bluuebunny/crossref_metadata_2025 huggingface dataset:
Isoaspartate as a biomarker for early diagnostics of neurodegenerative diseases
Authors: Wang Jijing , Zhang Ya‐Ru , Shen Xue‐Ning , Han Jinming , Cui Mei , Tan Lan , Dong Qiang , Zubarev Roman A. , Yu Jin‐Tai
Published: December 2022

Background

The formation of isoAsp via spontaneous asparagine (Asn) deamidation or aspartate (Asp) isomerization has been regarded as a molecular clock of aging that significantly correlates with neurodegenerative diseases (NDDs). Our earlier findings established a strong link between isoAsp and Alzheimer’s disease (AD). In this study, we aimed at validating the diagnostic value of blood isoAsp‐related biomarkers for NDD prediction.

Methods

The levels of isoAsp in plasma human serum albumin (HSA) and the immunoglobulin G (IgG) specific against artificially aged HSA were measured in two cohorts by indirect enzyme‐linked immunosorbent assay (ELISA). Cohort 1 contained patients with AD and controls, while Cohort 2 recruited subjects with mild cognitive impairment (MCI), vascular dementia (VD), frontotemporal dementia (FTD), Parkinson disease (PD) and healthy controls. Apart from the memory tests, other plasma biomarkers reported in literature were quantified as well, including amyloid beta (Aβ) peptides Aβ40 and Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau 181 (pTau181) protein.

Results

Cohort 1 confirmed as expected a significant increase of isoAsp in HSA and reduction of IgG against aged HSA in AD group compared to controls (P < 0.0001). Cohort 2 revealed similar trends in comparisons between controls and subjects of different NDDs (P < 0.05). The most exciting finding was the best performance of isoAsp‐related biomarkers in MCI prediction among all blood biomarkers. In addition, the levels of our biomarkers were strongly associated with the memory test scores (P < 0.01).

Conclusion

We demonstrated the diagnostic capacity of isoAsp‐related biomarkers in predicting NDDs at the early stage of disease. The biomarker levels correlated with cognitive decline, supporting their roles in NDD development. However, the specificity of these novel biomarkers seemed to be not limited to AD. Additional longitudinal studies with follow‐up data shall be conducted for validation of these findings.
pTau heterogeneity as a measure for disease severity in incipient Alzheimer's disease
Authors: Servaes Stijn , Lussier Firoza Z , Therriault Joseph , Tissot Cécile , Bezgin Gleb , Kang Min Su , Wang Yi‐Ting , Stevenson Jenna , Rahmouni Nesrine , Arias Jaime Fernandez , Benedet Andréa Lessa , Chamoun Mira , Pascoal Tharick A , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2022

Background

The presence of p‐tau in biofluids has previously been proposed to be a response to neurofibrillary tangle pathology, one of the hallmarks of Alzheimer’s disease (AD). However, the increase of p‐tau in cerebrospinal fluid (CSF) precedes detectable neurofibrillary tangle pathology, as indexed by tau Positron Emission Tomography (PET), by up to a decade, suggesting that soluble tau could be an indication of early tau pathology. With this study, we investigated the heterogeneity of p‐tau species in CSF to assess the disease status of participants of the Translational Biomarkers of Aging and Dementia (TRIAD) cohort.

Methods

Support vector machines were used to determine cutoff values of p‐tau181, p‐tau217, p‐tau231 and p‐tau235 in CSF, identifying a group of participants that were amyloid positive (58 from a total of 165 participants). Amyloid positivity was determined by using an [18F]AZD4694 SUVR threshold value of 1.55 in the neocortex. Using these cutoff values, signatures were calculated on an individual level to identify the number of phosphorylated sites. Based on the number of phosphorylated sites, [18F]MK6240 SUVR maps and [18F]AZD4694 SUVR maps were calculated.

Results

When combining different CSF p‐tau species, the largest contribution in identifying amyloid positivity came from p‐tau217, followed by p‐tau231, p‐tau181 and p‐tau235. Achieving the cutoff for multiple p‐tau species was associated with more tau pathology particularly in the later Braak stages (fig 1) and increased amyloid‐β plaque accumulation (fig 2).

Conclusion

Our findings suggest that heterogeneity in p‐tau species carries predictive power in the identification of disease severity in incipient Alzheimer’s Disease.
Baseline White Matter Neuroinflammation Predicts Cognitive Decline in Alzheimer Disease
Authors: Wang Qing , Wang Wenshang , Schindler Suzanne E. , McKay Nicole S. , Chen Gengsheng , Liu Jingxia , Wang Sicheng , Sun Zhexian , Hassenstab Jason J. , Fagan Anne M. , Morris John C. , Wang Yong , Benzinger Tammie L.S.
Published: December 2022

Background

Neuroinflammation, an intrinsic immune response of the nervous system, is important in an early phase of Alzheimer Disease (AD) pathogenesis. However, it is largely unclear how neuroinflammation promotes the clinical progression of AD. Extracellular water edema (ECW) from Neuro‐inflammation imaging (NII), a diffusion‐based MRI approach for neuroinflammation, has been utilized to asses white matter (WM) neuroinflammation in AD. This study aims to investigate the relationship between WM neuroinflammation and longitudinal cognitive changes in AD.

