bluuebunny/crossref_metadata_2025 huggingface dataset:
Objectively‐determined parental history of dementia is associated with increased posterior white matter hyperintensity volume
Authors: Lippert Rafael V. , Turney Indira C , Lao Patrick J. , Pyne Jeffrey , Kraal A.Zarina , Alshikho Mohamad J , Berroa Joncarlos , Gutierrez Jose , Mayeux Richard , Manly Jennifer J. , Brickman Adam M.
Published: December 2023

Background

Cerebrovascular disease is associated with risk for dementia and possibly Alzheimer’s disease (AD) pathogenesis. Most people diagnosed with AD have mixed pathology, including plaques, tangles, and cerebrovascular disease. Because parental history of dementia is a strong risk factor for AD, studying the extent to which markers of cerebrovascular disease in midlife aggregate with parental history of dementia can provide insight into how risk for dementia is transmitted from one generation to the next. We previously showed that white matter hyperintensities (WMH), a marker of small vessel cerebrovascular disease, is associated with genetic risk, diagnosis, and progression of AD, particularly when distributed in posterior areas. Here, we examined if parental history of dementia, determined via prospective evaluation, is associated with regional distribution of WMH in middle age.

Method

Six hundred thirty‐eight middle‐aged participants (mean±SD age = 54.4±10.5, 65% women, 70% Latinx, 21% Black, 9% non‐Latinx White) in the Offspring Study received MRI; regional WMH volumes were derived with in‐house software. Offspring Study participants are the adult children of participants in the Washington Heights Inwood Columbia Aging Project (WHICAP), a community‐based longitudinal study of cognitive aging and dementia in which participants are evaluated and diagnosed prospectively. A mixed design general linear model evaluated the severity and regional distribution of WMH between Offspring participants with and without parental history of dementia.

Result

Of the Offspring participants included, 214 (34%) had a parent in WHICAP with a diagnosis of dementia. Offspring participants with a parental history of dementia had increased WMH (main effect of parental diagnosis: F = 3.58, p = 0.05), which varied by region (Parental Diagnosis x Region: F = 2.71, p = 0.04). There was greater WMH with parental diagnosis in parietal (t = 2.18, p = 0.02) and occipital (t = 3.05, p = 0.003) but not in frontal (t = 1.36, p = 0.17) or temporal (t = 0.25, p = 0.79) lobes.

Conclusion

Middle‐aged adults with parental history of dementia have increased WMH volume, particularly in posterior brain regions, an anatomical pattern associated with risk and progression of AD. The results highlight the possibility that cerebrovascular disease is a core feature of AD, as WMH severity and parental history of dementia aggregate together.
Plasma biomarkers in relation to spatial distribution of Alzheimer’s disease neuropathology
Authors: Bilgel Murat , Shah Ishaan , Walker Keenan A. , Moghekar Abhay , Ashton Nicholas J. , Kac Przemyslaw Radoslaw , Karikari Thomas K , Blennow Kaj , Zetterberg Henrik , Thambisetty Madhav , Ferrucci Luigi , Resnick Susan M.
Published: December 2023

Background

The clinical utility of plasma biomarkers will in part be based on the information they convey regarding the distribution of neuropathology, especially beyond the information provided by demographics. We examined the associations of plasma biomarkers with cerebral amyloid and tau pathology determined by positron emission tomography (PET).

Method

In the Baltimore Longitudinal Study of Aging, plasma Aβ42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) concentrations were measured using Quanterix Simoa assays. Plasma concentrations of phosphorylated tau at threonine 181 (p‐tau181) and at 231 (p‐tau231) were measured using in‐house Simoa assays at University of Gothenburg. Using voxelwise linear regression models, we investigated cross‐sectional associations of plasma biomarkers with brain fibrillar amyloid and phosphorylated tau pathology as measured by PET with 11C‐Pittsburgh compound B (PiB) conducted on a GE Advance scanner (N = 189) and 18F‐flortaucipir (FTP) conducted on a Siemens High Resolution Research Tomograph (N = 107), respectively. In addition to unadjusted analyses, we conducted analyses adjusting for age, sex, and race. Results were corrected for multiple comparisons using permutation test‐based threshold‐free cluster enhancement (TFCE).

Result

Lower plasma Aβ42/Aβ40 was associated with higher PiB distribution volume ratio (DVR) in the unadjusted model, but not in the adjusted model (Figure 1). The remaining plasma biomarkers exhibited statistically significant positive associations with PiB DVR in both unadjusted and adjusted models. The plasma biomarker with the strongest and most widespread association with PiB DVR was p‐tau231 (Figure 2). Both p‐tau biomarkers exhibited statistically significant associations with FTP standardized uptake value ratio (SUVR) in both unadjusted and adjusted models. Aβ42/Aβ40, GFAP, and NfL did not exhibit statistically significant associations with FTP SUVR. Associations of p‐tau biomarkers with PiB DVR were stronger and more widespread than with FTP SUVR. We did not find any statistically significant associations when we repeated the analyses separately by binary PiB group.

