bluuebunny/crossref_metadata_2025 huggingface dataset:
Lower neocortical tau burden distinguishes Alzheimer’s pathology occurring with vs. without primary non‐Alzheimer’s pathology
Authors: Phillips Jeffrey S , Cousins Katheryn Alexandra Quilico , Irwin David J , Wolk David A , Lee Eddie B , Gibbons Garrett S , McMillan Corey T , Trojanowski John Q , Grossman Murray
Published: December 2020

Background

The NIA/AA research framework proposes a biological definition of Alzheimer’s disease (AD) based on the presence of both amyloid and tau. However, AD frequently co‐occurs with other non‐AD pathologies, and it is unclear how these pathologies affect the progression of AD‐associated amyloid‐β and tau. We investigated regional heterogeneity in AD pathology in a postmortem sample of either pure AD or co‐occurring non‐AD and AD pathology. We hypothesized that amyloid‐β and tau would be more likely to co‐localize in pure AD than in the mixed‐pathology group.

Method

We retrospectively identified two groups with intermediate or high levels of AD pathologic change by ABC criteria: 1) cases with a pathologic diagnosis of AD (AD‐pure; n=92) and minimal co‐pathology; and 2) those with a primary non‐AD pathology (frontotemporal lobar degeneration due to tau or TDP‐43; dementia with Lewy bodies; Parkinson’s disease; or amyotrophic lateral sclerosis) coupled with AD co‐pathology (AD co‐path; n=68). Primary outcomes were ordinal ratings (0‐3) of postmortem amyloid‐β and tau burden in the amygdala, entorhinal cortex, CA1/subiculum, superior/middle temporal gyrus, middle frontal gyrus, and angular gyrus; positivity was assessed by ratings of 2‐3.

Result

The AD‐pure group was younger at death (M=74.3, SD=12.2) than AD co‐path (M=78.6, SD=7.9) and was more likely to have high AD pathologic change (OR=18.0, p<0.0001). The AD co‐path group had fewer regions positive for both amyloid‐β and tau (M=0.50, SD=0.27) than the AD‐pure group (M=0.87, SD=0.23), independent of age and Braak stage. AD‐singular patients were more likely than AD co‐path patients to be tau‐positive in middle frontal (84% vs. 21%), angular (84% vs. 29%), and superior/middle temporal cortex (88% vs. 41%). A logistic regression model based on tau ratings in these three neocortical regions distinguished AD‐pure and AD co‐path with 82.4% accuracy. When the analysis was stratified by Braak stage, differences in neocortical tau were limited to Braak V/VI cases.

Conclusion

Autopsy data indicate AD co‐path cases may have lower neocortical tau burden than AD‐singular cases at end of life. These postmortem findings suggest that AD co‐path cases may be identifiable during life by assessing neocortical tau distribution using tau‐binding PET ligands.
Sex‐associated differences in pathology burden in early‐onset Alzheimer’s disease
Authors: Groh Jenna Rae , Stage Eddie , Logan Paige E. , Iaccarino Leonardo , Joie Renaud , Aisen Paul S , Eloyan Ani , Fagan Anne M. , Foroud Tatiana M. , Gatsonis Constantine , Jack Clifford R. , kramer Joel H. , Koeppe Robert A. , Saykin Andrew J. , Toga Arthur W. , Vemuri Prashanthi , Day Gregory S. , Graff‐Radford Neill R. , Honig Lawrence S. , Jones David T. , Masdeu Joseph C. , Mendez Mario F. , Onyike Chiadi U. , Rogalski Emily J. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G.
Published: December 2020

Background

Previous research has suggested that, compared to males, females are at greater risk for and have greater pathology burden in late onset. However, sex differences in early onset AD (EOAD) have not yet been studied.

Method

We included 167 participants [28 cognitively normal (CN, 68% females), 98 early onset AD (EOAD, 55% females), and 41 cognitively impaired amyloid‐negative (EOnonAD, 31% females] subjects from the Longitudinal Early‐Onset AD Study (LEADS) with available Flortaucipir PET, Florbetaben PET, and MRI data. Multiple linear regression (MLR) models including age and MMSE as covariates were used in the pooled sample to examine the effects of sex on hippocampal and white matter hyperintensity volume, mean cortical thickness, mean tau distribution by Braak regions and mean cortical amyloid SUVR. We also ran voxelwise MLR with sex as the predictor and cortical thickness, amyloid SUVR normalized to whole cerebellum, tau SUVR normalized to cerebellar crus, respectively, as the outcome measures while controlling for age, MMSE, and total intracranial volume (MRI only). Results are displayed at a cluster‐level FWE correction of p<0.05.

Result

There were no significant demographic differences between males and females in any diagnostic group. Across the pooled sample females showed significantly greater atrophy of the hippocampus (p=0.0001), greater tau SUVR in Braak regions 3&4 (p=0.05) and 5&6 (p=0.04) and trend for greater global amyloid uptake (p=0.074) (Table 2). The analyses in imaging space confirmed these findings and showed that the effects are driven by the EOAD group. Females showed greater amyloid deposition globally and greater tau deposition in the frontal, inferior parietal and temporal lobes (Figure 3).

