bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectories of plasma biomarkers of Alzheimer’s disease and neurodegeneration in the general population
Authors: Graff‐Radford Jonathan , Lesnick Timothy G. , Mielke Michelle M. , Ramanan Vijay K , Cogswell Petrice M , Algeciras‐Schimnich Alicia , Knopman David S. , Hofrenning Ekaterina I. , Stricker Nikki H. , Jack Clifford R. , Petersen Ronald C. , Vemuri Prashanthi
Published: December 2023

Background

Plasma biomarkers of Alzheimer’s disease (AD) and neurodegeneration have demonstrated diagnostic utility and associations with AD pathology. Our objective was to map the average trajectories over age of plasma biomarkers and more established biomarkers including cognition, amyloid PET, and hippocampal volume.

Method

We included 1731 cognitively unimpaired (CU) and 226 mild cognitive impairment (MCI) participants from the Mayo Clinic Study of Aging (mean age of 70.3 years; 46.3% female; 14.8 years of mean education) with one or more measurements of amyloid‐PET, MRI with hippocampal volume measurements adjusted for head size (HVa), and plasma biomarkers (Aβ42/40 ratio, p‐tau181, GFAP, and NfL measured using Quanterix Simoa assays). A global cognitive z‐score was created by averaging the z‐scores of memory, language, executive function, and visuospatial domains. Smoothing spline curves were calculated for the values of each variable over age and placed on the same plot. Since each variable has a different scale, the smoothed curves were centered at the predicted value at age 50 and scaled so that a value of 1 would be one standard deviation of the fitted values from ages 50‐80.

Result

At age 50, GFAP and NfL start to increase, and Aβ42/40 was observed to decrease. At age 55, amyloid‐PET and p‐tau181 had a smooth and upward‐curving increase. After age 70, the average values of p‐tau181 increased at a higher rate. Average cognition started declining after 55 years. HVa began to decline after age 60 and then showed a steeper decline at age 72.

Conclusion

This study demonstrates that predicted values of plasma GFAP, NfL, and Aβ42/40 across participants begin to change at younger ages than cognitive decline or increases observed in amyloid PET. The changes observed during middle age in GFAP and NfL likely reflect non‐AD pathologies and aging processes, while Aβ42/40 may be a leading indicator of future cerebral amyloidosis. Predicted plasma neurodegenerative biomarkers (GFAP and NfL) begin to change at younger ages than a traditional biomarker of neurodegeneration (HVa). Predicted ptau181 increases were observed in tandem with amyloid PET likely reflecting current amyloid status.
Tangle and neuritic burden from neurofibrillary tangle maturity markers in the hippocampus are differentially correlated to tau‐PET, MRI, and cognitive measures
Authors: Moloney Christina M. , Peng Zhongwei , Wood Ashley C. , Rothberg Darren M. , Rutledge Matthew H. , Hofrenning Ekaterina I. , Machulda Mary M. , Petersen Ronald C. , Jack Clifford R. , Dickson Dennis W. , Nguyen Aivi T. , Reichard Ross R. , Carter Rickey E. , Lowe Val J. , Vemuri Prashanthi , Murray Melissa E. , Murray Melissa E.
Published: December 2023

Background

There is a gap in knowledge concerning which tangle maturity levels (Moloney, Alzheimers Dement, 2021) are associated with antemortem measures (tau‐PET, MRI, cognitive testing). We hypothesized antemortem measures would be more strongly correlated with markers recognizing middling to advanced tangle maturity. We additionally sought to assess the strength of the relationship with tangle and neuritic pathology recognized by tangle maturity markers.

Method

Posterior hippocampi from n = 30 cases with antemortem measures ≤3 years prior to death were cut (5µm) and immunostained with tau antibodies to evaluate early (AT8), middling (PHF‐1), or advanced (2E9) tangle maturity. GENIE (pattern recognition software) separated tangle from neuritic burden (Figure). Hippocampus, parahippocampus, and fusiform were analyzed to correlate digital pathology with flortaucipir tau‐PET standard uptake value ratio (SUVr, cerebellar crus normalization), MRI volume/thickness, and cognitive measures which included Auditory Verbal Learning Test (AVLT) delayed recall, Mini‐Mental State Exam (MMSE), and Clinical Dementia Rating (CDR).

Result

The strongest relationships observed with flortaucipir were with PHF‐1 and 2E9 burden (Table). AT8 tangle and neuritic burden correlations with flortaucipir were relatively similar in the hippocampus but were stronger with neuritic pathology in parahippocampus and fusiform. PHF‐1 tangle and neuritic burden correlations were relatively similar with flortaucipir. 2E9 correlations were stronger with neuritic pathology in hippocampus. MRI measures were more strongly correlated with PHF‐1 and 2E9 burden. AT8 tangle and neuritic burden were correlated with fusiform thickness. The correlations between MRI measures and 2E9 tangle and neuritic burden were similar. Correlations between cognitive measures were similar between tangle maturity markers. AVLT delayed recall correlated with all tangle maturity markers, but neuritic burden was stronger for AT8 and 2E9 in hippocampus compared to tangle burden. MMSE correlated with neuritic burden for all tangle maturity markers. CDR remained statistically non‐significant.

