of dementia than the low TDI group, while the associations were smaller in moderate (HR = 1.31, 95% CI = 1.10‐1.57, p = 0.003) and high (HR = 1.43, 95% CI = 1.17‐1.74, p<0.001) PA groups.

Conclusion

Greater PA might, to some extent, help mitigate the detrimental effect of SED disparity in dementia risk, but further research is warranted to explore additional modifiable factors associated with health disparity elimination.
Using plasma ptau181 in Lewy Body Disease spectrum for the identification of Alzheimer’s disease co‐pathology
Authors: Abdelnour Carla , Shahid Marian , Smith Alena , Wilson Edward N. , Vossler Hillary , Plastini Melani J. , Young Christina B. , Winer Joseph R. , Kerchner Geoffrey A. , Andreasson Katrin I. , Henderson Victor , Mormino Elizabeth C. , Poston Kathleen L.
Published: December 2023

Background

Lewy body disease (LBD) patients frequently present with Alzheimer’s disease (AD) co‐pathology, which influences disease progression, cognitive decline, and brain atrophy. AD‐related pathology can be identified with new blood‐based biomarkers like plasma phosphorylated‐tau181 (ptau181).

We aimed to determine whether plasma ptau181 helps identify AD‐related co‐pathology in LBD, and whether plasma ptau181 is associated with clinical features, and AD cerebrospinal (CSF) biomarkers.

Method

From a total of 632 Stanford research participants, we selected 245: 115 cognitively normal (CN), 47 Parkinson’s disease (PD) with normal cognition, 47 on the LBD spectrum (31 MCI and 16 dementia), and 36 on the AD spectrum (14 MCI and 22 dementia). Plasma ptau181 levels were measured with Lumipulse G fully automated platform by Fujirebio with Lumipulse G Assays. A subset of the participants had available AD CSF biomarkers (N = 201) and/or 18F‐Florbetaben PET imaging (N = 73). Diagnostic accuracy was evaluated with area‐under‐the‐curve (AUC) values from receiver‐operating characteristic (ROC) analyses. Linear regression models adjusted for confounding factors were used to analyze effects of baseline plasma ptau181 levels on global cognition (MoCA), global function (CDR‐SOB), motor function (UPDRS Part III), and functional disability (Hoehn and Yahr).

Result

Plasma ptau181 levels were higher in the LBD spectrum group compared to CN and PD with normal cognition groups, but lower than in the AD spectrum group.

Plasma ptau181 levels predicted CSF ptau181/Aβ42 ratio in LBD spectrum patients with an AUC = 0.87. Including age, sex, years of education, and APOE E4 genotype levels improved the prediction of the model (AUC = 0.94).

In the LBD spectrum group, males and females showed similar plasma ptau181 levels, and we found no association between plasma ptau181 levels with age, sex, years of education, MoCA, CDR‐SOB, UPDRS Part III, or Hoehn and Yahr. Nevertheless, plasma ptau181 levels were associated with CSF ptau181 levels and amyloid‐β42/40 after controlling for age and sex.

Conclusion

Plasma ptau181 levels help identify LBD patients with AD co‐pathology, and are associated with AD CSF biomarkers. These findings support the use of plasma ptau181 as a screening tool for AD co‐pathology in patients with LBD and cognitive impairment.
Sex hormone binding globulin and total testosterone levels are associated with in vivo tau burden differentially between the sexes: findings from the Framingham Study
Authors: Buckley Rachel F. , McGrath Emer R , Scott Matthew R , Coughlan Gillian T , Boyle Rory , Seto Mabel , Ghosh Saptaparni , Jacobs Heidi I.L. , Satizabal Claudia L. , Thibault Emma G. , Vasan Ramachandran S , Murabito Joanne M , Sperling Reisa A. , Johnson Keith A. , Seshadri Sudha , Jasuja Ravi , Bhasin Shalender , Beiser Alexa S.
Published: December 2023