Conclusion

Female sex is associated with greater pathology burden in EOAD. Longitudinal studies will be needed to establish whether such difference translates in faster rates of progression in women relative to men.
Tau isoforms drive differential transposable element and gene expression
Authors: Grundman Jennifer Ann , Spencer Brian , Rissman Robert A.
Published: December 2020

Background

Tau isoform overexpression differs in several neurodegenerative. For instance, Alzheimer’s disease (AD) is characterized by overexpression of 3R and 4R tau, while progressive supranuclear palsy (PSP) and Pick’s disease (PiD) show overexpression of 4R and 3R tau, respectively. Tau’s role in nuclear processes have only just begun to draw focus, with studies showing it binds protectively to DNA and can contribute to heterochromatin relaxation (Sultan et al., 2011; Frost et al., 2014). Recently, tau has been implicated in activating transposable elements (TEs), which are normally repressed and can trigger immune responses and genomic stress (Guo et al., 2018; Sun et al., 2018). Yet tau isoforms’ role in these phenomena has not been examined and may reveal new details of tau‐driven pathology.

Method

SH‐SY5Y cells were differentiated and infected with lentiviral constructs of 0N3R tau, 2N4R tau, a 1:1 split of 0N3R and 2N4R, or a control construct before treatment with DMSO or Aβ‐42 oligomers. DNA damage and tau translocation were assessed using immunofluorescence and immunoblotting. RNA sequencing was performed and differential gene and TE expression measured using DESeq2 and TEtranscripts, respectively. For all cell‐based experiments, N=3. Further analysis was performed on RNA‐sequencing data of AD, PSP, and control patients (N=20 for each group), which is publicly available through AMP‐AD Knowledge Portal (doi:10.1038/sdata.2016.89).

Result

Results revealed more significant differences in gene and TE expression in the presence of overexpressed 4R tau than in overexpressed 3R tau alone. The most dysregulated TEs were ERVs, though all samples overexpressing tau showed dysregulation of LINEs. Notably, 4R tau overexpression also showed downregulation of nuclear processes and the ribosome.

Conclusion

These results provide novel insights into the effects of different tau isoforms and their interactions with Aβ‐42 and is the first study to show that tau isoforms uniquely affect TE expression. Our study bolsters support for future research into tau isoforms and tau‐driven activation of TEs and potential therapeutics that target them.
Evaluation of different partial volume correction methods for longitudinal tau PET imaging
Authors: Silva‐Rodríguez Jesús , Moscoso Alexis , Cortés Julia , Aguiar Pablo
Published: December 2020

Background

Previous studies have evaluated whole‐brain and region‐specific accumulation rates of tau using longitudinal 18F‐Flortaucipir (18F‐FTP) PET. 18F‐FTP is well known for presenting significant off‐target binding in regions such as the striatum, the white matter and the choroid plexus. However, the use of partial volume correction methods that do not model this off‐target binding is still common in the community, which might hamper optimal longitudinal 18F‐FTP quantification. The aim of the present study is to study the performance of different PVC methods for longitudinal 18F‐FTP PET studies.

Method

Serial 18F‐FTP PET and T1 images from 101 cognitively unimpaired (CU) and 77 cognitively impaired (CI) subjects were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). T1 images were segmented using the tools provided by the Computational Anatomical Toolbox (CAT12). Tissue probability maps were binarized to generate GM, WM and CSF masks. The GM was multiplied by the Hammersmith atlas to generate a GM patient‐specific atlas. The CSF was segmented in three different levels based on the maximum uptake in the PET image, so that the choroid plexus was segmented in high/low uptake regions. A traditional region deconvolution PVC, the reblurred Van‐Cittert (RVC) and 2 voxel‐based PVCs, the Region‐based voxel‐wise correction (RBV) and the iterative Yang (iY) were studied (Figure 1). Region‐specific tau accumulation rates were calculated for a medial temporal lobe region of interest, as well as for Braak areas generated by region aggregation. Longitudinal rates of change were estimated for amyloid‐β‐positive CU and CI subjects using linear mixed models and compared with a reference control group of cognitively normal, amyloid‐β‐negative older adults under age 70.

Result

Voxel‐based PVCs systematically improved the rate of change across all the studied regions in Aβ‐positive CU and Aβ‐positive CI, compared to deconvolution PVC and no PVC. Among the tested voxel‐based PVCs, the RBV was slightly superior to the IY method. Deconvolution‐based PVC provided similar change estimates as not applying PVC (Figure 2)

Conclusion

Voxel‐based PVCs that model off‐target binding maximize the annualized rate of change of 18F‐FTP uptake. Our findings suggest that simple deconvolution techniques should be substituted by Voxel‐based PVCs for longitudinal 18F‐FTP imaging.
Association of tau tangle burden with depressive symptoms in community‐dwelling older adults: A longitudinal study
Authors: Gatchel Jennifer R , Marshall Gad A , Locascio Joseph J , Yang Hyun‐Sik , Donovan Nancy J , Buckley Rachel F , Properzi Michael J , Quiroz Yakeel T , Rabin Jennifer S , Vannini Patrizia , Amariglio Rebecca , Chhatwal Jasmeer P , Rentz Dorene M , Blacker Deborah , Sperling Reisa A , Johnson Keith A , Hanseeuw Bernard
Published: December 2020

Background

Depressive symptoms are thought to be among the earliest behavioral changes in preclinical Alzheimer's disease (AD). However, the association between AD pathology and depressive symptoms in preclinical AD remains poorly understood. In the current study we examined the impact of pathology burden (amyloid and tau) on longitudinal change in depressive symptoms in cognitively unimpaired adults.

