bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in clinical indices of multimorbidity and frailty predict subsequent cognitive decline: Findings from the Look AHEAD and Look AHEAD MIND studies
Authors: Espeland Mark A. , Bahnson Judy , Evans Joni K. , Hayden Kathleen M. , Justice Jamie , Johnson Karen C. , Johnston Craig , Munshi Medha , Simpson Felicia R. , Kritchevsky Stephen B.
Published: December 2021

Background

Two common features of aging are increases in the number of chronic diseases and in the number of deficits in functional, behavioral, and clinical characteristics. Accordingly, indices of multimorbidity and deficit accumulation (i.e. frailty indices) have been promoted as clinical markers of biological aging. As such, it is to be expected that changes over time in these indices should be predictive of downstream changes in important functions, such as cognition.

Method

We examined associations that 8‐year changes in 1) a multimorbidity index comprised of 9 chronic diseases (e.g. CHD, cancer, depression) and 2) a frailty index (FI) based on deficit accumulation in 38 functional, behavioral, and clinical characteristics had with subsequent standardized measures of cognitive function over 10 years. We drew data from the Look AHEAD clinical trial of a multidomain intensive lifestyle intervention (ILI) in 3841 adults, aged 45‐76 years at baseline, who were at risk for accelerated biological aging due to overweight/obesity and type 2 diabetes mellitus, and who underwent cognitive assessment. The domains of memory, attention, and executive function were assessed with validated instruments and combined to form a composite cognitive measure.

Result

1501 (39%) of the cohort had increases of one and 867 (23%) had increases of >2 chronic diseases. Older individuals, males, and non‐Hispanic Whites tended to be over‐represented among those with the greatest increase in multimorbidities. The 33%ile of the distribution of FI changes was ‐0.005 and the 67%ile was 0.048. Greater FI increases tended to occur among individuals who were older, non‐Hispanic White, heavier, and who had greater baseline multimorbidity. Changes in multimorbidity and FI were moderately correlated (r=0.25; p<0.001). As seen in the attached table, greater increases in both multimorbidity and FI were associated with subsequently worse levels of executive function, attention, and composite cognitive function (p<0.001). While assignment to ILI was associated with smaller increases in both indices of aging, this did not translate overall to better cognitive functioning.

Conclusion

Accelerated aging, as captured by these geroscience‐informed indices, predicts subsequent poorer cognitive function. However, whether interventions generally targeting multimorbidity and FI reduce risks for cognitive impairment remains to be seen.
Assessing sex differences between mid‐life cardiovascular conditions or risk factors and mid‐life cognition decline
Authors: Huo Nan
Published: December 2021

Background

The association between mid‐life cardiovascular diseases or risk factors and cognition decline has been reported. However, sex differences in these associations have rarely been examined.

Method

We included 2,351 participants enrolled in the population‐based Mayo Clinic Study of Aging who were aged 30‐69 years at baseline. Participants were evaluated every 15 months by a coordinator, neurologic evaluation, and neuropsychological testing. The neuropsychological testing used nine tests to calculate global cognitive and domain‐specific (memory, language, executive function, and visuospatial skills) z‐scores. Nurse abstractors reviewed participant medical records to determine the presence and age at onset of cardiovascular diseases and risk factors. Linear mixed‐effect models evaluated the association between baseline cardiovascular conditions (coronary heart disease, myocardial infarction, atrial fibrillation, angina) or risk factors (hypertension, diabetes, dyslipidemia) and global and domain‐specific cognitive decline. Multivariable models adjusted for demographics, APOE, depression, and other medical conditions. Interactions between sex and each cardiovascular conditions or risk factors were examined; results were stratified by sex if the interaction was p<0.05.

Result

Overall, 1651 (70.3%) participants had at least one cardiovascular condition or risk factor; the proportion of men was higher than women (875 (74.9%) vs.777 (65.7%), p<0.0001). Cross‐sectionally, baseline cardiovascular conditions and risk factors were not associated with cognitive performance in multivariable analyses and there were no sex differences. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and/or domain‐specific z scores, with the exception of visual spatial z‐scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease, myocardial infraction, and angina were associated with global cognition decline only in women. Additionally, diabetes, dyslipidemia, and coronary heart disease were associated with language z‐score decline only in women.

Conclusion

Middle aged cardiovascular conditions and risk factors are associated with mid‐life cognitive decline. Moreover, some specific cardiovascular conditions and risk factors, such as coronary artery disease, myocardial infraction, and angina have stronger associations with cognition decline among women.
Air pollution and neighborhood racial composition and their association with memory and memory decline in NHATS
Authors: Dang Kristina , Weuve Jennifer , Haan Mary , Allen Isabel Elaine , Brauer Michael , Lane Kevin , Glymour M Maria
Published: December 2021

Background

Memory decline is a harbinger of Alzheimer’s disease (AD). Air pollution was recently added as a dementia risk factor by the Lancet Commission, and area‐level factors, such as neighborhood racial composition (a measure of structural racism) may modify the effects of air pollution. We examined the relationship between air pollution and neighborhood racial composition on memory and decline in a sample of older adults in the United States.