Background

In men and women, sex steroid hormones are associated with increased risk of Alzheimer’s disease (AD) dementia. In older men, lower levels of testosterone are associated with higher rates of AD dementia. The relationship between estradiol levels on AD dementia risk in post‐menopausal women, however, is less clear, with studies reporting protective, deleterious and no effects. Finally, higher levels of sex hormone binding globulin (SHBG), a glycoprotein that regulates, and actively influences sex hormones, has been consistently linked with increased risk for AD dementia. Studies have yet to examine mid‐life hormonal levels in association with later‐life in vivo AD biomarkers in cognitively healthy adults.

Method

175 women and 159 men from the Framingham Study 3rd Generation cohort underwent blood (hormones) collection in 2002‐2005, and 18F‐Flortaucipir (FTP)‐PET and 11C‐PiB‐PET scans in 2016‐2020 (Table1). We examined FTP‐PET signal (referenced to cerebellar grey) in six a priori regions that previously demonstrated sex differences (entorhinal, inferior temporal, rostral middle frontal, inf/sup parietal and lateral occipital). Linear regressions examined sex‐stratified analyses of free/total testosterone, estradiol, and SHBG in each region, adjusting for age, age2, PET camera and plasma‐PET date‐difference (mean = 15(±2)yrs). Separate models examined interactions with a neocortical PiB‐PET composite and APOEε4.

Result

In men, elevated SHBG was associated with lower FTP‐PET in entorhinal (p = 0.007), inferior temporal (p = 0.04) and rostral middle frontal regions (p = 0.02; Table2). Higher total testosterone was marginally associated with lower FTP‐PET signal in the latter region (p = 0.06), but other relationships were apparent. In women, higher total testosterone associated with lower FTP‐PET signal in inferior temporal (p = 0.05) and parietal regions (p = 0.04). Women APOEε4 carriers with higher estradiol showed higher levels of entorhinal FTP‐PET signal (p = 0.03;Table3).

Conclusion

Higher levels of SHBG are associated with lower risk of AD‐related comorbidities, such as osteoporosis, diabetes, and visceral weight gain. A strong link between higher SHBG levels and higher HDL‐cholesterol may suggest a potential protective cardiovascular pathway for men against higher tau burden later in life. A lack of protective effect of pre‐menopausal estradiol in female APOEε4 carriers supports the notion that the role of estrogen in AD risk is centered around timing of decline.
Impact of COVID‐19 infection on the cognition and emotion of Peruvians: analysis after 6‐12 months post‐infection
Authors: Zegarra‐Valdivia Jonathan Adrian , Arana‐Nombera Harold Alessandro , Perez‐Fernandez Leandro Aron , Matallana‐Sanchez Maribel Jesus , Alamo‐Medina Reyna Elizabeth , Rocio Casimiro‐Arana Milagros , Bustamante‐Delgado Diana Lisseth , Gallegos‐Manayay Viviana Nayelli , Álvarez‐Bravo Elizabeth Killasumac , Arteaga‐Cancino Tihany Liliana , Abanto‐Saldaña Eduardo Sebastián , Rosario Oliva‐Piscoya María , Ordinola Maria Celinda Cruz , Chavarry Patricia , Chino‐Vilca Brenda Nadia ,   Group of Neuroscience and Mental Health, Universidad Señor de Sipán, Chiclayo, Perú
Published: December 2023

Background

COVID‐19 pandemic significantly impacted different systems and organs (cardiovascular, metabolic, immune, brain, and others). More than two years after the first wave of COVID‐19 in Peru, we still do not know the consequences on cognition and emotion, and nowadays, different studies suggest the impact of COVID‐19 might trigger mild cognitive impairment, dementia, and neuropsychiatric syndromes in the future.