Method

252 adults (age: 70.8 ±8.2; 61% females) from the Harvard Aging Brain Study completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=5.87 annual visits). All were cognitively normal, without clinically significant depression at study entry (mean GDS=3.19±3.12; range: (0‐16)). All underwent tau (18F‐Flortaucipir) and amyloid‐β(11C‐Pittburgh Compound B) PET at study year 3 or 4 to derive measures of inferior temporal (IT) and entorhinal cortex (EC) tau and cortical amyloid. A mixed model was employed with dependent variable GDS (for each annual study visit), a random intercept and slope for each participant, and fixed predictors: tau (IT or EC, at study year 3/4), cortical amyloid (at year closest to tau), time (time of tau PET), covariates: age, sex, education; and the interaction of predictors with time.

Result

Baseline tau burden was associated with increasing GDS over time. In the model with predictor EC tau, EC tau X time was a significant predictor of GDS (β=0.48; t=3.80; 95% CI (0.23, 0.73); p=0.0002). Findings were similar for IT tau:(β = 0.71; t=3.67; 95% CI (0.33, 1.1); p=0.0002). By contrast, amyloid was not a significant predictor of longitudinal GDS in tau models: (β=‐0.14; t=‐1.58; 95% CI(‐0.23, ‐0.08); p=0.11).

Conclusion

Baseline tau, but not amyloid, is independently associated with increasing depressive symptoms over time. Future research incorporating longitudinal tau PET and individuals with more severe depressive symptoms is needed to delineate the temporal sequence of rising depressive symptoms and increasing tauopathy in preclinical AD.
Peripheral markers of vascular endothelial dysfunction show independent but additive relationships with brain‐based biomarkers in association with functional impairment in Alzheimer’s disease
Authors: Drake Jonathan D. , Chambers Alison , Ott Brian R. , Daiello Lori A.
Published: December 2020

Background

Current epidemiologic evidence suggests that potentially modifiable midlife vascular risk factors specifically influence propensity for later‐life Alzheimer's disease (AD)‐associated cognitive decline. Despite this, a large knowledge gap still exists with respect to characterization of the biological overlap of highly co‐morbid vascular and AD pathologies in clinical AD. Prior studies focusing on contributions of co‐existing imaging‐based white matter disease and amyloid burden have found independent and/or additive rather than interactive associations to risk for cognitive decline, however recent studies utilizing sensitive measures of vascular dysfunction or expanded panels of AD pathology indicate that more nuanced synergistic associations between these pathologies may exist in AD. We hypothesized that elevated plasma cell adhesion molecule (CAM) levels would correlate with severity of diagnosis and functional impairment in AD dementia and be concomitantly lower in mild cognitive impairment (MCI) and normal controls, respectively, and would act synergistically rather than independently with CSF AD biomarkers in this regard.

Method

Using generalized linear regression models, we examined cross‐sectional relationships of plasma vascular cell adhesion molecule‐1 (VCAM‐1), intercellular adhesion molecule‐1 (ICAM‐1), and E‐Selectin to baseline diagnosis and functional impairment staging (clinical dementia rating sum‐of‐boxes, CDR‐SB) in the Alzheimer's Disease Neuroimaging (ADNI) cohort (n=564). We also assessed for modifying effects of AD risk factors including ApoE‐ε4 genotype, and then tested for interactive association by combining CAMs with CSF biomarkers into CDR‐SB models in a subset with available CSF data (n=351).

Result

Higher mean VCAM‐1 (p=0.0026) and ICAM‐1 (p=0.0189) levels were found in AD versus MCI groups, however not in MCI versus cognitively normal groups. Only VCAM‐1 was linked with CDR‐SB scores (p=0.0157), and ApoE‐ε4 genotype modified this effect (p < 0.0001). Contrary to our expectation, we observed independent and additive rather than interactive associations of VCAM‐1 and CSF Aβ42, total tau, phosphorylated tau (P‐tau), and P‐tau/Aβ42 (all < p=0.01) in a combined CDR‐SB model (and ICAM‐1 to a lesser extent).

Conclusion

Our findings indicate independent rather than synergistic associations of plasma‐based biomarkers of vascular endothelial dysfunction and CSF biomarkers of AD pathology and neurodegeneration with AD‐related clinical impairment. Future longitudinal studies will be needed to validate these findings.
Diagnostic rates and amyloid positivity vary by definition of mild cognitive impairment
Authors: Jeffers Sharlene L. , Caldwell Jessica Z.K. , Miller Justin , Cummings Jeffrey L. , Bondi Mark W. , Wong Christina G.
Published: December 2020

Background

The concept of mild cognitive impairment (MCI) has evolved, and various approaches are used to classify MCI. Conventional MCI criteria, such as those used in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), rely on a single memory test to detect objective cognitive impairment. Actuarial neuropsychological criteria for MCI that incorporate comprehensive neuropsychological performance have been proposed to balance sensitivity and reliability. We applied both actuarial and conventional criteria to a sample of non‐demented older adults. Resulting groups were compared on diagnostic rates and amyloid positivity.

Method

51 cognitive normal (CN) and 62 MCI participants from the Center for Neurodegeneration and Translational Neuroscience were previously classified by a diagnostic consensus review. Actuarial criteria required impairment (>1 SD below means) on at least 2 tests within a cognitive domain. Conventional criteria were a modified version of ADNI criteria and required Mini Mental State Exam scores ≥ 24 and different cutoffs for Logical Memory based on education. Amyloid positron emission tomography (PET) determined amyloid status.