Conclusion

Plasma biomarkers convey information beyond age, sex, and race in relation to the cerebral distribution of amyloid, and to a lesser extent, tau. The smaller sample size of our FTP PET study might in part explain the weaker associations we observed with FTP SUVR compared to PiB DVR.
Racial disparities in epigenetic and cognitive aging
Authors: Yannatos Isabel , Brown Rebecca , Boen Courtney , Stites Shana D. , Xie Sharon X , McMillan Corey T
Published: December 2023

Background

Racial disparities in cognitive health are persistent and pervasive among older Americans. Black Americans have higher rates of cognitive impairment and dementia than their White counterparts and a significantly higher gap between epigenetic age and chronological age. Epigenetic aging measured by DNA methylation (DNAm) has been linked to cognitive outcomes in previous research, but these studies lacked racial diversity or did not account for important confounders. Rigorous evaluation of DNAm‐age’s contribution to cognitive health disparities is needed. We hypothesize that DNAm‐age gap, measured by two epigenetic clocks GrimAge and Dunedin Pace of Aging methylation (DPoAm), is associated with cognitive performance and decline and mediates significant portions of the Black‐White disparities in these outcomes.

Method

We performed retrospective analyses among 3278 non‐Hispanic participants (80.3% White, 19.7% Black) in the Health and Retirement Study whose 2016 epigenetic age is linked to survey responses and cognitive data. DNAm‐age gap is defined as the residual after regressing epigenetic age on chronological age. Cognitive outcomes are Telephone Interview for Cognitive Status (TICS) score in 2016 and change in TICS score from 2016 to 2018. We include age, gender, and measures of socioeconomic status, health status, and health behaviors as confounders. We implement multiple linear regression models to evaluate associations between DNAm‐age gap and cognitive outcomes and mediation models to evaluate the extent to which DNAm‐age gap mediates the relationship between race and cognitive outcomes.

Result

We found that although both GrimAge and DPoAm age gaps are associated with baseline cognitive performance and longitudinal decline in minimally adjusted models, only GrimAge remained a significant predictor after adjusting for confounders. Similarly, both GrimAge and DPoAm mediate a small but significant portion (∼6‐10%) of the racial disparities in cognitive performance and decline before adjusting for confounding variables. Socioeconomic status (education, wealth, and income) has the greatest attenuating effect.

Conclusion

Accelerated epigenetic aging for Black compared to White Americans may play a role in racial cognitive aging disparities. Follow‐up work is ongoing to determine the role of chronic psychosocial stressors and other important determinants of cognitive health in DNAm aging and racial disparities.
Efficacy results from the unique long‐term randomised controlled double‐blind LipiDiDiet trial with a multinutrient intervention in prodromal AD/MCI_AD
Authors: Hartmann Tobias , Solomon Alina , Visser Pieter Jelle , van Oudenhoven Floor M , Blennow Kaj , Kivipelto Miia , Soininen Hilkka ,   LipiDiDiet Research Group
Published: December 2023

Background

Lifestyle factors such as nutrition and diet are modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). A small number of interventions recently showed cognitive and functional benefits. It is unclear however how long these benefits will last, requiring long‐term studies.LipiDiDiet was the first AD double‐blind, placebo‐controlled trial clinical trial to show a significant and sustainable benefit, including a 45% reduction in decline on CDR‐SB performance in a prodromal study population evaluating a multinutrient formulation (Soininen Lancet Neurology 2017; Soininen Alz&Dem 2021). We now extended the analysis from 3 years to up to 6 years of active intervention to investigate long‐term effects.

Method

LipiDiDiet is a 6‐year randomised, double‐blind, placebo‐controlled trial, investigating the effects of a nutritional intervention in individuals with prodromal AD/MCIAD. 311 individuals with prodromal AD (IWG‐1) were randomized to active (125ml once‐a‐day drink; Fortasyn Connect [Souvenaid]) or a calorie‐matched control. Following the first 2 years of intervention, participants could opt‐in for annual extensions up to a maximum of 6‐year double‐blind intervention. Individual participants progressing to mild dementia were provided AD medication and/or open‐label active product and could continue in the trial. Main outcomes included Neuropsychological Test Battery (NTB) composites on cognition and memory, and the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Modified intention‐to‐treat analyses were performed over 4‐6 years of intervention using a joint model combining longitudinal and survival data.

Result

Adding data from all participants who completed the 4‐year visit while still on double‐blind treatment (n = 38) to the previously performed joint model analyses on the 3‐year data showed that the initially observed benefits on cognition, memory, and CDR‐SB appear to have continued beyond 3 years. These and other ongoing analyses are addressing the statistical challenges specific to long‐term AD trials including non‐random patterns of missing data.

Conclusion

In addition to the already demonstrated sustainable benefits of Fortasyn Connect in individuals with prodromal AD/MCIAD, combined with feasibility of its long‐term use without indications for health concerns, we now report first results indicating that benefits on cognition, memory, and CDR‐SB are sustained over 4 years.
Cross‐cultural properties of the Cross‐cultural Dementia Screening test and the European Cross‐Cultural Neuropsychological Test Battery
Authors: Delgado‐Álvarez Alfonso , Delgado‐Alonso Cristina , Gil‐Moreno María José , Nielsen T Rune , Goudsmit Miriam , Valles‐Salgado María , Matias‐Guiu Jorge , Díez‐Cirarda María , Matias‐Guiu Jordi A
Published: December 2023

Background

Cross‐cultural neuropsychological tests are essential to avoid potential cultural biases during the performance and score interpretation in diverse populations. We aimed to compare the performance of healthy controls in the Cross‐cultural Dementia Screening test and the European Cross‐Cultural Neuropsychological Test Battery in the majority and minority populations living in Spain.