Method

This study included 286 participants who were enrolled in ongoing research at the Knight ADRC at Washington University in Saint Louis. The CSF levels of Aβ42/Aβ40 and ptau181 measured with the automated Lumipulse platform were used to categorize participants as being positive or negative amyloid (A) and tau (T), respectively (Table 1). As measures of cognitive performance, the Knight ADRC Preclinical Alzheimer Cognitive Composite (Knight ADRC‐PACC) and a Global composite score were employed for each individual. The rates of change of cognitive measures were calculated for each individual. The NII was acquired with a multi‐b value scheme (bmax =1400s/mm2 and 25 directions). The total WM neuroinflammation (NII‐ECW) was obtained using TBSS (http://www.fmrib.ox.ac.uk/fsl) based WM skeleton. Randomise in FSL was utilized to examine voxel‐wise relationships between NII‐ECW and the rate of change of cognitive measures. Non‐parametric Kruskal‐Wallis and Chi‐square tests were employed for comparing continuous and categorical variables of the participants’ demographics, respectively. The group differences of NII‐ECW were tested using one‐way ANOVA. All statistical tests were conducted in R (R Core Team, 2020). Age, sex, and APOE ε4 carrier status were adjusted as covariates.

Result

Table 1 summarizes demographic data. When compared to the A‐T‐ group, the A+T+CDR0 and A+T+CDR0.5 groups had higher NII‐ECW (Figure 1). When the A+T+CDR1 group was compared to the other groups, there was no group difference in NII‐ECW. There were substantial negative associations between the NII‐ECW and the rates of change of cognitive measures in the widespread WM regions (Figure 2).

Conclusion

Our data suggest that neuroinflammation increases early in preclinical AD and decreases later in the disease. Furthermore, baseline neuroinflammation as measured by NII‐ECW predicts cognitive decline in AD.
Characterization of Longitudinal Brain Changes in a Community Cohort in Relation to Aging and Cognitive Impairment
Authors: Chwa Won Jong , Lopez Oscar L. , Kuller Lewis H , Raji Cyrus A.
Published: December 2022

Background

Brain atrophy in aging and Alzheimer’s Disease (AD) involve numerous cortical and subcortical regions. Though there is much overlap in atrophy patterns between aging and AD, there may be regional differences between these two conditions (Fjell et al., 2019). Few studies, however, have explored these patterns in large community samples. This study attempts to investigate longitudinal changes in brain volumes and thickness in relation to aging and cognitive impairment in a well‐characterized community cohort.

Method

Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study‐Cognition Study, a community cohort study of both healthy aging and probable AD patients. Two time points were investigated for each participant with a mean follow‐up time of 5.36 years. MRI post‐processing, cortical and subcortical volume measurements, including hippocampal subfields, and statistical analyses were performed using FreeSurfer, Version 7.1.1. Longitudinal changes were adjusted for multiple comparisons through cluster‐wise correction via the Monte Carlo Z simulation.

Result

Cortical volume was significantly decreased in the bilateral superior frontal (left: ‐2.322%, p = 0.0002; right: ‐3.03%, p = 0.0002), left superior parietal (‐3.451%, p = 0.0002) and bilateral inferior parietal (left: ‐3.129%, p = 0.0002; right: ‐3.656%, p = 0.003) regions. Cortical thickness was significantly reduced in the bilateral superior frontal (left: ‐1.435%, p = 0.006; right: ‐1.615%, p = 0.0002) and left inferior parietal regions (‐1.581%, p = 0.025). Overall gray and white matter volumes and hippocampal subfields, including the cornu ammonis regions, also demonstrated significant reductions. Cortical volume and thickness trajectories between cognitively declined and cognitively stable subjects were not significantly different.

Conclusion

Observed volume reductions were consistent with previous studies investigating patterns of brain atrophy (Salat et al., 2004). The magnitude of atrophy was comparable with MCI/AD changes than normal aging (Bakkour et al., 2013). As patterns of atrophy did not significantly differ regardless of cognitive decline, there exists significant overlap between AD‐vulnerable regions and effects of normal aging. These findings help characterize patterns of cortical atrophy that may be reflective of the general population. Larger studies replicating these results are important to more definitively establish population norms of aging and AD‐related neuroimaging changes.
Effects of Public intervention for family caregivers of people with dementia in South Korea: 6‐month follow‐up
Authors: Seo Hyun‐Ju , Choi Eun Jeong , Choo Il Han , Kim Seong Min , Park Jeong Min
Published: December 2022

Background

Family caregivers of people with dementia are at higher risk for perceived burden of caregiving. The current studies has shown the effectiveness of providing community‐based interventions for caregivers of people with dementia to lessen their burden. In this study, the observed follow‐up effects after the intervention were examined using healthcare utilization as well as quality of life and perceived burden of the family caregivers.

Method

Community indwelling people ranged from 18‐90 years old including Dementia Relief Centers were recruited in the study. The participants were non‐randomly allocated into control or experimental group. The experimental group received a 8‐week public intervention focused on increasing knowledge on dementia and abilities to caring for people with dementia, while the control group received no intervention. Resources and utilization in dementia (RUD), health‐related quality of life, and caregiver burden of family caregivers of people with dementia, were measured using a questionnaire at pre‐intervention, post‐intervention and 6‐month follow‐up. Eighty‐one family caregivers with valid data on caring for people with dementia were included in this study.

Result

The present study will show significant difference in the change of healthcare utilization, health‐related quality of life, and caregiver burden between groups at 6‐month follow‐up. The specific study findings will be demonstrated in poster presentation of the conference.

