bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced neuronal activity in Alzheimer’s disease and mild cognitive impairment measured by resting state fMRI
Authors: Haddad Seyyed Mohammad Hassan , Scott Christopher J.M. , Arnott Stephen R. , Ozzoude Miracle , Strother Stephen C. , Black Sandra E. , Borrie Michael , Finger Elizabeth , Tartaglia Maria Carmela , Kwan Donna , Beaton Derek , Symons Sean , Soddu Andrea , Menon Ravi S. , Montero‐Odasso Manuel , Bartha Robert
Published: December 2020

Background

Early pathological changes in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) gradually decrease neuronal metabolism and function measured by PET and functional MRI (fMRI). These changes are often associated with cognitive decline and can help in the diagnosis of AD. However more sensitive indicators of the earliest stages of disease must be developed to detect disease prior to cognitive impairment. Recently, a novel neuronal activity (NA) metric was introduced based on resting‐state fMRI (rs‐fMRI) signal oscillations, which showed dramatically lower NA in AD. Here we introduced a more sophisticated and potentially more sensitive NA metric to identify subtle NA differences between three groups: normal elderly controls (NEC), MCI, and AD.

Method

The rs‐fMRI scans (TR=∼2400, ∼10 minute acquisition) were acquired at 3T from 8 MRI scanners in the Ontario Neurodegenerative Disease Research Initiative (AD group, N=40, aged 71.8 ± 8.1, 42% female; and MCI groups, N=80, aged 70.3 ± 8.3, 46% female), and the Gait and Brain Study (NEC group, N=30, aged 71.3 ± 6.0, 23.33% female). The rs‐fMRI signal was pre‐processed using FMRIB Software Library (FSL) and decomposed into independent components (ICs) using IC analysis. The ICs were classified into neuronal and non‐neuronal using a support vector machine classifier. The proposed voxel‐wise NA metric was defined based on similarity (cross covariance) between rs‐fMRI signal and neuronal ICs. This metric was utilized to create resting‐state NA map in each subject, which were compared between groups.

Result

Single subject and group average NA maps are provided in Fig. 1. The % difference maps between each group are shown in Fig. 2. The average voxelwise % difference in NA between groups was 38% between NEC and MCI, 38% between NEC and AD, and 10% between MCI and AD. Average NA in whole gray matter, hippocampus, posterior cingulate cortex, and precuneus, in each group are also provided in Fig. 3.

Conclusion

Lower NA was clearly detected in AD and MCI groups compared to NEC. The large decrease in NA detected in MCI subjects compared to NEC suggests this metric is highly sensitive to early changes in neuronal function.
Education and its effect on risk and age at onset in Alzheimer disease (AD) in African Americans
Authors: Adams Larry D. , Slifer Susan H. , Ramos Jairo , Inciute Jovita D. , Starks Takiyah D. , Scott Aja M. , Lacroix Faina C. , Laux Renee A. , Haines Jonathan L. , Vance Jeffery M. , Cuccaro Michael L. , Byrd Goldie S. , Beecham Gary W. , Pericak‐Vance Margaret A.
Published: December 2020

Background

Increased years of education have been previously associated with a decreased risk of developing Alzheimer disease (AD) with cognitive reserve suggested as the source of the protective effect in Non‐Hispanic Whites (NHW). African Americans (AA) are twice as likely to develop AD compared to NHW. We investigated the hypothesis that education was similarly correlated with risk of AD in the AA population. We also examined the relationship of education and age at onset (AAO) of AD in AA.

Method

Participants consisted of 132 AA AD cases and 428 AA cognitively intact (CI) individuals with known years of completed education, ascertained for a genetics study of AD. Education levels were stratified into three categories: <8 years, 9‐12 years, >12 years. We used logistic regression to determine the effect of age, sex, education level and APOE4 status between cases versus controls. Additionally, using a linear model we examined the effect of education on AAO including sex and APOE4 status as covariates.

Result

Results showed that increasing years of education had a protective effect on AD risk. Initially including sex and age as covariates, both higher education categories were significant, with 9‐12 years (p = 0.02;OR = 0.461[0.23,0.9])) and >12 years (p = 1.30e0‐04;OR = 0.26[0.13,0.41]). Adding APOE4 dosage (0(Ref), 1,2 alleles) to the model (significant at p = 9.54e‐05; p = 5.27e‐07), the effect of education remained significant (p = 0.03;OR = 0.46[0.23,0.93]) and p = 4.84e‐05;OR = 0.22[0.10,0.46]) for 9‐12 and >12, respectively further supporting its role in AD risk. We examined the effect of education on AAO. Education (8‐12 years) trended in significance (p‐value = 0.07; β = ‐3.76[‐7.82,0.307]) with >12 years significant (p‐value = 1.63e‐04; β = ‐13.07,‐4.25]) supporting later AAO with higher education. The effect of APOE4 on AAO was not significant (p = 0.226). APOE4 added to the model as a covariate did not have a significant effect on AAO, however, education levels continued trending (8‐12; p = 0.07; β = ‐3.76[‐7.86,0.34]) and significant (>12; p = 3.71e‐04; β = ‐8.33[‐12.84,‐3.82]).