Conclusion

Interpretation of the strength of the relationship between tau burden and antemortem measures differed across tangle maturity markers. Neuroimaging measures may be more sensitive to middle/advanced maturity markers with limited differences between tangle and neuritic pathology. These findings may be biologically relevant and imply either a limited recognition of tangles depending on antibody epitope, and/or may represent the clinicoradiologic impact of increasing neuritic burden.
Development of innovative chalcone derivates targeting neuroprotective effects in Alzheimer disease
Authors: Haas Murillo Orsatto , Ruaro Thaís C , Gosmann Grace , Zimmer Aline R.
Published: December 2023

Background

Alzheimer’s Disease (AD) is a progressive neurodegenerative disturb that has reached global epidemic proportions. As a complex multifactorial disease affecting different cells in CNS, and with no effective treatment, developing new neuroprotective agents is critical (Therriault, J. et al, 2022). Based on that, a series of innovative molecules based on chalcones of natural origin was developed. Their cytotoxicity and neuroprotective effects were evaluated in silico and in vitro experimental platforms. Flavonoid derivatives are known for their anti‐inflammatory and antioxidant potential in AD (DAS, S. et al, 2017), however, there are few studies relating the action of the flavonoids' precursors called chalconoids (GOMES, M.N. et al., 2017).

Method

The research was carried out in two stages. The first stage was performed in silico, where virtual platforms were used to determine and predict the drug‐like characteristics of compounds and their ability to permeate by the blood‐brain barrier (BBB). The second stage evaluated the in vitro cytotoxicity in healthy cell lines (Vero and C6) and the neuroprotective effect against glutamatergic and oxidative insults in astroglial cells. In addition, the in vitro evaluation of cell viability was carried out using colorimetric methods (SRB and MTT). The neuroprotector effect was evaluated after pre‐exposure of cells to molecules under study.

Result

Regarding the tested compounds, nineteen in the series presented adequate drug‐like properties and low or no cytotoxicity. Among them, three showed significant neuroprotective potential against both insults (oxidative stress and glutamatergic excitotoxicity) in astroglial cells, keeping the cell viability between 70% and 80%. In addition, these compounds have a high potential to cross the BBB and will proceed to the in vivo pre‐clinical studies phase.

Conclusion

The designed chalconoids showed low cytotoxic potential and chemical characteristics compatible with oral use and passage through BBB. These results suggest chalcone derivatives as promising multi‐target agents preventing AD.
Cardio‐autonomic control and cognitive decline in older adults
Authors: Gao Chenlu , Lim Andrew , Yu Lei , Bennett David A. A , Gao Lei , Hu Kun , Li Peng
Published: December 2023

Background

Cardiovascular diseases may be linked to dementia pathogenesis. The cardio‐autonomic control (CAC) plays an important role in the development of cardiovascular diseases and may be implicated by dementia pathophysiology. We tested whether the CAC proxied by the complexity of beat‐to‐beat pulse rate intervals (PRI) predicted longitudinal cognitive decline in older adults.

Method

Continuous overnight pulse oximetry (photoplethysmography) data from 594 participants (mean age = 82.76±7.11 at oximetry assessment; 76% female) in the Rush Memory and Aging projects were studied. All participants completed cognitive assessments at oximetry baseline. Eighty‐four participants who had at least one follow‐up cognitive assessment were included in the analyses. After quality control, the feet of pulse waves in the photoplethysmography data were detected, and the consecutive foot‐to‐foot internals (i.e., PRI) time‐series within each 10‐min window were analyzed using the distribution entropy that evaluated the complexity of PRI (i.e., greater distribution entropy means more complex dynamics). To reduce behavioral and circadian effects, we used the mean distribution entropy values during 12AM‐3AM for each individual. Mixed‐effects models were constructed to associate distribution entropy to longitudinal cognitive changes, adjusting for age, sex, and education.

Result

At baseline, distribution entropy was normally distributed (mean = 0.33±0.14). On average, the global cognition score was 0.12 units (SD = 0.60). This score declined at an annual rate of 0.15 units (SE = 0.04; p = 0.0001). The distribution entropy was not associated with global cognition at baseline, but greater distribution entropy predicted slower cognitive decline. Specifically, a 1‐SD increase in distribution entropy correlated with a drop of 0.11 (SE = 0.04; p = 0.005) in the rate of cognitive decline.

Conclusion

The nighttime CAC (potentially during sleep) is linked with longitudinal cognitive profiles in older adults. As the CAC is regulated by an internal body clock—the circadian system, in which a dysfunction is involved in Alzheimer’s pathogenesis, it is possible that the CAC underlies the connections of cardiovascular disorders and circadian dysfunction with Alzheimer’s disease and its clinical outcomes. Future studies are warranted to test these hypotheses. Further studies should also investigate whether CAC at different times of the night has different correlations with cognitive changes and whether CAC predicts Alzheimer’s disease.
“Growing up we’re taught about physical activity, but very little mention of brain health, but it’s all brain health”: Exploring the Conceptualisation of Brain Health in 18–39‐year‐olds in Europe and North America
Authors: Booi Laura , Wells Katie , Gregory Sarah , An Hosanna , Marquez Melissa , Farina Francesca R
Published: December 2023

Background

It is widely theorised that the accumulation of risk factors for neurodegenerative diseases like Alzheimer’s and other dementias likely begins during young adulthood, yet there is limited understanding about how young adults conceptualise their own brain health. The NextGen research programs aims to explore brain health and exposure to risk factors in adults before mid‐life. In this study, we explored young adults’ (18‐39 years) understanding and attitudes towards their brain health.