Result

Actuarial criteria classified 58 CN and 55 MCI, resulting in 77% agreement with consensus diagnosis. Conventional criteria diagnosed 36 CN and 77 MCI, resulting in 62% agreement with consensus diagnosis. McNemar tests indicated that the proportion of CN and MCI diagnoses were not significantly different between the actuarial and consensus (p=.23) but were significantly different between the conventional and consensus classifications (p=.03), with a 25% false positive rate for the conventional criteria. Chi‐squares demonstrated amyloid positivity was higher in MCI compared to CN for both the actuarial criteria (χ2(1)=31.16, p<.001, Φ=.54) and conventional criteria (χ2(1)=4.71, p=.03, Φ=.21). However, actuarial MCI was twice as likely to be amyloid‐positive than amyloid‐negative (Figure 1), whereas conventional MCI showed similar frequencies of amyloid‐positive and amyloid‐negative status (Figure 2).

Conclusion

Comparisons between MCI diagnostic methods found higher agreement between actuarial criteria and consensus diagnosis versus conventional criteria, which tended to over‐diagnose MCI. A stronger association between amyloid positivity and MCI diagnosis was found using actuarial criteria. Findings support the use of comprehensive neuropsychological criteria to increase the accuracy of identifying individuals with MCI who are at risk for AD dementia.
N‐of‐1‐pathways transcriptomic analysis reveals distinct subtypes of Alzheimer’s disease
Authors: Uyar Asli , Pandey Ravi S. , Preuss Christoph , Kotredes Kevin P. , Oblak Adrian L. , Logsdon Benjamin A. , Rizzo Stacey J. Sukoff , Howell Gareth , Lamb Bruce T. , Sasner Michael , Carter Gregory W.
Published: December 2020

Background

Data from recent studies supports the hypothesis that Alzheimer’s disease (AD) is a heterogenous spectrum disorder characterized by multiple genotypes and phenotypes. Several subtypes of AD can be identified based on genetic makeup together with clinical phenotypes, neuroimaging and molecular signatures at different stages of the disease. N‐of‐1‐pathways approaches have been proposed for single‐subject gene expression analysis enabling disease subtyping at the transcriptome level.

Method

We analyzed existing RNA‐Seq data generated from post‐mortem brain tissue in the Religious Order Study and the Memory and Aging Project (ROSMAP). We calculated Mahalanobis distance based similarity measures between pair‐wise subjects per gene, and also per KEGG pathway. Using these similarity measures, we applied k‐means clustering algorithm to identify distinct subtypes of AD‐relevant transcriptomic signatures. Alignment of the subtypes with eight different mouse models of AD enabled determination of the mouse model(s) best representing each subtype.

Result

In the ROSMAP cohort, 144 and 81 subjects were labeled as AD and Control, respectively, according to predefined thresholds for COGDX, BRAAK and CERAD scores. A total of 186 KEGG pathways were assessed and AD subjects were clustered into four subtypes based on the Mahalanobis distance n‐of‐1‐pathway scores. Neuropathology related pathways, including neurotrophin signaling, axon guidance and long‐term potentiation, were altered in Subtype3 (n = 15). Transcriptomic signatures in the brain of 5XFAD and CR1 mouse models represented similarity with Subtype3. Subtype2 (n = 45) revealed a strong metabolic response with altered lysine and glycan metabolisms similar to ABCA7 and TREM2 mouse models. Immunity related pathways were enriched in Subtype3 (n = 48) mapping to ABCA7 and APOE4 mouse models. Subtype4 (n = 36) did not reveal a significant pathway enrichment.

Conclusion

Accurate identification of disease subtypes is critical for understanding the distinct molecular mechanisms of AD to provide effective personalized treatment options. To our knowledge, this is the first time that n‐of‐1‐pathways approach has been utilized for subtyping AD based on single‐subject transcriptomic signatures. The AD‐relevant pathways altered in each subtype was associated with specific mouse models suggesting a potential for utilization of the matching “mouse model/AD subtype” pairs for preclinical testing of therapeutic targets.
Introducing the Study of Healthy Aging in African Americans (STAR): Looking back to move forward
Authors: Whitmer Rachel A , Barnes Lisa L , Richards Ashley E , Miles Sunita , Mayeda Elizabeth Rose , Glymour M Maria , Mungas Dan M , DeCarli Charles , Quesenberry Charles P , Gilsanz Paola
Published: December 2020

Background

Rates of dementia and Alzheimer’s disease are 40‐100% higher in African Americans versus non‐Hispanic whites. Yet there’s a lack of information on cognitive aging starting from midlife in African Americans and on lifecourse risk and protective factors. The Study of Healthy Aging in African Americans (STAR; RF1AG050782) is an ongoing cohort study of African‐American men and women ages 50+ aiming to (1) characterize heterogeneity in longitudinal change in cognition; (2) evaluate effects of exposure to vascular risk, psychosocial factors and early life experience over 50 years; and (3) evaluate structural MRI imaging markers of brain status on domain‐specific cognitive function.

Method

Enrollment is ongoing and as of Dec 2019, STAR has enrolled 722 individuals of which 333 have completed a second visit. Eligible individuals were non‐demented Kaiser Permanente Northern California (KPNC) members age ≥50 (equal sampling of ages 50‐64 and 65+) who participated in KPNC Multiphasic Health Checkups (MHC) during at least 1 MHC phase (1964‐1973 or 1977‐1985) out of 5. MHC data and KPNC electronic medical record data are linked to lifecourse factors, psychosocial factors, the Spanish and English Neuropsychological Assessment Scales (SENAS), anthropometrics, physical function, and saliva samples from in‐person interviews. In‐person interviews will be repeated every 16 months for a total of 3 follow‐up visits, with a random subsample receiving MRI scans.

