bluuebunny/crossref_metadata_2025 huggingface dataset:
Hippocampal‐retrosplenial connectivity is associated with tau pathology and memory in cognitively normal older adults
Authors: Ziontz Jacob , Adams Jenna N. , Baker Suzanne L. , Jagust William J.
Published: December 2020

Background

Tau pathology is thought to spread transneuronally from medial temporal lobe (MTL) to medial parietal lobe (MPL) in cognitively normal older adults, but it is not known precisely which structures and processes are involved. We hypothesize that functional connectivity influences tau spread from hippocampus to the MPL, with consequences for cognition.

Method

Ninety‐seven cognitively normal older adults from the Berkeley Aging Cohort Study (76.4±6.1 years) received tau‐PET with 18F‐Flortaucipir, Aβ‐PET with 11C‐PiB, and resting state fMRI. We assessed unilateral resting state functional connectivity (FC) between retrosplenial cortex (RsC), an area of known connectivity with the MTL, and hippocampus (HC), anterolateral entorhinal cortex (alEC), and posteromedial entorhinal cortex (pmEC). We then used linear models to examine the association of FC strength (β‐weight) between RsC and the proportion of suprathreshold voxels for tau accumulation (SUVR>1.4) in MPL. Finally, we examined interactions between FC strength and tau to predict downstream tau accumulation and memory.

Result

Semipartial region‐region correlations revealed RsC FC with HC in both hemispheres [Left: β=0.33, p<0.001, Right: β=0.40, p<0.001], but not with alEC or pmEC in either hemisphere (Figure 1). Adjusting for age, sex, and amyloid status, proportion of suprathreshold voxels in MPL was associated with RsC‐HC connectivity strength bilaterally [Left: β=0.153, p=0.004; Right: β=0.186, p=0.002], but not RsC‐alEC or RsC‐pmEC connectivity strength (Figure 2). In addition, proportion of suprathreshold voxels in MPL was associated with the interaction between RsC‐HC connectivity strength and hippocampal tau (pvc‐SUVR) [Left: β=0.586, p=0.008; Right: β=0.613, p=0.022] (Figure 3a). Adjusting for age, years of education, and practice effects, the interaction between RsC‐HC connectivity strength and MPL tau (left hemisphere only) was associated with spatial memory performance [β=‐12.773, p=0.002] (Figure 3b).

Conclusion

In cognitively normal older adults, RsC exhibits FC with hippocampus but not alEC or pmEC, and the strength of this RsC‐HC connectivity predicts tau accumulation in the MPL, suggesting that tau pathology spreads to MPL through the hippocampus. Further, RsC‐HC connectivity modulated the relationship between MTL and MPL tau as well as between MPL tau and spatial memory, indicating that MTL‐MPL FC may influence the spread of tau and cognitive function.
ApoE4 associated with higher tau accumulation independent of amyloid burden
Authors: Neitzel Julia , Franzmeier Nicolai , Rubinski Anna , Binette Alexa Pichet , Poirier Judes , Villeneuve Sylvia , Ewers Michael ,   PREVENT‐AD Research Group and the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2020

Background

ApoE4 carriage is the strongest genetic risk factor for developing late‐onset AD. Previous studies suggest that ApoE is involved in the amyloid pathway, and that elevated AD risk in ApoE4‐carriers is conferred by higher beta‐amyloid levels. However, recent animal work suggests that ApoE4 is also associated with increased tau pathology (Shi et al, 2017, Nature). Yet, it is unclear whether this association between ApoE4 and tau pathology translates to humans. Thus, the main aim of the current study was to test whether ApoE4 has an amyloid‐independent effect on cross‐sectional and longitudinal tau‐PET in humans.

Method

For longitudinal analyses, we included baseline AV45 amyloid‐PET and longitudinal AV1451 tau‐PET (∼1.3 years follow‐up) from 111 ADNI participants (42ε4+,69ε4‐) including cognitively normal (CN), mild cognitive impairment (MCI) and AD dementia (ADD). For cross‐sectional analyses, we additionally included tau‐ and amyloid‐PET from 254 CN and MCI participants (83ε4+,171ε4) from ADNI (not overlapping with the longitudinal ADNI sample) plus 128 CN participants (53ε4+,75ε4‐) from the PREVENT‐AD cohort (Table 1). Average baseline PET‐SUVR and annual change rates were quantified within 68 Freesurfer‐defined cortical brain regions (Figure 1). Analysis of covariance (ANCOVA) was used to investigate differences in cross‐sectional tau‐PET or longitudinal tau‐PET changes between ApoE4 carriers versus non‐carriers, controlling continuous measures of global amyloid‐PET. Post‐hoc subgroup analyses tested potential ApoE4 effects with a more rigorous control of amyloid‐PET by including only participants with the same amyloid status.