Methods

This qualitative study recruited community‐based adults aged 18‐39 years from the NextGen Programme of research, a large‐scale, international, multi‐centre research programme. Participants (N = 39; 18 female) had a mean age of 26 years (SD = 3.68) and were equally represented from North America (n = 20) and Europe (n = 19). Most participants identified as Black (76%), followed by White (15%), Asian (6%) and mixed race (3%). Data collection took place over focus groups using video conference technology and a semi‐structured discussion guide. A live Illustrator was present for each focus group to provide an immediate visual output of the group discussion. Data were analysed using thematic analyses by the research team.

Results

Preliminary themes highlight discrepancies between individuals’ awareness and understanding of their brain health, in relation to their general health, family history of dementia and personal experience of brain health issues (e.g., traumatic brain injury). Regarding factors that can positively affect brain health, participants highlighted the importance of rest, good nutrition and physical exercise. Regarding factors that can negatively affect brain health, participants highlighted exposure to racism and discrimination, poor quality sleep, stress, and excessive alcohol consumption. Participants also reported being unsure about many factors, such as screen‐time, cannabis use, engagement with social media and video games.

Conclusion

Findings from this study are among the first to explore young adults’ perceptions around brain health. We found that young adults had a moderate level of awareness of brain health risk factors, but they often did not connect these factors to risk of Alzheimer’s disease or other dementias. Outputs from this study will be used to inform a large‐scale, international survey to explore brain health awareness, understanding and exposure to risk factors among 18‐39‐year‐olds.
Translational investigation of apathy and affective symptom hub genes in Alzheimer’s disease
Authors: Dunn Jeffrey T , Keszycki Rachel M , Fisher Daniel W , Rodriguez Guadalupe , Bennett David A. A , Wilson Robert S. , Dong Hongxin
Published: December 2023

Background

Approximately 90% of Alzheimer’s disease (AD) patients experience at least one neuropsychiatric symptom (NPS) over the course of disease progression. However, little is known about the neural mechanisms underlying NPS in AD, leaving treatment options for these symptoms underdeveloped. Here we use a translational approach to refine hub gene candidacy for the two most common NPS domains in AD (i.e., apathy, affective) and identify targets for investigation of causal relationships between genes and behavior.

Method

Weighted gene co‐expression network analysis (WGCNA) was performed on RNA‐sequencing data from human postmortem anterior cingulate cortex of 60 individuals with AD and antemortem clinical evaluations of NPS. Human and mouse protein‐protein interaction networks (PPIs) were constructed from WGCNA modules that significantly correlated with NPS domains. Expression levels of potential hub genes discovered in humans were measured in the prefrontal cortex (PFC) of 16‐month‐old wild type (WT) and 5xFAD mice by RT‐qPCR and correlated with composite z‐scores for representative apathy‐ and affective‐like behaviors.

Result

WGCNA revealed that a microglial phagocytic pathway and complement cascade module was uniquely correlated with apathy. PPI analyses refined the list of 43 WGCNA potential apathy hub genes to 21 candidate hub genes suitable for translational investigation. Further, human and mouse PPI analyses identified TYROBP as the highest‐ranking apathy hub gene. Expression levels of Tyrobp were significantly higher in the PFC of 5xFAD mice than in WT controls and positively correlated with apathy z‐scores. Only two genes retained affective domain hub gene candidacy (Tgfb1 and Nfkbia) in mice. Whereas Tgfb1 expression was elevated in the 5xFAD PFC, Nfkbia was not differentially expressed. Z‐scores for affective‐like behavior did not significantly correlate with either Tgfb1 or Nfkbia expression levels.

Conclusion

Our results suggest that the complement system is uniquely implicated in cases of AD with apathy; Tyrobp is a strong candidate gene for the regulation of that relationship. 5xFAD mice are an appropriate model for future investigation of Tyrobp‐complement‐apathy mechanisms in AD. Further study is needed to evaluate Tgfb1 and Nfkbia as possible regulators of affective behavior in models that exhibit other AD pathology(s) (e.g., tau) alone or in conjunction with pathologic amyloid‐beta.
CSF Abeta 3‐42/1‐42 ratio and neurogranin as biomarkers of interest in dementia with Lewy bodies
Authors: Pillai Jagan A. , Popp Whitney , Bekris Lynn M. , Wang Ming , Lerner Alan J. , Leverenz James B , Miyagi Masaru
Published: December 2023

Background

Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are the among the most common neuropathologies. Amyloid and tau biomarker changes are often incorporated in the clinical diagnosis of AD. The current DLB criteria does not include robust biofluid biomarkers. However differences in amyloid plaque and CSF neurogranin in DLB has been of interest based on neuropathology and prior CSF reports. Our objective was to determine if Abeta modifications Abeta 3‐42 and Abeta 1‐42 along with neurogranin could be used to differentiate DLB from AD.

Method

This cohort study among 45 MCI stage of AD meeting NIA/AA 2011 criteria and 15 DLB participants meeting the 2017 Mc Keith criteria. We evaluated the CSF levels of Abeta 3‐42, Abeta 1‐42 by Liquid chromatography‐mass spectrometry (LC‐MS/MS) techniques and CSF neurogranin by standard ELISA to explore the differences between groups. Two sample t‐tests both without and with data imputation for samples not meeting lower levels of detection and linear regression models by considering the confounding variables of age, sex and education were assessed.