Methods

An ex‐post facto study was carried out with two groups, considering a neurocognitive evaluation (general cognition, verbal fluency, attention, and executive function) and emotion (depression, anxiety, and stress) and performed between 6 and 18 months after the first confirmed diagnosis of COVID‐19 in Peruvians (by PCR or antigen test). The mean age was 37.03 ± 15.57 (age range between 17 and 86 years old), and 60.5% were Female. We use the following instruments: INECO Frontal screening, Addenbrooke’s Cognitive Examination‐Revisado (ACE‐R), Verbal Fluency, TMT A/B, and DASS‐21.

Results

No specific differences in general cognition were found. However, we found an effect in the INECO Frontal Screening (IFS) and the DASS‐21 (Anxiety scale). Patients diagnosed with COVID‐19 by PCR or antigen test have a slightly reduced frontal function (executive function).

Conclusions

COVID‐19 impacted high hierarchical frontal functions, but these effects are not well identified with general cognitive testing. Similarly, an increase in anxiety was found. More specific evaluation and sensitive techniques are needed to elucidate future COVID‐19 consequences on brain function.
Frailty and behavioral and psychological symptoms of dementia: a single center study
Authors: Calsolaro Valeria , Rogani Sara , Coppini Giulia , Lemmi Bianca , Taverni Irene , Bianchi Elena , Pullia Rosanna , Carlo Ludovica Di , Okoye Chukwuma , Virdis Agostino , Monzani Fabio
Published: December 2023

Background

dementia is a clinical syndrome characterized by progressive cognitive decline and loss of independence in activities of daily living. Alongside the cognitive symptoms, Behavioral and Psychological Symptoms of Dementia (BPSD) may arise, causing considerable distress to both patients and caregivers

Method

aim of this retrospective study was to evaluate the correlation between frailty and BPSD in a population of older patients with dementia. BPSD were classified in three clusters: “mood/apathy”, “psychosis” and “hyperactivity”. Using the Clinical Frailty Scale (CFS), patients were categorized as “severely frail”, “mild/moderately frail” and “robust” (CFS ≥ 7, 4‐6 and ≤ 3, respectively). In order to better understand the complex pattern of relationships between the different factors, we performed a network analysis.

Result

209 patients (71.3% women, mean age 83.24±4.98 years) with a clinical diagnosis of dementia were enrolled. The most represented group was the mild/moderately frail one (n = 155, 74%); lower numbers were seen in the robust (n = 18, 9%) and severely frail (n = 36, 17%) ones. Among the “severely frail” the percentage of BPSD was higher compared to the “mild/moderate” and “robust” groups. A significant correlation between frailty and “hyperactivity” cluster emerged, both at baseline and follow up visits (p<0.001, p = 0.022, p = 0.028 respectively). At the network analysis, the degree of frailty related to behavioral and psychological symptoms of the hyperactivity cluster, such as agitation and motor aberrant activity; the relationship was still positive although not so strong with other symptoms like apathy and hallucinations.

Conclusion

in this study an association between frailty and the number of neuropsychiatric symptoms of the “hyperactivity” cluster was found; however, whether the loss of independence is a possible cause of frailty or viceversa is still to be determined. The assessment of frailty may help identifying patients at risk of developing behavioral and psychological symptoms of dementia, and could provide the clinicians with a time‐window to target intervention in the earliest phases of both frail condition and BPSD.
Effect of Age Range on Power for a Clinical Trial Investigating the Effect of Intensive Systolic Blood Pressure Control on White Matter Hyperintensity Volume Accumulation
Authors: Pruzin Jeremy J. , Chen Yinghua , Chen Kewei , Koijs Daniel , Newby Danielle , Winchester Laura M , Thomas Ronald G. , McGrath Emer R , Su Yi , Reboussin David M. , Pajewski Nicholas M. , Beiser Alexa S. , Seshadri Sudha , Tariot Pierre N.
Published: December 2023

Background

Epidemiological evidence has repeatedly demonstrated elevated systolic blood pressure (SBP) in midlife as a modifiable risk factor for Alzheimer’s Disease and Related Dementia (ADRD) later in life. Despite SBP being readily treatable with safe and inexpensive medications, no clinical intervention implementing a lower SBP goal (<120 mm Hg) in midlife to lower future ADRD risk has ever been attempted. Clinical outcomes are not practical in the age range of interest (45‐65 or 45‐70) during an initial trial period of 5 years however robust evidence demonstrates white matter hyperintensity volume (WMHV) as an MRI finding associated with and predictive of incident ADRD.