Method

Three hundred cognitively healthy participants were enrolled (58% women, age range 18‐90). One hundred from majority population (Spaniards), one hundred from minority population from Colombia, and one hundred from different minority populations, including participants from Latin America (66%, excluding participants from Colombia), Spaniards of Romani (gipsy) ethnicity (14%), Arab League (10%), and East Europe (10%). We matched the three groups controlling for sex, age, and level of education. All scores on CCD and CNTB were compared and correlated with an acculturation scale, controlling for age and years of education.

Result

There were no differences between groups in most of the items. Only processing speed measures of the CCD (Sun‐Moon test) and verbal fluency tasks of the CNBT showed statistically significant differences between groups. Scores on the acculturation scale were not associated with the neuropsychological test performance of all participants.

Conclusion

The absence of differences between groups or acculturation influence on the scores supports the favourable cross‐cultural properties of the CCD and the CNTB. However, some tasks could still be more influenced, especially those associated with processing speed and verbal fluency, which suggests the need to further study and develop new tests and paradigms with better cross‐cultural properties.
Personality and cognition in mild cognitive impairment: predictive role of neuroticism
Authors: De Lucia Natascia , Carraturo Fabio , Belgarbo Alessandra , Maisto Stefano , Merenda Raffaella , Rengo Giuseppe , Maldonato Nelson Mauro , Femminella Grazia Daniela
Published: December 2023

Background

Personality traits are usually defined as recurrent and distinctive patterns of thoughts, sensations and actions that present in response to specific requests. In the elderly, personality functioning has been associated with dementia risk. However, the relationship between personality traits and cognitive function in subject at risk of cognitive decline has not been explored yet. The aim of this study is to assess the predictive role of personality traits on cognitive and psychopathological function in subjects with mild cognitive impairment (MCI).

Method

45 subjects (mean age: 73.6±8.9; mean education: 11.2±4.7) with a diagnosis of MCI e 50 healthy older adults (OA) (mean age: 70.8±6.9; mean education: 9.7±3.7) were enrolled. All participants underwent a neuropsychometric assessment including the evaluation of visuo‐spatial, executive and memory functions, as well as behavioural symptoms with the Neuropsychiatric Inventory questionnaire. Personality traits were evaluated with the Eysenck Personality Questionnaire (EPQ‐R).

Result

MCI subjects showed significantly poorer performances on visuo‐spatial, executive and memory tasks compared to OA, as well as more severe depression, apathy, irritability, and sleep disturbances. MCI subjects had higher prevalence of neurotic and introvert traits on the personality test. In MCI subjects, neuroticism was correlated with performance on word repetition test and stroop test, as well as with higher agitation and depression. Introvertion trait was correlated with MMSE and Trail Making test scores. Regression analysis showed a signtificant association between neuroticism, executive function and depression in MCI.

Conclusion

Specific personality traits, especially neuroticism, might represent a predictive factor for executive functions decline and for depression in MCI. A deeper understanding of personality functioning in subjects with MCI might help develop more tailored treatments aimed at dementia prevention in these subjects.
The BetterBrains Trial: Baseline characteristics and trial progress of an online multi‐domain lifestyle intervention trial to delay cognitive decline in middle‐aged adults at risk of dementia
Authors: Rosenich Emily , Pirotta Stephanie , Mills Andrea , Norfolk Maya , Da Costa Gabrielle , Barker Anna L , Yassi Nawaf , Churilov Leonid , Sinnott Richard , Buckley Rachel F. , Brodtmann Amy , Rajaratnam Shanthakumar W , Pase Matthew P. , Bush Ashley I , Maruff Paul , Ayton Darshini , Lim Yen Ying ,   BetterBrains Research Group
Published: December 2023

Background

BetterBrains is a prospective, blinded endpoint, 24‐month randomised controlled trial (RCT). It aims to test the effectiveness of an online, person‐centred, modifiable risk factor (RF) management program in delaying cognitive decline in middle‐aged adults (aged 40‐70) with a family history of dementia. This study aims to describe blinded baseline characteristics of the randomised sample and provide trial engagement statistics.

Method

Participants enrolled in BetterBrains (betterbrains.org.au) complete all assessments on an online platform. RF assessment related to vascular health, sleep, mood, and social/cognitive engagement was conducted and participants with ≥1 RF were eligible. Participants complete assessments of cognition, general health, medical history, and lifestyle habits at baseline, 12, and 24‐months post‐randomisation. Primary outcome is absence of decline on at‐least one out of four cognitive tests at 24‐months. Participants randomised to the intervention arm receive a minimum of 6 person‐centred telehealth consultations over 12‐months with an allied health clinician trained in motivational interviewing. All participants receive monthly educational blogposts.

Result

Since August 2021, 1518 participants have enrolled and 856 (56%) were randomised (Figure 1). Blinded baseline analyses reveal that randomised participants are mostly female (84%), white (93%), live in metropolitan areas (73%), and all report a first‐degree dementia family history. Mean age is 60 years (±6.7) and participants have 15.4 years of education (±3.9) on average. Mean number of reported RFs is 5 out of a possible 19. Readiness to change lifestyle behaviours to reduce dementia risk was high, with 71% of participants indicating implementation of at‐least some lifestyle changes prior to trial entry. Only 3% of randomised participants have withdrawn. Of participants who have reached 12‐months post‐randomisation (N = 349), 74% have completed follow‐up cognitive testing.

