bluuebunny/crossref_metadata_2025 huggingface dataset:
Noninvasive and remote measurement of sleep‐active glymphatic function in the human brain by dynamic impedance spectro‐tomography
Authors: Iliff Jeffrey J , Levendovszky Swati Rane , Vanderweerd Carla , Jaffe Michael , Lowenkron Jeffrey , Singh Tarandeep , Giovangrandi Laurent , Lim Miranda , Dagum Paul
Published: December 2023

Background

Perivascular glymphatic exchange contributes to the clearance of amyloid β, tau, and α synuclein primarily during sleep. Glymphatic function has been assessed in human populations solely through neuroimaging, including contrast‐enhanced magnetic resonance imaging (CE‐MRI). Using a newly developed investigational medical device (IMD) to measure brain parenchymal resistance to fluid flow by dynamic impedance spectro‐tomography, we evaluated the performance of this putative measure of glymphatic function against “gold‐standard” CE‐MRI.

Method

Healthy 55‐65 y/o participants were enrolled in a cross‐over randomized control clinical trial encompassing one night of sleep/sleep deprivation followed by 4hr morning window of wake/sleep. Intravenous CE‐MRI was obtained prior to (T0) and following (T1) the 4hr window. Participants were instrumented with the IMD to measure continuous changes in brain parenchymal resistance (R). For the ROIs of interest, contrast enhancement (CE) was measured as the ratio of the T1/T0 MRI signal. The ratio CEp/CEd of anatomically proximal ROIs (CEp) to distal ROIs (CEd) was used to measure increasing (CEp/CEd ≤ 1) or decreasing (CEp/CEd > 1) net contrast movement. The predictive value of the R measured by the IMD, multiple EEG powerbands, and time spent in N2, N3 and REM sleep were tested against the CE‐MRI ROI ratios. Data from fourteen intervention periods were available for analysis.

Result

IMD parenchymal resistance R predicted IV CE‐MRI contrast movement through blood, cerebrospinal fluid, and interstitial brain compartments (Table 1, Figure 1). EEG slow power predicted contrast movement into more proximal ROIs only. Other powerbands and hypnogram sleep stages were not predictive of contrast movement.

Conclusion

EEG powerbands (increased slow, reduced beta) were weakly associated with increased glymphatic exchange measured by CE‐MRI. Parenchymal resistance R measured by the IMD were robust predictors of contrast movement from proximal (ventricles, subarachnoid) CSF compartments, through parenchymal compartments (gray matter, white matter). These findings begin to validate IMD‐derived parenchymal R as non‐imaging measure of glymphatic function. Detection of glymphatic impairment in real‐world settings may permit (i) early identification of individuals at‐risk for developing sleep‐related Alzheimer’s disease pathology, and (ii) enable precision targeted enhancement of glymphatic function to enhance glymphatic function and pathological protein clearance.
Tau “islands” affects axonal transport in vitro and in vivo
Authors: Moretto Edoardo , Panzi Chiara , Stuart Skye , Huff Emily , Rocque Samantha De La , Schiavo Giampietro
Published: December 2023

Background

Tau is a protein abundantly expressed in neurons where it modulates the stability of axonal microtubules, thus contributing to the regulation of axonal transport of several organelles. Tau aggregates in a group of neurodegenerative diseases named tauopathies, which include frontotemporal dementia (FTD) and Alzheimer’s disease. Recent in vitro work has uncovered the existence of tau “islands”, a microtubule‐bound multimeric state of tau, which is distinct from pathological aggregates. However, whether these structures exist in intact neurons remains unclear.

Method

We investigated both cultured mouse neurons and mice in vivo, using immunoistochemistry, live imaging and two photon microscopy.

Results

we found that human tau showed regions of higher density along axons, reminiscent of tau islands. FTD‐linked mutations, known to increase pathological phosphorylation and aggregation of tau, induces larger islands, an effect that is reversed by inhibition of p38 MAPK, known to phosphorylate tau at multiple sites. Functionally, axonal transport of BDNF‐containing secretory granules is affected by FTD‐linked mutant tau as assessed both in vitro and in vivo by using a new assay based on two‐photon microscopy. Interestingly, this impairment occurred very early on, before overt tau aggregation. Inhibition of p38 MAPK was able to partially rescue the defects in axonal transport both in vitro and in vivo.

Conclusion

Our data suggests that tau island size regulates axonal transport, an effect dependent on tau phosphorylation. Inefficient organelles transport may have severe consequences on the activity and plasticity of neuronal circuits. The evidence that reducing tau phosphorylation by inhibiting p38 MAPK potentiated axonal transport points towards inhibition of p38 MAPK as a promising therapeutic strategy in tauopathies.
Blood‐based biomarker profiles of community cohort of rural‐dwelling older adults
Authors: Miller Justin B , Wong Christina G. , Kinney Jefferson W , John Samantha E , Cummings Jeffrey L. , Caldwell Jessica ZK , Calvin Kirsten , Pasia Lorenzo G , Ritter Aaron
Published: December 2023

Background

Geography may influence Alzheimer’s disease risk, but there have been few prospective studies with biomarker characterization among rural‐dwelling individuals. We present preliminary biomarker data from the rural cohort followed by the Nevada Exploratory Alzheimer’s Disease Research Center, with comparisons to a harmonized urban cohort.