Conclusion

A public community‐based intervention focused on supporting family caregivers of people with dementia will be effective strategy for decreasing the frequency of healthcare utilization as well as improving health‐related quality of life and caregiver burden of family caregiver of people with dementia even beyond the period of intervention.
Assessing everyday functioning using a novel smartphone app in cognitively normal adults: A pilot study of the Assessment of Smartphone Everyday Tasks (ASSET)
Authors: Dubbelman Mark A. , Hall Tia C. , Levesque Isabella M. , Mimmack Kayden J. , Sikkes Sietske A.M. , Fischer Shira H. , Tatar Daniel , Rentz Dorene M. , Sperling Reisa A. , Papp Kathryn V. , Amariglio Rebecca E. , Marshall Gad A
Published: December 2022

Background

Cognitively complex everyday tasks may be affected in early stages of Alzheimer’s disease. Performance‐based digital assessments could facilitate more precise measurement of subtle changes in everyday functioning. We piloted a novel smartphone app ‘Assessment of Smartphone Everyday Tasks’ (ASSET), to investigate its utility for measuring everyday functioning in cognitively normal older adults. ASSET consists of Patient Portal and Calendar tasks for renewing prescriptions, making payments, and scheduling urgent and recurring appointments (Figure1). It tracks response time and accuracy.

Method

ASSET was piloted in 34 participants (n = 20 cognitively normal young adults (YN): 21.3±2.6 years, 85%female, median 14.5 years of education; n = 14 cognitively normal older adults (ON), 75.1±4.8 years, 71%female, median 18 years of education). At baseline, participants completed the first version of ASSET and the Preclinical Alzheimer’s Cognitive Composite (PACC5) in the research clinic. ON participants and their study partners completed the Alzheimer’s Disease Cooperative Study Activities of Daily Living – Prevention Instrument (ADCS ADL‐PI). We calculated accuracy rates (correct responses/task duration) for both tasks and computed Pearson’s r correlation coefficients between subtasks (internal consistency) and with PACC5 and ADCS ADL‐PI (construct validity). To investigate test‐retest reliability, participants subsequently completed the first and five alternate versions of ASSET remotely on a fixed, biweekly schedule.

Result

At baseline, the Patient Portal and Calendar tasks were highly correlated (r = 0.78, 95% confidence interval (95%CI) = [0.60,0.89]). YN performed better on both tasks than ON, completing them faster and making fewer errors (Patient Portal: Cohen’s d = ‐3.0, 95%CI = [‐4.2, ‐1.8]; Calendar: d = ‐1.6, 95%CI = [‐2.4, ‐0.7]). Performance was moderately correlated with PACC5 (Patient Portal: r = 0.59, 95%CI = [0.49,0.67]; Calendar: r = 0.48, 95%CI = [0.37,0.58]). Among ON, performance on ASSET was not significantly correlated with either self‐ or study partner‐reported ADCS ADL‐PI. Over repeated assessments, Patient Portal accuracy increased, while Calendar accuracy increased but dropped at the last assessment among all participants (see Figure2).

Conclusion

Initial results show that ASSET may have good internal consistency and good ability to distinguish young from older cognitively normal adults. Future research should aim to corroborate current findings and extend with Alzheimer’s disease biomarkers to better understand the value of ASSET in detecting early changes in everyday functioning.
Comparison of midlife offspring cohorts based on family history of Alzheimer’s Disease: multi‐domain risk factors and cognitive function
Authors: Zhang Xuan , Mbangdadji Djass , Li Zhiguang , Sigurdsson Sigurdur , Gudnason Vilmundur , Meirelles Osorio , Launer Lenore J.
Published: December 2022

Background

Maintaining healthy clinical indicators and behavior is positively related to cognitive protection from midlife. However, limited population‐based studies have explored the role of family history on these factors in midlife. Therefore, we examined cognitive‐related risk factors in two midlife cohorts from the same source population in the Age, Gene/Environment Susceptibility‐Reykjavik Study.

Method

We included 446 offspring (aged 61, 49% women) from the random sample (RS) without Alzheimer’s Disease (AD) and 499 offspring (aged 63, 49% women) to AD cases at baseline and during follow up from the main study. Accordingly, we labeled the offspring with and without AD family history as offspring AD and offspring RS, respectively. Clinical factors included BMI, systolic (SBP) and diastolic blood pressure (DBP), cholesterol, fasting glucose, inflammatory factors, and medication. Socio‐behavioral factors included education, smoking, problems of doing usual activities. Cognitive function was evaluated by MMSE and STROOP. To address the potential correlation between siblings within one family, we compared these characteristics with the random effects intercept mixed model by family ID. We also did a sensitivity analysis by comparing people under age 65 to assess reverse causation for specific traits. All models were adjusted for age and sex. Fasting glucose, triglycerides, and inflammatory factors were log‐transformed due to skewness. We consider p<0.05 as statistically significant.

Result

As shown in the table, socio‐behavioral factors, cognitive function, or most clinical characteristics did not differ in the two groups. The Offspring AD had 2.71‐unit lower SBP and 0.03‐unit higher log(glucose) (3% increased glucose) than the RS (p<0.05). The sensitivity analysis among people under age 65 showed a similar pattern, except for the insignificant difference in fasting glucose between offspring AD and RS.