Result

Mean age 67.67 (SD5.13) years, 33% Female. Mean neurogranin levels in DLB 325.9 (SD 200.34 were lower than in MCI‐AD 707.7 (SD 489.94) pg/ml, (p = 0.0006 from two‐sample t‐test). Mean levels of Abeta 3‐42 were 51.63(SD = 19.6) and 43.63(SD = 13.5)fmol/l, and Abeta 1‐42 848.7 (SD = 248.4) fmol/l and 981.5(SD = 265.0) in DLB and MCI‐AD, respectively and were not significantly different. The ratio of Abeta 3‐42/Abeta 1‐42 was higher in DLB 0.06 (SD = 0.02) than MCI‐AD 0.04 (SD = 0.01) (p = 0.008 from two‐sample t‐test). In the multivariable regression models after adjusting for confounding variables the ratio of Abeta 3‐42/Abeta 1‐42 (Est = 67.19,SE = 29.62, p = 0.02) and neurogranin (Est = ‐0.0069,SE = 0.0026,p = 0.009) were significant discriminators between DLB and MCI‐AD .

Conclusion

Higher ratio of CSF Abeta 3‐42/Abeta 1‐42 and lower CSF levels of neurogranin were noted in the DLB group compared to MCI‐AD. Lower levels of CSF neurogranin in DLB has been reported, while higher ratio of CSF Abeta 3‐42/Abeta 1‐42 in DLB is a novel biomarker finding. Differences in Abeta species in DLB could be potential biomarkers in separating DLB from AD.
Detecting Alzheimer’s risk with cognitive dispersion on neuropsychological testing
Authors: Lee Athene KW , De Vito Alyssa N. , Leng Xiaoyan , Farias Sarah Tomaszewski , Sachs Bonnie C. , Chan Michelle L , Snyder Heather M , Baker Laura D , Papp Kathryn V. ,   The U.S. POINTER Neuropsychology Team for the U.S. POINTER Study Group
Published: December 2023

Background

Cognitive dispersion refers to the within‐person variability across tasks. Relative to the normative approach, cognitive dispersion may be more sensitive to subtle changes in preclinical Alzheimer’s disease. Greater dispersion has been associated with increased risk for conversion to mild cognitive impairment and faster rates of medial temporal lobe atrophy. This metric can be derived from a regular neuropsychological assessment and complement traditional outcome approaches, particularly in those underrepresented in normative data. This study evaluated cognitive dispersion as an independent predictor of clinical status across racial and ethnic groups.

Method

Baseline data on 1811 cognitively unimpaired older adults with high vascular risk from the U.S. POINTER multisite lifestyle intervention study were examined. Sample characteristics included mean age of 68 (SD = 5.2), 70% female, 30% less‐than‐college education, and 29% underrepresented groups (301 Black, 231 Other). Correlations between cognitive dispersion and other brain health risks (vascular, subjective cognitive decline (SCD), physical activity) were tested. Cognitive dispersion was defined as the standard deviation of individuals’ z‐transformed scores of 8 cognitive tests. Vascular risk burden was the sum of 5 conditions (hypertension, diabetes, hypercholesterolemia, heart disease, obesity). Self‐report SCD was measured by the Cognitive Function Instrument (CFI) and Measurement of Everyday Cognition (ECOG12). Logistic Regression Models were fitted to predict Clinical Dementia Global Ratings (CDR 0.5 vs. 0) to evaluate cognitive dispersion as an independent predictor in the whole sample, White participants and Black participants, controlled for demographics, vascular risk, and physical activity. Logistic Regression Models were also evaluated with CFI or ECOG12 as additional covariate.

Result

Greater cognitive dispersion was correlated with older age, greater vascular burden and less physical activity, but not SCD. Cognitive dispersion was significantly higher in men, Black participants, and participants with less education. Cognitive dispersion predicted CDR in Black participants (OR = 4.7, p<0.01), and trended in the whole sample (OR = 1.6, p = 0.05), but was not significant in White participants (OR = 1.2, p = 0.63). Results hold when controlled for SCD (Table 1).

Conclusion

Results supported cognitive dispersion as a sensitive objective metric, in addition to self‐report SCD, to identify individuals showing the earliest clinical signs of decline, particularly among those underrepresented in traditional norms.
Exploring Quality of Life Rated by Caregivers and Care Recipients Among People Living With Dementia
Authors: Labovic Dubravka , Papazyan Anna , Josephson Karen , McCurry Susan M , Teng Edmond , Alessi Cathy A , Martin Jennifer L , Song Yeonsu
Published: December 2023

Background

Quality of life (QOL) of people living with dementia (PLWD) does not necessarily decrease as the disease progresses and understanding multiple aspects of QOL is an integral part of dementia care. Prior evidence suggests a discrepancy between caregiver‐ and care recipient‐rated QOL of PLWD, yet factors related to this QOL are still lacking. We aimed to examine the relationship between QOL of PLWD rated by both the caregivers and care recipients and characteristics of PLWD and caregivers.

Methods

We analyzed data from 40 caregivers and 29 PLWD enrolled in a clinical trial testing a dyadic sleep intervention for PLWD and their family caregivers. Measures included QOL‐Alzheimer’s Disease (QOL‐AD), caregiver characteristics (age, education, White vs Non‐White, spouse vs non‐spouse, Center for Epidemiological Studies of Depression [CESD], Zarit Burden Interview [ZBI]), and care recipient characteristics (Revised Memory and Behavior Problems Checklist [RMBPC], Activities of Daily Living [ADLs] and Instrumental ADL [IADLs], Mini‐Mental State Examination [MMSE]). Pearson correlation analyses were conducted.