Result

For cross‐sectional analyses, we found ApoE4 carriers to show higher tau‐PET compared to non‐carriers after controlling global amyloid‐PET (Figure 2). Across samples, medial temporal areas (entorhinal cortex,parahippocampus) showed the strongest ApoE effect. The amyloid‐independent effect of ApoE4 on medial temporal tau‐PET remained significant in post‐hoc analyses of only amyloid‐positive ADNI or amyloid‐negative PREVENT‐AD participants (data not shown). For longitudinal analyses, we found significantly higher tau‐PET changes in ApoE4 carriers controlled for baseline amyloid‐PET (Figure 3). Strongest effects were found in posterior brain areas (lateral occipital, superior parietal) which remained significant in post‐hoc subgroup analyses.

Conclusion

The current results suggest that there is an amyloid‐independent association between ApoE4 and elevated tau‐PET specifically in medial temporal regions.
Sensory impairments and cognition in a diverse cohort: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study
Authors: George Kristen M , Peterson Rachel , Gilsanz Paola , Mayeda Elizabeth Rose , Mungas Dan M , Glymour M Maria , Brenowitz Willa D , Whitmer Rachel A
Published: December 2020

Background

Sensory impairments have been associated with poor cognition in primarily non‐Latino White cohorts. We used the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study to examine racial/ethnic differences in the association between sensory impairments and cognition.

Method

KHANDLE includes diverse, community‐dwelling adults ages 65+ living in North California and aims to evaluate how race/ethnicity influence brain health. Analysis included 1,623 Asian (24%), Black (26%), Latino (18%), and White (32%) individuals. Participants rated their hearing and vision and were classified as impaired (self‐report of “Fair” or “Poor”) or not impaired (“Excellent,” “Very Good,” or “Good”) in hearing, vision, or both. Cognition was measured using the Spanish and English Neuropsychological Assessment Scales (SENAS). Cognitive test scores for executive function, semantic memory, and verbal episodic memory were z‐standardized and averaged for a global z‐score. Linear regression was used to estimate the associations between sensory impairments and cognition, adjusted for age, gender, race, education, income, waist circumference, physical activity, alcohol consumption, and ever smoking tobacco. Race/ethnicity interaction terms were tested.

Result

Participants had a mean age of 76 (SD=7). Whites (23.9%) were the most likely to report hearing impairment followed by Latinos (19.4%), Asians (18.0%), and Blacks (11.6%). Latinos (13.2%) were the most likely to report vision impairment followed by Blacks (12.5%), Asians (10.3%), and Whites (8.6%). Blacks (16.0%) were the most likely to report concurrent vision and hearing impairment followed by Latinos (11.8%), Asians (11.3%), and Whites (9.8%). Associations between sensory impairments and cognition did not differ by race/ethnicity. Associations remained consistent across the cognitive domains but were strongest for semantic memory. Hearing impairment was not associated with global cognition [β(95% CI):‐0.04(‐0.12, 0.05)]. Participants with visual impairments had worse global cognition than those without visual impairment [β:‐0.18(‐0.27, ‐0.09)]. Compared to those with no impairments, global cognition did not differ for participants with one impairment [β:‐0.03(‐0.12, 0.05)], but was significantly worse in those with dual sensory impairments [β:‐0.20(‐0.33, ‐0.08)].

Conclusion

We found no racial/ethnic differences in the association between sensory impairments and cognition. Self‐reported vision impairment was associated with poor cognition, but self‐reported hearing impairment was not.
Neurocognitive testing in a diverse linguistic setting: Measurement invariance of ICMR‐Neuro Cognitive Tool Box across five languages
Authors: Alladi Suvarna , Varghese Feba Anna , Paplikar Avanthi , Sharma Meenakshi ,   ICMR Neurocognitive Tool Box Consortium
Published: December 2020

Background

Recently there have been ongoing efforts to harmonise research across dementia cohorts from different centres and countries. Establishing comparability of cognitive test performance across languages and educational levels therefore becomes crucial. Differences due to educational disparity or linguistic variability will need to be differentiated from more genuine differences due to disease. This is especially important in countries like India that are characterised by a socioculturally heterogeneous population. To address this, the Indian Council of Medical Research‐Neuro Cognitive Test Battery (ICMR‐NCTB) was developed and validated to diagnose dementia in five Indian languages. In this study, we aimed to investigate the cognitive construct and comparability of the ICMR‐NCTB across five Indian languages using confirmatory factor analysis and measurement invariance.

Methods

991 healthy literate controls with normal cognition (Telugu = 302; Hindi = 191, Malayalam = 195; Bengali = 135 and Kannada = 168) were assessed with the ICMR NCTB which includes tests of attention/executive function, verbal and visual episodic memory, language and visuospatial Functions. The dimensional structure of ICMR‐NCTB was studied with regard to its cognitive constructs, and measurement invariance across five different Indian languages was evaluated.