Conclusion

These data support the hypothesis that higher education results in a decreased risk of AD in AA regardless of APOE4 status. We also found a similar protective effect for a later AAO. Thus, the potential outcome of education on cognitive reserve appears across multiple racial backgrounds.
Development of a platform for the discovery of new Alzheimer’s disease drugs targeting stress‐induced neuroinflammation
Authors: Sebastian Maria , Pasinetti Giulio Maria Maria
Published: December 2020

Background

Sterile inflammation plays a detrimental role in neurodegenerative disorders, having an extraordinary impact on Alzheimer’s disease (AD). Stress signals, such as the alarmin high mobility‐group box‐1 (HMGB‐1), trigger activation of inflammasome complexes —as NLRP3 or NLRC4— and the subsequent oligomerization of the associated speck‐like protein containing‐CARD (ASC), which is critical for stress‐induced depressive behavior and promotes AD phenotypes. Indeed, ASC specks promote Aβ aggregation, presenting both intracellular and extracellular prionoid activities.

Method

We developed a platform for the discovery of new anti‐inflammasome drugs. We modeled the target and performed a chemical library. We validated in‐vitro, using murine primary microglial cultures, the ability of the hits from the screening to inhibit NLRP3 and NLRC4‐mediated IL‐1β production. We further characterized the most potent inhibitors, studying their ability to inhibit processes downstream of inflammasome activation. Thus, we evaluated whether our compounds inhibit ASC oligomerization using fluorescently tagged‐ASC murine macrophages, and we determined their anti‐pyroptotic effect. Finally, we analyzed the ability of a lead compound to reduce neuroinflammation in the brain of LPS injected mice.

Result

We built a 3D homology model for NLRP3 that provides an accurate description of the active site. Through computational screening, we identified 100 hits. The 20% of the hits inhibited NLRP3 in‐vitro, and six among them reduced the activity of the inflammasome below 80%. The three most potent compounds presented IC50 values, for NLRP3‐mediated IL‐1β secretion, in the low micromolar range (9.24, 8.26, and 3.5 μM). Among them, we selected the third one, C77, to characterize it further. C77 inhibited NLRP3 at the protein level, being its IC50 for the ATPase activity 40 nM. Interestingly, C77 inhibited NLRC4 with similar potency, as well as processes downstream of both inflammasomes. Noticeable, C77 inhibited ASC specks formation in response to the stress alarmin HMGB1, at concentrations as low as 10 nM. Finally, C77 also reduced IL‐1β in the brain of mice LPS‐injected.

Conclusion

We developed a platform to identify and characterize new AD drugs, targeting neuroinflammation, and using this methodology to identify a lead compound. Future experiments will demonstrate the beneficial effect of our lead compound in AD murine models.
Nutrition status and eating habits of patients with mild cognitive impairment (MCI) or Alzheimer’s dementia (AD)
Authors: Cussigh Barbara , Rakusa Martin
Published: December 2020

Background

The purpose of the study was to determine the eating habits of patients with MCI or AD and to determine their nutritional status.

Methods

patients with MCI or AD were recruited in the dementia outpatient clinic. Cognitive status and nutritional status were evaluated. Each patient or his/her caregiver fill out full Mini Nutritional Assessment scale (MNA). Maximal score on MNA was 30, patients at risk of malnutrition scored between 17 and 23.5. Patients with less than 17 were considered malnourished. Descriptive statistic for age, body mass index (BMI), arm/calf circumference and total MNA score was performed. MNA score was compared between MCI, mild and moderate AD group using one‐way Anova, and the correlation between the degree of cognitive impairment and MNA score was performed.

Results

Mean age of all patients was 74 years (10 years SD), mean MNA score was 24.6 (SD 3.2). The results showed that patients do not consume enough of the recommended nutrients, especially proteins, fruits and vegetables, daily. Measurements of the median circumference of the forearm and calf revealed that more than (60%) patients had decreased muscle mass, although the Body Mass Index was in the normal range in more than 90% of patients. Six patients had moderate, 34 had mild AD, and 38 had MCI. Only one patient was malnourished, while 23 (29.5%) were at risk of malnutrition. All patient with MCI had normal MNA score. Patients with moderate AD had significantly lower MNA score than patients with MCI (21.5, SD 4 vs 25.5 SD 3.4). No differences were found between other groups. A significant correlation was found between cognitive impairment and MNA (r=0.31, p<0.001)

Conclusion

Our results suggest that patients with AD need nutritional assessment, especially in the advanced phase. It would be worthwhile to make a nutritional assessment at the first and every subsequent visit of the patient to the outpatient clinic to monitor his or her nutritional status.
Baseline cerebrospinal fluid biomarkers of amyloidosis, phosphorylated tau, and total tau relate to greater longitudinal atrophy in regions susceptible to Alzheimer’s disease‐related neurodegeneration
Authors: Moore Elizabeth E. , Khan Omair A. , Liu Dandan , Pechman Kimberly R. , Acosta Lealani Mae Y. , Bell Susan P. , Landman Bennett A. , Blennow Kaj , Zetterberg Henrik , Hohman Timothy J. , Gifford Katherine A. , Jefferson Angela L.
Published: December 2020

Background

Cerebral atrophy patterns can distinguish normal cognition from Alzheimer’s disease (AD), but neuropathological drivers of these patterns are still not well understood. This study examined baseline cerebrospinal fluid (CSF) biomarkers of AD pathology (amyloid‐beta (Aβ), phosphorylated tau (p‐tau)); neurodegeneration (total tau (t‐tau)); synaptic dysfunction (neurogranin); and neuroaxonal injury (neurofilament light (NFL)) in relation to longitudinal atrophy patterns for two common AD neuroimaging signatures.