Results

Mean QOL‐AD scores rated by caregivers and care recipients were 32.25 (SD 6.14) and 37.41 (SD 5.96), respectively. The scores were not significantly associated with each other. There were significant correlations between caregiver‐rated QOL‐AD scores and caregiving burden (r = ‐0.45, p = 0.004), depressive symptoms of caregivers (r = ‐0.52, p<0.001), frequency of dementia related behaviors (r = ‐0.57, p<0.001), caregivers’ distress associated with these behaviors (r = ‐0.54, p<0.001), and ADLs (r = 0.44; p = 0.004) and IADLs of PLWD (r = 0.43, p = 0.006). However, no caregiver or care recipient characteristics were associated with care recipient‐rated QOL‐AD scores.

Conclusion

Our findings confirm a discrepancy between caregiver‐ and care recipient‐rated QOL of PLWD. Among caregivers, higher levels of caregivers’ burden and depressive symptoms as well as lower levels of physical function and greater numbers of dementia‐related behaviors were associated with lower levels of perceived QOL‐AD, but not with the care recipient‐rated QOL. Further research should examine the possible mechanism underlying discrepancy of QOL‐AD rated by caregivers and care recipients to identify possible targets for interventions to improve QOL among PLWD.
Affordable, accessible, community‐delivered hearing care among individuals with cognitive impairment: Lessons from the HEARS RCT
Authors: Nieman Carrie L , Betz Joshua , Morales Emmanuel E. Garcia , Suen Jonathan J , Trumbo Jami , Marrone Nicole L , Han Hae‐Ra , Szanton Sarah L , Lin Frank R , Oh Esther S
Published: December 2023

Background

Hearing loss is highly prevalent and associated with adverse health outcomes but undertreated among individuals with cognitive impairment, particularly African Americans. The incorporation of community health worker (CHW)‐partnered models may increase access and reduce disparities.

The HEARS intervention is a hearing care program delivered by CHWs that provides a low‐cost amplification device. To assess the efficacy of CHW‐delivered hearing care provided to community‐dwelling older adults, including those with cognitive impairment, a randomized clinical trial was conducted.

Method

An open label randomized clinical trial took place in 13 community sites in Baltimore, Maryland. 348 older adults were screened and 151 participants with hearing loss were randomized to receive a CHW‐delivered hearing care intervention versus 3‐month waitlist control.

The primary outcome was change in communication function (Hearing Handicap Inventory for the Elderly‐Screening [HHIE‐S]) from baseline to 3‐months post‐randomization. The average treatment effect was estimated using the doubly‐robust weighted least squares estimator. This pre‐specified subgroup analysis was stratified by cognitive status using the total MoCA score (≤25: cognitive impairment; post hoc sensitivity analysis using ≤22).

Result

Among 149 randomized participants with MoCA data, 100 individuals were cognitively impaired (Mean adjusted MoCA: 21(SD 3.5); 52% African American; 70% low‐income). At 3‐months post‐intervention, 66% with cognitive impairment reported daily device use versus 76% for those without cognitive impairment. Communication function significantly improved among individuals with cognitive impairment compared with the control, with an estimated average treatment effect of ‐13.92 HHIE‐S change (95% CI:‐16.84,‐10.86), comparable to those without cognitive impairment (‐11.47; 95% CI:‐18.04,‐4.17). Post hoc sensitivity analysis using a ≤22 MoCA cut‐off for cognitive impairment yielded similar findings.

Conclusion

Among individuals with cognitive impairment, a CHW‐delivered low‐cost amplification device intervention, compared with a waitlist control, significantly improved communication function. The improvements were comparable to participants without cognitive impairment and similar in magnitude to improvements documented for older adults who received conventional clinic‐based hearing care with hearing aids fit by audiologists. To the authors’ knowledge, this trial was the largest trial to date of a hearing care intervention in the U.S. of African American older adults and low‐income older adults with hearing loss and cognitive impairment.
Co‐morbidity of sensory loss (hearing, vision, olfaction) in persons with or at risk for dementia: Implications for brain structure and function
Authors: Phillips Natalie
Published: December 2023

Background

Hearing, vision, and olfactory loss have each independently been associated with cognitive decline and increased risk for dementia. Research has examined their individual relationships with brain structure and function, but these predictors have not been examined together in older adults who vary along a spectrum of risk for dementia. We examined groups who range from relatively low risk (those with normal cognition and no cognitive complaints (NC)), to those with higher risk, namely individuals with subjective reports of cognitive decline (SCD) but normal cognition and those with mild cognitive impairment (MCI).

Method

We used data from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study. Hearing loss was assessed with a pure‐tone screening protocol and a speech‐in‐noise test, vision was assessed with the MNRead for visual acuity and the MARS test for contrast sensitivity, and olfaction was assessed with the Brief Smell Identification Test (BSIT). We examined the frequency of sensory deficits in 60 NC (mean age = 69 years; mean education = 16 years), 55 participants with SCD (age = 70; education = 17), 102 with MCI (age = 72; education = 16), and 47 with Alzheimer’s disease (AD, age = 75; education = 15). Participants were matched on age and education, except for AD participants who were older.

Results

The frequency of having at least one impairment in at least one sensory domain increased across groups (55% NC, 62% SCD, 75% MCI, 96% AD). A deficit in olfaction was the most common single deficit. Sensory deficits became increasing more co‐morbid across the risk spectrum. Hearing loss and olfaction loss were each associated with lower hippocampal volume and hearing loss was associated with alterations in functional brain connectivity in the default mode network.