Results

Confirmatory factor analysis of the data demonstrated that a five factor model in which the tests were divided into the cognitive domains: attention/executive function, verbal memory, non‐verbal memory, language and visuospatial functions provided the best model fit both within and across all five languages. Analysis of factorial invariance across groups indicated that configural and metric invariance were achieved, thereby suggesting that the tests of the ICMR‐NCTB measure the same cognitive construct across different languages. On analyzing scalar invariance, non‐invariance of intercept was demonstrated, indicating a possible measurement bias between the different language groups.

Conclusions

The study results indicate that cognitive constructs measured by the tests in the ICMR‐NCTB across the five different Indian languages are the same. However, there are differences that influence the performance of subjects across languages groups. The study findings have significant implications for harmonising cognitive test data in dementia research that involves linguistically diverse cohorts.
Pharmacokinetics and safety profile of intramuscular administration of allopregnanolone in patients with Alzheimer’s disease
Authors: Hernandez Gerson D. , Lopez Claudia M. , Wang Yiwei , Rodgers Kathleen E. , Schneider Lon , Brinton Roberta Diaz
Published: December 2020

Background

Allopregnanolone (Allo) is a novel regenerative therapeutic that also reduces the burden of Alzheimer’s disease (AD) pathology. We have previously established safety, tolerability and a pharmacokinetic profile of Allo administered intravenously in AD patients. In this phase 1b trial, we assess the safety, tolerability and pharmacokinetics of Allo administered via an intramuscular injection in patients with AD.

Method

An open label, multiple ascending dose, phase 1b clinical trial was conducted in patients ranging from mild cognitive impairment due to AD to moderate AD. Men and women age ≥ 55 years, with a MMSE score ≥10 were recruited to the study. Patients had previously participated in the phase 1 study of Allo administered IV. Participants received weekly intramuscular injections with a dose escalation regimen of 4, 8, 12 and 16mg of Allo. Blood was collected before the injection and after at the following timepoints: 5, 15, 30, 45 minutes; 1, 2, and 4 hours. Primary outcomes included safety and tolerability parameters. Secondary endpoints included PK parameters: tmax (time to reach maximum plasma concentration), Cmax (maximum plasma concentration), AUC0‐last (area under the plasma concentration‐time curve from time zero to time of the last measured concentration above the limit of quantification), AUC0‐inf (area under the plasma concentration‐time curve from zero to infinity), t½ (terminal elimination half‐life).This is part of an IV to IM bridging study to determine the IM formulation dose that is equivalent to the IV Allo dosing (Clinicaltrials.gov: NCT03748303).

Result

A total of 6 participants have completed the pharmacokinetic assessment. Injection was well tolerated and did not elicit adverse events. Pharmacokinetic profile indicates direct rank order and near dose proportionality for both Tmax and AUCinf. Second group dosing and study procedures are currently underway.

Conclusion

Intramuscular administration of allopregnanolone was well tolerated, and did not elicit adverse effects in the initial cohort. Pharmacokinetic profile indicates direct rank order and near dose proportionality for both Tmax and AUCinf. Acknowledgments: Alzheimer’s Association Part The Cloud, Alzheimer’s Drug Discovery Foundation.
Sex differences in body composition in non‐demented individuals with autosomal dominant Alzheimer’s disease
Authors: Ramirez‐Gomez Liliana A , Fuller Joshua T , Rabin Jennifer S , Bocanegra Yamile , Guzman‐Velez Edmarie , Vila‐Castelar Clara , Pardilla‐Delgado Enmanuelle , Schoemaker Dorothee , Gatchel Jennifer R , Baena Ana , Giraldo‐Chica Margarita , Munoz Claudia , Tirado Victoria , Henao Eliana , Lopera Francisco , Quiroz Yakeel T.
Published: December 2020

Background

Body mass index (BMI) is a known risk factor for Alzheimer’s disease (AD). Research with autosomal dominant Alzheimer’s disease (ADAD) has shown a relationship between lower BMI, greater amyloid burden and worse memory performance in presymptomatic mutation carriers. Women have a higher incidence of AD, and may be more susceptible to AD‐ related pathology. However, little is known about the effects of sex/gender on BMI in individuals at increased risk for AD. As carriers of ADAD mutations are destined to develop early‐onset dementia, they allow us to investigate sex differences without aging confounds known to vary by sex (i.e., life expectancy, menopause). We sought to examine sex differences in BMI in non‐demented mutation carriers and non‐carriers from a Colombian kindred with ADAD.