Method

We used four data sets (SPRINT, Wisconsin Registry for Alzheimer’s Prevention, Framingham, and UK Biobank) with longitudinal MRI data to examine the effect of age range on power for a clinical trial proposal investigating the effect of intensive SBP control on annualized rates of WMHV accumulation in persons starting in middle age. Analyses were conducted separately in each data set. We calculated mean, standard deviations, and annualized rates of WMHV accumulation (derived from T2 FLAIR MRI), using the linear rate of change for accumulation rate, first stratifying by SBP (≥132 mm Hg vs <132mm Hg except in SPRINT where groups were stratified by goal SBP group) and then by various age ranges. Next, we examined the effect of age range on necessary sample size with 80% power and two‐tailed alpha of 0.05 for a prospective clinical trial.

Result

As expected, annualized WMHV accumulation rate is lower with younger age in all data sets. However, variability decreased (all four data sets) and the percent reduction achieved at lower SBPs is higher at younger ages (3/4 data sets), thus increasing power when excluding older individuals (e.g., >65 years old, Table 1).

Conclusion

Restricting age to individuals to ≤65 years‐old may unexpectedly increase power in a clinical trial designed to investigate the effect of goal SBP<120 mm Hg on annualized WMHV accumulation rate. 45‐65 years‐old is a practical age range for the first ever clinical trial intended to investigate the effects of a lower SBP goal in middle age to reduce future ADRD risk.
Optimising speech‐testing to predict prodromal Alzheimer’s disease: head‐to‐head comparison study of tasks and analysis methods
Authors: Meepegama Udeepa , Skirrow Caroline , Weston Jack , Ropacki Michael T. , Fristed Emil
Published: December 2023

Background

Changes in speech occur in early‐stage Alzheimer’s disease. A range of approaches have been used for eliciting and automatically analysing speech, but limited research has directly compared these methods.

Method

Participants from the AMYPRED‐UK (NCT04828122) and AMYPRED‐US (NCT04928976) studies completed four speech‐elicitation tasks: the Automatic Story Recall Task (ASRT), the Logical Memory Test (LMT), Semantic (Animals, Vegetables, Fruit) and Phonemic Verbal Fluency (F, A, S) Tasks. Responses were recorded and automatically transcribed. Analyses were completed with Novoic’s speech analysis software, using four key approaches: (1) feature extraction, (2) representations from large language models (LLM), (3) text‐similarity evaluation, and (4) autoscoring. Together, these evaluated audio, linguistic, and temporal speech domains. Outputs were entered into logistic regression models predicting Mild Cognitive Impairment (MCI)/mild AD and Amyloid positivity in MCI/mild AD. Area under the ROC curves (AUC) were evaluated via 5‐fold cross‐validation.

Result

165 older adults (including N = 74 MCI and 9 mild AD; of which N = 38 MCI/mild AD and amyloid beta positive) provided data for all tasks. Strength of model predictions varied by task, analytic approach and domain (Fig 1). AUCs predicting MCI/mild AD were generally higher for ASRTs compared to other tasks (Fig 1A). Text‐similarity approaches (G‐match: similarity of word embeddings between the source text and retelling, and V‐match: string‐based matching), produced the highest AUC for ASRTs (G‐match AUC = 0.87‐0.88), and the LMT (V‐match AUC = 0.83‐85). Autoscoring tasks produced the strongest predictor for the semantic fluency (AUC = 0.85), and also one of the strongest for phonemic fluency (AUC = 0.72). Changes in linguistic and temporal characteristics were more sensitive to MCI/mild AD, compared to audio‐only metrics. Amyloid in MCI/mild AD predictions were overall less strong (Fig 1B), with the most consistent pattern being better performance of text‐similarity approaches on story recall tasks (up to AUC = 0.77 for ASRTs, 0.73 for LMT).