Conclusion

Low attrition and high follow‐up rates suggest high acceptability and feasibility of the online BetterBrains methodology. The sample is likely at increased risk of dementia, due to high prevalence of first‐degree dementia family history, female gender, and co‐occurrence of multi‐domain modifiable dementia RFs. Presentation of findings will include a detailed breakdown of study methodology, baseline demographic/risk characteristics, and trial progress.
Diversity of sociodemographic backgrounds and healthcare utilization in cognitively impaired older adults
Authors: Rahemi Zahra , Malatyali Ayse , Adams Swann Arp
Published: December 2023

Background

With increasing life expectancy, cognitive impairments have become an important public health issue worldwide and in the U.S. Socioeconomically‐disadvantaged populations, including racial/ethnic minorities, are more vulnerable as they have higher rates of underlying conditions and cognitive impairments, such as Alzheimer’s disease and related dementia. With progressive impairments in cognition, behavior, and functionality, patients, families, and healthcare systems face challenges associated with healthcare, including increased costs of care for emergency department visits, hospitalizations, and revisit rates. Our purpose was to examine the relationships between sociodemographic variables and healthcare utilization in older adults with cognitive impairment.

Method

The Health and Retirement Study (HRS), Rand data (2014), were used to understand sociodemographic predictors of healthcare utilization (hospital stay days, nursing home days, home care days, and numbers of doctor’s visits). Due to the skewness of the data, we grouped each category for the length of healthcare utilization into never, short, medium, and long. Only those persons with dementia or impaired cognition were included.

Result

Of the 3,924 older adults from the HRS sample, 22% had a diagnosis of dementia and 78% had impaired cognition. Ethnicity, education, and age were significantly associated with the length of hospital stay. Hispanics and those with lower education and younger were less likely to use long hospital stays than others. Ethnicity, marital status, gender, and age were predictors of nursing home length of stay. Blacks, Hispanics, men, and married and younger respondents were less likely to stay long in nursing homes. Blacks and younger respondents were less likely to have long home care utilization. Race, ethnicity, rurality, gender, education, and age were predictors of doctor’s visits. Blacks, Hispanics, rural residents, men, those with lower education, and younger had fewer doctor’s visits. Race, ethnicity, and education were consistent predictors across utilization types.

Conclusion

This study provides evidence of the need to understand how older adults with cognitive impairments and multiple marginalized identities (i.e., age, gender, race, ethnicity) can access and use healthcare. This study is important to provide the groundwork for further studies to explore the intersectionality of healthcare utilization and socioeconomic status in patients with cognitive impairments.
Measurement Invariance of the NIH Toolbox‐Cognition Battery Across Demographic Characteristics
Authors: Pal Subhamoy , Reader Jonathan M , Gregoire Allyson , Bhaumik Arijit K , Fisher Jordan , Goldstein Felicia C , Gershon Richard C. , Weintraub Sandra , Giordani Bruno
Published: December 2023

Background

The tablet‐based NIH Toolbox‐Cognition Battery (NIHTB‐CB) was compared against the established NACC Uniform Data Set 3.0 (UDS 3.0) neuropsychological battery (used across Alzheimer’s Disease Research Centers). NIHTB‐CB factor invariance is critical for drawing appropriate cross‐demographic conclusions. Invariance was assessed across both batteries for consensus‐driven clinical diagnosis, sex, and age in a large sample of participants from the Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study. Goals of this project were to establish the factor relationship of these two batteries and examine their invariance across the aforementioned demographic characteristics.

Method

NIHTB‐CB tasks measure Crystalized and Fluid ability. Tests were administered to 571 participants aged 65 to 99 years (mean age 77.2±7.8, 41% female) with normal cognition or amnestic mild cognitive impairment. Groups were classified for age (< = 85 and > 85), gender, and diagnosis. Exploratory Factor Analysis (EFA) was tested for each group with confirmatory factor analysis. If the model fit sufficiently between groups for the configural model, then metric, scalar, and strict invariance models were also examined. Uncorrected standard scores were used for analyses.

Result

A four‐factor model emerged as the best fitting model and was invariant across all demographic groups through adjustments. Factor 1: Language (MINT Total, Oral Reading, Picture Vocabulary); Factor 2: Auditory retention (Digits Forward Total and Digits Backward Total); Factor 3: Learning/Memory (List Sorting Working Memory, Picture Sequence Memory, Craft Story 21 Immediate Recall, Craft Story 21 Delayed Recall, Benson Delayed Recall, Animals Category, Vegetables Category, and MoCA Total Score); Factor 4: Attention/Executive Functioning (Dimensional Card Sort, Flanker, Trails A, Trails B, Pattern Comparison Processing Speed, and Benson Recall). We found strong support for strict invariance across the assessed demographic characteristics.