Conclusion

In general, there was no difference in AD‐related health profile among midlife offspring with and without AD family history. This analysis of standard cardiovascular and cognitive impairment‐related risk factors suggests that these variables alone will not help identify at‐risk individuals for later‐life cognitive impairment.
The Care Ecosystem: The Effectiveness and Implementation of Telephone‐Based Collaborative Dementia Care
Authors: Possin Katherine L , Sideman Alissa Bernstein , Dulaney Sarah , Lee Kirby , Merrilees Jennifer , Bonasera Steve , Chiong Winston , Hooper Sarah M , Kiekhofer Rachel , Robinson‐Teran Joanne , Allen Isabel Elaine , Braley Tamara , Guterman Elan , Rosa Talita D , Harrison Krista L , Hunt Lauren , Kahn James G , Lanata Serggio , Miller Bruce L. , LaRoche Ashley , Sawyer Robert John , Brungardt Adreanne , Lum Hillary , Hess Mailee , Ward Katie , Kuebrich Mary Beth , Hodges Marian , Olney Nicholas , Barclay Michelle , Rosenbloom Michael H
Published: December 2022

Background

Health systems are increasingly interested in collaborative dementia care. Implementation challenges include the limited dementia specialist workforce, time pressures of high‐volume care, increasing use of telemedicine, and inadequate reimbursement. The Care Ecosystem is a telephone‐based collaborative dementia care model designed to augment existing healthcare services and be amenable to scale. Here we present the latest evidence for the Care Ecosystem, including the effects among subpopulations at risk for health disparities (rural and Hispanic/Latino), and facilitators from the early phase of Care Ecosystem implementation at 6 diverse health systems.

Method

Effectiveness was evaluated in a single‐blind, randomized clinical trial (N = 804). Persons with dementia (PWD)‐caregiver dyads were randomized to receive 12 months of the intervention (N = 527) or usual care (N = 277). Outcomes were measured via telephone surveys at 6 and 12 months after randomization and medical record review. Subgroup analyses were performed for the 124 dyads who identified as Hispanic/Latino, and the 66 who lived in rural Nebraska or Iowa. The intervention was primarily delivered by an unlicensed, trained care team navigator, who provided education, support and care coordination with supervision and help from a dementia specialist team (advanced practice nurse, social worker, and pharmacist). Implementation facilitators were evaluated through observation and qualitative interviews with clinical teams at 6 health systems implementing the model.

Results

The PWD‐caregiver dyads lived in California (n = 476), Nebraska (n = 286), or Iowa (n = 42). Compared with usual care, the Care Ecosystem improved PWD quality of life, reduced emergency department visits, reduced the use of potentially inappropriate medications, and decreased caregiver depression and caregiver burden. Effect sizes were similar or greater in Hispanic/Latino and rural subgroups on most outcomes. Facilitators of Care Ecosystem implementation included open‐access implementation tools (online training, care protocols), the adaptability of the care model, the care team navigator role, and remote care delivery.

Conclusion

Effective dementia care can be delivered by care team navigators via telephone to mitigate the burdens of dementia, including for underserved PWD living in rural areas or who identify as Hispanic/Latino. Implementation is a challenge although features of the care model appear to facilitate adoption.
Pleiotropic effect of LRRK2 on Parkinson‐associated proteins and processing of pathological alpha‐synuclein in myeloid cells
Authors: Nykanen Niko‐Petteri , Yang Chengran , Harari Oscar , Davis Albert A , Cruchaga Carlos , Benitez Bruno A.
Published: December 2022

Background

Mutations in the LRRK2 gene, which encodes leucine‐rich repeat kinase 2 (LRRK2), are a cause of autosomal dominant Parkinson’s disease (PD). Single‐nucleotide polymorphisms (SNP) in the LRRK2 locus are one of the most consistently replicated in multiple genome‐wide association studies in sporadic PD and with inflammatory diseases. We recently found that a PD‐associated risk SNP (rs76904798, p = 2.0×10−28) in the LRRK2 locus is also associated with cerebrospinal fluid (CSF) levels of granulins (PGRN, p = 8.6×10−9), glycoprotein nmb (GPNMB, p = 2.3×10−9), Ectonucleoside triphosphate diphosphohydrolase‐1 (ENTPD1, p = 2.3×10−9) also known as CD39 and Cathepsin B (CTSB, p = 2.5×10−4). Yet, functional validation in cellular models is lacking.

Methods

Human monocytic cells (U937) were differentiated (dU937) into macrophages to test the effect of LRRK2 on CTSB, CD39, GPNMB, PGRN and alpha‐synuclein (aSyn). LRRK2 kinase activity and expression level were modulated using pharmacological inhibitors and lentivirus‐mediated overexpression. Protein levels were assessed using western blotting and ELISA. dU937 cells were treated with human aSyn pre‐formed fibrils (haSyn PFFs). We analyzed CSF somaLogic data from the Parkinson’s Progression Marker’s Initiative (PPMI) cohort (Data accessed November 2021).