Method

NHATS is a nationally‐representative sample of 8,245 participants 65+ years at baseline (2011). Annual averages of fine particulate matter (PM2.5, IQR = 2.2 μg/m3), nitrogen dioxide (NO2, IQR = 5.5 ppb), and ozone (O3, IQR = 8.4 ppb) at baseline and Census ACS data were assigned to the Census tract of participants. The Index of Concentration at the Extremes, defined as: [(number in most disadvantaged extreme, i.e., Blacks) ‐ (number in most privileged extreme, i.e., Whites)]/(total people) was calculated for each census tract as a measure of neighborhood racial composition. A composite measure of episodic memory was constructed as the average of z‐scored delayed and immediate word list recall. We used linear mixed effects models to examine the association between each air pollutant and neighborhood racial composition with memory and memory decline over 6 years, adjusting for a number of individual‐ (age, race/ethnicity, gender, education, smoker, practice effects) and area‐ (census division, urban tract) level covariates, with random effects for census tract and participant.

Result

Increases in air pollution (per IQR) were weakly associated with worse memory at baseline [PM2.5 ‐0.02 (95% CI: ‐0.05, 0.006); NO2 ‐0.03 (‐0.06, 0.002); O3 ‐0.03 (‐0.06, ‐0.0004) SD‐units in memory]. PM2.5 increased the rate of memory decline by ‐0.01 (‐0.02, ‐0.0008); while NO2 increased the rate of memory decline by ‐0.008 (‐0.01, ‐0.0007). Neighborhood racial composition was significantly associated with worse memory (for more disadvantaged neighborhoods) in all air pollution models, but it did not modify the effect of air pollution on memory nor memory decline.

Conclusion

In this cohort of older adults, we found that PM2.5 and NO2 increase the rate of memory decline, while neighborhood racial composition does not modify this effect of air pollution.
Phase‐specific health system costs of dementia in Ontario, Canada: A propensity score‐matched cohort study
Authors: Bronskill Susan E , Maclagan Laura C , Mondor Luke , Fu Longdi , Guan Jun , Sewell Isabella J , Iaboni Andrea , Wodchis Walter P , Swartz Richard H , Maxwell Colleen J , de Oliveira Claire
Published: December 2021

Background

Due to increases in the prevalence of dementia across Canada, the economic burden of dementia on provincial health systems is expected to rise. A better understanding of the phase‐specific costs of dementia care, such as periods immediately prior to and following diagnosis as well as other critical points in the life course are needed to support capacity planning. We estimated the phase‐specific costs of dementia over time among older adults and by sex.

Method

We identified a cohort of 164,640 Ontario residents aged 66+ years, ascertained with incident dementia and residing in the community between April 1st, 2010 and March 31st, 2017. Controls, who had no previous dementia diagnosis, were 1:1 propensity‐score matched to persons with dementia and individuals were followed to death or study end (March 31st, 2018). Costs included inpatient care, emergency department care, ambulatory care, home care, long‐term care, physician and healthcare professional services, and prescription drugs. Phase‐based costing methodology examined mean net costs of dementia care throughout four phases of disease progression (pre‐diagnosis, initial, continuing, terminal) and 5‐year net costs.

Result

Persons with dementia and matched controls (mean age 81.3 years; 58.7% female) were followed for an average of 3.2 years. Mean net costs of dementia were highest in the terminal phase ($32,679), followed by the initial ($17,656) and continuing phases ($13,423). Higher costs in the dementia group in the terminal phase were driven by acute care (net cost: $16,324, 95% CI [15,478, 17,170]) and long‐term care ($14,006, 95% CI [13,848, 14,164]). Net home care costs were highest in the initial phase ($1,839, 95% CI [1,796, 1,882]). The net 5‐year cost of dementia was $48,077 (95% CI [$47,183, $48,970]; women had higher 5‐year net costs than men ($50,158, 95% CI [$49,053, $51,263] vs. $44,800, 95% CI [$43,323, $46,277]).

Conclusion

Observed higher net costs of dementia in specific phases (terminal) and sectors (acute care, long‐term care, home care) highlight where to target interventions to optimize healthcare use and costs that respects quality of life for older adults with dementia and their family care providers.
Quantifying the longitudinal cognitive resilience to Alzheimer’s disease and other neuropathologies
Authors: Wagner Maude , Wilson Robert S , Leurgans Sue E , Bennett David A , Grodstein Fran , Capuano Ana W
Published: December 2021

Background

Cognitive resilience (CR) refers to the ability to maintain a better‐than‐expected cognitive level or slope of cognitive change based on the degree of brain pathology. Different approaches have been used to quantify CR as a continuous variable. These approaches examine cognitive level at a single point or examine cognitive change over time irrespective of cognitive level and assuming a linear change. We propose a continuous measure of CR that reflects cognitive level while taking into account the entire observed non‐linear cognitive trajectory.

Method

We used data from 1220 individuals with ≥2 measures of global cognition and brain autopsy in the Religious Order Study and Rush Memory and Aging Project to compute three versions of CR. The CR1 focuses on cognitive level at a single point. It was calculated as the standardized residuals obtained proximate to death in a linear regression model, with demographics and 8 neuropathologies as covariates. The CR2 represents the residual (random) slope of cognition obtained in a latent process mixed (LPM) model assuming a linear cognitive change. Finally, the proposed CR3 examines cognitive levels over time. It was computed as the mean of differences between person‐specific and marginal error‐free predictions of cognition from a LPM model with time approximated by natural cubic splines. The LPMs of CR2 and CR3 included interactions of demographics and pathology with time. To assess the validity of our approach, we compared the continuous associations of CRs with established reserve risk factors (e.g., cognitive activity) and dementia risk factors (e.g., depressive symptoms, neuroticism) at cohort baseline.