Result

Among the first 722 participants enrolled, average baseline age was 68.4. The sample was 68.7% female and a greater proportion of women than men were 50‐64 yrs (46.2% vs 36.3%). 58.4% of men and 36.1% of women were married or living with a partner. 15.1% of the sample had ≤high school education and 18.6% completed graduate school. 30.9% report excellent or very good health and 34.2% were born in a Southern state. 20% of men and 18% of women reported ever being unfairly denied a bank loan. Participants had an average of 2.3 out of 5 MHC phases; almost 15% participated in all 5 phases.

Conclusion

STAR is an unprecedented lifecourse study of late‐life cognitive among African Americans with extensive prospectively collected health history.
Higher arterial stiffness but not blood pressure is associated with brain amyloidosis and preclinical AD in healthy adults: Results from the Emory Healthy Brain Study
Authors: Hajjar Ihab , Quyyumi Arshed , Zhao Liping , Hanfelt John , Goldstein Felicia C , Levey Allan I , Lah James J
Published: December 2020

Background

Hypertension increases the risk of Alzheimer’s Disease (AD) but blood pressure (BP) in older adults and cognition associated has been conflicting. We reported that arterial stiffness, which may antedate hypertension, better predicts cognitive decline. We investigated the association between BP and arterial stiffness with cerebrospinal fluid (CSF) levels of Amyloid beta 1‐42 (Ab42), tau, and P‐tau in the Emory Healthy Brain study (EHBS).

Methods

EHBS is an ongoing cohort study of cognitively normal adults (50‐75 years) established in 2016. Participants undergo CSF sampling and cognitive, BP and anthropometrics and arterial stiffness (carotid ‐femoral pulse wave velocity [PWV] measured using Sphygmocor device (Atcor Medical, Sydney, Australia) measurements. General Linear Model (GLM) analyses and logistic regression with receiver operator curve (ROC) were used. Preclinical AD was defined in this population at Ab42/tau<5.7 . Covariates included age, gender, race, hypertension diagnosis, and body mass index (BMI).

Results

In this analysis, 630 participants were included (age= 63 (SD=7), 70% women, 87% White, education mean= 16 (2) years, BMI=25.36 (3.57) kg/m2, MoCA score=26.6 (2.3), mean BP = 143/83 mm Hg, 35% were hypertensive, and PWV=6.3 (1.8) m/sec. Mean Ab42=565.7 (151.3), total tau=52.0 (22.8), P‐tau= 29.4(12.5), and Ab42/tau=12.8 (6.2) and 48 (7.6%) participants fit criterion for preclinical AD. Higher PWV was associated with lower CSF Ab42 (p<0.0001, Ab42 was lower by ‐14.1 pg/dl per each 1 m/s increase in PWV). After adjusting for covariates this decreased to ‐10.6 pg/dl for each unit increase in PWV (p=0.003). Neither SBP (p=0.98) nor DBP (0.45) were associated with Ab42. Higher PWV, but not BP, was also associated with pre‐clinical AD: for each unit increase in PWV, adjusted odds ratio for preclinical AD=1.35, 95%CI (1.18‐1.56), ROC=0.68. This remained true after adjusting for SBP and for all covariates. There was no association between PWV or BP and total tau or P‐tau (p>0.5).

Conclusion

Higher PWV, reflecting increased arterial stiffness, but not brachial BP is associated with greater brain Ab42 levels and the odds of preclinical AD in cognitively normal adults. PWV may offer a non‐invasive method for identifying healthy individuals with higher likelihood of pre‐clinical AD.
Clinical evaluation of allogeneic mesenchymal stem cells for Alzheimer's disease
Authors: Oliva Anthony A. , Baumel Bernard , Brody Mark , Agronin Marc , Herskowitz Brad , Bookheimer Susan Y , McClain‐Moss Lisa , Hitchinson Ben , Ramdas Kevin , Pena Andrea , Diaz Liliana A. , Green Geoff , Perez Carmen , Fuquay Ana , Castaneda Ricardo , Rodriguez Savannah , Delucca Johanna , Hare Joshua M.
Published: December 2020

Background

Therapeutic interventions that can broadly target the complex multiple pathological features of Alzheimer’s disease (AD) would be highly desirable approaches for treating these disorders. Mesenchymal stem cells (MSCs) have pleiotropic mechanisms of action that make them highly attractive as therapeutic candidates for AD. These include powerful anti‐inflammatory properties, ability to improve vascular functioning, ability to promote intrinsic regenerative mechanisms, and ability to promote beta‐amyloid clearance. Given these highly desirable properties of MSCs, we set out to clinically evaluate their safety and therapeutic potential for AD, using a proprietary formulation called Longeveron Mesenchymal Stem Cells (LMSCs).

Method

Central to this study is a Phase I clinical trial powered to evaluate the safety of LMSCs for mild AD. Provisional efficacy is also being evaluated. This trial is double‐blinded, randomized, and placebo‐controlled, and registered with ClinicalTrials.gov (NCT02600130). Trial oversight includes FDA, an IRB, and an independent Data Monitoring Safety Board (DSMB). Subjects are enrolled after passing a 3‐step screening process, which sequentially consists of clinical diagnosis of mild AD, a confirmatory MRI, and a confirmatory PET scan using a beta‐amyloid tracer. Enrolled subjects are randomized to receive a single intravenous infusion of a low‐dose of LMSCs (20 million cells), a high‐dose of LMSCs (100 million cells), or placebo. Evaluated for safety and effect are performed over the 1‐year follow‐up.