Method

Community‐dwelling adults over age 50 are enrolled and followed annually. Core assessments include medical exam, cognitive assessment, and blood‐based biomarkers of neurofilament light (NFL), phosphorylated tau (pTau181), and glial fibrillary acidic protein (GFAP) measured from plasma samples via the Quanterix Single Molecular Array (Simoa) HD‐X platform. Biomarker values exceeding 3 standard deviations from the combined sample mean were removed from analyses. Primary comparisons included ANCOVAs with main between‐group effects of cohort and cognitive status, accounting for both age and sex; interactions between cohort and impairment status were also explored. Correlations between biomarkers and cognitive screening (MoCA) were also assessed. Raw biomarker data were log transformed prior to analysis.

Result

NFL was associated with age (F(1,143) = 53.26, p<.001) main effects of impairment status were found (F(1,143) = 9.81, p<.001) but there was no association with sex or differences between urban and rural cohorts. The interaction between impairment status and cohort was significant, such that NFL concentrations were lower for cognitively normal rural‐dwellers, but higher among those with impairment (F(1,143) = 9.95, p<.01). GFAP was associated with age (F(1,136) = 31.05), p<.001) and sex (F(1,136) = 12.46), p<.001), but there were no main effects of cohort or impairment status, and there was no interaction. Tau was associated with age (F(1,153) = 11.08, p<.01) but not sex, and there were no main effects of cohort or impairment status, and no interaction was found. NFL was not correlated with cognition in the urban cohort (r = ‐.11), but was inversely correlated in the rural cohort (r = ‐.34). All other correlations were significant.

Conclusion

Rural‐dwelling older adults with cognitive impairment had higher concentrations of NFL compared to an urban cohort from the same region, though among cognitively unimpaired individuals, rural‐dwellers had lower concentrations of NFL. There were no rural‐urban differences in pTau or GFAP. Neurodegeneration may be a more sensitive indicator of cognitive impairment relative to other biomarkers, which may facilitate detection of geographic health disparities.
Association of periodontal condition with cognitive impairment and the mediating role of accelerated biological aging among US older adults
Authors: Qi Xiang , Wu Bei
Published: December 2023

Background

Increasing evidence has shown the associations between periodontitis and cognitive impairment or dementia; however, few studies have explored the role of accelerated biological aging that affects this association. Biological aging is the gradual and progressive decline in system integrity that occurs with advancing age. In this study, we examined the mediating effect of biological aging on the association between periodontal conditions and cognitive impairment in US older adults.

Method

We analyzed data from 2,186 participants aged 60 and older from the US National Health and Nutrition Examination Survey 2011‐2014. Data included sociodemographic, behavioral, and health‐related characteristics, periodontal status (measured by mean clinical attachment loss and pocket depth), blood‐chemistry measures of biological age (using KDM‐biological age and PhenoAge algorithms), and cognitive functioning (measured by Digit Symbol Substitution Test). We created an accelerated biological aging measure using residuals from regressing each blood‐chemistry measure on chronological age. The biological ages’ residual discrepancies with chronological age were defined as the biological age accelerations (BAA). Mediation analysis, weighted for complex survey design, assessed the effect of BAA on the association between periodontal conditions and cognitive functioning.

Result

After adjusting for covariates, participants with periodontitis exhibited greater KDM BAA (β [SE] = ‐0.40 [0.17]), PhenoAge BAA (β [SE] = ‐0.57 [0.21]), and lower level of cognitive function (β [SE] = ‐1.50 [0.33]) than those without periodontitis. Both KDM and PhenoAge BAA were significantly associated with lower cognitive functioning (β [SE] = ‐0.27 [0.10] and β [SE] = ‐0.29 [0.07]), mediating 11.0% and 9.7% of the total effects of periodontitis on cognitive functioning, respectively. Furthermore, KDM and PhenoAge BAA mediated 11.7% and 5.8% of the association between mean pocket depth and DSST, respectively.

Conclusion

Our findings suggest that periodontitis is partially associated with worse cognitive functioning through accelerating the biological aging process. Efforts to improve oral health or slow biological aging have the potential to help reserve cognitive health in later life.
The association between microstructural MRI biomarkers and sequential amyloid and tau‐related cortical changes in asymptomatic elderly individuals
Authors: Weston Philip SJ , Coath William , Brown Thomas M. , Scott Catherine J , Malone Ian B , Arstad Erik , Awais Ramla , Sander Kerstin , Thomas David L , Dickson John , Schöll Michael , Richards Marcus , Fox Nick C , Zhang Hui , Cash David M , Schott Jonathan M
Published: December 2023

Background

In Alzheimer’s disease, early amyloid‐β and tau deposition may have differential downstream effects on synaptic function and neuronal loss in a stage‐dependent manner. Amyloid‐related synaptic changes are thought to precede tau accumulation, which starts in the medial temporal lobe before propagating and leading to neurodegeneration. We explored whether microstructural MRI measures can detect these different sequential cortical changes.

Method

Seventy‐nine healthy, asymptomatic individuals, recruited from the Insight 46 study of the British 1946 birth cohort underwent combined PET/MR with [18F]florbetapir Aβ‐PET at ∼73yrs, and [18F]MK‐6240 tau‐PET at ∼76yrs. Standard uptake value ratios were calculated using a whole cerebellar reference for florbetapir and an inferior cerebellar reference for MK‐6240. Multi‐shell diffusion MRI was acquired; neurite orientation dispersion and density imaging was used to quantify neurite density (NDI) and orientation dispersion (ODI, a proxy measure of dendritic morphology/complexity), with DTI measuring mean diffusivity (MD), a less specific measure of degenerative change. PET and microstructural MRI biomarkers were assessed in a neocortical composite ROI and across Braak stages.