Conclusion

A four‐factor structure comprised of NIHTB‐CB and UDS 3.0 tests supports the validity of the NIHTB‐CB by matching both UDS 3.0 and NIHTB‐CB measures as expected. Strong support for strict invariance reflects the psychometric equivalence of the NIHTB‐CB construct across the groups. The psychometric properties of the NIHTB‐CB subtests therefore are generalizable across samples. By satisfying the assumption of measurement invariance, inferences made using the NIHTB‐CB about between‐group differences are presumed valid.
Cardiovascular Disease Risk Scores and Risk of Cognitive Decline and Dementia in Older Men and Women
Authors: Vishwanath Swarna , Hopper Ingrid , Chowdhary Enayet , Wolfe Rory , Freak‐Poli Rosanne , Reid Christopher , Tonkin Andrew M , Murray Anne , Shah Raj C , Chong Trevor T.‐J. , Woods Robyn , McNeil John J , Orchard Suzanne , Nelson Mark , Steves Claire J , Ryan Joanne
Published: December 2023

Background

Risk factors for cardiovascular disease (CVD) also increase the risk of dementia. However, whether commonly used CVD risk scores are associated with dementia in older adults who do not have a history of CVD remains unclear. The aim of this study was to determine whether CVD risk scores are associated with subsequent cognitive decline and dementia in initially healthy older men and women.

Method

Participants were from a prospective cohort of 19,114 individuals aged 65+ years without prior CVD event or major cognitive impairment. The Atherosclerotic Cardiovascular Disease risk score (ASCVDRS) and the Framingham risk score (FRS) were calculated at baseline, with women and men analysed separately due to large differences in overall level of CVD risk. Dementia was adjudicated by clinical experts according to DSM‐IV criteria. Cognitive decline was defined as a >1.5 SD decline in cognitive score from their own baseline value on any of the four cognitive tests looking at global cognition, episodic memory, psychomotor speed or verbal fluency.

Result

Over a median follow‐up of 6.4 years, 4,325 individuals had cognitive decline and 850 individuals developed dementia. ASCVDRS, was associated with dementia and cognitive decline, in men and women, whether considered as a continuous measure and as tertiles. For example, men and women in the highest ASCVDRS tertile had a 41% and 45% increased risk of dementia compared to the lowest tertile respectively (HR [95%CI] men: 1.41 [1.08,1.85], women: 1.45 [1.11,1.89]). However, higher FRS was not associated with incident dementia and only associated with an increased risk of cognitive decline among women (FRS continuous: 1.08 [1.01,1.26]; highest vs. lowest tertiles: 1.13 [1.01‐1.26]).

Conclusion

These results provide some evidence for ASCVDRS as a measure of shared CVD risk factors for identifying/predicting risk of dementia and cognitive decline in healthy older adults regardless of sex. Further research is needed to confirm the findings and to validate these results in more heterogeneous populations.
Inhibition of mitochondrial carbonic anhydrases prevents Amyloid β‐induced cell death and blood brain barrier permeability in cerebrovascular endothelial cells
Authors: Lemon Nicole L , Ilies Marc A , Fossati Silvia
Published: December 2023

Background

The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS) which has been observed to become dysfunctional in Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA). Amyloidosis disrupts the function of cerebrovascular endothelial cells (ECs) through the activation of the intrinsic apoptotic pathway, and the induction of blood brain barrier (BBB) permeability. Previous findings in our lab demonstrate that Acetazolamide (ATZ) and methazolamide (MTZ), pan‐Carbonic Anhydrase (CA) inhibitors, prevent mitochondria mediated apoptosis in cerebrovascular ECs through the reduction of Aβ induced cytochrome C release from the mitochondria, caspase‐9 activation, and mitochondrial H2O2 production. Due to the reduction of mitochondria mediated cell death via pan‐CA inhibitors we hypothesize that the mitochondrial isoforms, CA‐VA/B, are involved in cell death and other deleterious mechanisms induced by Aβ. Thus, we anticipate using selective CA‐V inhibitors will reduce cerebrovascular EC apoptosis and prevent the loss of BBB resistance.

Method

Human cerebral microvascular ECs (hCMECs) were treated with Aβ40‐Q22 Dutch mutant alone and in combination with a CA‐V inhibitor. We measured outcomes of mitochondria mediated apoptosis and BBB integrity. Apoptosis was evaluated by measuring the changes in the protein expression of caspase‐9, BAX, and BCL‐2 with western blot. We used live‐cell imaging to measure active caspase‐3. The release of cytochrome C and the mitochondrial membrane potential was detected using immunocytochemistry (ICC). Mitochondria H2O2 production was measured by isolating mitochondria and using a commercially available kit, Amplex Red (Invitrogen). We assessed the permeability of hCMECs using the ECIS ZΘ technology. The changes in protein expression of EC activation markers, VCAM‐1 and ICAM‐1, were determined with western blot.

Result

Inhibition of CA‐VA/B prevented Aβ40‐Q22 induced DNA fragmentation, caspase‐9 and ‐3 activation, cytochrome C release from the mitochondria, loss of mitochondria membrane potential, and mitochondrial H2O2 production in human cerebrovascular ECs. The inhibition of CA‐VA/B also reduced Aβ40‐Q22 induced BBB permeability and increase in vascular adhesion protein VCAM‐1 in hCMECs.