Method

Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=153, 72±6 years) underwent baseline fasting lumbar puncture for CSF collection and serial T1
‐weighted neuroimaging at 3T (baseline, 18‐months, 3‐years, 5‐years). Images were post‐processed using FreeSurfer. AD imaging signatures were calculated using published guidelines (McEvoy et al., 2009; Schwarz et al., 2016). Linear mixed effects models related each baseline CSF biomarker to each AD signature trajectory using biomarker x follow‐up time interactions, adjusting for age, sex, race/ethnicity, education, diagnosis, apolipoprotein (APOE)‐ε4 status, and follow‐up time. Secondary models tested CSF biomarker x APOE‐ε4 interactions on longitudinal AD signature trajectory.

Result

Mean follow‐up time was 3.4±1.1 years. Lower baseline CSF Aβ (p<0.001), higher t‐tau (p=0.04), and higher p‐tau levels (p=0.01) were associated with a faster rate of cortical thinning in the McEvoy AD signature. Baseline CSF biomarkers were unrelated to Schwarz AD signature trajectory (p‐values>0.16). APOE‐ε4 interacted with baseline CSF p‐tau, t‐tau, neurogranin, and NFL on both AD signatures (p‐values<0.04). APOE‐ε4 also interacted with CSF Aβ on the Schwarz AD signature (p=0.008). Associations linking baseline CSF Aβ, p‐tau, t‐tau, and neurogranin with faster atrophy patterns were driven by APOE‐ε4 carriers (p‐values<0.05).

Conclusion

Increased baseline evidence of cerebral amyloidosis, phosphorylated tau, and neurodegeneration related to faster rates of cortical thinning in AD‐affected regions over a mean 3.4 year follow‐up period. Associations linking amyloidosis, phosphorylated tau, neurodegeneration, and synaptic dysfunction to cortical thinning are driven by APOE‐ε4 carriers, suggesting grey matter regions susceptible to the longitudinal neurodegenerative effects of AD pathology may be even more susceptible in APOE‐ε4 carriers, perhaps due to the effects of APOE‐ε4 on blood‐brain barrier compromise, vascular dysregulation, or inflammatory activation.
Ubiquilin‐2 exacerbates tau toxicity in vivo
Authors: Gerson Julia E. , Pistorius Stephanie , Welday Jacqueline , Gregory Jordan , Rodriguez Aleija L. , Sharkey Lisa M. , Paulson Henry L.
Published: December 2020

Background

Ubiquilin‐2 (UBQLN2) is a protein quality control protein involved primarily in shuttling ubiquitinated substrates to the proteasome for degradation and by modulating autophagy. UBQLN2 has been implicated in neurodegenerative disease due to its accumulation in neuropathological deposits and its potential role in regulating protein dyshomeostasis common across different neurodegenerative disorders. The relationship of UBQLN2 to one of the most common aggregating proteins in disease, tau, is unknown.

Method

To evaluate whether UBQLN2 regulates tau clearance, we assessed levels of tau in human embryonic kidney‐293 cells with and without UBQLN2. To determine whether UBQLN2 acts on tau in vivo, P301S tau transgenic mice were crossed with UBQLN2 transgenic and knockout mice and brain levels of tau were assessed at 3, 6 and 9 months of age. To define changes in UBQLN2 in human disease, we measured levels of soluble and insoluble UBQLN2 in human tauopathy brain tissue.

Result

Co‐expressed UBQLN2 markedly lowered levels of tau in a cellular model. Conversely, siRNA knockdown of UBQLN2 significantly elevated levels of tau. Surprisingly, a UBQLN2 mutant incapable of binding ubiquitin was more effective at lowering tau than wildtype UBQLN2, suggesting that ubiquitin‐independent pathways may allow UBQLN2 to “handle” tau. In contrast, wildtype UBQLN2 overexpression in vivo did not alter total levels of tau at 3, 6 or 9 months of age. However, UBQLN2 overexpression specifically increased phosphorylated tau while UBQLN2 knockout decreased phosphorylated tau at 9 months. Furthermore, UBQLN2 overexpression increased premature hindlimb paralysis and fatality. The possibility that UBQLN2 also undergoes alterations in disease was evidenced by the fact that UBQLN2 solubility is decreased in human brains with tau pathology.

Conclusion

Our findings highlight a new role for UBQLN2 in altering tau in the brain. Collectively, our results suggest that while on a rapid time scale UBQLN2 can decrease tau levels, long‐term expression of UBQLN2 in vivo exacerbates tau toxicity. Ongoing research will determine how changing UBQLN2 levels alters components of proteostasis pathways to affect tau toxicity and whether ubiquitin‐independent processes may compete with UBQLN2’s function as a ubiquitin‐proteasome shuttle factor to yield differential effects on tau toxicity.
Severity of subjective cognitive complaints and worries in older adults are associated with cerebral amyloid‐β load
Authors: Schwarz Claudia , Lange Catharina , Benson Gloria , Horn Nora , Wurdack Katharina , Lukas Mathias , Buchert Ralph , Wirth Miranka , Flöel Agnes
Published: December 2020

Background

Subjective cognitive decline (SCD) is considered an early risk stage for the development of Alzheimer's disease (AD) and pathological brain alterations, including the aggregation of amyloid‐β plaques (Jessen et al., Alzheimer's & Dementia 2014). This prospective study evaluates the association between specific features of SCD, including severity of subjective cognitive complaints and trait worry, and regional cerebral amyloid‐β load in cognitively normal older individuals.