Results

LRRK2 mutation (G2019S and R1441G) carriers from the PPMI cohort exhibit significantly increased CSF levels of PGRN (p = 2.1×10−22), GPNMB (p = 1.6×10−29), CTSB (p = 2.5×10−16) and CD39 (p = 1.8×10−18) compared to age and gender‐matched non‐carriers (N = 1158). dU937 cells overexpressing LRRK2 showed an increase in the phosphorylation of LRRK2‐Ser935 and Rab10‐T73 and intracellular levels of lysosomal proteins CTSB and Saposin D without affecting LAMP1 or M6PR. LRRK2 also reduced extracellular CD39, PGRN and GPNMB levels and the levels of intracellular endogenous aSyn dimers in dU937 cells. HaSyn PFF treatment induced a time‐dependent reduction of CTSB and GPNMB levels, increased PGRN levels and altered intracellular aSyn processing pattern in dU937 cells overexpressing LRRK2. Pharmacological LRRK2 kinase inhibition decreased intracellular CTSB levels. LRRK2 co‐immunoprecipitates with PGRN in cells and in human brain.

Conclusions

LRRK2 modifies lysosome‐associated proteins and regulate aSyn proteostasis. Pathogenic LRRK2 mutations increased CSF levels of PGRN, GPNMB, CTSB and CD39 in the PPMI cohort. Our in vivo and in vitro data supports a pleotropic role of the LRRK2 locus as a genetic modifier of PD‐associated proteins.
Lipid oxidation as a marker of apathy and executive dysfunction in patients at risk of vascular cognitive impairment
Authors: Bawa Kritleen Kaur , Ba Joycelyn , Kiss Alex , Wang RuoDing , Feng Vivian , Swardfager Walter , Andreazza Ana C. , Gallagher Damien , Marotta Giovanni , Herrmann Nathan , Lanctôt Krista L.
Published: December 2022

Background

Apathy and executive function decline are hallmarks of vascular dysfunction in neurodegeneration and cognitive impairment. People with mild vascular cognitive impairment (mVCI) display a combined etiology of both cognitive impairment and vascular comorbidities; hence, patients with vascular risk factors are at risk for mVCI. The co‐occurrence of apathy and executive dysfunction is prevalent; however, the physiological pathway underlying these manifestations is yet to be investigated. Oxidative stress is often present in vascular dysfunction. This study investigated the relationship between oxidative stress, specifically markers of lipid oxidation, apathy, and executive dysfunction in patients at risk of mVCI.

Method

Patients at risk of mVCI were recruited from a population of patients with coronary artery disease in a Cardiac Rehabilitation Program. Apathy was assessed using the Apathy Evaluation Scale and executive function with Trial Making Test B, phonemic fluency test and animal naming test. Fasting blood was collected and serum concentrations of early and late lipid oxidation markers, lipid hydroperoxides (LPH) and 8‐isoprostane (8‐ISO) respectively, were measured.

Result

Participants (n=206, Age= 63.0±7.5, 80% men, total years of education= 15.9±3.4, AES score= 28.3±8.8, composite z score for EF= 0±1) demonstrated significantly different ratios of late to early lipid oxidation markers (8‐ISO/LPH) between groups (F(3, 202) = 10.915, p <0.001) with increasing levels in the following order: no apathy or executive dysfunction, only executive dysfunction, only apathy, and both apathy and executive dysfunction. A multivariate linear regression model adjusting for demographics found that lipid oxidation was significantly associated with apathy (B= 4.63, p < 0.001) and executive function (B= ‐0.19, p= 0.018); however, when controlling for both demographics and vascular risk factors, lipid oxidation was significantly associated with apathy alone (B= 3.11, p= 0.002).

Conclusion

The results highlight an important involvement of lipid oxidation in the co‐occurrence of apathy and executive dysfunction in patients at risk of mVCI. Our results show that increased oxidative stress may contribute to the development of apathy, which may relate to why apathy is a strong risk factor for progression to dementia in at‐risk populations.
Variability of response to exercise‐primed tDCS in those with mild cognitive impairment and Alzheimer’s disease (the EXPRESS study): a preliminary analysis
Authors: Koo Grace KY , Herrmann Nathan , Gallagher Damien , Rapoport Mark J. , Charles Jocelyn , Papneja Purti , Rajji Tarek K. , Andreazza Ana C. , Oh Paul I. , Marzolini Susan , Kiss Alex , Swardfager Walter , Vieira Danielle , Song Bing Xin , Rivet Luc , Lanctôt Krista L.
Published: December 2022

Background

Studies investigating the use of transcranial direct current stimulation (tDCS) to improve outcomes in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) have reported mixed findings. Such variability may be explained by inter‐individual differences such as demographics or disease pathology. Given the increased prevalence of cardiovascular risk factors with aging and the potential changes in neurobiology of those exhibiting additional vascular etiology, we evaluate the influence of etiology on tDCS outcomes in patients with mild AD or MCI.

Method

Participants were diagnosed with mild or major neurocognitive disorder due to AD or mixed AD/vascular disease according to The Diagnostic and Statistical Manual of Mental Disorders (DSM–5) criteria. Participants completed a 2‐week, blinded, randomized trial examining the effects of exercise primed tDCS where they were randomized to receive either exercise with tDCS, exercise with sham tDCS, or tDCS only. Cognitive tests assessing episodic memory (ADAS‐Cog Word Recognition and Word Recall Tasks) and working memory (N‐Back) were administered before and after intervention. Independent t‐tests were used to assess for differences in demographics between groups, and paired t‐tests were used to evaluate the influence of etiology on tDCS outcomes.