Result

Thirty‐six participants were amyloid positive, 18 of whom were tau positive (eight Braak stage 1‐2, four Braak 3‐4, six Braak 5‐6). Across all participants, in the neocortical composite, significant differences between amyloid positive and amyloid negative individuals were found in both tau PET (p = 0.0092) and ODI (p = 0.030) but not for other measures. Within the amyloid positive group, in the cortical composite, significant differences in MD (p = 0.0093) but not ODI were seen when comparing those who were tau positive and negative. In the amyloid positive group, there was an association between tau PET and MD in the MTL (Braak 1‐2) (r = 0.34, p = 0.040) and Braak 3‐4 (r = 0.37, p = 0.025), with an association between tau and ODI (r = 0.48, p = 0.0031) in Braak 3‐4 only. After adjusting for volume, only the association between tau PET and ODI in Braak 3‐4 remained (p = 0.038).

Conclusion

Our results are consistent with amyloid deposition causing dendritic/changes (as assessed by ODI) with consequent synaptic dysfunction. Later tau propogation is then associated with frank neuronal breakdown (as measured by MD). dMRI cortical imaging biomarkers have the potential to provide proxy measures of underlying AD stage/pathology prior to symptom onset.
Independent associations of plasma GFAP with amyloid‐β and tau in Alzheimer’s disease
Authors: Jia Wan Lu , Rahmouni Nesrine , Tissot Cécile , Servaes Stijn , Therriault Joseph , Macedo Arthur C. , Arias Jaime Fernandez , Wang Yi‐Ting , Lussier Firoza Z , Kunach Peter , Gauthier Serge , Zimmer Eduardo R , Karikari Thomas K , Benedet Andrea L. , Ashton Nicholas J. , Zetterberg Henrik , Pascoal Tharick A. , Blennow Kaj , Rosa‐Neto Pedro
Published: December 2023

Background

Glial fibrillary acidic protein (GFAP) is a reactive astrogliosis biomarker, shown to increase in individuals with preclinical Alzheimer’s disease (AD). First thought to be a great marker of amyloid‐β (Aβ) pathology, recent post‐mortem research has linked it to tau accumulation only. Here we investigate the independent associations of plasma GFAP with imaging markers of AD along the disease spectrum.

Method

126 individuals from TRIAD cohort underwent [18F]MK6240 tau‐PET and [18F]AZD4694 Aβ‐PET and plasma GFAP assessment using an in‐house assay. Voxel and region of interest regression models evaluated the relationship between PET tracers and plasma GFAP. Models with [18F]AZD4694‐PET as the outcome were adjusted for [18F]MK6240‐PET voxel‐wise and vice‐versa. All models were corrected for age and sex, and RFT was used to correct for multiple comparisons.

Result

Plasma GFAP was associated with [18F]AZD4694 signal throughout the cortex (Figure1A), independently of [18F]MK6240. Additionally, it was positively correlated with [18F]MK6240 in the medial temporal and occipital lobes and the anterior cingulate cortex, independently of [18F]AZD4694 (Figure1B). Voxel‐wise findings were confirmed by region‐of‐interest‐based analyses.

Conclusion

Our findings indicate that plasma GFAP is independently associated with both Aβ and tau pathologies in AD. Aβ‐PET showed associations throughout the entire cortex, suggesting its effectiveness as a reliable marker of Aβ pathology across the AD spectrum. On the other hand, tau‐PET correlations were observed in specific regions associated with memory and behavioral impairments that exhibit early deposition of tau. Overall, these results demonstrate that GFAP, an astrogliosis marker, is independently associated with Aβ and tau.
Dementia associated with early‐onset Parkinson’s disease: Description of a family case in Colombia
Authors: Lopez Greizy , Gelvez Nancy , Duran Clemencia , Garcia Deissy Milena , Reyes Pablo A , Matallana Diana
Published: December 2023

Background

Parkinson’s Disease (PD) is a motor neurodegenerative disorder of the dopaminergic neurons in the substantia nigra1. One of the frequent complications is dementia and often is a late symptom1,2. Some studies suggest that around 10% of patients with PD develop dementia per year2,3. Mutations in PLA2G6 are responsible of PARK14, an autosomal recessive L‐DOPA responsive dystonia/parkinsonism with early/adult onset4. This phenotype presents a high clinical variability, which consists in the occurrence of cerebral and cerebellar atrophy, iron accumulation in the basal ganglia, and cognitive decline4. In this study, we describe the genotype of two brothers diagnosed with early onset PD and a phenotype with FTD‐like characteristics.

Method

A complete clinical evaluation consisting of geriatric, psychyatric, neurologic and neurpsychologic evaluation, was carried out in two affected male individuals, and their family. NGS was performed (PD targeted panel, WES, WGS) and MLPA on the two affected individuals.

Result

The two affected individuals were diagnosed around their thirties, presenting classic motor symptoms of PD. Subsequently, dementia associated to frontotemporal disease was diagnosed. No iron accumulation in the basal ganglia was found in either of the affected siblings. Genetic tests showed the pathogenic variant in heterozygous state c.2132C>G, p.Pro711Arg in PLA2G6 gene in the two affected brothers and their healthy mother.

Conclusion

Atypical frontotemporal dementia in two siblings with early‐onset PD is described. Additional studies should be performed to identify another variant or another gene in this family. Some studies have risen the hypothesis that even heterozygous PLA2G6 mutations may cause PARK144.