Method

Cerebral amyloid‐β load was assessed by positron emission tomography with 18F‐florbetaben in 30 individuals with SCD (age 67 ± 4 years) at baseline in an ongoing interventional study (clinicaltrial.gov: NCT03094546) and in 10 healthy older adults (age 72 ± 8 years) following the same baseline protocol. Regional amyloid‐β load was quantified for frontal, temporal, parietal, and cingulate cortex using whole cerebellum as reference. Subjective complaints regarding different cognitive domains (memory, language, visuospatial abilities, planning, organization, and divided attention) were determined using the 39‐item Everyday Cognition Scales. Trait evaluation of pathological worry was captured by the self‐reported 16‐item Penn State Worry Questionnaire. Associations between specific features of SCD and cerebral amyloid‐β load were tested by age‐adjusted Spearman rank partial correlation analyses, uncorrected for multiple testing.

Result

Across all participants, severity of subjective cognitive complaints regarding memory, organization, and divided attention was positively correlated with amyloid‐β load in the frontal cortex (p = .008, .018, .024, respectively). Severity of subjective cognitive complaints regarding planning was positively correlated with amyloid‐β load in the parietal cortex (p = .025). Higher trait level of pathological worry was associated with higher amyloid‐β load in the frontal cortex (p = .031).

Conclusion

In cognitively normal older individuals, severity of subjective cognitive complaints and level of trait worry are positively associated with cortical amyloid‐β burden, particularly in the frontal cortex. This region is considered a core region of the default mode network that is affected early in AD (Palmqvist et al., Nature Communications 2017). Interventions aiming to reduce rumination and worries may help prevent amyloid deposition in these regions, a hypothesis to be tested in future interventional trials.
Moving together: Livestream virtual group movement classes for persons living with dementia and caregivers—Feasibility and satisfaction
Authors: Benjamin Cynthia , Lee Amanda , Lee Jennifer Ann , Mehling Wolf , Chesney Margaret A , Sudore Rebecca L , Barnes Deborah E
Published: December 2020

Background

Paired PLIÉ (Preventing Loss of Independence through Exercise) is an in‐person, group movement program for people living with dementia (PLWD) and caregivers (CGs) that targets physical movements, mindful body awareness, and social engagement. We have previously found Paired PLIÉ to be associated with CG‐reported improvements in physical, cognitive, social/emotional function, and relationship quality. However, CGs also reported logistical challenges related to attending in‐person classes. To address these challenges, our goal was to assess feasibility and satisfaction with an online version of the program developed by Together Senior Health, Inc., called Moving Together.

Method

Study participants were PLWD and CGs who participated in Moving Together livestream virtual classes from home using their existing technology. Feasibility was assessed based on completion of the 12‐week program. Satisfaction at 12‐weeks was assessed using a 5‐point Likert scale (highly satisfied to highly unsatisfied). Open‐ended questions asked what participants liked and found challenging about the online program.

Result

Twenty‐one people participated (11 PLWD: 36% women, mean age 78±12 years; 10 CGs: 70% women, mean age 70±16 years). Fifteen (70%; 8 PLWD, 7 CGs) successfully completed the program, of whom all (100%) reported being highly satisfied with online delivery. Participants described physical, social and emotional benefits of participating: “I liked the activities with partner and that I could feel various parts of my body getting massage and movement (PLWD);” “Really enjoyed this class, so did my body, brain and my spirit (CG);” and “[I liked] feeling part of a group and seeing the range of issues with others (CG).” Despite reporting challenges with technology related to broadband internet access and older devices, participants strongly supported the online format: “[I liked] BEING AT HOME! …Getting ready to go out, going out and coming home takes a lot of energy and we are not sure we would participate if it were not online (PLWD).”

Conclusion

We found that online delivery of Moving Together is feasible and acceptable to PLWD and CGs. Offering livestream virtual group movement classes such as Moving Together could enhance accessibility to evidenced‐based programs for PLWD and CGs.
Neuropsychological, clinico‐pathologic, neuroimaging, and biomarker profiles of the MGH FTD Unit posterior cortical atrophy (PCA) cohort
Authors: Wong Bonnie , McGinnis Scott , Putcha Deepti , Dev Sheena Isha , Lucente Diane E. , Quimby Megan , Brandt Katie , Eldaief Mark C. , Sherman Janet C. , Frosch Matthew P. , Dickerson Brad C.
Published: December 2020

Background

Objective: To present comprehensive data on the MGH FTD Unit PCA cohort. PCA is a neurodegenerative clinical syndrome usually arising from Alzheimer’s Disease (AD) neuropathologic changes (ADNC). While visuoperceptual and spatial problems are typical early presenting symptoms, patients also report problems with spelling, calculation, and word retrieval. Due to significant heterogeneity in the syndrome, further classification of PCA by subtypes based on predominant cognitive impairments (dorsal, ventral, caudal, dominant parietal) has also been proposed. We launched our multidisciplinary MGH PCA program in 2008 to address the special care needs of this population, and to advance our scientific understanding of PCA and its treatment.

Methods

39 participants were recruited for research participation based on clinical diagnostic criteria consistent with PCA, including a dominant hemisphere variant (i.e., progressive Gerstmann‐like syndrome minimal visuospatial disturbance). Participants underwent structured review of symptoms and history; systematic neurological exam; comprehensive neuropsychological and speech‐language assessments; multimodal imaging (MRI and/or functional MRI and FDG, amyloid, and tau PET); and CSF analysis. Some patients have come to autopsy. We used the Neuropsychological Assessment Rating (NAR) scale to quantify performance in cognitive domains pertinent to PCA and for subtype classification.