Result

Of the 28 participants (17 males [58.6%], mean [±SD] age 74.8±8.9 years, education 16.3±2.2 years) included, 17 participants had mixed vascular/AD etiology and 11 participants had AD (without vascular) etiology. Both groups did not differ significant in demographics. Participants with mixed vascular/AD etiology showed significant improvement in episodic memory (Word Recognition 1.71±2.97, t(16) = 2.365, p = 0.031; Word Recall 0.65±1.12, t(16) = 2.257, p = 0.038), while those without vascular etiology did not (Word Recognition 0.36±2.80, t(10) = 0.43, p = 0.676; Word Recall ‐0.09±0.63, t(10) = ‐0.472, p = 0.647). No significant improvement in working memory in either group was observed.

Conclusion

Factors such as etiology should be taken into consideration when considering the efficacy of tDCS on improving cognition in patients diagnosed with AD/MCI. Further analyses upon unblinding will confirm whether patients with mixed AD/vascular etiology respond differently to tDCS.
Antidepressant use in relation to long‐term dementia risk and imaging markers of neurodegeneration: a population‐based study of potential adverse effects
Authors: vom Hofe Ilse E. M. , Stricker Bruno , Vernooij Meike W. , Ikram M. Arfan , Wolters Frank J.
Published: December 2022

Background

In Europe, one in five adults uses antidepressants, with an increase in prescriptions of 20% per year. It has been suggested that antidepressant use might ultimately lead to adverse cognitive outcomes due to their anticholinergic properties. However, this impact remains largely undetermined, as randomised trials have limited follow‐up duration. We aimed to determine the association between antidepressant use and the long‐term risk of dementia in a population‐setting. In addition, we assessed the effect of antidepressant use on change in brain volume as measured with MRI.

Method

Between 2005‐2008, we included 5551 cognitively healthy participants of the population‐based Rotterdam Study (57.6% women, mean age 70.5 years). Detailed information on type of antidepressant (ATC‐coded), number of prescriptions, days of use and daily dose was extracted from pharmacy dispensing records from 1991 until baseline. Participants underwent neuropsychological testing and brain MRI every 2‐4 years. We determined the association of antidepressant use with incident dementia until 2018 using a Cox model, and with change in cognitive performance and brain MRI measures using linear mixed‐effects modelling. Models were adjusted for demographics, lifestyle variables, comorbidity and comedication. Furthermore, we explored the effect of slowed metabolization of antidepressants based on CYP2D6 genotype.

Result

During a mean follow‐up of 10.2 years, 640 participants developed dementia. Antidepressant use was not associated with risk of all‐cause dementia (hazard ratio (HR) [95% confidence interval (CI)]: 0.87 [0.70;1.08]). This was similar for tricyclic antidepressants and serotonin‐reuptake inhibitors, and regardless of dose and duration. Antidepressant use was not associated with decline in general cognition (mean difference [95% CI] per standard deviation: 0.01 [0.00;0.01], nor with change in brain volume (mean difference [95% CI] per mm3; total volume: 15.19 [‐210.22;240.60], grey matter: ‐52.23 [‐179.45;74.99], white matter: 71.49 [‐93.03;236.01], hippocampus: ‐3.70 [‐8.18;0.78], amygdala: ‐0.60 [‐3.49;2.30], thalamus: 0.87 [‐6.14;7.88]). Similarly, among antidepressant users only, CYP2D6 genotype was not related to dementia risk (HR [95% CI] for amitriptyline users: 0.88 [0.76;1.02], paroxetine users: 0.83 [0.67;1.02]).

Conclusion

In this population‐based study, antidepressant use was not associated with long‐term adverse effects on cognition or subclinical brain injury. These results are reassuring regarding safe prescription of antidepressive medication with respect to cognitive decline.
Diverse representation in Frontotemporal Dementia research studies: implications for clinical trials.
Authors: Piña‐Escudero Stefanie Danielle , Franco Teresita Ramos , Slachevsky Andrea , Yokoyama Jennifer S.
Published: December 2022

Background

The Multi‐Partner Consortium to Expand Dementia Research in Latin America (RedLat) study is a niche for the implementation of clinical trials on Frontotemporal Dementia in Latin America. We identified that one of the main limitations of recruitment was a lack of clinicians with comprehensive knowledge on Frontotemporal Dementia in the region. We aimed to fill these gaps by creating an online training for physicians.

Method

A group of American and Latin American brain health experts trained at the Global Brain Health Institute at the University of San Francisco California is delivering an abridged online behavioral neurology training project to a pilot group of 30 neurologists, geriatricians, and psychiatrists from Latin America. The training highlights important aspects such as culturally appropriate neuropsychological assessment and functional assessment to adequately classify participants under the frontotemporal dementia umbrella. A component about the importance of research including clinical trials is also being delivered. Baseline evaluations about the quality of their medical training regarding dementia and a dementia knowledge evaluation were conducted and we are expecting to conduct an evaluation in the third and sixth months.

Result

On the baseline evaluation, 80% classified the information they received as “poor”, 12% classified the information as “sufficient” and 8% classified it as “good”. Regarding baseline dementia knowledge, the mean score was 5.2 (SD ± 2.5) out of a maximum score of 10 points. We expect an increase in these numbers during the upcoming evaluations. As a side outcome, participants from this project are building pipelines to increase recruitment in RedLat.