Result

The proposed CR3 was highly correlated with CR1 (r=0.81) and moderately correlated with CR2 (r=0.51). The established reserve risk factors were all associated with CR1 and CR3 but not with CR2, and effect estimates were largest for CR3. All CRs were negatively associated with depressive symptoms and neuroticism (all‐P<.0004), but none was associated with ApoE‐ε4 (all‐P>.508). In a sensitivity analysis, we showed that findings remained consistent when randomly reducing repeated measures of cognition or allowing only a 10‐year follow‐up.

Conclusion

Incorporating longitudinal cognitive levels is an alternate way to quantify CR in cohort studies.
Plasma Ab42/40 levels differ by postmenopausal stage
Authors: Maki Pauline M. , Ances Beau M. , Terpstra Melissa , Salat David H. , Woods Roger , Essen David , Barch Deanna M. , Bookheimer Susan Y.
Published: December 2021

Background

Although all women who live into late life experience reproductive aging (menopause), there is little understanding about how reproductive aging, as distinct from chronologic aging, influences the development of AD. Studies indicate that some AD biomarkers differ between peri‐ and postmenopausal women, but no studies to date have examined AD biomarkers across (sub)stages of the postmenopause. Here we compared plasma Ab42/40 levels in Early versus Late Postmenopausal women. We hypothesized that plasma levels of Ab42/40 would be lower in the Late versus Early Postmenopause group.

Method

Participants included women from the Human Connectome Aging Project who had plasma Ab42/40 and were either in the Early Postmenopause (i.e., Stages +1a, +1b or +1c; >0 and <6 years after the final menstrual period; FMP) or Late Postmenopause (Stage +2; > 6 years after the FMP) according to the Stages of Reproductive Aging Workshop +10 criteria. Plasma Aβ42/40 was measured using an immunoprecipitation and liquid chromatography‐mass spectrometry assay. A univariate analysis of variance was conducted to compare plasma Ab42/40 in Early versus Late Postmenopause groups controlling for age, education, MOCA score, and ApoE carrier status.

Result

The sample included 42 women (mean age=66.2 years; mean MoCA=25.88; 73.8% white). Plasma Ab42/40 were significantly higher in the Early (n=10; mean age=55.77) versus Late Postmenopause (n=32; mean age=69.44) groups with mean values of 0.11 (SE=.002) and 0.103 (SE=.001), respectively, F(1,28)=7.23, p=.01. We restricted a second analysis to women age 60 years and under to optimally control for age differences between the groups (n=18, mean age=56.56 years; mean MOCA=26.04; mean education=17.17 years; 56% white, Early n=10). Again, plasma Ab42/40 were significantly higher in the Early (n=10; mean age=55.77) versus Late Postmenopause (n=32; mean age=57.56) groups with mean values of 0.11 (SE=.002) and 0.105 (SE=.003), respectively, F(1,13)=6.52, p =.025.

Conclusion

Advanced reproductive stage, independent of chronologic age, may be associated with a lower plasma Ab42/40, a pattern shown to be predictive of the development of AD. These findings add to a body of AD biomarker studies showing differences between perimenopausal and postmenopausal women, and suggest that AD biomarkers also differ within distinct stages of the postmenopause.
Exercise: Just what the doctor ordered, but why? Elucidating mechanisms for women’s increased HDL benefit from exercise
Authors: Bernier Rachel A. , Banks Sarah J. , Clark Alexandra L. , Shepherd Alyx L. , Sundermann Erin E.
Published: December 2021

Background

High‐density lipoprotein (HDL) is protective against cardiovascular disease (Di Angelantonio et al., 2009), a risk factor for AD pathogenesis (Brickman et al., 2015). Aerobic exercise can increase HDL concentration (Hsu et al., 2019), and evidence suggests this HDL benefit occurs more so in women than in men (Werner et al., 1995). Both HDL and exercise are associated with tumor necrosis factor alpha (TNFα), a proinflammatory cytokine (Park et al., 2003). Given known sex differences in the immune response (Hanamsagar & Bilbo, 2016), TNFα levels may represent a potential mechanism by which women’s HDL levels benefit more so from exercise. We sought to replicate the stronger exercise‐HDL link in women versus men and examine TNFα as a potential mediator in a group of cognitively normal (CN) older adults.

Method

This study included 2957 CN participants (51% women; 41% Black, 59% White; mean age=73.6 (SD=2.9) years) from the Health, Aging, and Body Composition (Health ABC) study who underwent a blood draw for biomarker analysis of HDL and TNFα levels. Exercise level was measured via a standardized physical activity questionnaire categorized (0‐6) based on Kcal/week for all types of walking, exercise, and recreation, and examined continuously. Regression analyses were employed to examine exercise‐by‐sex interactions on HDL‐level (mg/dL) and the mediating effect of TNFα (pg/mL). Covariates included age, race, and body mass index.

Result

Regressions adjusting for covariates revealed significant exercise‐by‐sex interactions on HDL (ß=0.12, p=.022), whereby higher levels of exercise related to higher HDL in women (ß=0.06, p=.023) but not in men (ß=‐0.01, p=.653). TNFα level negatively related to HDL in women (ß=‐0.24, p<.001), and adjusting for TNFα eliminated the female‐specific exercise‐HDL association (ß=0.04, p=.150).