Conclusion

Selection of task and analytic approach is important for developing more sensitive speech‐based testing. The best performing tasks (ASRT, Semantic Fluency) and metrics (text‐similarity metrics and autoscoring) have been incorporated in Novoic’s Storyteller automated remote speech‐based test.
Gait and balance measures and tools for early detection of dementias: A systematic review
Authors: Cepukaityte Giedre , Newton Coco , Chan Dennis
Published: December 2023

Background

Brain mechanisms supporting gait and balance are vulnerable to early neurodegenerative changes and identification of alterations in these behaviours has great potential for the detection of different dementia‐causing diseases. This systematic review aimed to identify the most promising gait and balance measures for early detection and technologies suitable for capturing these data and future deployment at scale in clinical practice.

Method

We performed literature searches following PRISMA guidelines across two databases (PubMed and Web of Science). Keywords were designed to capture literature on preclinical and prodromal stages of dementias and high‐risk populations that investigated gait and balance cross‐sectionally and longitudinally. We included studies written in English and published until August 2022. Exclusion criteria included case, intervention, and uncontrolled studies. Studies on established dementia were also excluded.

Result

From 2086 titles, 182 were screened at full‐text stage, with 95 included in the systematic review. Most investigated gait and balance in association with preclinical or prodromal AD [n = 38], Parkinson’s [n = 18] or Lewy body [n = 17] dementias, with very few on FTD [n = 1] or vascular cognitive impairment [n = 2]. Twenty‐two studies utilised a term “dementia”. Fifty‐one unique metrics were used to characterise gait, with 12 balance metrics identified. The most common differentiative metric was gait speed (n = 44 studies), which declined across populations, and was often measured using a stopwatch. Twenty‐seven studies utilised pressure carpets, force platforms and body‐worn sensors, enabling quantification of finer‐grained metrics of gait and balance, e.g., variability, asymmetry, and movement jerkiness. These metrics were shown to be sensitive, especially under dual‐task conditions, and specific to different pre‐dementia states. Only three studies utilised smartphone‐based assessment, potentially the most scalable platform for at‐scale application.

Conclusion

Gait and balance measures can detect early neurodegenerative diseases but measurement using scalable off‐the‐shelf technologies in real‐world settings is currently limited. These findings will guide the selection of gait‐measuring devices for the next generation EDoN (https://edon‐initiative.org) toolkit for early detection.
Retinal Manifestations of Alzheimer’s Disease: MicroRNAs and Microglial Phenotypes
Authors: Matsubara Joanne A , Wijesinghe Printha , Irani Lyden , Nassrallah Wissam , Li Charles , Yin Phoenix , Bhandol Harjot , Xu Qinyuan (Alis) , Campbell Matthew , To Eleanor , Xi Jeanne , Cui Jing , Pham Wellington , Lee Sieun
Published: December 2023

Background

As part of the CNS, retina is a promising site for studying Alzheimer’s disease (AD) and developing potential biomarkers for accessible screening and early diagnosis. Our group has previously investigated retinal amyloid beta (Aβ) deposition, glial cell degeneration, drusen aggregation, microRNA (miRNA) analysis in AD mouse models, and in vivo fluorescence in the retinas from AD donor eyes and AD animal models. We report on our updated work on miRNA expression in mouse models and microglia morphology in the human AD retina.