Result

This multi‐site trial has proceeded ahead of schedule, and was fully enrolled as of September 2019. The trial was designed to enroll 30 patients; ultimately, 33 patients were enrolled. Results support the high safety profile LMSCs for AD: the DSMB has found no safety concerns, and the primary objective of no treatment‐related serious adverse events (SAEs) within 1 month post‐treatment was met. Preliminary data suggest the feasibility of biomarker analyses for evaluating effect changes, and the final lock and unblinding is anticipated in late 2020.

Conclusion

The results support the conclusion that LMSCs are safe in AD patients, and that advancing to higher phase clinical studies is warranted. We thank the Alzheimer’s Association for supporting this research through the Part the Cloud Challenge on Neuroinflammation grant awards #PTC C‐16‐422443 and PTC‐CS‐19‐623225.
Neuroinflammation is associated with non‐REM sleep reduction in individuals without dementia
Authors: Tissot Cécile , Blais Hélène , Thompson Cynthia , Benedet Andréa Lessa , Pascoal Tharick A. , Therriault Joseph , Chamoun Mira , Lussier Firoza Z. , Savard Melissa , Rahmouni Nesrine , Stevenson Jenna , Mathotaarachchi Sulantha , Gauthier Serge , Gosselin Nadia , Rosa‐Neto Pedro
Published: December 2020

Background

Sleep disturbances and especially reduction of non‐REM (NREM) sleep are common in aging with accumulating evidence showing it might contribute to cognitive decline as well as increase the risk of developing dementia due to Alzheimer’s disease (AD). Lately, sleep disturbances and AD separately have been linked to increase in systemic inflammation. NREM sleep is thought to allow clearance of extracellular Aβ, which led to studies suggesting NREM could be an early biomarker of AD risk. The main objective of this study was to see the relationship between NREM sleep as assessed with polysomnography and neuroinflammation in vivo.

Method

25 individuals (18 cognitively unimpaired (CU) and 7 mild cognitive impairment (MCI)) underwent a [11C]PBR28 neuroinflammation‐PET scan, an MRI a full neuropsychological evaluation as well as a polysomnography. [11C]PBR28 standardized uptake value ratios (SUVRs) used the cerebellum grey matter as the reference region and was calculated between 0‐90 min post‐injection. A voxel based regression model evaluated the relationship between neuroinflammation as assessed by PET, and the total minutes of NREM sleep. The model’s covariates were age and diagnosis.

Result

We found a negative correlation between neuroinflammation and the total minutes of non‐REM sleep measured by a polysomnography. The regions showing neuroinflammation were the reticular formation, the arcuate nucleus of the medulla, the frontal cortex and especially the vmPFC as well as the insula and temporal poles. When we corrected for sex and years of education, results were similar.

Conclusion

These preliminary results show that less NREM sleep correlates with neuroinflammation, in the brain of CU and MCI individuals. The regions impacted, such as the reticular formation, the vmPFC and the insula are needed for arousal and alertness. The arcuate nucleus of the medulla is required for proper breathing. Finally, temporal poles are part of the first regions affected in AD, and later on in the disease, the medial frontal cortex also starts degrading. Our study adds to previous research showing a link between sleep disturbances and neuroinflammation in vivo and identifies anatomical correlates.
Interaction between amyloid and neuroinflammation on apathy along the Alzheimer’s disease spectrum
Authors: Stevenson Alyssa , Tissot Cécile , Kang Min Su , Benedet Andréa Lessa , Rahmouni Nesrine , Therriault Joseph , Pascoal Tharick A. , Chamoun Mira , Lussier Firoza Z. , Savard Mélissa , Mathotaarachchi Sulantha , Thomas Emilie , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

The Apathy Inventory is a rating scale given to informants in order to assess levels of apathy globally. This neuropsychiatric symptom is the most common noncognitive symptom in Alzheimer’s disease (AD), and it causes a great burden on diseased individuals and their caregivers. Even though it has been closely related to cerebrospinal fluid levels of neuroinflammation and amyloid, the interactive effect of pathologies is still unclear. Here we test the interaction between amyloid and neuroinflammation in the brain with apathy, along the AD spectrum.

Method

We assessed 59 individuals (38 cognitively unimpaired, 15 mild‐cognitive impairment, 6 AD) with [11C]PBR28‐neuroinflammation positron‐emission tomography (PET) and [18F]AZD4694‐amyloid PET. [11C]PBR28 and [18F]AZD4694 uptake value ratios (SUVRs) used the cerebellum grey matter as the reference region and were calculated 0‐90 min post‐injection and 40‐70 min post‐injection respectively. A voxel‐based regression model evaluated the relationship between the interaction of [18F]AZD4694 and [11C]PBR28 with Apathy scores. The model’s covariates were age, gender, education and diagnoses of the participants.

Result

We found a strong positive correlation between the interaction of [18F]AZD4694 and [11C]PBR28 with apathy. The most impacted regions were the medialfrontal cortex, in the superior portion and prefrontal cortex, as well as the anterior nucleus of the thalamus.

Conclusion

These preliminary results corroborate the link between amyloid and neuroinflammation, that potentiating the neuropsychiatric symptom apathy. The regions impacted are involved in proper behavior, such as the mediofrontal cortex. This study supports previous findings showing that amyloid and neuroinflammation are related to apathy.
Science and biomarkers of vascular contributions to cognitive impairment and dementia (VCID)
Authors: Corriveau Roderick A.
Published: December 2020

Background

The scientific framework of vascular contributions to cognitive impairment and dementia (VCID) was introduced in 2013 in response to the fact that most individuals diagnosed with Alzheimer’s dementia also have cerebrovascular pathology. The science of VCID brings into focus the hypothesis that vascular lesions may be a cause of cognitive impairment and dementia that occurs independently or, much more frequently, in the absence of a vascular diagnosis and in combination with one or more other brain pathologies.