Method

191 carriers of the Presenilin‐1 E280A mutation (104 females; age range: 18‐55 years) and 261 age‐matched non‐carriers (165 females) were included. All participants completed clinical and cognitive assessments, including BMI (kg/m2) measures, MMSE and CERAD Word List tests. Mann‐Whitney‐U test was used to examine sex differences on BMI. General linear models were used to examine the associations between BMI, MMSE and memory, controlling for age and education.

Result

Compared to non‐carriers, carriers had lower BMI (carriers: 23.05 +/‐ 3.65; non‐carriers: 24.26 +/‐ 3.92, p=0.002). In carriers, lower BMI was associated with worse performance on MMSE (r=0.49, p=0.001). Compared to male carriers, female carriers had greater BMI (males: 22.4 +/‐ 3.3, females: 23.5 +/‐ 3.7, p=0.04), and performed worse on the MMSE (males: 28.19 +/‐1.8, females: 27.91 +/‐1.91, p=0.04). There was a trend for female carriers to also have worse memory performance (p=0.06). Sex differences were not observed in non‐carriers. There were no associations between BMI and memory.

Conclusion

There are sex differences in body composition in carriers of ADAD without dementia. These findings suggest that changes in BMI may reflect early signs of abnormal systemic responses to AD‐related pathology. Future studies should examine longitudinal changes in BMI, from preclinical to clinical stages, and other contributing factors (e.g. vascular risk factors and sex hormones) to determine the potential role of BMI as a risk factor for dementia.
Physical activity and vascular cognitive health: Who may benefit most?
Authors: Shaaban C Elizabeth , Chang Chung‐Chou H , Ganguli Mary
Published: December 2020

Background

The majority of people with dementia in the population have mixed neurodegenerative and cerebrovascular pathology. Stroke and dementia share many risk factors, and both have potential to impair function and quality of life. Therefore, a comprehensive understanding of vascular brain and cognitive health should integrate stroke and dementia. The association of physical activity (PA) with lower dementia risk suggests PA is a promising strategy to reduce stroke and dementia, and it is critical to understand who may benefit most.

Methods

Within a population‐based cohort study, with up to 10 years of follow‐up, we indexed PA by cumulative weekly minutes walked for exercise. We used survival analysis classification and regression trees (CART) to test which sub‐groups are at greatest risk for a composite outcome of stroke/dementia and to determine optimal PA cutoffs associated with no stroke/dementia in sub‐groups of interest.

Results

Of 1,982 participants recruited from voter rolls, 1,624 were free from stroke and dementia at baseline and had follow‐up visits. 62% were female, 5% Black, 42% had > high school education, 21% were APOE4+, and 65% were hypertensive at baseline. During 9,354 person‐years of follow‐up, N=133 developed stroke/dementia. The median cumulative walking time was 60.0 minutes. Among those with high PA, a group aged 82‐94 + APOE4+ had the highest risk (relative hazard ratio(RHR) of 6.4). In those with low PA, a group aged 82‐99+≥HS education+Black had the greatest risk of dementia/stroke (RHR=4.1). When examining thresholds in women, those APOE4‐, and those with hypertension (HTN), the optimal cutpoint was around 40‐50 minutes across a mean follow‐up time of nearly 6 years. Thresholds could not be determined for men, APOE4+, and those without HTN, likely due to smaller within strata sample sizes; however, the overall population cutpoint of 160 minutes suggests that thresholds in men, APOE4+, and those without HTN may be higher.

Conclusions

Our results add evidence that PA can reduce risk of stroke and dementia. Women, those who are APOE4‐, and those with HTN may need fewer minutes of PA than the overall population in order to benefit. These findings are relevant from a personalized medicine perspective.
Plasma neurofilament light chain levels reflect caregiver burden and social cognition measures in familial frontotemporal lobar degeneration (FTLD)
Authors: Heuer Hilary W. , Rojas Julio C. , Toller Gianina , Rankin Katherine , Brushaber Danielle , Appleby Brian , Bordelon Yvette M. , Dickerson Brad C. , Kimiko Domoto‐Reilly , Faber Kelley , Foroud Tatiana M. , Forsberg Leah K , Ghoshal Nupur , Grant Ian , Graff‐Radford Neill R. , Grossman Murray , Hsiung Ging‐Yuek Robin , Huey Edward D. , Karydas Anna M. , Kaufer Daniel , Kerwin Diana R. , Lagone Emma , Litvan Irene , Ljubenkov Peter A. , Mackenzie Ian R. , Mendez Mario F. , Miller Bruce L. , Onyike Chiadi U. , Ramos Eliana Marisa , Rascovsky Katya , Roberson Erik D. , Tartaglia Carmela , Weintraub Sandra , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. ,   ARTFL/LEFFTDS Investigators
Published: December 2020

Background

Plasma NfL is a sensitive marker of axonal injury that is elevated in symptomatic FTLD and asymptomatic carriers of FTLD‐associated genetic mutations at short‐term risk of phenoconversion to mild behavioral or cognitive impairment or dementia. In carriers of FTLD‐associated genetic mutations, NfL is associated with clinical measures of disease severity.