Conclusion

This female‐specific association was eliminated when adjusting for TNFα, suggesting that exercise may benefit HDL in women through ameliorating effects on the neuroinflammatory pathway. Findings underscore the importance of exercise as a mitigator of vascular risk and, in turn, AD risk, particularly in women. Future studies should examine these interrelationships longitudinally and across the AD spectrum.
Evaluation of class C CpG ODN efficacy and safety profile in a squirrel monkey model of AD pathology
Authors: Patel Akash G , Nehete Pramod N , Nehete Bharti P , Karimi Sohail G , Genovese Thomas S , Debure Ludovic , Drittel Brian D , Guttman Daniel Ezra , Williams Lawrence E , Wisniewski Thomas , Scholtzova Henrieta
Published: December 2021

Background

A drawback of current immunotherapeutic approaches is limited effectiveness against cerebral amyloid angiopathy (CAA) and CAA‐linked complications. The failures of many Alzheimer’s disease (AD) clinical trials have been related to poor translatability of promising rodent data to humans. Our initial study using a non‐human primate (NHP) model of AD amyloid pathology with a propensity for developing abundant CAA, squirrel monkey (SQM), indicates that chronic administration of TLR9 agonist, Class B CpG ODN, safely ameliorates CAA. Here, we advanced our work to evaluate the long‐term efficacy and safety of Class C CpG ODN, which has shown favorable safety profiles in a variety of human diseases. The present study was designed to assess CpG ODN immunostimulatory patterns and to monitor disease progression by a combination of behavioral measures and biomarker signatures of pathology development.

Method

Geriatric SQMs received either CpG ODN or saline every 4 weeks as part of an ongoing long‐term treatment study (currently in month 22). Changes in mRNA expression levels were periodically evaluated in isolated PBMCs prior to and 24hrs after representative injections using the Nanostring nCounter System. SIMOA and Luminex assays were used to measure AD related fluid biomarkers. Both treatment groups were subjected to locomotor activity testing prior to cognitive assessment.

Result

Longitudinal Nanostring analyses demonstrated significant up‐regulation of IFN‐inducible genes (e.g., IFIT2, Mx2/MxB, GBP1, MIG, IP10), specific cytokine‐chemokine genes, and TLR9 signaling genes (e.g., UNC93B1) following CpG ODN injections. Ongoing SIMOA examination of neurofilament light, a biomarker of neurodegeneration, showed higher plasma levels in the control group compared to CpG ODN group. Our preliminary measurements of a biomarker of glial injury, YKL‐40, indicated increased plasma levels in control animals compared to CpG ODN‐treated animals. Monitoring of additional AD pathology and cerebrovascular dysfunction biomarkers throughout the treatment period will further assess CpG ODN efficacy and safety. Importantly, no significant differences were observed between treatment groups in locomotor performance. Cognitive assessments are underway.

Conclusion

Overall, the present findings provide essential information prior to any clinical use of CpG ODN in AD. The use of this advantageous model is important to reach efficient translation for human benefit.
The dementia policies in Australia relating to the COVID‐19 pandemic
Authors: Goh Anita MY , Dow Briony
Published: December 2021

Background

Australia has a population of 26 million, and on January 28th 2021, 28,794 COVID‐19 infections and 909 deaths. 685 deaths were at residential aged care facilities, and data from the Australian Bureau of Statistics revealed that 72.7% of the people who died of the coronavirus in Australia (up to 31 August 2020) had at least one pre‐existing chronic condition listed on their death certificate, with dementia the most common (noted on 41% of death certificates). This presentation will present and discuss the key Australian dementia policy interventions implemented during the pandemic.

Method

A scoping review of published academic, media, policy papers, white papers, and grey literature was conducted. We extracted relevant information pertaining to policies relating to dementia care during the COVID‐19 pandemic.

Result

The Australian government is managing the COVID‐19 outbreak as a health emergency, and have developed and funded a comprehensive response. For the older population and those with ADRD, the key policies include the National Health Plans, specific plans for people with disabilities, telehealth expansions, mental health and wellbeing pandemic response plans, home delivery of prescriptions, the establishment of an Aged Care Health Emergency Response Operations Centre, and a National COVID‐19 Aged Care Plan. In Victoria, the Victorian Aged Care Response Centre was established. The Pfizer/BioNTech vaccine will be given to priority groups from February 2021, which include aged care and disability care residents and workers (people with dementia account for 52% of all residents in aged care facilities).

Strict policies were put in place for aged care facility visitations, and for the aged care workforce, such as the use of personal protective equipment and limiting staff to work in only one facility. Advocacy bodies were also key, and Dementia Australia and Dementia Support Australia, for example, developed advice to support people experiencing behavioural and psychological symptoms of dementia during the pandemic.

Conclusion

There are currently no active cases in residential aged care in Australia, zero locally acquired cases for several weeks, with the (minimal) new cases emerging from the hotel quarantine system. Health policies have managed to limit the spread of COVID‐19 infection in Australia.
Use of neural precursors as a therapy to alleviate Alzheimer’s disease neuropathology and cognitive impairment
Authors: Ruiz Nazaret Gamez , Morales Rodrigo , Gutierrez Antonia , Moreno‐Gonzalez Ines
Published: December 2021

Background

Current treatments for Alzheimer´s disease (AD) only ameliorate the symptoms, but none of them delays or halts disease progression. In recent years, stem cells have received growing attention as a potential therapy for brain disorders. Patients’ self‐derive stem cells offer the possibility to avoid rejection and a more personalized treatment. However, there is an urgent need to replace the conventional intracerebral stem cell therapy for a less invasive method to avoid some of the technical challenges. Our recently published results indicate that peripheral treatment with neural precursors (NPs) ameliorates clinical symptoms by reducing the disease‐associated neuroinflammation in a mouse model of Parkinson’s disease. Therefore, we hypothesize that intravenous administration of NPs could be considered as a non‐invasive therapy to ameliorate memory impairment in mouse models of AD.