Results

Of seven individuals for whom we have autopsy‐confirmed neuropathology, five had ADNC; one had lobar atrophy and tau pathology in a cortico‐basal degeneration (CBD) distribution; and one had Frontotemporal Lobar Degeneration TDP43 Type A (GRN mutation). 22 patients had biomarkers consistent with ADNC (17 with elevated PiB PET imaging signal, 5 with AD‐like CSF ). Mean NAR domain scores (impairment level ratings: 0=Normal, .5=questionable/very mild, 1=mild, 2= moderate, 3=severe) revealed relatively normal Attention/Processing Speed (0.2); mildly impaired Executive Function (0.8) and Memory (1.1); questionably/very mildly impaired Language (0.5); and moderately impaired Visuospatial Function (2).

Conclusion

The MGH PCA program has a robust cohort of patients with a comprehensive data set that includes standardized characterization of the PCA neurocognitive and neurologic profiles, high‐resolution MRI (structural, functional), multimodal PET imaging, CSF biomarkers, and in some cases neuropathology. This data set will allow for detailed examination and improved understanding of this atypical neurodegenerative syndrome. Additional analyses are ongoing, including tau imaging profiles.
Diffusion kurtosis imaging suggests sex‐specific alteration of white matter in mild cognitively impaired participants
Authors: Mishra Virendra R , Ritter Aaron , Cordes Dietmar , Caldwell Jessica ZK
Published: December 2020

Background

Sex differences in Alzheimer’s disease (AD)‐dementia is well documented. However, whether sex differences in white‐matter (WM) microstructural integrity could serve as potential biomarker to identify sex‐specific participants progressing to AD‐dementia is currently unexplored.

Method

78 participants were recruited at our center, of which 38 were diagnosed with MCI based on expert consensus, using results of a neuropsychological test battery and the Clinical Dementia Rating (CDR) interview (Table.1). Isotropic 1.5mm3 multi‐shell dMRI (b‐values=500s/mm2, 1000s/mm2, and 2500s/mm2) each with 71 directions was acquired for each participant. Diffusion kurtosis (DKI) model was fitted from every participant along with conventional single‐tensor (ST) diffusion tensor imaging (DTI) model. DKI metrics such as axonal water fraction (AWF), axonal kurtosis (AK), radial kurtosis (RK), and mean kurtosis (MK) was estimated at every voxel. Tract‐based Spatial Statistics (TBSS) was used to extract the WM skeleton from ST‐fractional anisotropy (FA), and various DKI‐derived metrics were mapped to a common space using the registration parameters from ST‐FA. Nonparametric statistical comparisons were conducted between each group to test for mean difference in these metrics. Significance was established at familywise error corrected (FWE) p<0.05.

Result

Male‐HC showed a significantly higher AK as compared to female‐HC in the WM regions encompassing corpus‐callosum, cingulum, inferior longitudinal fasciculus, and thalamic and cerebellar WM fibers. However male‐MCI only showed a higher AK in the thalamic and cerebellar WM fibers (Fig.1). There were also significant differences in other metrics such as MK and RK, both within (male vs female HC and MCI) and between groups of HC and MCI (Fig.1). Significantly lower AWF was observed in male‐HC as compared to female‐HC, and in male‐MCI as compared to female‐HC in the entire WM skeleton but selectively sparring the corpus callosum (Fig.1). DTI metrics showed no significant sex‐specific differences within groups in our cohort.

Conclusion

Multi‐shell dMRI imaging is a promising avenue to explore sex‐specific alterations in the WM microstructural integrity in MCI participants, and could be utilized to identify the most promising imaging biomarker to predict AD‐dementia which is sex‐specific. Similar analysis with other complex models such as free‐water corrected DTI and NODDI models are currently underway.
Cognitive indices correlate with [18F]GTP1 tau PET signal and white matter hyperintensities in prodromal‐to‐mild Alzheimer's disease: Baseline data from the Tauriel Study
Authors: Teng Edmond , Manser Paul T. , Pickthorn Karen , Blendstrup Mira , Anegondi Neha , Krishnan Anithapriya , Song Zhuang , Carano Richard A.D. , Keeley Michael , Wildsmith Kristin R. , Weimer Robby , Bohorquez Sandra Sanabria
Published: December 2020

Background

In prior cross‐sectional studies using [18F]GTP1 or other tau PET tracers across a spectrum of Alzheimer’s disease (AD) severity, tau PET signal has independently correlated with cognition, even after adjustments for β‐amyloid (Aβ) load and atrophy. However, it remains uncertain how robust these correlations are in more homogeneous patient populations (e.g., clinical trial participants) and after adjustment for MRI white‐matter hyperintensities (WMH). We sought to address this question by examining baseline data from the Phase 2 Tauriel study (NCT03289143), which is investigating the safety and efficacy of semorinemab (an anti‐tau antibody) in prodromal‐to‐mild AD.

Method

We analyzed data from a subset of Tauriel participants who underwent baseline [18F]GTP1 tau PET imaging and met criteria for probable AD dementia (n=244) or mild cognitive impairment (MCI; n=137), with MMSE of 20‐30, global Clinical Dementia Rating (CDR) of 0.5 or 1, significant Aβ pathology (PET or CSF), and significant episodic memory impairment on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Other screening/baseline assessments included the 13‐item version of the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog13) and MRI (WMH scored with Fazekas scale). Relationships between cognitive indices, whole cortical gray (WCG) [18F]GTP1 SUVR, WMH, and age were assessed using Pearson correlations and multiple linear regression.