Method

Plasma NfL was measured using single molecule array technology in baseline blood samples from 290 participants in the ARTFL/LEFFTDS consortia. Participants included 181 asymptomatic mutation carriers (C9orf72, GRN, and MAPT); 45 with mild impairment (MBI/MCI), and 64 with dementia. 103 family members without FTLD‐associated mutations served as asymptomatic controls. Social cognition scales were obtained through clinical evaluation at baseline, year 1, and year 2. Stepwise linear regressions assessed NfL relationships with baseline social cognition measures. Linear mixed models were used to test the ability of baseline NfL to predict longitudinal changes. Analyses corrected for age, sex, and genotype.

Result

At baseline, plasma NfL correlated with all measures of social cognition, regardless of genotype. Associations were strongest for the Revised Self‐monitoring Scale (RSMS;β = ‐.50, p < .001), total score of the Social Norms questionnaire (β= .48, p < .001), and caregiver burden (Zarit burden;β = .55, p < .001). Regardless of disease severity, baseline NfL related to worse RSMS scores over time (‐3.7 points at year 2/ LogNfL unit increase, 95% CI ‐1.7 to ‐5.7, p < .001). In MBI/MCI, higher baseline NfL was associated with worse longitudinal scores on the Social Norms questionnaire (‐5.9 points at year 2/LogNfL unit increase, 95% CI ‐1.1 to ‐10.7, p = .016). No associations were seen in asymptomatic non‐carriers.

Conclusion

In this familial FTLD cohort, plasma NfL is correlated with clinical measures of social cognition and caregiver burden. Higher baseline plasma NfL concentrations are associated with worsening self‐monitoring and social norms scores over time. These associations suggest that NfL is correlated with clinically meaningful measures that may be relevant to therapeutic development.
The role of Native American ancestry in Alzheimer’s disease and related dementias
Authors: Sariya Sanjeev , Rentería Miguel Arce , Reyes‐Dumeyer Dolly , Arango Silvia Mejia , Obregon Alejandra Michaels , Samper‐Ternent Rafael , Wong Rebeca , Mayeux Richard , Barral Sandra , Tosto Giuseppe
Published: December 2020

Background

Despite several genetic variants identified by large genetic studies, late‐onset Alzheimer’s disease and related dementias (ADRD)’s missing heritability remains extensive. Aging has accelerated globally and over 70% of the elderly population reside in developing countries; by 2050 people with dementia in Latin America is projected to increase 4‐fold. Hispanics are the largest ethnic minority in the US, and have a unique genetic background characterized by admixture of various proportions of European, African, and Native‐American ancestry. Although studies have reported higher incidence and prevalence of ADRD in Hispanics, there are limited investigations on the effect of ancestry on ADRD, in particular Native‐American ancestry.

Method

The analysis sample consisted of 1,702 Mexicans from urban and rural areas, part of the national sample of the Mexican Health and Aging Study (MHAS) for whom genotyping array, sociodemographic and clinical data were available (128 cases, 524 mild cognitive impairment [MCI], 1050 controls; 57% female; age 60‐98). Estimated proportions of European, African, and Native American ancestries were employed as predictors in regression and survival models (3‐year follow‐up) to study their associations with risk of ADRD or conversion from cognitively normal to MCI or ADRD.

Result

The MHAS sample exhibited a large Native‐American component (63%) followed by European (33%) and African (4%) (N = 1,702; Figure 1, right panel). For comparison purposes, we show Mexicans from the 1000genomes project (N = 66; Figure 1, left panel) which exhibited a larger European component (48%), and lower Native‐American component (48%). Regression analyses showed Native‐American ancestry to be significantly associated with higher risk of ADRD (OR = 1.19, 95%CI: 1.12‐1.28). Native ancestry also significantly predicted conversion from cognitively intact status to MCI or ADRD (HR = 1.11, 95%CI: 1‐1.24). APOE‐e4 was not associated with ADRD (OR = 1.5, p‐value = 0.720)

Conclusion

The MHAS provides a true representation of the genetic landscape of Mexico yielding a Native‐American enriched cohort, compared to small, geographically‐limited studies such as the 1000 genomes project. Native‐American ancestry increases the risk for ADRD and might explain the observed higher frequency of ADRD among Hispanic populations. Lastly, we confirmed lack of association for APOE as previously reported in smaller investigations.
Transcriptomic profiling of brain amyloidosis using peripheral blood‐based gene expression
Authors: Sanjay Apoorva Bharthur , Svaldi Diana Otero , Apostolova Liana G.
Published: December 2020

Background

In an effort towards pre‐symptomatic risk assessment, precision medicine and biomarker development in AD, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data with respect to brain amyloidosis.