Method

NPs derived from mesenchymal stem cells and induced pluripotent stem cells were intravenously injected into APP/PS1 and P301S mice before and after brain pathology is stablished. At the age of 7 months old, experimental and control animals were subjected learning and memory tasks and brain analyzed.

Result

NP‐treated mice demonstrated a significant decreased of cognitive impairment compared to PBS‐injected animals as well as improved motor coordination in P301S mice. Histological analysis showed that although amyloidogenic deposits were slightly reduced, microglial activation decreased after the treatment.

Conclusion

The preclinical analysis of NPs peripheral inoculation suggests that these cells could be considered as a potential treatment to reduce AD‐related pathology.
Delivering probes and clinical candidates to test precision medicine therapeutic hypotheses
Authors: Watterson Daniel Martin , Roy Saktimayee M , Van Eldik Linda J , Arancio Ottavio
Published: December 2021

Background

. There is a need for selective clinical candidates that allow testing of explicit precision medicine hypotheses emerging from diverse clinical data acquisition, analysis and archiving initiatives. Candidates that target pathophysiology progression mechanisms would offer the potential for disease modification. Appropriate clinical candidates would, ideally, facilitate clinical hypothesis testing in order to find the right drug at the right dose at the right time for the right patient. In this regard, we developed a discovery and development platform focused on altering pathophysiology progression mechanisms and delivers novel small molecule candidates with good bioavailability, safety profiles and potential for evaluation in proof‐of‐concept clinical trials.

Method

Synaptic dysfunction and neuroflammation are pathophysiology progression mechanisms. Our discovery starts with molecular scaffolds emerging from pharmacoinformatic analysis of prior CNS drugs and their clinical utility. Medicinal chemistry diversification is driven by chemoinformatics related to small molecule drug properties in biological systems and by pharmacoinformatics related to pharmacology and toxicology potential. Campaigns can target single molecular entities (e.g., a serine/threonine protein kinase), pathways (e.g., cytokine biosynthesis dysfunction) or combinations (e.g., serotonin receptor linked dysfunction). Efficient medicinal chemistry approaches include diversifications based on [Target:Inactive Molecular Fragment] complexes or us of SOSA variations (systematic optimization of side activities). Best‐in‐class candidates emerge from IND‐enabling preclinical safety pharmacology and tractability of GMP production and delivery.

Results

MW150, MW189 and MW151 are example deliverables that continue to exhibit utility in human subjects. MW150 is a highly selective CNS S/T protein kinase inhibitor deliverable entering phase 2a safety trials for AD patients. MW150 exhibited selectivity in hierarchal kinome‐wide and large scale functional GPCR screens and absence of activity in standardized screens related to ADMET liabilities. Preclinical safety testing according to FDA/ICH guidelines provided the foundation for regulatory approval of clinical trial initiation. MW189 and MW151 are clinical trial stage deliverables where design and synthesis of a curated small chemical library was based on SOSA rationale and functional vetting was based on attenuation of cytokine biosynthesis dysfunction.

Conclusion

Overall, the platform continues to be validated for delivery of novel small molecule candidates for human studies.
Selective targeting of intracellular, misfolded, pathogenic TDP‐43 with rationally designed intrabodies
Authors: Zhao Beibei , Louadi Sarah , Dijkstra Anke A. , Plotkin Steven S , Kaplan Johanne , Cashman Neil R
Published: December 2021

Background

Cytoplasmically mislocalized aggregates of TDP‐43 have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) through direct toxicity, loss of function of normal TDP‐43, induction of misfolding of other neuronal proteins, and prion‐like, cell‐to‐cell propagation of disease. We generated monoclonal antibodies (mAbs) selective for the misfolded form of TDP‐43 and derived single chain intrabody constructs to allow for intracellular targeting of pathogenic TDP‐43 without interfering with physiological forms of TDP‐43 important for normal cell function.

Method

Monoclonal antibodies (mAbs) were generated by immunization with an unfolded N‐terminal domain (NTD) linear epitope predicted to become exposed in cytoplasmically mislocalized aggregates of TDP‐43 but otherwise buried in natively folded TDP‐43. The selectivity of mAbs for pathogenic, aggregated TDP‐43 was assessed by immunocytochemistry (ICC) of HEK293FT cells transfected with mutant TDP‐43 (DNLS‐TDP‐43) and by immunohistochemistry (IHC) on patient samples. Single chain (scFv) intrabody constructs were derived from selective antibodies and HEK293FT cells were co‐transfected with plasmids encoding intrabodies and misfolding DNLS‐TDP‐43. The selective interaction of expressed intrabodies with cytoplasmic DNLS‐TDP‐43 aggregates was assessed by ICC, and clearance of the aggregates was evaluated by western blot analysis of cell lysates.