Conclusion

These analyses indicate that sensory loss is highly frequent and co‐morbid in persons with or at risk for dementia. These findings have implications for cognition, brain function, functional activities, and care delivery for persons with or at risk for dementia.
Impact of Single Compared to Dual Sensory Loss in People with Dementia on Care Partner Outcomes
Authors: Alexopoulos Panagiotis , Hann Mark , Leroi Iracema
Published: December 2023

Background

Both hearing and vision loss impact significantly on outcomes in people with dementia as well as their care partners. The study aimed to compare the impact on care partner outcomes of hearing loss alone and dual sensory (both hearing and vision) loss in people with dementia

Methods

The study sample includes data from the SENSE‐Cog Trial (www.sense‐cog.eu). Care partner psychological distress was ascertained using the 12‐item General Health Questionnaire and the Hospital Anxiety and Depression Scale. Caregiving intensity was assessed using the care partner items of the RUD Lite. Dementia symptoms were assessed with the MOCA, the 12‐item Neuropsychiatric Inventory and the Bristol Activities of Daily Living scale. Vision loss was defined by the presence of binocular visual acuity of not more than 6/9.5 and greater than 6/60 in Snellen metric using the Portable Eye Examination Kit (PEEK) vision tool and visual field greater than 10° using confrontation visual field test. Hearing loss was defined by a bilateral hearing difficulty, indicated by failure of a pure tone hearing screening test in both ears. Statistical analyses included comparison between groups with different sensory losses (hearing‐ vs. dual loss) and regression analyses.

Results

Data of dyads of people with dementia and either hearing loss (N = 150) or dual sensory loss (N = 92) and their care partners (female 72.5%; male 27.5%) were considered. Participants had Alzheimer’s dementia (65%), vascular dementia (16%) or mixed dementia (19%), with mean MOCA score 16.6 (range 10 – 28). 73% of patients lived with partner or family and 24% alone. Higher caregiving intensity and higher psychological distress were observed in care partners of patients with dual sensory loss compared to care partners of people with hearing loss only after controlling for the impact of cognitive deficits, neuropsychiatric symptoms, performance on activities of daily living and demographic characteristics.

Conclusions

Dual sensory loss in people with dementia increases care partner distress and caregiving intensity compared to single hearing loss. Shedding light on sensory loss in dementia may pave new ways towards more effective symptom management and higher quality of life of both patients and their care partners.
Production of a PSEN1 genetically engineered marmoset model of early‐onset Alzheimer’s Disease
Authors: Park Jung Eun , Carter Gregory W , Silva Afonso C , Strick Peter L , Rizzo Stacey J Sukoff , Homanics Gregg E
Published: December 2023

Background

The lack of an adequate animal model of Alzheimer’s disease (AD) that mirrors the natural onset and progression of the human disorder has been a substantial barrier to basic and translational research into AD. Consequently, many fundamental questions remain about the key mechanisms that initiate the disease and the factors that promote its progression. While rodents are valuable AD models, nonhuman primates (NHPs) offer many advantages and have greater translational relevance. The common marmoset (Callithrix jacchus) is a small, prolific New World NHP that is amenable to genetic engineering and is rapidly becoming a valuable model organism, especially for neuroscience research.

Method

We used CRISPR/Cas9 technology to generate marmosets with C410Y or A426P point mutations in the PSEN1 gene. In humans, these mutations lead to familial early‐onset autosomal dominant Alzheimer’s Disease. Briefly, we designed, synthesized, and injected CRISPR/Cas9 reagents into single‐cell embryos that were subsequently transferred to synchronized recipient females. One adult C410Y founder animal was bred to a wild‐type mate.

Result

To date, we have produced seven live‐born marmosets harboring the PSEN1 C410Y (3 males, 1 female) or A426P (1 male, 2 females) mutations. One male founder animal, a compound heterozygote harboring C410Y and 1bp insertion PSEN1 alleles, has successfully sired three litters and transmitted the C410Y substitution (n = 6) and the 1bp insertion (n = 5) alleles to F1 offspring. We are currently characterizing the founders and F1 offspring using fluid‐based biomarkers, non‐invasive neuroimaging, and behavioral assessment to identify early markers of disease progression.

Conclusion

CRISPR/Cas9 gene editing was used to successfully establish a line of genetically engineered marmosets expected to model early‐onset AD. This nonhuman primate model will bridge the rodent‐to‐human translational gap and enable detailed studies of the early‐life molecular determinants of AD pathogenesis.
A Phase 2a proof‐of‐concept double‐blind, randomized, placebo‐controlled trial of nicotinamide in early Alzheimer’s disease
Authors: Grill Joshua D. , Tam Steven , Thai Gaby , Pierce Aimee , Green Kim N , Gillen Daniel L , Teng Edmond , Kremen Sarah , Beigi Maryam , Rissman Robert A , Leger Gabriel , Zhang Jing , Jin Shelia , Messer Karen , Feldman Howard H.
Published: December 2023

Background

Nicotinamide is a co‐enzyme involved in cellular oxidation‐reduction reactions that can act as an inhibitor of the class III histone deacetylases (HDACs), or sirtuins. HDAC inhibition may have myriad therapeutic pathways, including reducing phosphorylation of tau.

Method

We performed a randomized, placebo‐controlled, Phase 2a proof‐of‐concept trial to evaluate the safety and tolerability of nicotinamide, and its effects on change in cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 231 (p‐tau231) and other Alzheimer’s disease (AD) biomarkers and clinical measures in participants with early AD (Mild Cognitive Impairment or mild dementia) as confirmed by CSF biomarkers. We tested whether 1500 mg BID nicotinamide was superior to placebo in reducing CSF p‐tau231 (primary outcome), with secondary outcomes of p‐tau181, total tau, amyloid beta 40 (Ab40), Ab42, ADAS‐cog13, ADCS‐ADL‐MCI, and CDR‐SB.