Method

The scope of VCID research is defined as the aging neurovascular unit integrating, and failing to cope with, biological insults due to vascular disease, proteinopathy including Alzheimer’s pathology, metabolic disease, and immune activity. Moreover, the direct role of each pathology, and other co‐morbidities, in causing dementia is the subject of hypotheses that must be rigorously tested to move toward successful interventions.

Result

In addition to better mechanistic and clinical understanding of VCID, which will result in targets, rigorously validated clinical trial ready VCID biomarkers have emerged as a critical priority for addressing the burden of dementia worldwide. Barriers include leveraging traditional research measures into bona fide clinical trial ready biomarkers, determining whether risk measures can provide sufficiently robust signals to serve as a valuable clinical biomarkers, and ensuring that VCID biomarkers that move forward are valid and useful for clinical trials and interventions across diverse populations as well as in populations that experience health disparities. Large scale efforts are underway to meet these goals to provide VCID biomarkers to promote effective clinical trial engagement in VCID.

Conclusion

Because of the proven ability to prevent and treat cardiovascular disease and hypertension with population benefits for heart and stroke outcomes, it has now been proposed by many that understanding and targeting the biological mechanisms of VCID can have a similarly positive impact on public health. The development of VCID biomarkers is of critical importance in realizing this potential.
Selective loss of episodic memory of odor percepts is associated with progression to amnestic MCI or Alzheimer’s disease in cognitively healthy seniors
Authors: Albers Mark W , Albers Alefiya , Keim Abigail C , Cunin Camille , Hyman Bradley T , Gomez‐Isla Teresa , Blacker Deborah , Das Sudeshna , Locascio Joseph J
Published: December 2020

Background

Accumulating evidence indicates that the pathological changes of AD begin 15 years prior to symptom onset. There is an unmet need for accessible, affordable, and accurate means to screen cognitively normal individuals for preclinical AD. We previously developed the Percepts of Odor Episodic Memory (POEM) test battery, which assesses identification, memory and discrimination of odor percepts. In a pilot study, we demonstrated that elderly individuals with odor memory scores that fell below the 50% confidence intervals of the memory scores predicted by their odor discrimination and odor identification scores; these individuals were deemed “at risk” for progression to mild cognitive impairment and AD based on an enrichment in biomarkers for AD.

Method

We tested our olfactory “at risk” status as a predictor of future decline by administering the POEM test battery to 61 older individuals who were cognitively normal (CN) or expressed subjective cognitive concerns (SCC) and were followed longitudinally in the Massachusetts Alzheimer’ s Disease Research Center. These individuals were added to our original sample of 140 participants who had undergone olfactory testing. A Cox Proportional Hazards model was used in a subset of this expanded cohort (n=127) who were followed over an average of 4.22 years to determine whether the olfactory “at risk” status predicted a risk of clinical progression to a diagnosis of amnestic MCI or Alzheimer’s disease.

Result

28% of the CN and SCC participants followed longitudinally were deemed “at risk” based on a selective odor memory loss. These “at risk” participants demonstrated a higher risk of progressing to amnestic MCI or AD (HR = 3.45, (95% CI:1.13‐10.72, p=0.0278) over time while controlling for age, education, and sex. The effect of Group (CN vs SCC) and its interaction with “at risk” status were not significant.

Conclusion

Our results indicate that probing olfactory function with a threshold based on personalized identification and discrimination abilities identifies cognitively healthy seniors who progress to amnestic MCI or AD at faster rate over time. Future work is focused on developing a remote version of this test for self‐administration that can be used to screen cognitively healthy individuals for research studies and clinical trials.
Baseline findings of the Filipino Multicomponent Intervention to Maintain Cognitive Performance among High‐Risk Populations (FINOMAIN) study
Authors: Moral Maria Clarissa Ora Del , Dominguez Jacqueline C , Phung Thien Kieu Thi , Guzman Ma Fe P , Moral Reizelle Marie O Del
Published: December 2020

Background

FINOMAIN is an on‐going community study which integrates nutrition counselling (“the Philippine plate” or pinggang Pinoy), standard vascular care, and physical exercise in the form of a ballroom dance protocol known as INDAK (Improving Neurocognition through Dance and Kinesthetics). The multicomponent intervention will last for 48 weeks. Nutrition counselling and standard vascular care are given every third month, and INDAK is given twice a week for 60 minutes each session.

Method

FINOMAIN is a two‐arm, single‐blind, cluster randomized controlled trial of a multicomponent intervention to prevent cognitive decline among at‐risk elderly. A total sample of 71 participants (intervention=38, control=33) from 8 community clusters in Quezon City, Metro Manila joined the pilot study. Baseline data included demographics, cognitive profile, behavioural and functional profile, anthropometric measures, and medical and laboratory measures.