Result

ICC showed mAb reactivity with cytoplasmic aggregates of transfected DNLS‐TDP‐43 but not endogenous wild‐type nuclear TDP‐43. IHC of ALS and FTLD CNS sections confirmed immunoreactivity specifically with pathogenic TDP‐43 in patient samples. Similarly, co‐transfection of DNLS‐TDP‐43 and scFv intrabody constructs showed intracellular interaction of intrabodies with misfolded cytoplasmic aggregates of TDP‐43 but not with normal, nuclear TDP‐43. In agreement with a lack of interference with normal TDP‐43, the robust expression of intrabodies did not affect cell viability. Intracellular clearance of the aggregates was observed in western blots of the cell lysates and was enhanced by the inclusion of a lysosomal targeting signal in the intrabody constructs.

Conclusion

Immunization with an NTD epitope of misfolded TDP‐43 gave rise to mAbs selective for pathogenic vs physiologically important forms of TDP‐43. Intrabody constructs derived from these mAbs were able to promote clearance of intracellular pathogenic TDP‐43 without toxicity to the cells.
Local neurodegeneration and global connectivity adaptation across the FTD‐AD spectrum
Authors: Brown Jesse A. , Lee Alex Jihun , Pasquini Lorenzo , Friedberg Adit , Rabinovici Gil D. , Kramer Joel H , Tempini Maria Luisa Gorno , Rosen Howard J. , Miller Bruce L. , Seeley William W.
Published: December 2021

Background

Neurodegenerative diseases involve weakened functional connectivity in disease‐targeted brain areas. Equally important but overlooked is the hyperconnectivity that appears in other brain areas (Hillary and Grafman, TICS 2017). Hyperconnectivity has been attributed to processes like disinhibition, imbalance, compensation, and reserve. It is critical to understand the neuroanatomical mechanism underlying hyperconnectivity because this functional process may accelerate subsequent disease progression. We performed structure‐function mapping for patients across subtypes and stages of the frontotemporal dementia‐Alzheimer’s disease atrophy spectrum. Our goal is to develop a comprehensive model relating diverse focal atrophy patterns to corresponding brain‐wide functional connectivity reconfigurations.

Method

We studied patients with Alzheimer’s disease (AD), behavioral variant FTD (bvFTD), semantic and nonfluent variant primary progressive aphasia (svPPA/nfvPPA), cortical basal syndrome (CBS), and healthy controls (HC). We included subjects who received a clinical diagnosis at the UCSF Memory and Aging Center and had structural and task‐free functional MRI scans (n=281). Each subject’s gray matter atrophy map was measured using voxel‐based morphometry volume loss in 273 ROIs. Functional connectivity matrices (273x273) were derived for each subject. We combined data for all patients and controls into a structural data matrix (281x273) and a functional data matrix (281x37128). We then performed partial least squares regression to find components that maximized the covariance between structure and function.

Result

The first PLS component captured the relationship between global atrophy burden and a distributed pattern of functional connectivity loss in unimodal cortical areas and enhancement in subcortical‐cortical pathways (r=0.64; Figure 1). The second PLS component showed svPPA‐like anterior temporal atrophy corresponding to atrophy‐proximal connectivity deficits, with enhancements in contralateral frontoparietal areas (r=0.67). The third PLS component revealed a spectrum from anterior (bvFTD) to posterior (AD), contrasting frontal‐insular atrophy, connectivity deficits, and parietal connectivity enhancements versus parietal atrophy, connectivity deficits, and frontal connectivity enhancements (r=0.51).

Conclusion

Specific atrophy subtypes across the FTD‐AD spectrum associate with proximal functional connectivity reductions. Intriguingly, these subtypes also exhibit concomitant functional connectivity enhancements in more distal areas. The enhancements are of the same magnitude as the deficits and may represent a general principle of functional “load‐shifting” (Jones et al, Brain 2016) away from disease‐targeted areas.
Self and informant‐rated mild behavioral impairment and genetic risk for AD: The respondent matters
Authors: Creese Byron , Arathimos Ryan , Brooker Helen , Corbett Anne , Aarsland Dag , Lewis Cathryn , Ballard Clive , Ismail Zahinoor
Published: December 2021

Background

Late‐life onset neuropsychiatric symptoms (NPS) have received increasing attention in recent years because of their prognostic potential for neurodegenerative disease. As focus intensifies, appropriate measurement will be critical. The emergence of Mild Behavioral Impairment ‐ which describes late‐life onset apathy, mood/anxiety symptoms, impulse dyscontrol, social inappropriateness, and psychosis ‐ and the MBI‐Checklist (MBI‐C), developed to capture these symptoms in accordance with the ISTAART‐AA MBI criteria, has been a step forward. Previous work has demonstrated only modest correlation between proxy informant and self‐rated MBI‐C responses, but the significance of these differences in responses is not yet understood. Moreover, there is relatively less work examining non‐affective late‐life NPS. To explore both of these factors, we examined the relationship between genetic risk for Alzheimer’s disease and the five MBI domains in a sample of cognitively normal older adults.

Method

Genetic and clinical data from 2,529 cognitively normal participants aged ≥65 in the PROTECT study were analysed. MBI was evaluated using the MBI‐C; individual domain scores were calculated, and participants dichotomised into domain ‘present’ or ‘absent’. Polygenic risk scores (PRS) for Alzheimer’s disease were used as predictors in binary logistic regression models with the MBI domains, each rated by self and by proxy, as separate outcomes. To evaluate whether AD PRS was associated with depression, the most commonly considered NPS in older adults, we also tested the association between AD PRS and PHQ‐9 score (>=5 or <5).