Conclusion

The inhibition of CA‐V is protective to cerebrovascular ECs in models of amyloidosis, through the prevention of mitochondria‐mediated cell death and loss of cerebral EC barrier function.
Familial FTD in India
Authors: Alladi Suvarna , Ramakrishnan Subasree , Arshad Faheem ,   Cognitive Neurology Research Group, NIMHANS
Published: December 2023

Background

The burden of dementia in India is estimated to increase by 197% by 2050, and Frontotemporal dementia (FTD) is among the leading causes of young‐onset dementia. With recent advances in molecular pathology, genetic mechanisms and emerging therapies in FTD, it is important to understand familial FTD patterns in the heterogeneous sociocultural context of India. High genetic diversity is characteristic of India, and its population bears genetic imprints of European, Asian and even African genomes. The objective of this presentation is to provide an account of FTD in India, with a focus on familial FTD and genetic mechanisms recently being identified.

Method

The prevalence of FTD in clinical dementia cohorts across different geographic regions in India, frequency of familial FTD, clinical presentations in the context of sociolinguistic and ethnic diversity, and genetic mechanisms are reported.

Result

The reported prevalence of FTD in clinical and research groups across India varies from 7% to 26%. The proportion of familial FTD ranges from 9.5% in Kolkata in the east, 15% in Trivandrum in the south, 24.6% from Hyderabad and more recently, as high as 40% in a recent study from Bangalore. Few genetic mutations were reported in early studies. In a recent large effort from Bangalore, India, 200 patients with FTD syndromes underwent three generation pedigree analysis, clinical and neuropsychological evaluation and MRI according to ADNI protocol. Nearly half underwent genetic analysis by next generation sequencing and RT‐PCR was done to analyse C9orf 11 in a subset. Novel gene mutations including SQSTM1, GRN, MAPT, PSEN2, TBK1 and C9orf were detected. Of these mutations, 11 were pathogenic in 11 and 26 were variants of unknown significance (VUS). Apart from abnormal protein accumulation due to MAPT and GRN, we also identified CSF1R, TREM2 and TYROBP, that are recognised as primary microgliopathies. A few examples of VUS include PRNP, LRRK2, GBA and PANK2 mutations.

Conclusion

Research from familial FTD cohorts in India is contributing to growing evidence of a wider spectrum of genetic mechanisms for FTD. Our findings provide compelling evidence to increase harmonised global efforts to reduce risk and develop novel treatment strategies for FTD.
Cognitive reserve and resilience of cognitive networks in ageing
Authors: Habich Annegret , Abbatantuono Chiara , Garcia‐Cabello Eloy , Taurisano Paolo , Dierks Thomas , Barroso Jose , Ferreira Daniel
Published: December 2023

Background

In the ageing process, different cognitive functions decline at different time points and at different rates. Additionally, the inter‐individual variability in cognitive decline could partially depend on cognitive reserve, which represents a resilience factor against age‐related cognitive decline. These complex relationships can be captured with advanced multivariate methods such as graph theory, that can be applied to investigate cognitive networks. The present study aimed to examine the association between cognitive reserve and cognitive networks across age.

Method

A total of 334 cognitively healthy participants were stratified into early‐middle‐age (37‐50 years; n = 110), late‐middle‐age (51‐64 years; n = 106), and elderly (65‐78 years; n = 118) groups. Within each age group, individuals were further subdivided into two cognitive reserve levels (high, low) based on a crystallized intelligence proxy. For each subgroup, cognitive networks were constructed based on correlations between 47 z‐scored cognitive variables. Applying graph theory, different global and nodal network measures were compared between subgroups.

Results

Graph‐theoretical analyses revealed that individuals with high cognitive reserve were characterized by a stable cognitive network across age groups. The only consistent difference between the high cognitive reserve groups emerged in modularity with the late‐middle‐age group showing decreased modularity compared to early‐middle‐age and elderly groups. In contrast, individuals with low cognitive reserve showed a marked reconfiguration of cognitive networks across age groups with a pronounced dedifferentiation in late‐middle‐age. This was reflected as a decrease in global efficiency and increase in mean network strength and small‐worldness in the late‐middle‐age group compared to the early‐middle‐age group. The elderly group had a higher global efficiency and lower mean network strength and small‐worldness compared to the late‐middle‐age group.

Conclusion

A high cognitive reserve was associated with the resilience of the cognitive connectome during the ageing process, while individuals with low cognitive reserve showed prominent changes in their cognitive connectome with increasing age. Gaining further insights into these mechanisms will contribute to our understanding of age‐related cognitive decline and guide the development of strategies to preserve cognitive function in ageing.
Investigating associations of age at natural menopause with neuroimaging indicators of brain health in later‐life, using a British population‐based birth cohort
Authors: Needham Louisa P , Nicholas Jennifer M , Barnes Jo , Sudre Carole H , Cash David M , Coath William , Malone Ian B , Lu Kirsty , Schott Jonathan M , Richards Marcus , James Sarah‐Naomi
Published: December 2023

Background

Earlier menopause age associates with poorer cognitive performance post‐menopause, but links with dementia risk are mixed and the potential mechanisms underlying such associations are unclear. Few studies have examined the relationship between menopause age and later‐life brain health.