Method

356 participants were identified from the ADNI cohorts who had corresponding blood gene expression, Florbetapir SUVR, neurodegeneration measures and CSF measures (Table 1) (CN=120, EMCI=130, LMCI=72 and AD=34). Differentially expressed genes between diagnostic groups from ∼50,000 transcripts(p<0.001) were identified. Pairwise Euclidean distance between genes was used to construct a gene‐gene distance matrix followed by K‐means clustering to identify clusters of genes which shared similar transcriptomic profile (Figure 1). Gene enrichment analysis was performed to identify the most relevant biological process associated with each cluster. Principal component analysis was done to assign the weight of first principal component as the “eigen” gene; a data vector representing the whole cluster. The eigen genes were used to assess the association of the clusters with amyloid SUVR, hippocampal volume, entorhinal thickness, CSF Abeta and p‐tau measures. We defined driver genes, within each cluster, as transcripts whose correlation exceeded the eigen gene’s association with amyloidosis. Finally, classification algorithms (logistic‐regression and SVM) using the driver genes identified from ADNI were used to assess the diagnostic prediction (control vs amnestic MCI) in an external (ImaGene) dataset.

Result

We identified five clusters with overrepresentation of biological processes highly relevant to AD pathogenesis ‐ mitochondrial function, protein oligomerization, TGF beta signaling, protein autophosphorylation and MAPK activation. All five clusters were significantly associated with Florbetapir SUVR and CSF Abeta measures (p<0.05) (Figure 2). Many of the driver‐genes showed similar correlation with amyloid SUVR in ImaGene (Table 2). The SVM and logistic‐regression classifiers achieved an AUC of 0.81 and 0.82 respectively in predicting amnestic MCI from driver‐gene data in ImaGene (Figure 3).

Conclusion

We identified five AD‐relevant clusters of transcripts from peripheral blood and validated this association in an independent dataset. Systems level genetic signatures from blood can serve as a highly important risk analysis and screening tool for amyloidosis.
Dietary intake of the bioactive pelargonidin may slow decline in multiple cognitive abilities
Authors: Holland Thomas Monroe , Agarwal Puja , Wang Yamin , Desai Pankaja , Dhana Klodian , Barnes Lisa L , Bennett David A , Booth Sarah , Morris Martha Clare
Published: December 2020

Background

Research has demonstrated a positive relationship between cognitive abilities and dietary intake of flavonoids, bioactives found in foods that have known antioxidant and anti‐inflammatory characteristics. We advance past research by investigating the association of dietary intake of an anthocyanidin subclass constituent, pelargonidin, found in berries especially, strawberries, on change in global cognition, episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability.

Methods

This study was conducted in 961 Rush Memory and Aging Project (MAP), a prospective cohort study, consisting community‐dwelling participants in Chicago (aged 58 to 100 years), who were followed for an average of 6.3 (±2.7) years. MAP participants were asked to complete a validated semi‐quantitative food frequency questionnaire at baseline. Cognitive abilities were assessed annually using a battery of 19 standardized tests. Cognitive domain scores were regressed on baseline energy‐adjusted flavonoid pelargonidin, which was distributed into quartiles based on dietary intake in linear mixed models.

Results

Our analytical sample of 961 participants had an average age of 81.4 (±7.2) years, and 15 (±3) years of education, 74% were female, 22% had at least one APOE‐ɛ4 allele, and 42% had a smoking history. Higher intake of pelargonidin, intake was inversely associated with decline in global cognition and multiple cognitive domains. In models adjusted for age, sex, education, APOE‐ɛ4, late life cognitive activity, smoking and physical activity, dietary intake of the highest quartile versus lowest quartile of pelargonidin was associated with slower decline in global cognition (β estimate=0.02, p=0.03; p‐trend=0.02), episodic memory (β=0.03, p=0.045; p‐trend=0.03), semantic memory (β=0.03, p=0.02; p‐trend=0.02), perceptual speed (β=0.02, p=0.02; p‐trend=0.01) and visuospatial ability (β=0.03, p=0.02; p‐trend=0.050). Non‐significant working memory was suggestive (β=0.02, p=0.07; p‐trend=0.07).

Conclusion

Dietary intake of the anthocyanidin subclass constituent, pelargonidin, may slow decline of cognitive abilities in multiple domains with older age.
Neuropsychological test performance among Hispanic and white older adults
Authors: Guerrero‐Berroa Elizabeth , Kluger Alan , Schmeidler James , Sailor Kevin , Lizardi Humberto , Phillips Ruby , Golomb James , Reisberg Barry
Published: December 2020

Background

Neuropsychological tests are useful in the assessment of cognitive functioning, but whites have consistently performed better than other racial/ethnic groups. The utility of some of these tests has not been fully established for Hispanic elderly, and especially among relatively highly educated Spanish‐speaking Hispanics.