Result

AD PRS was associated with a greater risk of apathy and impulse dyscontrol in proxy MBI‐C ratings but not in self‐report MBI‐C ratings (OR: 1.2 [95% CI: 1.06‐1.40], p=0.004; OR: 1.12 [95% CI: 1.01‐1.24], p=0.03, respectively). There was no association between AD PRS and PHQ‐9 symptoms.

Conclusion

Proxy informant and self‐reported MBI‐C elicit different associations in analysis of AD genetic risk. These findings suggest that even in cognitively normal older adults, proxy informant ratings are important to consider in the evaluation of NPS and risk of dementia. There was no association between PHQ‐9 symptoms and AD PRS, highlighting the importance of the multi‐domain MBI‐C as a specific tool to capture late‐life NPS as risk factors for dementia.
Interactions between dietary patterns and genetic factors in relation to incident dementia among 70‐year‐olds
Authors: Samuelsson Jessica , Najar Jenna , Wallengren Ola , Wetterberg Hanna , Fässberg Madeleine Mellqvist , Zetterberg Henrik , Blennow Kaj , Lissner Lauren , Rothenberg Elisabet , Skoog Ingmar , Zettergren Anna
Published: December 2021

Background

Genetic and lifestyle factors influence the risk of developing dementia. Diet is one of the modifiable lifestyle factors thought to affect risk, but it is unclear whether there is an interplay with genetic risk factors in relation to incident dementia.

Method

Data was derived from the population‐based Gothenburg H70 Birth Cohort Studies based in Sweden, including 602 dementia‐free 70‐year‐olds (born 1922 or 1930; 64% women) with dietary and genetic data followed for incident dementia until 2016. Two dietary patterns were derived with reduced rank regression analysis, one healthy (e.g., fruits, vegetables, fish) and one western (e.g., full‐fat dairy products, refined bread, red and processed meat). Genetic risk was determined by APOE ε4 status and four non‐APOE AD‐polygenic risk scores (AD‐PRSs). Gene‐diet interactions in relation to incident dementia were analysed with cox regression models. If an interaction at a p‐value threshold of p< 0.20 was detected, stratified analyses were performed. Analyses were adjusted for sex, energy intake, birth year, age at examination, educational level, physical activity level, cardiovascular risk factors and 10 principal components (to correct for population stratification).

Result

There was an interaction between APOE ε4 status and a healthy and a western dietary pattern in relation to incident dementia (p=0.13 and p=0.07), while no interactions were found between AD‐PRSs and dietary patterns. Those with higher adherence to a healthy dietary pattern had a reduced risk of dementia (HR 0.77; 95% CI 0.64–0.94, p=0.008) among ε4 non‐carriers, but not among ε4 carriers. There was a borderline association between a western dietary pattern and an increased risk of dementia among ε4 carriers (HR 1.25; 95% CI 0.97–1.61, p=0.08), while no association was observed among ε4 non‐carriers.

Conclusion

The results suggest an interplay between APOE ε4 status and adherence to dietary patterns in relation to incident dementia. The findings from this study could be of importance for dementia prevention strategies and for future intervention studies investigating the effect of dietary patterns in relation to dementia incidence.
Can we improve clinical trial design in Alzheimer’s disease? The participants point of view
Authors: Ottenhoff Lois , Vijverberg Everard G.B. , Visser Leonie N.C. , Verrijp Merike , Prins Niels D. , van der Flier Wiesje M , Sikkes Sietske A.M.
Published: December 2021

Background

Pivotal to clinical trial success is the recruitment and retention of participants. To improve both, it is important to know which trial features increase willingness to enroll and are appreciated by participants. We examined experiences of trial participants, and their suggestions on how to optimize clinical trial design.

Method

In this mixed‐methods study, we included participants via the Dutch Brain Research Center (11 different international sponsor‐initiated Alzheimer’s disease trials). An online study‐specific questionnaire was distributed among current and past participants addressing four topics; participant’s motives to enroll, experienced burden, preferred frequency of visits, and attitudes towards participation. Subsequently, we organized three focus groups to gain more in‐depth understanding of negative and positive aspects of trial design. Audio recordings from focus group interviews were transcribed verbatim and analysed by thematic content analysis by two independent raters.

Results

The questionnaire was completed by 71 participants (age 69±6.5, 54% female, 19 cognitively normal, 19 Mild Cognitive Impairment (MCI), and 33 Alzheimer’s dementia). To benefit future generations was most frequently (34%) reported as a motive for enrolment, Figure 1. The lumbar puncture (40%) and memory assessments (15%) were most often experienced as being of high burden. The most frequently mentioned features to increase the likelihood and willingness to enroll were a low probability to get allocated to the placebo group (27%), and the possibility to obtain personal test results (21%). Negative trial experiences according to focus group participants (N=12, 8 cognitively normal, 4 MCI) included the themes ‘not obtaining their own results during or at the end of a clinical trial’ and ‘no follow up enquiries after participating in the trial’. Among the positive aspects were ‘professionalism’, ‘accuracy’ and ‘empathy of research staff’.