References:

1. Hanagasi HA, Tufekcioglu Z, Emre M. Dementia in Parkinson’s disease. J Neurol Sci. Mar 15 2017;374:26‐31. https://doi.org/10.1016/j.jns.2017.01.012

2. Garcia‐Ptacek S, Kramberger MG. Parkinson Disease and Dementia. J Geriatr Psychiatry Neurol. Sep 2016;29(5):261‐70. https://doi.org/10.1177/0891988716654985

3. Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson’s disease. Brain Pathol. May 2010;20(3):633‐9. https://doi.org/10.1111/j.1750-3639.2009.00369.x

4. Ferese R, Scala S, Biagioni F, et al. Heterozygous PLA2G6 Mutation Leads to Iron Accumulation Within Basal Ganglia and Parkinson’s Disease. Front Neurol. 2018;9:536. https://doi.org/10.3389/fneur.2018.00536
Altered resting state hippocampal connectivity associated with amyloid and tau in older adults without dementia from a population‐based cohort study
Authors: Roberts Anna T , Andreescu Carmen , Cohen Annie , Villemagne Victor L , Lopresti Brian J. , Nadkarni Neelesh K. , Minhas Davneet S , Laymon Charles M , Snitz Beth E. , Karim Helmet T.
Published: December 2023

Background

Alzheimer’s disease (AD) is characterized by amyloid beta plaques and tau‐containing neurofibrillary tangles with disrupted (high and low) resting state hippocampal connectivity. One potential factor that may underlie these differences is that early stages of disease may contribute to greater connectivity and later stages may contribute to lower connectivity (i.e., quadratic associations between amyloid/tau and connectivity). Early stages may be associated with greater recruitment of intranetwork connectivity to compensate, which fails at later stages. Late stages may be associated with greater recruitment of internetwork connectivity, that fails in advanced cognitive impairment. Understanding these dynamics may help us understand resilience to amyloid and tau in cognitively unimpaired individuals.

Method

We recruited 115 adults >65 years old (67‐96, mean 76years) from a population‐based study into a neuroimaging sub‐study. The study area is a formerly heavy manufacturing industrial small‐town area. Participants (106 (92%) CU with CDR = 0) underwent PET imaging for amyloid (PiB) and tau (AV‐1451) and global SUVR measures were computed after appropriate preprocessing. Participants underwent resting state fMRI and hippocampal connectivity was computed for the left/right and anterior/posterior hippocampus. Regression analyses between connectivity and both linear and quadratic terms for amyloid and tau were adjusted for age, sex, race, and education. We adjusted for multiple comparisons using SnPM with FWE correction with α = 0.05 (p‐value threshold of 0.001).

Result

We found a negative quadratic association between left anterior hippocampus with default mode network (DMN) including the posterior cingulate and supramarginal gyrus, where greater amyloid and lower amyloid was associated with low connectivity. Similar effects were found for the right anterior hippocampus. Right anterior hippocampus to cuneus connectivity shows positive U‐shape with amyloid but negative linear relationship with tau. Greater right anterior hippocampus‐inferior parietal and right posterior hippocampus‐inferior temporal connectivity was associated with greater tau. Left posterior hippocampus to left middle temporal showed negative U‐shape with tau.

Conclusion

Amyloid and tau showed complex inverse U‐shaped associations between heightened intranetwork connectivity and moderate amyloid/tau, but low connectivity with higher severity. Internetwork connectivity was heightened with greater tau. These may reflect altered connectivity due to changes in amyloid and tau in older adults without dementia.
Hearing the Older Adults and Caregivers Voice in Medication Optimization Initiatives
Authors: Brandt Nicole J
Published: December 2023

Background

Engaging older adults, caregivers and family is necessary to produce relevant and meaningful evidence. Patient‐centered‐outcomes research (PCOR) engages these individuals as research partners. For instance, the process of shared decision‐making about deprescribing (reducing or stopping potentially inappropriate medications) between people living with dementia and their carers (consumers), and clinicians, is complex.

Method

Various tactics were employed by the Elder Care Medicine Network (ECMN) and stakeholder steering groups from USA and Australia. These initiatives describes efforts to increase capacity of local communities – older adults, their caregivers, healthcare providers and researchers – to participate in medication related PCOR as well as the development of a tool (PRIME) to help with deprescribing medications for individuals with dementia.

Result

There are over 120 active participants in the ECMN. After they shared their PCOR training needs, trainings were held as Discussion sessions where Council members and network participants shared their medication experiences and talked about participating on a PCOR research team. Network participants also identified what they felt were meaningful research questions on medication‐related PCOR (video). Additionally the PRIME tool was developed via an iterative process utilizing one‐to‐one semi‐structured interviews and a focus group session with 39 participants (people living with dementia, carers, and clinicians) to determine the usability and comprehensibility of the PRIME tool. Iterative changes were made to improve the content and layout of the tool.

Conclusion

These two initiatives illustrate the importance of co‐design and incorporating the older adults and caregivers voice in medication optimization efforts in individuals with dementia.
Sex‐specific Patterns in Dementia Incidence among older Asian and Pacific Islander Adults
Authors: Lo Joan C , Chandra Malini , Lee David R , Lee Catherine , Gilsanz Paola
Published: December 2023

Background

Dementia risk is lower for US Asian adults in aggregate compared to non‐Hispanic White (NHW) adults. However, examining Asian adults in aggregate masks subgroup heterogeneity as previously reported, including higher risk and slightly higher risk among 6210 Filipino and 4478 Japanese adults, respectively, and non‐significantly lower risk among 197 South Asian adults compared to 8384 Chinese adults (Mayeda, et al. PMID 28406845). We build on this prior work by examining sex‐specific dementia incidence in an expanded contemporary cohort of US Asian/Pacific Islander (PI) and NHW adults in the same integrated healthcare delivery system.