Result

The comprehensive assessment included (1) cognitive measures (Clinical Dementia Rating‐Sum of Boxes, Alzheimer’s Disease Assessment Scale‐Cog, Alzheimer’s Disease 8, Montreal Cognitive Assessment‐Philippines, Mini Mental State Examination‐Philippines, Verbal Fluency [animal and vegetables categories], Digit Symbol Substitution Test, Trail Making Test A and B, Number Cancellation Task, Logical Memory [immediate recall, delayed recall, and recognition], Digit Span [forward and backward], and Boston Naming Test), (2) behavioural and functional measures (Neuropsychiatric Inventory, Geriatric Depression Scale, EQVAS Health‐Related Quality‐of‐Life, Lawton’s Instrumental Activities of Daily Living, Disability Assessment for Dementia, Time Up and Go, Sit to Stand Test, Grip strength, Tinetti Balance and Gait, and Berg Balance Scale), (3) anthropometric measures, and (4) medical and laboratory measures (lipid profile, cholesterol level, fasting blood glucose, vitamin B deficiency, osteoarthritis, anemia, depression episode history, alcohol use, smoking history, and blood amyloid [MDS‐AD test]). The intervention and control groups are comparable in all baseline measures (p’s>0.05). A random sample of 38 was drawn from 52 individuals who attended an 8‐week INDAK training, to compose the intervention group. Compliance to INDAK protocol was 97.4% (>/=80%).

Conclusion

FINOMAIN is a much‐needed study to confirm the efficacy of multicomponent interventions in preventing cognitive decline among at‐risk elderly in a community setting. Data can be compared with other multicomponent programmes to select the most effective interventions for specific at‐risk populations.
Associations between depression symptoms and executive function in older adults with mild cognitive impairment: One‐year follow‐up
Authors: Costa Mônica Vieira , Ávila Rafaela , Cintra Marco Túlio , Pires Lívia Rabelo , Pires Ricardo Lage Guerra Lott , de Paula Jonas Jardim , Bicalho Maria Aparecida
Published: December 2020

Background

Psychiatric disorders are among etiologies for Mild Cognitive Impairment (MCI), one of the main one is depression. The relationship between depression and Alzheimer's disease (AD) is not yet fully understood and it is considered both, isolated risk factor and prodrome stage of AD. The aim of this work is to investigate if older adults with MCI associated with significant depressive symptoms, compared with those without these symptoms, will have different executive functions outcomes after one‐year follow‐up.

Method

Repeated measures ANCOVA with Bonferroni post‐hoc analysis was used with cognitive variables at baseline and follow up evaluation as dependent, presence of significative depression symptoms at baseline as independent while controlling for covariates age, gender and years of formal education. Depressive symptoms were measured by 15‐item geriatric depression scale and the cutoff point was 6. Executive functions as inhibitory control e cognitive flexibility were assessed by Five Digit Test, working memory by Digit Span Test and phonemic verbal fluency by letter S. Patients started depression treatment at baseline.

Result

Were included 170 participants (125 without depressive symptoms and 45 with symptoms), mean age 74.44, 68 women, mean years of formal education was 4,54. Among these, 99 (29 with depressive symptoms) complete all tests in the two assessments. Due to cognitive impairment, some of them were unable to even start cognitive flexibility test. Results indicated there was a significant effect of depression symptoms at baseline on cognitive flexibility ability [F (1.94) = 7,271, p = 0.008). Participants with depression presented a significant improvement (p = 0.006) on cognitive flexibility average from baseline (11.60) to the end of follow up (7.24). For those without symptoms of depression at baseline, the averages were 6.32 at baseline and 5.98 at follow‐up. There was no significant effect of depressive symptoms on the other cognitive skills assessed when considering these covariates.

Conclusion

Comparing participants with and without depression symptoms at baseline, there was an improvement in cognitive flexibility in the former group. We think this result could be related to effect of depression treatment.
Tau deposition assessed by [18F]MK6240 PET is associated with longitudinal decrease in grey matter density across the spectrum of Alzheimer’s disease
Authors: Lussier Firoza Z. , Pascoal Tharick A. , Therriault Joseph , Tissot Cécile , Savard Mélissa , Benedet Andréa Lessa , Kang Min Su , Arias Jaime Fernandez , Wang Yi‐Ting , Mathotaarachchi Sulantha , Stevenson Jenna , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2020

Background

Reduction in grey matter (GM) is a well‐established neuroimaging finding in Alzheimer’s disease (AD). Here, we sought to determine whether baseline tau‐PET using the high‐affinity tracer [18F]MK6240 is predictive of longitudinal changes in GM across the AD spectrum.

Method

Baseline [18F]MK6240 PET data and longitudinal structural MRI was acquired for 79 participants in the TRIAD cohort (47 CN, 20 MCI, 12 AD). [18F]MK6240 standardized uptake value ratio (SUVR) were calculated 90‐110 minutes post‐injection using cerebellar GM as the reference region. T1‐weighted MR images were segmented into probabilistic GM and WM maps, which were non‐linearly registered to the ADNI template using DARTEL and smoothed with an 8mm FWHM Gaussian kernel. Voxel‐based morphometry (VBM) was run on GM and WM maps. Longitudinal changes in GM density were indexed by voxel‐wise percentage change in VBM‐derived GM. Voxel‐based regression analyses were conducted to examine associations between baseline [18F]MK6240 SUVR and change in GM density, with age, gender, years of education, diagnosis, and time interval between MRI acquisitions employed as covariates.

Result

Baseline [18F]MK6240 SUVRs in Braak I/II, III/IV, and V/VI were significantly correlated with longitudinal decrease in GM density in the lateral and medial temporal lobe, including hippocampal regions. All results survived correction for multiple comparisons using random field theory at p < 0.001.

Conclusion

Our results suggest that tau pathology at baseline is associated with the progression of GM atrophy over time in brain regions vulnerable to AD pathological changes, providing evidence that tau‐PET may identify individuals who are more susceptible to atrophy.