Method

Our study included 126 women from Insight 46, the neuroscience sub‐study of the 1946 British birth cohort, which included combined amyloid PET and MRI scanning at mean age 70.7 years (standard deviation = 0.66). Age at natural menopause was self‐reported, during midlife, as years since birth at the time of period cessation; women who reported surgical menopause were excluded (n = 63). We tested for interactions of menopause age with APOE‐ε4 status and used multivariable regression analyses to test associations of menopause age with later‐life total brain volume (TBV) and hippocampal volume. A generalised linear model with log‐linked gamma distribution tested associations with white matter hyperintensity volume (WMHV). Models were cumulatively adjusted for total intracranial volume and age at scan (model 0/M0), hormone therapy (HT) use (M1:M0+HT) and for prospective early‐life and sociodemographic (M2:M1+childhood cognition, education, adult socioeconomic position), reproductive (M3:M2+menarche age, parity), and health‐related (M4:M3+smoking, BMI and blood pressure at age 36 years, APOE‐ε4 status) covariables.

Result

The association of menopause age with WMHV was modified by APOE‐ε4 status (p = 0.024); each 1‐year increase in menopause age associated with a 7.4% decrease in WMHV for ε4 carriers (n = 35) and a 2.4% WMHV increase for non‐carriers (n = 90). Menopause age did not associate with hippocampal volume, but there was a positive association with TBV (Table 1) which remained significant until we accounted for health‐related factors in model 4 (Figure 1). In post‐hoc analysis, adjustment for blood pressure at age 36 attenuated the association by 11.24%, explaining more of the attenuation than other model 4 covariables.

Conclusion

We find evidence for links between age at natural menopause and later‐life neuroimaging measures. Later menopause associated with greater brain volume, partly explained by midlife blood pressure. Interactive effects of APOE‐ε4 status on associations with WMHV, an indicator of brain pathology, warrant further investigation.
Which cortical regions affect the prediction of cerebrospinal fluid amyloid beta from PET images by novel residual neural network (ArcheD)
Authors: Tagmazian Arina , Vuoksimaa Eero , Pitkänen Esa , Schwarz Claudia
Published: December 2023

Background

Amyloid‐β (Aβ) aggregation, as a biological hallmark of Alzheimer’s disease (AD), is a key component of biological classification of AD in the AT(N) framework. This research aimed to develop a new deep learning model for predicting Aβ cerebrospinal fluid (CSF) measures from amyloid PET scans and explore which cortical regions are most important contributors in the model’s prediction.

Method

We developed a Residual Network model (ArcheD) to predict Aβ CSF from amyloid PET images, and trained it on 1,870 PET scans from the Alzheimer’s Disease Neuroimaging Initiative. We registered PET scans to MNI152 template and used the Neuromorphometrics atlas to derive cortical gray matter (GM) regions. We extracted brain regions’ contributions to model decision‐making by guided backpropagation, and visualized these contributions as relevance heatmaps. We used bootstrapping, Welch’s t‐test and FDR correction in testing significance of brain regions’ relevance to predictions in the whole cohort, and separately in clinical diagnostic classes of AD, mild cognitive impairment (MCI), and cognitively normal (CN) cases.

Result

ArcheD showed high accuracy in predicting Aβ CSF (r = 0.81; p<0.00001). According to the relevance analysis for all samples (n = 1,390) temporal (mean 0.106; 95%CI [0.105, 0.108]) and parietal (0.105; 95%CI [0.104, 0.107]) lobes were the most important GM regions for the model decision‐making. Occipital (0.098; 95%CI [0.098, 0.100]) and frontal lobes (0.091; 95%CI [0.089, 0.92]) showed noticeably fewer relevance values. Based on between‐classes comparison, these regions contribute significantly more to CSF prediction in AD and MCI individuals compared to CN (p<0.05). Analysis of 49 smaller regions showed an almost 7‐fold difference between the most and least contributing regions.

Conclusion

We developed a deep residual neural network model that predicted Aβ CSF from amyloid PET scans with high accuracy, and found that temporal and parietal lobes have the highest influence on Aβ CSF predictions. In the next step, we will validate the model in independent data and aim to develop the model further for clinical use.
Understanding the role of biological aging on cognitive vulnerability among individuals at risk of Alzheimer’s disease
Authors: Rodríguez‐Fernández Blanca , Sánchez‐Benavides Gonzalo , Minguillon Carolina , Fauria Karine , De Vivo Immaculata , Navarro Arcadi , Gispert Juan Domingo , Molinuevo Jose Luis , Sala‐Vila Aleix , Vilor‐Tejedor Natalia , Crous‐Bou Marta ,   for the ALFA study
Published: December 2023

Background

Leukocyte telomere length (LTL) is an objective biomarker of biological aging and has been proposed to play a crucial role in AD progression by impairing cognitive resilience. However, a limited number of studies have evaluated the role of LTL in cognition, showing inconsistent results, particularly in the context of AD pathology. The main objective of this study was to evaluate the association between LTL and cognitive performance in middle‐aged cognitively unimpaired individuals at increased risk of AD.

Method

The study included 1,532 participants from the ALFA cohort. LTL was determined by qPCR in peripheral blood leukocytes. LTL values were log‐transformed, normalized by computing z‐scores and residualized (rLTL) against age and sex using a linear regression model. A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing, and executive function. Episodic memory (EM), executive function, and global cognitive composites were calculated by averaging normalized raw scores of all subtests in each domain. Generalized linear models were implemented to assess the cross‐sectional association between rLTL and cognitive performance. Association analyses were performed separately in the accelerated aging group (rLTL < percentile 50th) and decelerated aging group (rLTL > percentile 50th). Stratified analyses by sex were conducted.