Conclusion

Overcoming existing educational barriers of diagnosis of Frontotemporal Dementia as well as generating awareness of the importance of clinical trials in Latin America will hopefully be a key tool to increase the representation of persons with Frontotemporal Dementia. We will discuss the importance of adequate diagnosis and classification of frontotemporal dementia by the professionals who serve these underrepresented populations and the importance that this first step has to adequate recruitment into clinical trials.
Metabolomics profiling reveals distinct signatures in the serum and brain metabolomes in mouse models of Alzheimer’s Disease
Authors: Pandey Ravi S , Hoffmann Brian , Arnold Matthias , Greene Andrew S , Kaddurah‐Daouk Rima F. , Carter Gregory W
Published: December 2022

Background

Progress in development of efficacious therapies for Alzheimer’s disease (AD) is hampered due to our limited understanding of underlying pathological mechanisms. Increasing evidence suggests that metabolic impairments prior to symptom development can contribute to disease mechanisms and subsequent dementia. Signals in metabolomic pathways conserved across species could provide a promising entry point to translate experimental findings in preclinical mouse models to humans.

Method

In this study, first we systematically investigated sex‐stratified differences of serum and brain metabolites between the APOE4.Trem2*R47H and the 5XFAD mouse models of AD to C57BL/6J controls at six months of age. Metabolite levels were measured using the targeted AbsoluteIDQ®‐p180 platform (Biocrates AG, Innsbruck, Austria). Next, we did P500 panel and supplemented it with four mode discovery metabolomics for the C57BL/6J controls, APOE4.Trem2*R47H, and hAPP.APOE4.Trem2*R47H mouse models at 12 months of age.

Result

We identified strong metabolic sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Further, we identified that serum levels of glycerophospholipids were reduced in APOE4.Trem2R47H mice compared to C57BL/6J controls, while levels of these metabolites in the same animals were greater in both male and female brains of APOE4.Trem2R47H and 5XFAD mice. Several of these findings were consistent with recent results in humans, which suggested a similar decrease in the same metabolites in serum of APOE4 carriers and indicates a serum‐based effect of APOE genotype in the ADNI and ROSMAP cohorts. We simultaneously observed an increase in the same metabolites in brain, consistent across humans and mice. Further, we observed comparable results across different metabolic platforms.

Conclusion

Overall, metabolomic signatures were notably different between brain and serum in mouse models. The 5xFAD mice exhibited stronger effects in brain, whereas the APOE4.Trem2R47H mouse showed more pronounced effects in serum. These findings are consistent with high levels of amyloid pathology in 5xFAD mouse brains and the modifications of serum biomarkers in APOE4.Trem2R47H mice. We were able to identify patterns of metabolic changes related to human AD in our mice models. Our work thus represents a first roadmap towards translating metabolic dysregulation from model organisms to human AD.
Asymmetries in the theta/beta ratio distinguish cognitively normal elderly from those with mild cognitive impairment
Authors: Martin Tim , Giordani Bruno , Kavcic Voyko
Published: December 2022

Background

The search for psychophysiological markers that distinguish normal from abnormal aging has produced many candidate EEG dynamics, but relatively little research has been done (or at least reported) on the theta/beta ratio or brain wave asymmetries.

Methods

We previously reported frontal asymmetries (frontal alpha and frontal beta asymmetry) originally investigated in the context of anxiety and approach‐avoidance motivation that distinguish MCI from healthy, cognitively normal persons (HC). Another potentially more cognitively‐involved marker, the ratio of theta to beta frequencies (TBR), originally investigated as a marker of attention deficits, might also usefully distinguish cognitive HC from MCI. We took advantage of a previously collected data set to conduct an exploratory analysis of the pattern of TBR in HC and MCI participants. Resting state EEG (rsEEG) was measured before and after a simple motion direction discrimination task. We investigated the standard frontal TBR as measured at frontal electrode FZ. We estimated power spectral density in the resting state (eyes closed) for both pre‐ and post‐task, extracting estimates of TBR at electrode Fz.

Results

We found that MCI had significantly higher TBR than cognitively normal elderly, F(1,95)=4.98, p=0.028, with no effect of timepoint and no interaction. We then explored the possibility that TBR itself has meaningful asymmetries, calculating the TBR asymmetry at the following electrode pairs: F3‐F4, C3‐C4, CP3‐CP4, P3‐P4, PO3‐PO4. This analysis revealed an interesting pattern, with group (HC vs. MCI) interacting with location, F(4,380)=5.25, p<0.001. Relative to HC, MCI participants had higher TBR on the right (positive TBR asymmetry) in frontal electrodes (F3‐F4), but higher TBR on the left (negative TBR asymmetry) over parietal‐occipital sites (P3‐P4 and PO3‐PO4). The parietal asymmetry may reflect the early spread of lesions from inferior temporal regions to areas subserving language and visuospatial processing, but the frontal asymmetry is less obviously tied to known progression of brain lesions, and may reflect heterogeneity in the underlying pathogenesis of this sample of people with MCI.

Conclusion

TBR asymmetries obtained in rsEEG can contribute significantly to successful discrimination of older persons with MCI from those with normal cognitive functioning.
Analytical Validation of the Quanterix Neurofilament Light Chain (NfL) Advantage Assay in Plasma
Authors: Figdore Daniel , Campbell Michelle R , Syrjanen Jeremy A. , Mielke Michelle M. , Petersen Ronald C. , Bornhorst Joshua A , Algeciras‐Schimnich Alicia
Published: December 2022

Background

Neurofilament light chain (NfL) is an emerging blood‐based biomarker useful for assessing neuro‐axonal injury in several neurological conditions. Plasma NfL concentrations reflect the extent of axonal damage, making it a general marker of neurodegenerative disease progression. This study evaluates the analytical performance characteristics of the Quanterix NfL Advantage method in EDTA‐plasma.