Result

Arms were well balanced for demographic and clinical characteristics (Table 1). Of 47 participants enrolled, one dropped out prior to treatment initiation and six dropped before completion, 2 in the nicotinamide and 4 in the placebo arm. Nicotinamide was well‐tolerated; adverse events were largely balanced by study arm, with few attributed to treatment. There was no statistically significant benefit of nicotinamide on the primary outcome of change in CSF p‐tau231 (ANCOVA; estimated mean difference in change between arms = 2.06, std. error = 4.03; p = 0.61), although the observed mean decline in CSF p‐tau231 was greater in the nicotinamide arm (‐4.7±14.5) than in the placebo arm (‐2.3±10.6; Table 2). No significant effects of treatment were observed on secondary biomarker outcomes (CSF p‐tau181, Ab40, Ab42, and total tau) in similar models (all p‐values>0.05), although observed mean changes in CSF p‐tau181 (0.4±29.8 vs 10.4±41.8) and total tau (8.4±228.6 vs 60.5±237.5) favored nicotinamide compared to placebo. Nicotinamide was associated with significantly less change on CDR‐SB (MMRM; estimate = ‐1.42, std. error = 0.65; p = 0.03), but not on cognitive (ADAS‐cog; estimate = ‐1.93, std. error = 1.93; p = 0.32) or functional (ADCS‐ADL‐MCI; estimate = ‐3.10, std. error = 1.86; p = 0.10) assessments. No adjustments for multiple comparisons were performed.

Conclusion

These results may suggest that nicotinamide warrants further study as a treatment for early AD.
#FTDQuickQuestions: An FTD Disorders Registry (FTDDR) Monthly Engagement Survey to Gather Real‐time Insights to Inform Research
Authors: Harlass Sherry , Vincent Lakecia , Reddy Sweatha , Reinecker Robert , Dacks Penny A. , Wheaton Dianna K.H.
Published: December 2023

Background

Frontotemporal degeneration is a group of rare brain diseases that cause progressive changes to behavior, personality, language, and movement with onset typically before age 60. There are no treatments or cures. FTDDR is an international, web‐based registry (participants n>5,700) that facilitates clinical trial enrollment by collecting disease insights, summarizing data, and mobilizing potential research volunteers. FTDDR uses various data collection and engagement tools to interact with participants and the community at large. Quick Questions was concepted as a mechanism to gather real‐time, cross‐sectional, anonymous data from a broad response‐base not limited by Registry participation.

Method

#FTDQuickQuestions campaign incorporates social, email, and web to reach members and visitors to collect their data, strengthen existing relationships, connect with people who could benefit from Registry services, and inform research. Each month a pre‐approved question was posted to Facebook and Twitter, linking to a webform with polling options and collected for 2 weeks. Respondent’s location is indexed through IP address. Additionally, the question was emailed to FTDDR participants with brief highlights of the previous survey and a link to view results for it and prior surveys. Full summaries were posted as weblogs.

Result

The survey was launched in June 2022 with the question: Have you tried to get genetic testing for FTD over the last 3 years? Questions have related to FTD research participation, age of diagnosis, age first symptom appeared, where diagnosed person lived. At least one other demographic question is asked to characterize the respondent, including gender or relationship to FTD‐diagnosed person. Number of respondents for the first 7 questions ranged between 555‐857; monthly average 735. Except the initial survey, >75% of responses were received within 24 hours of email. Responses reflect 41 countries; including all 50 U.S. states and the District of Columbia; and 10 Canadian provinces/territories. Majority are women (62%); a third men (35%); 3% declined providing gender.

Conclusion

FTDDR’s #FTDQuickQuestions is a successful monthly engagement mechanism that enables quick, timely responses to questions about this disease and the people affected by it. While related questions cannot be compared nor connected, this valuable information serves as a cross‐sectional snapshot to inform FTD research.
Application of a digital ambulatory protocol to assess the associations of level and consistency of sleep with daily cognitive performance and cognitive variability
Authors: Derby Carol A. , Gao Qi , Katz Mindy J. , Ji Linying , Buxton Orfeu M. , Wang Cuiling
Published: December 2023

Background

Most prior work regarding sleep and cognition in older adults has not examined the relation of sleep health to daily cognitive performance measured in real world settings. Fewer studies have examined the extent to which both level and consistency of sleep are related to variability in daily cognitive performance. We applied daily ambulatory assessment methods to examine whether associations of objective and daily subjective measures of sleep quality and duration were related to mean and day‐to‐day variability in cognitive performance.

Method

Adults (N = 261) age ≥ 70 years (mean 77.2 ± 4.7) in the Einstein Aging Study sleep project wore an actigraphy watch and completed smart‐phone cognitive assessments over two weeks. All participants were free of dementia (47% Non‐Hispanic White, 40% Non‐Hispanic Black, 13% Other race/ethnicity; mean years education 15 ± 3.6; 67% female). Brief (4‐5 minute) cognitive tests were completed 6 times/day to assess processing speed (Symbol Match Test‐SMT), Visual short term memory binding (Color Shape Test‐CST) and spatial working memory (Grid Memory Test‐GMT). Wake after sleep onset (WASO), night sleep duration (hours), and daytime napping (minutes) were estimated. All measures were summarized as mean over the 2‐weeks and day‐to‐day variability (SD). Linear regression was used to examine associations of mean and variability of sleep with mean and variability (SD) of cognitive performance, adjusting for age, sex, race, and education.