Method

Ten candidate miRNAs were investigated in the brain and eye tissues and tear fluids of transgenic APP‐PS1 mice, non‐carrier siblings, and wildtype (WT, C57BL/6J) controls at young (∼3months) and old (∼10months) ages. 3D microglia morphology was quantitatively and qualitatively analysed in Z‐stacks of human donor retinal tissues stained for microglia (IBA1), activated microglia (CD68) and retinal vessels (UEA‐lectin).

Result

Relative miRNA expression levels were similar in APP‐PS1 mice and non‐carrier siblings compared with WT, suggesting the miRNAs were mostly intergenic. Relative miRNA expression was lower in neocortex‐hippocampus, eye tissues, and tear fluids compared to other regions in young transgenic mice, but the same regions showed higher relative miRNA expression in old transgenic mice. miRNAs associated with Aβ misfolding (miRNA‐101a, ‐15a and ‐342) and proinflammation (miRNA‐125b, ‐146a, and ‐34a) showed significant upregulation in tear fluids with disease progression tracked by cortical Aβ load and reactive astrogliosis. Custom software analysis suggest distinct populations of microglia in the AD retina vs. age‐matched control human retina based on 1) morphology (e.g., ramified to amoeboid), 2) their activation state and 3) retinal vessel proximity.

Conclusion

Our results demonstrate the non‐invasive potential for analysis of miRNAs from tear fluids and the in vivo imaging of the retinal microglial for tracking AD progression.
The Moderating Effect of Apolipoprotein E Genotype on the Relationship Between Total Cholesterol and Memory
Authors: Emrani Sheina , Kunicki Zachary J. , Villa Priscilla , George Kristen M
Published: December 2023

Background

Hyperlipidemia is associated with increased risk of Alzheimer’s disease and related dementias (ADRD). Apolipoprotein E (APOE) plays a key role in lipid transport and is regulated by APOE. APOEe4 carriage may increase ADRD risk by altering lipid metabolism in the brain. We sought to understand the relationship between total cholesterol and memory when moderated by APOEe4 carriage hypothesizing that the negative effects of elevated total cholesterol on memory would be strongest among APOEe4 carriers.

Method

Participant data were extracted from the Alzheimer’s Disease Neuroimaging Initiative (ADNI‐1) database. Total cholesterol and APOEe4 carriage were measured from blood samples collected at baseline. Rey Auditory Verbal Learning Test (RAVLT) measured delayed recall and recognition normed using the Mayo’s Older Americans Normative Studies (MOANS). We used multiple regression to examine the relationship between total cholesterol, APOEe4, and cognition, controlling for age, gender, and education. Total cholesterol by APOEe4 carriage interactions were tested using a p<0.1.

Result

Among 1776 participants, 55% (n = 978) were male and average age was 74 (SD = 7). APOEe4 non‐carriers had a mean total cholesterol of 192 (SD = 40) mg/dL compared to 197 (SD = 40) among APOEe4 heterozygotes and 200 (SD = 42) among APOEe4 homozygotes (Table 1). Higher total cholesterol was associated with better delayed recall performance (β = 0.01, p = .01). There was a significant interaction (β = ‐0.01, p = .07) such that higher total cholesterol among APOEe4 non‐carriers was associated with better delayed recall (β = 0.01) whereas higher total cholesterol among APOEe4 homozygotes was associated with worse delayed recall (β = ‐0.004) (Figure 1). When modeling recognition, there was no main effect of total cholesterol; however, there was a significant interaction between total cholesterol and APOEe4 (β = ‐0.01, p = .09). This interaction showed a positive relationship between total cholesterol and recognition in APOEe4 non‐carriers (β = 0.003) but a negative relationship in APOEe4 homozygotes (β = ‐0.01) (Figure 1).

Conclusion

Compared to non‐carriers, APOEe4 carriers, particularly homozygotes, may be especially sensitive to the deleterious effects of elevated total cholesterol on memory performance. This study adds to the extant literature demonstrating an effect of APOEe4 allele on the relationship between cholesterol and cognition.