Method

Seventy‐five pairs of Spanish‐speaking Hispanics and whites with normal to moderately impaired cognitive functioning (Global Deterioration Scale [GDS] were matched on sex, GDS rating, and clinical diagnosis; and strongly overlapped on age (Mean±SD, Spanish‐speaking Hispanics = 67.7±10.1, whites = 68.2±10.4) and years of education (Mean ±SD, Spanish‐Speaking Hispanics = 12.4±3.8, whites = 13.3±3.5) in a cross‐sectional study. Repeated measures analyses of covariance (ANCOVA) compared performance on seven neuropsychological tests in the two ethnic groups. Additional analyses compared English‐speaking Hispanics to whites (GDS 4).

Result

Spanish‐speaking Hispanics performed more poorly than whites on the WAIS‐Digit Symbol Substitution subtest (p< .001), a task of executive function and psychomotor speed. This result was significant after adjustment for multiple comparisons (seven neuropsychological tests).Two other tests showed significantly poorer performance (p< .05) in the Hispanics, delayed recall of the NYU‐Guild Paragraph Test (p= .029) and delayed recall of the Guild Paired Associates subtest (p= .010). For all seven neuropsychological tests,nondemented (GDS 3) Spanish‐speaking Hispanics tended to have lower scores than matched whites. In contrast, Spanish‐speaking Hispanics with dementia (GDS ≥ 4) showed relatively similar (and sometimes better) performance than their white counterparts on some of the tasks. There were no significant differences in performance among English‐speaking Hispanics and matched whites on any neuropsychological tests.

Conclusion

Careful interpretation of test scores on tasks of executive function/psychomotor speed should be considered for Spanish‐speaking Hispanics without AD. These results extend others’ findings by demonstrating that executive function/psychomotor speed is compromised even among relatively highly educated Spanish‐speaking Hispanics compared to whites. These findings highlight the potential influence of acculturation on these tasks and the importance of using appropriate group norms. Future studies should be aimed at examining the longitudinal associations of neuropsychological test scores with cognitive decline in cognitively normal Spanish‐speaking Hispanics.
[18F]Flortaucipir PET to autopsy pathology comparisons in Alzheimer’s disease and other neurodegenerative diseases
Authors: Soleimani‐Meigooni David N. , Iaccarino Leonardo , La Joie Renaud , Baker Suzanne L. , Bourakova Viktoriya , Boxer Adam L. , Edwards Lauren , Eser Rana A. , Tempini Maria Luisa Gorno , Jagust William J. , Janabi Mustafa , kramer Joel H. , Lesman‐Segev Orit H. , Mellinger Taylor J. , Miller Bruce L. , Pham Julie Q. , Rosen Howard J. , Spina Salvatore , Seeley William W. , Strom Amelia , Grinberg Lea Tenenholz , Rabinovici Gil D.
Published: December 2020

Background

Few studies have evaluated the relationship between in vivo [18F]Flortaucipir (FTP) PET and post‐mortem pathology.

Method

We sought to compare antemortem FTP‐PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative diseases. 80‐100 min FTP‐PET standardized uptake value ratio (SUVR) images were created using an inferior cerebellar gray matter reference. W‐score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. Mean SUVRs were calculated for Braak stage regions of interest (ROIs), and these values were compared to SUVRs derived from young, non‐autopsy, cognitively normal controls used as a standard for tau negativity.

Result

Nineteen patients were included (mean age at PET 61 [range 34‐76]; 8 female; mean PET‐to‐autopsy time of 30 months [range 4‐59 months]; Table 1). Eight patients had primary Alzheimer’s disease (AD) pathology, 9 had non‐AD tauopathies (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], argyrophilic grain disease [AGD], and frontotemporal lobar degeneration [FTLD] with tau inclusions), 2 patients had non‐tau related FTLD. There was excellent correspondence between areas of FTP retention and neurofibrillary tangle (NFT) distribution in patients with primary AD neuropathology. Patients with non‐AD tauopathies showed a range of tracer retention that was less than AD and more than age‐matched, cognitively normal controls, with CBD and FTLD due to MAPT mutations showing the most extensive and distinct binding patterns (Figure 1). Patients with non‐tau related FTLD also showed small areas of tracer retention (Figure 1). Overall, binding across both tau‐positive and tau‐negative non‐AD disorders did not reliably correspond with post‐mortem tau pathology. Quantification of FTP‐PET SUVR images at Braak stage ROIs reliably detected high Alzheimer’s Disease Neuropathologic Change (Braak VI) pathology. However, patients with earlier Braak stages did not show elevated tracer uptake in these regions compared to young, tau‐negative controls (Figure 2).