Methods

Among 479,250 NHW adults and 34,222 Chinese, 34,637 Filipino, 9,355 Japanese, 6,246 South Asian, 3,913 Vietnamese, 2,779 Korean, 2,343 Native Hawaiian/PI (NHPI), and 14,967 other/ethnicity‐unspecified Asian/PI members of a northern California health plan aged ≥65 years in 2010‐2019 (with five years prior membership and without prior dementia), incident dementia up to 2022 was identified by hospital, institutional stay, ambulatory (or virtual care) encounter diagnoses. Race and ethnicity were obtained from self‐reported data sources. Dementia incident rate ratios (IRR) were examined using log‐Poisson regression, adjusting for 5‐year age group and calendar year.

Results

Among 479,250 (54.9% female) NHW and 108,462 (54.4% female) Asian/PI adults, mean age at entry was 70.4±7.1 and 69.3±6.1 years and mean follow‐up 7.6±4.0 and 7.4±3.9 years, respectively. Overall, 12.0% of NHW and 8.7% of Asian/PI adults developed incident dementia. Among men, dementia IRRs (reference: NHW) were significantly lower for Asian men in all subgroups but higher for NHPI men (Figure 1). Among women, dementia IRRs were significantly lower for Chinese and Japanese women, but not Filipina, Vietnamese, Korean, South Asian, and NHPI women (Figure 2). NHPI, Filipino and Japanese men and NHPI, Filipina, South Asian, Vietnamese, and Korean women had significantly higher incidence of dementia than Chinese counterparts (Table).

Conclusion

This study further characterizes the heterogeneity in dementia diagnosis incidence among Asian/PI subgroups, including sex‐specific differences. Further research is needed to identify environmental, social, clinical, and genetic factors that may explain the observed heterogeneity in dementia risk among Asian/PI ethnicities, which could inform interventions aimed to improve healthy brain aging for everyone.
Covid‐19 may have a detrimental impact on sensorimotor function
Authors: Goss Monica , Bernal Rebecca , Patel Vibhuti N , Li Karl , Garbarino Valentina R. , Nair Rejani R , Snyder Heather M , de Erausquin Gabriel A. , Ganguli Mary , Snitz Beth E. , Girard Timothy D. , Jacobs Heidi I.L. , Hosseini Akram A. , Ibrahim Tamer , Vahidy Farhaan S , Satizabal Claudia L. , Himali Jayandra Jung , Seshadri Sudha
Published: December 2023

Background

The long‐term impact of COVID‐19 on global health is still unknown. Sensorimotor biomarkers may be promising indicators of lasting effects of COVID‐19. Although normal aging may cause changes in sensorimotor function, more severe changes may indicate the subsequent impacts of COVID‐19 on brain health. The objective of this study was to investigate the association between COVID‐19 and sensorimotor markers (grip strength, gait, and smell) in the 7T neuroCOVID consortium, which is comprised of 5 sites: The University of Texas Health Science Center at San Antonio, Houston Methodist Research Institute, The University of Pittsburgh, Massachusetts General Hospital, and Nottingham University (UK).

Methods

We studied 101 adult participants (mean age 60.9 ± 8.5 years, range 45‐80 years, 51% women) without prior cognitive impairment or cerebrovascular disease from the 7T consortium across 3 US and 1 UK sites. The sample included 77 COVID‐19 survivors and 24 healthy controls. Sensorimotor markers were measured for olfaction (n = 59; 12‐item Brief Smell Identification Test (B‐SIT)), grip strength (n = 97; measured using a hand dynamometer), and Gait (n = 101; 4‐meter normal walk time and n = 99; 4‐meter fast‐paced walk time). To assess the association between COVID‐19 and sensorimotor outcomes, we performed a series of linear regression models adjusting for age, sex, site, and handedness (grip strength only). Statistical significance was set at a 5% level.

Results

As compared to healthy controls, COVID‐19 survivors, on average had a significantly reduced hand grip in the right hand (β ± standard error: ‐0.18 ± 0.07, p = 0.006). We also observed associations with reduced gait speed. COVID‐19 survivors, on average, had a slower walk time in both normal (0.17 ± 0.06, p = 0.004) and fast‐paced (0.04 ± 0.02, p = 0.022) as compared to healthy controls. We did not observe any statistical associations between COVID‐19 survivors and left‐hand grip strength or B‐SIT.

Conclusions

These results highlight that Covid‐19 infection may have a detrimental impact on sensorimotor function. Additional analysis with a larger sample size are ongoing, which will allow us to further assess the effect of infection severity. Future studies will look to evaluate the association between sensorimotor markers, cognition, and ultra‐high field 7T MRI‐based imaging markers.

Funding:

R56AG074467

P30AG066546
Motor alterations associated with cognitive impairment in a third‐level hospital
Authors: Ruiz‐Castillo Karla Paulina , Silva Itzel Alejandra Hernandez , Cuautle Karina Arellano , Chable Adiel Eleazar Dzul , Reyes Brandon Alexis Reyes
Published: December 2023

Background

Cognition and motor function declines have been shown to precede cognitive impairments, and motor changes have been proposed as potential clinical biomarkers to help predict dementia syndromes; there are reports that gait speed declined a decade before the diagnosis of MCI and preceded declines in cognitive function tests. The slow gait speed associated with cognitive complaint, motor cognitive risk syndrome is a clinical biomarker for high risk of neurologic degeneration.