Result

Individuals at accelerated aging had higher systolic blood pressure and a different distribution of familiar history of AD than those at decelerated aging [Table 1]. Longer rLTL was associated with better performance in the EM domain only among individuals within the accelerated aging group. Remarkably, only free recall measurements remained significant after correction for multiple comparisons. Conversely, longer rLTL was associated with worse psychomotor speed in the whole sample and among individuals in the decelerated group [Table 2]. Women mainly drove these results. Among men, longer rLTL had a beneficial effect on semantic fluency but a detrimental effect on cued recall among those at decelerated aging [Table 3].

Conclusion

rLTL has a differential effect on cognitive domains among cognitively unimpaired individuals at accelerated/decelerated biological aging. Moreover, results differed depending on sex and cognitive domain. Our results suggest a complex heterogeneity in biological aging mechanisms that appear to change in individuals at increased risk of AD.
The association between cognitive reserve and age‐related neuroimaging features in homozygous APOE ε4 carriers
Authors: Lee Wei‐Ju , Chen Hung‐Chieh , Yang Yu‐Hsiu
Published: December 2023

Background

Alzheimer’s disease (AD) is the most common neurodegenerative dementia syndrome, which is characterized by irreversibly progressive cognitive decline, neuropsychiatric symptoms, and impaired function of independent daily living. The majority of AD occurs in individuals aged over 65 years and is termed late‐onset AD. The apolipoprotein E (APOE) ε4 allele is the highest individual risk factor. Despite lifelong influences of APOE ε4, not all APOE ε4 carriers develop cognitive decline, some APOE ε4 carriers appear to be better than others in maintaining structural and functional properties of their brains while aging. Although previous studies showed that the AD patients with higher levels of cognitive reserve had more advanced Alzheimer’s type pathology in the comparable clinical severity, the underlying mechanism is unclear. Thus, the association between the individual’s cognitive reserve and the aging‐related brain pathologies need further investigation.

Method

This study recruited dementia free homozygous APOE ε4 allele carriers and all participants’ cognitive statuses were evaluated by neuropsychological tests. Cognitive reserve was evaluated by Cognitive Reserve Index questionnaire (CRIq). In neuroimage study, we collected brain MRI images and analyzed the severity of hippocampal atrophy and white matter hyperintensities (WMH). The relationship between different kinds of cognitive reserve and age‐related neuroimaging findings were analyzed.

Result

In total, 39 participants carrying two APOE ε4 alleles were analyzed, with an average age of 61.5 years, an education level of 13.1 years, and an average MMSE of 26.4 points. Correlation analysis showed significant associations between CRI and neuropsychological tests, especially in short‐term memory, visuospatial function, and language function tests. In neuroimaging analysis, CRI‐education was associated with hippocampal atrophy, which suggested more education might help to prevent the hippocampal atrophy. The correlation between WMH severity of brain MRI and the CRI was not statistically significant.

Conclusion

Cognitive reserve is associated with the cognitive function in dementia free homozygous APOE ε4 allele carriers and education might prevent hippocampal atrophy.
Structural modeling of clinical factors for simultaneous validation and prediction of future conversion to mild cognitive impairment
Authors: Ram Sebastiaan R , Strange Bryan A , Zhang Linda , Ser Teodoro , Lorenzo Elizabeth Lucia Valeriano , Valentí Meritxell , Zea‐Sevilla María Ascensión , Frades Belén , Heskes Tom , Larrañaga Pedro , Bielza Concha , Sanchez‐Juan Pascual
Published: December 2023

Background

Identifying risk factors of future conversion from cognitively normal to mild cognitive impairment is crucial for dementia prevention and understanding the clinical processes that result in the development of cognitive deterioration. One challenge which is faced with this task is that, when identifying these factors, not only the individual contribution but also its coherency with other indicators must be measured.

Method

To map the relationship between clinical risk factors and conversion to mild cognitive impairment, we created and validated a set of structural equation and growth mixture models based on input from clinical experts in the field of dementia research. These models are powerful as they allow the researcher to test hypotheses between observed variables and their underlying latent constructs. In addition to verification of the factor structure, we integrated a method for predicting individual factors, such as mild cognitive impairment, on out‐of‐sample converters and controls directly on the structural model, a feature which is normally uncommon in structural equation modeling partly due to its sensitivity for model misspecification.

Result

In a study of 1213 elderly participants we found that these structural models perform similar to current state‐of‐the‐art logistic regression models in terms of Area‐Under‐the‐Curve (AUC) score on a 1‐year prediction (AUC > 0.9), yet offer a significant increase in flexibility and insight into the direct and indirect effects of endogenous variables on conversion to mild cognitive impairment. We also observe a substantial increase in predictive power for models fitted with baseline data compared to baseline with follow‐up visit for both 5 and 9‐year prediction on neuropsychological and demographic data alone (AUC increase +‐ 0.05), allowing us to monitor the development of cognitive health in subjects over time.

Conclusion

The results from this study suggest a powerful technique for creating structural models with the ability to perform robust path analysis, longitudinal monitoring of cognitive health and prediction of future conversion to mild cognitive impairment. We expect that clinical experts can use this method to continue testing and validating new hypotheses in dementia research.