Result

Univariate analyses revealed significant correlations between all cognitive indices [MMSE, CDR Sum of Boxes, ADAS‐Cog13, and RBANS] and [18F]GTP1 SUVR across the whole cortical gray (WCG; p’s<0.001). Significant univariate correlations were also seen between WMH and ADAS‐Cog13 scores (p=0.035) and between age and RBANS scores (p<0.001). Multivariate linear regression analyses that included all three factors consistently identified both WCG [18F]GTP1 SUVR and WMH as independent predictors of cognitive performance across all indices (p’s<0.05), with a much larger proportion of variance attributable to WCG [18F]GTP1 SUVR.

Conclusion

Amongst participants with prodromal‐to‐mild AD enrolled in the Tauriel study, [18F]GTP1 tau PET signal was more strongly associated with baseline cognitive performance than the extent of WMH. These data suggest that even in AD participants with co‐morbid cerebral microvascular ischemic disease, therapeutic interventions targeting tau have the potential to ameliorate subsequent cognitive decline.
Biomarker profiles in a memory clinic population according to new Alzheimer diagnostic framework
Authors: Öhlund Ulf , Wiggenraad Fleur , Hagman Göran , Rosenberg Anna , Kivipelto Miia
Published: December 2020

Background

Different research diagnostic criteria and frameworks for Alzheimer’s disease have recently been proposed, but their applicability in clinical settings is unclear. This cross‐sectional study aimed at classifying biomarker profiles of memory clinic patients according to the ATN scheme and assessing patient characteristics in each category.

Method

284 consecutive patients from the Karolinska University Hospital, Theme aging, memory clinic with available CSF, MRI and clinical data were included (50% diagnosed with SCI, 24% with MCI, 26% with dementia). ATN classification was based on CSF β‐amyloid42 (A), CSF phosphorylated tau (T), and medial temporal atrophy (N), and clinical cut‐offs were used to determine biomarker positivity. When available, automated ratings of medial temporal lobe atrophy were used in the classification. Comparisons between the ATN categories were conducted with Kruskal‐Wallis and chi‐square tests.

Result

The most frequent biomarker profile was A‐T‐N‐ (49% of the whole study population). 36% had a SNAP profile (A‐T+N‐, A‐T‐N+ or A‐T+N+) and 15% had any Alzheimer profile, i.e. abnormal amyloid (A+T‐N‐, A+T+N‐, A+T‐N+ or A+T+N+). Proportion of A+T+N+ patients increased with the severity of symptoms (0% in SCI and MCI, 22% in dementia), whereas the opposite was observed for A‐T‐N‐ patients (72% in SCI, 39% in MCI, 14% in dementia). Some biomarker profiles (A+T‐N‐, A+T‐N+, A+T+N‐) were underrepresented in the whole sample and in all diagnostic groups. Compared to normal biomarker profile, patients with an Alzheimer profile were older and more often APOE4 carriers, had a poorer cognitive performance (MoCa, MMSE, memory, attention), and had fewer depressive symptoms. Except for age and depressive symptoms, same differences were observed between SNAP and normal biomarker profile categories. There were no differences in white matter hyperintensities or education level between the profile categories.

Conclusion

Proportion of patients with either a normal or SNAP biomarker profile was high in this memory clinic‐based study. Many of the proposed ATN categories were also not relevant in this patient population. Follow‐up studies are needed to assess cognitive decline and disease progression in the different ATN categories.
Exploring polypharmacy and hyperpolypharmacy in dementia
Authors: Zafeiridi Evi , McMichael Alan J , McGuinness Bernadette
Published: December 2020

Background

Polypharmacy is defined as receiving multiple medications and has been shown to increase the risk for developing dementia. Polypharmacy is also prevalent in people with dementia (PwD) who transition to a care home. This study explored whether people receiving multiple medications are more likely to be diagnosed with dementia. Another aim was to assess the prevalence of polypharmacy (≥4 drugs) and hyperpolypharmacy (≥10 drugs) in community‐dwelling PwD and care home residents in Northern Ireland, as well as to investigate whether higher polypharmacy scores are associated with increased likelihood of transitioning to a care home for PwD. Data from the Enhanced Prescribing Database and other national databases was linked through the Honest Broker Service. Data extraction included over 50,000 people, half of which were prescribed at least one anti‐dementia medication between 2010‐2016. The results showed that, although polypharmacy was not associated with the risk of developing dementia, higher scores of polypharmacy were associated with lower risk of transitioning to a care home for PwD. A possible explanation could be the increased mortality rates in people who received four or more medications. Within care homes, polypharmacy was more prevalent to PwD compared to controls. These findings can inform policies and clinical practices for the effect of prescribing multiple medications to PwD.
Preventing Loss of Independence through Exercise (PLIÉ): Evaluation of implementation at a VA community living center
Authors: Akram Alirameen , Martin Lynn , Lee Maria , Nicosia Francesca M , Martinez Steven , Woo Michele , Ordonez Cherry , Lee Jennifer Ann , Barnes Deborah E
Published: December 2020

Background

Preventing Loss of Independence through Exercise (PLIÉ) is an integrative group movement program developed to improve quality of life and daily function in people with mild‐to‐moderate dementia. We implemented PLIÉ at a VA Community Living Center (CLC) and conducted a formative evaluation.