Method

This report is a secondary analysis from a transversal study, the inclusion criteria include adults from 60 or older, who complete evaluations at the baseline in a from a dementia clinic at a tertiary care center in Mexico. Gait performance were evaluated in all the participants which had to walk 10 meter distance and timed, slow gait were considered as those more than 1 meter/second. Variables such as sex, age, education, marital status, occupation, depression, anxiety, frailty, cognitive impairments and geriatric syndromes were considered for the analysis. The outcome was the description of the characteristics of gait disturbance in the follow‐up evaluation and their relationships with the variables discussed.

Result

Finally, 222 patients were studied, highlighting a prevalence of 73% (n = 158) being female and 28% (n = 64) being male. A total of 72% (n = 160) of patients presented a speed <1m/s and 28% (n = 62) with a speed >1m/s. Polypharmacy, intestinal habit disorder, sensory deprivation, and housewife occupation were associated with a decrease in gait speed. The group with mild cognitive impairment, 32% (n = 72), predominantly had a gait speed of less than 1 m/s. Regarding functionality, we found that the moderate dependence group, 31% (n = 71), and pre‐frail patients, 32% (n = 72), had a greater association with a decrease in gait speed. A significant association was found between MMSE and gait speed (p = 0.003).

Conclusion

It was found that female patients have a prevalence of slow walking speed <1m/sec. In addition, patients with mild cognitive impairment have a higher prevalence, which suggests that walking speed may be a prodromal sign for mild cognitive impairment. Only was significative sex, polypharmacy, and fraility.
Neuropsychiatric symptoms and caregiver’s burden in Colombian relatives of people with dementia
Authors: Buitrago Carlos Felipe , Garcia Deissy Milena , Botero Felipe , Giraldo Claudia Irene , Moreno Maria Jose , Forero Laura Valentina , Triviño Cristian , Reyes Pablo A , Matallana Diana
Published: December 2023

Background

Neuropsychiatric symptoms are part of the psychopathological dimension of dementias. From a psychosocial approach, the direct and indirect costs of the disease increase, generating a greater demand to the caregiver. We aim to show the relationship between neuropsychiatric symptoms and the caregiver’s burden in a group of 100 caregivers of patients with a dementia diagnosis.

Method

Sample of 51 caregivers of patients with Alzheimer’s disease and 49 with Fronto‐Temporal Dementia (FTD). Caregivers were patient’s relatives, mean age 58 y.o. and most of them had a college degree. To patients, we applied The Clinical Dementia Rating (CDR), The Neuropsychiatric Inventory (NPI) and a sociodemographic questionnaire. Additionally, we implemented the Zarit caregiver burden test to the caregivers.

Result

Categorized three groups of caregivers: without burden (n = 42), mild burden (n = 25), and severe burden (n = 33). There were not statistical differences between caregiver’s age (p = .067), schooling (p = .429), nor how long they were caring for the patient (p = .057). Nonetheless, there’s higher burden scores when they have more economic difficulties (p<.05), more psychosomatic symptoms (p<.05), even when implementing strategies to handle stress (p<.05). Also, the burden is present the more neuropsychiatric symptoms the patients have (p<.05). Age (Beta = .021; p = .934) is not associated with burden level, however, scholarship (Beta = ‐.679; p<.05) and neuropsychiatric symptoms (Beta = 1.141; p<.001) are significantly associated.

Conclusion

Sociodemographic caregiver’s characteristics and the symptom’s severity of the patients may establish a risk profile for caregivers. The study shows the importance of the development of support programs for caregivers.

Shin, I. S., Carter, M., Masterman, D., Fairbanks, L., & Cummings, J. L. (2005). Neuropsychiatric symptoms and quality of life in Alzheimer disease. The American journal of geriatric psychiatry, 13(6), 469‐474.

Hiu, S. K. W., Bigirumurame, T., Kunonga, P., Bryant, A., & Pillai, M. (2022). Neuropsychiatric Inventory domains cluster into neuropsychiatric syndromes in Alzheimer’s disease: A systematic review and meta‐analysis. Brain and Behavior, 12(9), e2734.

Monfort, J. C., Lezy, A. M., Papin, A., & Du Montcel, S. T. (2020). Psychogeriatric Inventory of Disconcerting Symptoms and Syndromes (PGI‐DSS): validity and reliability of a new brief scale compared to the Neuropsychiatric Inventory for Nursing Homes (NPI‐NH). International psychogeriatrics, 32(9), 1085‐1095.
Brain transcriptomic and proteomic analyses in an in vivo AD model further elucidate the role of the sigma‐2 receptor modulator CT1812 in Alzheimer’s disease
Authors: Caro Valentina Di , Cho Eunah , Caldwell Jill , Pandey Kiran , Duong Duc M. , Seyfried Nicholas T , Caggiano Anthony O , Hamby Mary E
Published: December 2023

Background

CT1812 is a first in class small molecule sigma‐2 receptor (S2R) modulator, currently in Phase II clinical trials for Alzheimer’s disease (AD), that selectively displaces Aβ oligomers from synapses. CT1812 prevents synaptotoxicity and restores cognitive performance in a transgenic mouse model of AD. To better understand and identify the biological process that S2R modulator can impact, we performed transcriptomic and proteomic analysis in brain from an in vivo mouse model of AD treated with our leading investigational therapeutic CT1812.