Method

The assay was performed per manufacturer’s instructions on the Quanterix Simoa HD‐X Analyzer. Analytical validation included analyte stability, imprecision, lower limit of quantification (LLOQ), analytical measurement range (AMR), accuracy, and interferences. One‐sided reference intervals were established using quantile regression methods among 1100 cognitive normal individuals, age 20 to 95 years without known chronic kidney disease, stroke, or myocardial infarction.

Result

NfL was stable in plasma three days ambient, seven days refrigerate, 90 days frozen (‐20C), and over 3 freeze/thaw cycles. Intra and inter‐assay imprecision, expressed as % coefficient of variation (%CV), ranged from 3.4 – 6.0% and 5.9 – 11.6% respectively. The LLOQ was evaluated using patient plasma pools at concentrations of 1.7 and 3.6 pg/mL. %CVs were 16.8% and 9.7% respectively, and the LLOQ was set at 3.0 pg/mL. Accuracy was assessed by spiking 5 plasma samples with NfL calibratoran 87% average recovery (range 81‐94%) was observed. The AMR of 3.0 – 1500 pg/mL was verified with a regression slope of 0.93 and r2 > 0.99. Additionally, plasma admixtures covering the AMR showed acceptable linear response (slope of 1.02 and r² >0.99). The assay was not affected by icterus to 100 mg/dL, lipemia to 1000 mg/dL, hemolysis to 1000 mg/dL at NfL concentrations >30 pg/mL or to 200 mg/dL at NfL concentrations ≤30 pg/mL. NfL increased with age but did not differ by sex. The data supported age‐based reference intervals broken down into 10‐year intervals. The 97.5th percentile limits were: 20s: ≤8.4 pg/mL, 30s: ≤11.4 pg/mL, 40s: ≤15.4 pg/mL, 50s: ≤20.8 pg/mL, 60s: ≤28.0 pg/mL, 70s: ≤37.9 pg/mL, 80+: ≤51.2 pg/mL.

Conclusion

The analytical performance characteristics of the plasma Quanterix NfL advantage assay were deemed acceptable for clinical laboratory implementation. The establishment of NfL reference intervals will aid in the clinical interpretation of patient plasma NfL concentrations.
Recognizing human functional patterns in IADLs through hand detection and artificial intelligence
Authors: Babatope Eyitomilayo Yemisi , Rodriguez Mario Lopez , García‐Vázquez Mireya Saraí , Álvaro Ramírez‐Acosta Alejandro
Published: December 2022

Background

Cognitive impairment is one of the characteristics shown by patients with Alzheimer's dementia (Montenegro et al., 2020; Kelley & Petersen, 2007). This affects the executive functions of most of these patients from the early stage (Guarino et al., 2019) and consequently, have difficulty in carrying out their daily activities (Dubbelman et al., 2020). These activities require precise coordination of the person's movements and interaction with their environment, so instrumental activities of daily living (IADLs) are predictors of such impairment (Barberger‐Gateau & Dartigues, 1993), as several research studies have shown(Brovelli et al., 2017). Therefore, assessing the performance of IADLs by analyzing human biomechanical markers such as hand movements is of great interest. This, together with the application of artificial intelligence techniques, in particular deep learning, will allow the development of technological tools for the creation of an automated model to support the early diagnosis of Alzheimer's disease.

Method

This work was inspired by the development of Alejandro Acosta et al, where human biomechanical markers were analyzed throughout the performance of IADL activities to recognize the human functional pattern (Acosta‐Franco et al., 2021). To improve the accuracy of the baseline model, we propose a hand detection algorithm based on a probabilistic approach considering skin color as a descriptor. To test the proposed algorithm, we used the dataset of egocentric videos containing the performance of IADL activities, which is organized into four classes, based on the prehensile patterns of the hands: force and precision, and on the kinematics of the instruments: displacement and manipulation.

Result

With the improvement made to the base model we obtained an accuracy higher than 74% in recognizing movement patterns of displacement and manipulation of objects, and a good prediction of the depth of the anatomical planes.

Conclusion

Our improved model obtained a good percentage of recognition accuracy for the instrument's kinematics, which can help in the development of technological tools for the creation of an automated model to support the diagnosis of early Alzheimer's disease.
Alzheimer’s Disease in Bilingual Latinos: Clinical Decisions for Diagnosis and Treatment Planning
Authors: Diaz‐Santos Mirella , Yanez Janet J , Suarez Paola A
Published: December 2022

Early and accurate identification of cognitive and functional decline in bilingual Latino/a older adults with Alzheimer's disease and related dementias continues to be a substantial public health concern. This paper highlights the heterogeneity in the clinical expression of Alzheimer's disease among bilingual Latino/as, the clinical decisions leading to a culturally and linguistically congruent neuropsychological assessment, and the interdisciplinary, multi‐setting partnerships needed to ensure a healthy longevity post‐diagnosis for the patient, the caregiver, and the family. Psychologists play an important role in advocating for the best standard of care, as the patients and families endure the long journey of care with dignity and respect.