Result

Both mean and SD of sleep were associated with mean cognitive performance: Higher mean and greater SD WASO were associated with worse mean SMT and CST (all p <0.04). Greater SD duration was associated with worse mean GMT (p = 0.003) and greater SD napping was associated with worse SMT (p = 0.04). Sleep was also associated with daily variability in cognition. Greater mean napping was associated with greater SD GMT (p = 0.009), while SD WASO, SD duration and SD napping were each associated with greater variability in GMT (all p <0.01).

Conclusion

Both level and consistency of optimal sleep health are related to both average levels of cognitive functioning and day‐to‐day variability in cognitive function. Consistency of sleep health may be particularly important for minimizing variability in spatial working memory.
The association of late‐life volunteering with cognitive function and cognitive decline in the KHANDLE and STAR cohorts
Authors: Lor Yi , Chanti‐Ketterl Marianne , Hokett Emily , Fletcher Evan , Zlatar Zvinka , Gilsanz Paola , Mayeda Elizabeth Rose , Glymour M. Maria , Barnes Lisa L. , Whitmer Rachel A.
Published: December 2023

Background

Prior studies have shown that volunteering in late life is associated with better physical health, social activity, and cognition, but the bulk of evidence is limited to non‐Latino White or Asian populations. The purpose of this analysis was to determine whether volunteering is associated with differences in domain‐specific cognition or cognitive change in a diverse cohort.

Method

Kaiser Healthy Aging and Diverse Life Experiences Study (KHANDLE) and Study of Healthy Aging in African Americans (STAR) are harmonized cohort studies of long‐term Kaiser Permanente members ages + and 50+ respectively, consisting of 48% Black, 20% White, 17% Asian, and 14% Latinx individuals. Participants self‐reported performing volunteer work for the 12 months prior to baseline for religious, educational, health‐related, or charity organizations. Executive function (EF) and verbal episodic memory (VEM) were measured across three waves using the Spanish and English Neuropsychological Assessment Scales (SENAS) and scores were z‐standardized to the baseline. Linear mixed‐models with random intercepts and slopes evaluated the association of volunteering with baseline cognition and cognitive change over 3 visits (mean follow‐up = 1.2 years) with years since baseline as the timescale and adjusting for baseline age, sex, education, income, practice effects, and interview mode (phone vs in‐person)

Result

Of the 2476 participants with average baseline age of 73.7 (SD = 8.2) years, 1167 (42.3%) had volunteered in the 12 months prior to baseline (Table 1). Those who volunteered had on average higher baseline EF (β = 0.184; CI = 0.110, 0.257) and VEM (β = 0.114; CI = 0.040, 0.189) compared to those who did not report volunteering (Table 2, Model 2). There were no statistically significant associations of volunteering and EF or VEM decline, though the direction of the associations suggested that those who volunteered had slower cognitive decline than those who did not volunteer.

Conclusion

In this diverse cohort, volunteering was associated with significantly higher baseline cognition, and suggested to be associated with less cognitive change over an average of 1.2 years, though not statistically significant. With additional follow up, we will examine whether volunteering is protective against cognitive impairment, and how physical and mental health may mediate this relationship.
Detection of mild cognitive impairment using digital assessments of cognition
Authors: Wang Cuiling , Gao Qi , Hall Charles B , Cerino Eric S. , Sliwinski Martin J. , Lipton Richard B. , Katz Mindy J. , Derby Carol A. , Garza Angel Garcia De La
Published: December 2023

Background

Conventional cognitive assessment typically provides a single measure of performance at a single point in time in a laboratory setting. Smartphone‐based ecological momentary assessments (EMA) facilitate short‐term intensive assessment of cognitive performance in people’s natural environments. Though heterogeneous variance in digital cognitive assessments has been observed between older adults with mild cognitive impairment (MCI) and cognitively unimpaired (CU), the independent contribution of intra‐individual variability in performance to detection of MCI is poorly characterized in diverse populations of older adults. We examine the ability of digital cognitive assessments of processing speed in discriminating MCI from CU in older adults from a racially/ethnically diverse community sample.

Method

Einstein Aging Study (EAS), smartphone‐based digital assessments of cognition, included the response time‐based symbol match test of processing speed. This was assessed 6 times per day over two weeks and was repeated annually. MCI was defined based on in‐house neuropsychological evaluations using Jak‐Bondi criteria. Statistical methods for modeling MCI using digital cognitive assessments include pattern‐mixture discriminant analysis based on heterogeneous linear mixed effects model for digital cognitive measures given MCI, joint modeling using shared random effects with random location scale for digital cognitive measures, and quadratic logistic regression models. All methods take into account the unbalanced adherence rate among individuals and control for covariates including age, sex, years of education, and race/ethnicity. Stratified analyses by race/ethnicity among non‐Hispanic (NH) Whites and Blacks were performed.

Result

Among 311 systematically recruited community‐dwelling non‐demented older adults from the EAS (Mean age = 77.5 years, SD = 4.8; 67.5% Female; 45.3% non‐Hispanic (NH) White, 40.8% NH‐Black), 97 (31.2%) individuals had MCI. Adherence to the EMA protocol was slightly better in individuals who were CU compared to those with MCI. Results from the quadratic logistic model (the easiest to apply) showed evidence of contribution from the quadratic terms that reflect heterogeneous intra‐individual variability in all samples and particularly among NH‐Blacks (p = 0.008).

Conclusion

We observe evidence that intra‐individual variability in processing speed improves the ability to discriminate cognitive impairment, particularly among NH‐Black older adults. Leveraging digital technology and performance variability across frequent assessments in the smartphone‐based EMA offers novel opportunities to identify cognitive impairment.