Method

Non‐transgenic or transgenic AD (hAPPsl) mice were dosed with vehicle and/or CT1812 (10 mg/kg, given orally, once daily) for 7 days. Animals were sacrificed 24 hr after last dose, and brain collected. Unbiased RNA‐Sequencing and tandem‐mass tag mass spectrometry (TMT‐MS) proteomic measurements and analyses were performed of mouse hippocampus (N = 10 per group) to evaluate differential expression between transgenic and non‐transgenic mice, and to assess effect of CT1812 compared to vehicle. STRING and MetaCore pathway analyses were performed on both RNA‐Seq and proteomics analysis using gene lists of P ≤ 0.05.

Result

For the first‐time the hAPPsl mouse model has been characterized at both transcriptomic and proteomic level, and data indicate that specific aspects of AD are recapitulated in this model, e.g. APP is the most upregulated protein (p<0.05). In the brain, treatment with CT1812 altered the expression level of protein and mRNA (219 proteins and 2,031 mRNA transcripts were changed (p ≤ 0.05)). Pathway analysis by STRING and MetaCore (p<0.05) indicated a role of CT1812 in altering key pathways including membrane trafficking, autophagy, inflammation, cytoskeleton remodeling and WNT/β‐catenin signaling. Comparative analysis of the differentially expressed proteins between the proteomic and RNA‐Seq highlights 36 proteins that may be regulated transcriptionally, including Rab8b, Lamtor3, and Opa1, all which are associated with AD phenotype.

Conclusion

Our RNA‐Seq and proteomic analysis data have demonstrated that S2R modulators can impact the neuron function at a molecular level. These new findings help elucidate the molecular mechanism of action CT1812 in Alzheimer’s disease.
7 Tesla Brain MRI: A Paradigm Shifting Technology for Clinical Research in Aging and Dementia Science
Authors: Ibrahim Tamer , Santini Tales , Farhat Nadim , Alkateeb Salem , Sajewski Andrea , Diniz Eduardo , Berardinelli Jacob , Li Jinghang , Jin Hecheng , Chu Robin , Liou Jr‐Jiun , de Almeida Bruno , DeFranco Anthony , Salmon William , Berardo Jeremy
Published: December 2023

Background

As the usage of MRI for biomedical research increases, an ongoing goal for extending the usefulness of MRIs has been the increase of the magnet’s field strength to 3T, 7T, and beyond. The 7T field strength has recently been given FDA‐approval for clinical use, due to recognition of its safety and ability to characterize “smaller structures and subtle pathologies” 1 when compared to 3T (Fig. 1.)

Technological developments at the 7 Tesla Bioengineering Research Program (7TBRP) at University of Pittsburgh is currently enabling neuroimaging translational research for 35 active 7T‐based NIH research projects with projected ∼ 7000 7T scan sessions that focus on studying aging, AD, COVID‐19 among several other neurodegenerative diseases.

Methods

We have developed a new (Fig. 2 and 3) device (Version 2 of Tic Tac Toe radiofrequency (RF) coil system) composed of 60 transmit channels – first of a kind ‐ and 32 receive channels. The coil has been deployed to Pittsburgh’s Imaging Community and is currently being used in a wide variety of NIH‐funded studies.

Results

Compared to other commercially available coils, this new RF coil system provides more homogeneous excitation, signal/contrast to noise ratio, and extended coverage of hard‐to‐reach regions at 7T (brain stem/temporal lobes/cerebellum.) Furthermore, the new RF coil system is also an anti‐claustrophobia solution at 7T as it provides a face opening in the front of the head resulting in more comfortable breathing, less claustrophobia, and a better overall 7T MRI experience for the participants.

Conclusion

Among several other neurodegenerative diseases, advances in 7T MRI technology have allowed us to explore the common biology underlying aging, Alzheimer disease as well as the neurological sequelae following infection with SARS‐CoV‐2 (from imaging data harmonized across 3 different 7T sites)

Funding: R56AG074467, R01MH111265 and R01AG063525

1. https://www.fda.gov/news-events/press-announcements/fda-clears-first-7t-magnetic-resonance-imaging-device
Longitudinal analysis of qEEG in subjects with autosomal dominant Alzheimer’s disease due to PSEN1‐E280A variant
Authors: Aguillon David , Guerrero Alejandro , Vasquez Daniel , Cadavid Valeria , Henao Veronica , Suarez Ximena , Jaramillo‐Jimenez Alberto , Márquez Isabel C , Lopera Francisco , Pineda David , Quintero Carlos Andrés Andrés Tobón , Ochoa John F
Published: December 2023

Background

Alzheimer’s disease (AD) is the leading cause of dementia in the world. Synaptic dysfunction is a pathophysiological event that alters neuronal connections at multiple scales: molecular, cellular, brain networks, cerebral cortex, among others. There are different mechanisms that interact to trigger alterations in the homeostasis of synaptic function, among them the most prominent are amyloidosis, tauopathy and inflammation. EEG has been used in recent years as a cost‐effective, portable, and noninvasive alternative for the study of biomarkers in Alzheimer’s disease.

Method

All participants were members of families with PSEN1‐E280A genetic variant and healthy controls recruited voluntarily. A longitudinal follow‐up was planned, this study collects data from the initial visit and in the first year of follow‐up. At each visit, neurological and neuropsychological evaluation and electroencephalogram were performed. We analyzed the resting state EEG spectral power bands and the Alpha/Theta reactivity index.