Conclusion

Our findings provide input for how priorities of participants can be used in clinical trial design to optimize recruitment and ensure trial success. Relevant factors include expectation management and careful planning of high burden assessments, provision of individual feedback and prioritizing professionalism and empathy throughout conduct of the trial. Thus selection of experienced and well‐equipped trial centres is a key component.
Lifelong music practice as reserve factor: Associations with cognition and brain structure in older adults
Authors: Wirth Miranka , Böttcher Adriana , Höppner Angela , Fabel Klaus , Köbe Theresa , Teipel Stefan J , Peters Oliver , Priller Josef , Schneider Anja , Wiltfang Jens , Buerger Katharina , Perneczky Robert , Laske Christoph , Spottke Annika , Jessen Frank , Düzel Emrah , Wagner Michael , Roeske Sandra
Published: December 2021

Background

Regular music practice is suggested to be protective against age‐related cognitive decline and Alzheimer’s disease (AD) 1. This study investigated associations between music making during the entire life, late‐life cognitive performance and gray matter (GM) structure in the DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE, DRKS‐ID: DRKS00007966).

Method

Cognitively unimpaired participants (age: ≥60 years including normal controls, participants with subjective cognitive decline, and first‐degree relatives of AD patients) were included in this study. Frequency of music practice over lifetime was self‐reported by each participant using the Lifetime of Experiences Questionnaire (LEQ 2). A group with regular lifelong music practice (n=72) was identified and compared to a control group (n=72) that did not practice any music during life. The control group was selected to match for age, sex, education, crystallized intelligence, socioeconomic status and diagnostic group. Multivariate analyses included group comparisons on late‐life cognition using composite scores 3, GM volumes in the entire cortex and in combined posterior AD regions (adjusted for TIV) and interaction effects.

Result

Lifelong music practice was associated with better late‐life performance in global cognition (Fig. 1, left side), working memory, and executive function (p’s < 0.05). A similar effect was not seen for episodic memory. No significant direct associations were found between lifelong music practice and GM volumes in the cortex and within AD regions. Global cognition (Fig. 1, right side), working memory, and executive functions were enhanced in those individuals with both lifelong music practice and greater cortical GM volume (p’s < 0.05).

Conclusion

Regular music making over life may help preserve late‐life cognitive performance in executive function and working memory, mirroring existing findings 4. This cognitive benefit appears to be related to superior ability to recruit brain resources, rather than greater brain reserve per se. Music practice could represent an enrichment strategy that may to a certain degree provide cognitive reserve in older age. References: (1) Verghese J, et al. N Engl J Med 2003. (2) Valenzuela MJ, Sachdev P. Psychol Med 2007. (3) Wolfsgruber S, et al. Neurology 2020. (4) Mansens D, et al. Aging & Mental Health 2018.
Chronic low‐grade inflammation predicts greater decline in verbal fluency and word‐list learning on 10 years' follow‐up
Authors: Kipinoinen Teemu , Toppala Sini , Viitanen Matti , Rinne Juha O. , Jula Antti , Ekblad Laura L.
Published: December 2021

Background

Processes leading to the clinical presentation of Alzheimer´s disease (AD) start to develop years or even decades beforehand. Chronic low‐grade inflammation is suggested to play a role in the pathogenesis of many aging‐related chronic illnesses, including AD. The aim of this study was to evaluate whether low‐grade inflammation, commonly associated with obesity and the metabolic syndrome, is associated in cognitive decline after 10 years. We hypothesized that low‐grade inflammation at midlife, estimated by tumor necrosis factor alpha (TNF‐α), Interleukin‐6 (IL‐6) and high‐sensitivity CRP (hs‐CRP), predicts cognitive decline.

Method

915 subjects aged 45 to 74 years (median age 54, 55% women) participated a Finnish nationwide, population‐based Health 2000 Examination Survey, its supplemental cardiovascular and metabolic examinations in 2000‐2001 and the follow‐up Health 2011 Survey. Associations between baseline low‐grade chronic inflammation and cognitive performance at follow‐up in 2011 and the change in cognition from baseline to follow‐up were evaluated. TNF‐α, IL‐6 and hs‐CRP were measured in 2001. Categorical verbal fluency (VF), word‐list learning (WLL) and word‐list delayed recall (WLDR) were used as measures of cognitive performance at baseline and at follow‐up. Statistical analyses were performed with multivariable linear models adjusted for age, sex, education, APOEε4 genotype, type 2 diabetes, hypertension, hypercholesterolemia, body mass index, depressive symptoms and smoking, and for the change in cognition also baseline cognition.

Result

Higher TNF‐α and IL‐6 at baseline individually predicted poorer performance in all three cognitive tests at follow‐up (VF: TNF‐α slope:‐2.29, p=0.003, IL‐6 slope:‐1.71, p<0.0001; WLL: TNF‐α slope:‐1.02, p=0.02, IL‐6 slope:‐0.80, p=0.002; WLDR: IL‐6: slope:‐0.30, p=0.02). TNF‐α and IL‐6 predicted also a greater decline in VF (TNF‐α slope:‐1.69, p=0.009, IL‐6 slope:‐1.34, P=0.0009) from baseline to follow‐up. IL‐6, but not TNF‐α predicted greater decline in WLL (IL‐6 slope:‐0.71, p=0.02) and WLDR (IL‐6: slope:‐0.30, p=0.01). Baseline hs‐CRP was not associated with cognitive performance or decline after 10 years.

Conclusion

In this middle‐aged population, low grade inflammation measured with TNF‐α and IL‐6 predicts worse cognitive performance and IL‐6 predicts greater decline in cognitive function over a 10‐year follow‐up. Potentially, developing interventions that target these inflammatory processes could help reduce cognitive decline in the future.