Methods

We provided 12 weeks of experiential training to two local clinical champions. Approximately 9 months later, we evaluated implementation based on the following outcomes: 1) reach (number of post‐training classes offered and attendance) and 2) effectiveness (anonymous surveys administered to residents, staff, and family who attended >1 class; clinical progress notes for program participants). Surveys included satisfaction ratings (5‐point Likert scale) and open‐ended questions (changes in themselves and others due to PLIÉ, what they liked most and least, and other comments). Four independent coders performed a qualitative content analysis to identify key domains of change associated with PLIÉ participation.

Results

A total of 45 1‐hour PLIÉ classes were offered over 9 months. Residents attended an average of 13 +/‐ 12 classes with an average of 14 residents, 4 staff members and 2 family members per class. Anonymous survey respondents (15 residents, 14 staff, and 8 family members) were highly satisfied with the PLIÉ program (mean: 4.8, 4.4, and 4.9 on 5‐point Likert scale, respectively). Respondents reported improvements in themselves and/or others in four domains: 1) psychological, 2) physical, 3) cognitive, and 4) social. Psychological improvements included feelings of happiness/well‐being, enjoyment, and self‐empowerment. Physical improvements included mobility, strength, and energy. Cognitive improvements included engagement, communication ability, and focus/attention. Social improvements included connection, social skills, and social support. Domains identified were similar for residents, staff, family members, and clinical progress notes (Table). Negative comments were primarily related to logistics and suggesting that the class occur more frequently.

Conclusion

PLIÉ was successfully implemented in a VA nursing home with high satisfaction among residents, staff and family members. Residents experienced clinically meaningful psychological, physical, cognitive, and social benefits. We are currently developing and testing an implementation training program for other CLCs and nursing homes.
Investigating the relationship between neuropsychiatric symptoms and cognition in mild cognitive impairment and Alzheimer’s disease patients undergoing an exercise‐primed transcranial direct current stimulation clinical trial (The EXPRESS Study)
Authors: Lanctot Krista L. , Gallagher Damien , Rapoport Mark J. , Oh Paul I. , Marzolini Susan , Charles Jocelyn , Papneja Purti , Rajji Tarek K. , Andreazza Ana C. , Kiss Alex , Liu Celina , Vieira Danielle , Herrmann Nathan
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are common features of Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD), and are associated with poorer cognition. Transcranial direct current stimulation (tDCS), a non‐invasive type of brain stimulation, has been investigated for the treatment of some NPS in a few small AD studies, but with negative results for apathy and depression. Priming the brain with an excitatory intervention, such as exercise, may elicit greater changes if applied prior to tDCS. Using data from an ongoing blinded study, we aimed to evaluate the relationship between NPS and cognition in MCI and mild AD.

Method

MCI or mild AD participants were enrolled in a two‐week, randomized, blinded clinical trial investigating the effects of exercise‐primed tDCS for cognition using the Montreal Cognitive Assessment (MoCA). NPS were measured using the Neuropsychiatric Inventory (NPI) subscales. A Pearson’s correlation determined the relationship between NPI scores and the MoCA at baseline in patients who received exercise‐primed tDCS or tDCS alone. A repeated measures analysis of variance compared changes in NPI scores between the two treatment groups over time. As the study is ongoing, the treatment groups have been randomly coded as Group 1 and Group 2 to avoid unblinding.

Result

At baseline, participants (N=13) were 76.5±7.2 years of age, MoCA score= 20.9±3.6, 53% female, and 53% MCI. Nine (69.2%) participants reported having at least one NPS (NPI Score ≥ 1). Apathy (46.2%), sleep disturbances (38.5%), agitation (30.8%), and anxiety (30.8%) were the most prevalent NPS. At baseline, only anxiety was negatively correlated with MoCA scores (r=‐0.57, p=0.041; Figure 1). There were no significant differences between treatment groups on anxiety scores over time (F(1,10)= 2.4, p=0.16). However, after controlling for baseline MoCA scores, there was a significantly greater reduction on anxiety scores in Group 1 (‐0.83±1.3) compared to Group 2 over time (0±0; F(1,9)= 5.3, p=0.047).

Conclusion

Recruitment is ongoing (total N=30). Only anxiety was associated with poorer cognition at baseline. There were differences between treatment groups on anxiety scores over time, after controlling for baseline MoCA scores. It remains to be seen, after unblinding, whether the group with reduction in anxiety was receiving the primed intervention.
Carotid artery stenosis as a risk factor for Alzheimer’s disease
Authors: Vitali Francesca , Beach Thomas G. , Alexander Gene , Reiman Eric M. , Arias Juan Aristizabal , Brinton Roberta Diaz , Altbach Maria , Weinkauf Craig
Published: December 2020

Background

The role of extra‐cranial carotid artery disease (ECAD) in Alzheimer’s disease (AD) is not clear but of significance because treatments including carotid endarterectomy (CEA) are available yet not offered for the indication of dementia prevention. Here, we conducted a preliminary study to elucidate if ECAD can be considered a risk factor for Alzheimer’s disease (AD) and if CEA can improve cognitive impairment and dementia opening new views on possible treatment intervention options.

Method

Using Banner Alzheimer’s Brain Bank, post‐mortem pathological analyses were conducted on 48 patients with ECAD treated with CEA and 92 subjects with ECAD without CEA. Neurofibrillary tangles and white matter lesion burden were quantified by post‐mortem histology and scored at autopsy by pathologists. Student’s t‐test was performed to compare patients with ECAD with and without carotid endarterectomy (CEA).