Result

Alpha1 and Alpha2 frequency bands did not have significant changes in the follow‐up year, in the Beta3 frequency band in component 20 and Beta2 in component 22 statistically significant differences were found. However, the distribution of the data in the shift graphs for the Beta frequency band presents some slopes, which indicates a modest effect sizes and low precision.

Conclusion

The Beta frequency band is a potential neurophysiological marker that in preclinical stages of ADAD show statistically significant differences between asymptomatic carriers and non‐ carriers. This signal is related to components whose origin is estimated in posterior regions, which highlights the importance of previous findings in the precuneus. However, the effect sizes were modest and with low precision. It would recommend larger samples and longer following in future research.
Astrocyte calcium dysregulation and cerebrovascular impairments in the 5XFAD mouse model of familial Alzheimer’s disease
Authors: Weiss Blaine E. , Gant John C , Sompol Pradoldej , Thibault Olivier , Kraner Susan D. , Norris Christopher M.
Published: December 2023

Background

Amyloid deposits (Aβ) in the brain are a primary diagnostic marker of Alzheimer’s disease, and are associated with the degeneration of synapses and cognitive decline. However, recent advances in cell specific approaches have revealed that glial processes may also contribute to the progression of disease pathology. Astrocytes are a glial cell in the brain responsible for a plethora of essential functions in the brain, such as the removal of synaptic glutamate, and control over cerebrovascular function. Astrocyte Ca2+ signaling is closely coupled to these functions. These pathways are dysregulated with disease onset, and contribute to astrocyte reactivity. Our group showed previously in a diet model of VCID, that changes in astrocyte calcium signaling and network synchronicity were associated with deficits in cerebrovascular function. Here we examined the spatial and temporal relationship of astrocyte Ca2+ signals to neurovascular coupling in 5XFAD mice to determine the relationship between reactive astrocytes and cerebrovascular function.

Method

5XFAD and littermate controls aged to 6 months were injected with AAV2/5‐Gfa104‐jGCaMP8f into barrel cortex before cranial window installation. At 7 months, mice were briefly anaesthetized before retroorbital injection of 500kb rhodamine dextran. Mice were then imaged awake under a two‐photon microscope for functional hyperemia measures in response to timed air puff whisker stimulation. Spontaneous and evoked Ca2+ transients were measured by ∆F/F calculation of Ca2+ peaks extracted by custom MATLAB algorithms. Analysis of astrocyte endfoot Ca2+ was measured along vessels stimulated for neurovascular coupling to relate vasoactivity to Ca2+ signaling kinetics and intensity.

Result

5XFAD mice showed a significant reduction is astrocyte Ca2+ rise time kinetics compared to wild type controls, as well as parameters of functional hyperemia. Timing of neurovascular coupling in response to stimulation and the latency of astrocyte calcium kinetics was characterized for the 5XFAD model and shown to differ between soma and endfoot processes.

Conclusion

Amyloid induced pathology induces changes in astrocyte Ca2+ signaling. Dysregulation of astrocyte signaling may have a mechanistic role in the kinetics of neurovascular coupling and/or cerebrovascular dysfunction with disease progression. However, further analysis of astrocyte endfoot coverage and manipulation of astrocyte signaling during functional hyperemia is needed to further clarify mechanism.
Mental health in Colombian dementia patients: the impact of COVID‐19
Authors: Garcia Deissy Milena , Buitrago Carlos Felipe , Moreno Maria Jose , Forero Laura Valentina , Triviño Cristian , Reyes Pablo A , Matallana Diana
Published: December 2023

Background

The COVID‐19 pandemic related to the new coronavirus SARS‐CoV‐2 has generated new challenges in healthcare systems worldwide. In Colombia, different measures were adopted, such as preventive isolation, to reduce the number of infections considering its high transmissibility. However, this led to changes in the mental health of older individuals affected both by this confinement situation and by the consequences of the disease in this population group.

Method

The objective is to determine if there are cognitive changes associated with the disease and confinement due to the new coronavirus infection in a sample of 70 individuals with dementia. To achieve this, an analysis of one of the COVID‐19 questionnaires proposed in the RedLat project is performed, in which relatives and patients report their perception of changes in their mental health. The impact of the confinement situation and the disease itself is analyzed.

Result

In general, a significant change is found in the cognitive, affective, and social sphere of each individual with dementia.

Conclusion

These findings are relevant as they allow for the proposal of alternative rehabilitation strategies following COVID‐19 and the generation of other mental health promotion programs in older individuals with cognitive impairment.

References:

Bombón‐Albán, P. E., & Suárez‐Salazar, J. V. (2022). Manifestaciones cognitivas y neuropsiquiátricas de COVID‐19 en el Adulto Mayor con y sin demencia: Revisión de la literatura. Revista de Neuro‐Psiquiatria, 85(2), 117‐126.

Parra, M. A., Baez, S., Sedeño, L., Gonzalez Campo, C., Santamaría‐García, H., Aprahamian, I., … & Ibanez, A. (2021). Dementia in Latin America: paving the way toward a regional action plan. Alzheimer’s & Dementia, 17(2), 295‐313.

Duran‐Aniotz, C., Sanhueza, J., Grinberg, L. T., Slachevsky, A., Valcour, V., Robertson, I., … & Ibáñez, A. (2022). The Latin American Brain Health Institute, a regional initiative to reduce the scale and impact of dementia. Russo, M. J., Cohen, G., Campos, J., & Allegri, R. F. (2021). COVID‐19 y adultos mayores con deterioro cognitivo:¿ puede influir el aislamiento social en la enfermedad?. Neurología Argentina, 13(3), 159‐169.