Result

Preliminary results indicate that patients with CEA had significantly lower burden of white matter lesions (P = .05) and neurofibrillary tangles (P = .04). Additional analyses will evaluate whether CEA improves cognition in a cohort of patients with ECAD.

Conclusion

Outcomes of these analyses provide proof of concept indicating impact of ECAD on changes in brain structure associated with dementia. These outcomes provide a foundation on which to test hypotheses regarding the mechanisms contributing to ECAD associated AD.
The state of the science on synchronous video‐conferencing interventions for care partners of persons with dementia
Authors: Tarter Robin R , Tran Leslie , Lindauer Allison
Published: December 2020

Background

The need for effective clinical interventions to prevent the potentially deleterious health impact of providing unpaid care to friends and family members with Alzheimer’s disease and related dementias (ADRDs) has become increasingly urgent. Synchronous video‐conferencing in which ADRD care partners interact in real time with trained healthcare professionals has emerged as an especially promising method for telehealth interventional research. Here we report on the designs and outcomes of such interventions for care partners of persons with ADRDs.

Method

A scoping review was undertaken following Arksey and O’Malley’s systematic methodological framework. Articles were identified through a comprehensive search of PubMed, PsychINFO, and CINAHL. Inclusion criteria were peer reviewed, data‐based research articles published between 2015 and 2020 reporting results of synchronous video‐conferencing interventions specifically designed to address the needs of care partners of persons with ADRDs. Reviews, scale development, protocols, and case studies were excluded.

Result

Full text screening of 159 articles resulted in the identification of seven articles reporting the results of six independent interventions. Included studies fell into two categories, psychoeducational behavior modification interventions delivered by nursing professionals and facilitated peer support interventions delivered by psychologists and social workers. Interventions varied based on technological mode of delivery, level of interaction among participants and between participants and interventionists, duration and frequency of sessions, and outcomes measured or described. Articles reported evidence of efficacy for decreasing care partner loneliness, depression, burden, and increasing care competence. Feasibility and acceptability of the technological interface varied between interventions, but was high overall.

Conclusion

By comparing and contrasting these 6 synchronous video‐conferencing interventions, we are able support the viability of synchronous video‐conferencing as an effective mode of intervention for care partners of persons with ADRDs, and generate information to inform future research. Despite evidence that care partners need stage‐specific interventions, none of the reviewed studies were tailored to specific dementia stages, and there was a glaring lack of diversity in most study samples. Our results suggest that future research with care partners should not be limited to earth‐bound, face‐to‐face interventions, and that synchronous video‐conferencing has benefits above and beyond other approaches.
Diffusion MRI‐derived free water fraction may be a sensitive imaging biomarker that could improve identification of mild cognitive impairment participants progressing to Alzheimer’s disease dementia
Authors: Mishra Virendra R , Caldwell Jessica ZK , Cordes Dietmar , Shan Guogen , Ritter Aaron
Published: December 2020

Background

We hypothesize that diffusion MRI (dMRI)‐derived free‐water‐fraction (fiso) of not only hippocampus but also of limbic and temporal cortex along with fiso of white matter (WM) of cingulate, corpus‐callosum, and frontotemporal tracts will show significant difference in participants progressing to Alzheimer’s disease (AD)‐dementia as compared to non‐progressors. Incorporating these measures may improve identification of mild cognitive impairment (MCI) participants progressing to AD‐dementia.

Method

7 MCI‐Stable (M2M) and 4 MCI‐Converters (M2A) over a period of one‐year, each with at least one ε4 allele, positive PET‐quantified amyloid‐beta, and matched demographics were recruited at our center. MCI and AD diagnoses were based on expert consensus, using results of a neuropsychological test battery and the Clinical Dementia Rating (CDR) interview. Isotropic 1mm3 T1‐weighted MPRAGE along with a 213 directions multi‐shell dMRI (b‐values=500s/mm2, 1000s/mm2, and 2500s/mm2) at an isotropic 1.5mm3 resolution was acquired on a 3T Siemens Skyra scanner. Average volumes and fiso within each FreeSurfer defined region‐of‐interest (ROI), and average fiso in twenty major WM fiber tracts was estimated for each participant at each timepoint. Only those ROIs and WM fiber tracts that showed at least 10% change in fiso longitudinally within each group were selected for further analysis.

Result

Bilateral hippocampus showed lower volume (Figure 1) and elevated fiso (Figure 2) within M2A group. However, volume of other ROIs (e.g.: Anterior corpus callosum, posterior cingulate cortex, tranverse‐temporal cortex etc.) did not show a lower volume longitudinally, even though there was a 10% increase in fiso longitudinally in those ROIs. Furthermore, a complex correlation between fiso and volume was observed at each timepoint (Figure 3). Interestingly, hippocampal tail was found to be driving the effect seen in right hippocampus, with an opposite slope at each timepoint between M2A and M2M group (Figure 4). Contrary to our hypothesis, right cingulate WM tract and genu of corpus‐callosum (FMinor) showed a decrease in fiso within M2A group (Figure 5).

Conclusion

Our pilot analysis, albeit with small sample size and potentially underpowered, revealed that fiso of tail of hippocampus, frontal and temporal cortex, and WM fibers of limbic cortex and FMinor may be included as potential predictive imaging biomarkers of AD‐dementia from MCI.