Conclusion

In summary, PET‐to‐autopsy correlations confirm that FTP‐PET is a reliable biomarker of advanced tau pathology in AD. The tracer cannot reliably differentiate non‐AD tauopathies and may not detect early Braak stages of NFT pathology.
What’s the cut‐point? A systematic review of tau pet thresholding methods
Authors: Weigand Alexandra J. , Eglit Graham M.L. , Maass Anne , Bondi Mark W.
Published: December 2020

Background

With increasing use of Alzheimer’s disease (AD) biomarker staging schemes, derivation of thresholds to determine biomarker positivity is becoming a critical methodological step. Recent advances in tau PET have made this modality a primary method for in vivo assessment of tau pathology. Given the heterogeneity in methodological decisions around tau PET positivity thresholding across studies, we conducted a systematic review of articles deriving tau PET thresholds to chronicle and compare these methods.

Method

Studies were excluded if they used animal models, included non‐AD and related dementias patients (e.g., Parkinson’s disease), used cerebrospinal fluid data, used a tracer other than flortaucipir, or included tau PET as a continuous variable only. Search terms included “tau PET positivity,” “tau PET threshold,” “tau PET cutoff,” and “tau PET cutpoint,” with these searches then repeated after replacing “tau PET” with “flortaucipir.” Of the 405 studies reviewed, a total of 19 studies were identified that matched inclusion criteria for the review.

Result

Of the 19 studies identified, 7 thresholded tau positivity in a manner conditional on amyloid positivity (e.g., maximally discriminating amyloid‐negative and amyloid‐positive), leading to SUVR cut‐points ranging from 1.19 to 1.33. The other most used method involved thresholding at 2‐2.5 SDs above the SUVR for young (n = 6) or old (n = 1) controls (cut‐points from 1.17 to 1.36). Other approaches included using conditional inference regression discriminating clinical diagnoses or global cognition (n = 4; cut‐points from 1.13 to 1.40) and clustering into high and low tau (n = 1; cut‐point = 1.25). Regions used differed greatly between studies, ranging from individual cortical regions (n = 5) to a temporal meta‐ROI (n = 10) to PET‐recapitulated Braak stages (n = 4).

Conclusion

There exists significant variability in tau PET cut‐points derived even within a particular thresholding method, which may be attributable to differences in sample composition, preprocessing methods (e.g., normalization, partial‐volume correction), or regions selected. Notably, although a large proportion of studies thresholded tau conditionally upon amyloid status, this may lead to bias in the estimated proportion of AT(N) groups. Consensus in thresholding methods, and particularly those that threshold tau and amyloid independently of the other, are needed given the increasing use of biomarker cut‐points within AD diagnostic frameworks.
Association of brain copper with cognitive decline in a community‐based neuropathologic study
Authors: Agarwal Puja , Dhana Klodian , Schneider Julie A. , Ayton Scott , Wang Yamin , Agrawal Sonal , Bennett David A. , Barnes Lisa L. , Leurgans Sue E. , Bush Ashley I. , Morris Martha Clare
Published: December 2020

Background

Copper (Cu) is an essential metal for brain health. Limited studies reported no association of plasma Cu and inverse association of Cu in human hair with cognitive abilities in older adults. However, no study investigated the association of Cu levels in the human brain with the long‐term change in cognitive functioning before death. Thus, we aim to examine the association of brain Cu with cognitive decline in a community‐based cohort study.

Method

Using data from 625 deceased participants from the Rush Memory and Aging Project. Brain copper levels were measured using ICP‐MS in gray matter from inferior temporal, mid frontal, anterior cingulate, and cerebellum. Composite global cognition and specific domains were derived from z‐scores of a 19‐panel cognitive tests that were performed annually for up to 14 years proximate to death. We used linear mixed‐effects models to examine associations of Cu (grouped in tertiles) in the brain with cognitive decline. All the models were controlled for age at death, sex, education, late‐life cognitive activity, physical activity, smoking, and APOE‐ɛ4 status.

Result

The mean age at first cognitive assessment was 82.7 (±5.8) years, 71% were women, and 25% carried an APOE‐ɛ4 allele. Participants in the highest and the middle tertile of Brain Cu in the inferior temporal region had a slower annual rate of cognitive decline (T3 vs. T1:β= 0.027; T2 vs. T1: β= 0.032; p for trend= 0.007). Similar associations were found for specific domains, including episodic memory (T3 vs. T1: β= 0.027; T2 vs. T1: β= 0.033; p for trend= 0.03), semantic memory ((T3 vs. T1:β= 0.040; T2 vs. T1: β= 0.050; p for trend= 0.001) and perceptual speed (T3 vs. T1:β= 0.024; T2 vs. T1: β= 0.035; p for trend= 0.03). Concentrations of Cu in the other brain regions were not associated with cognitive decline.

Conclusion

The association of higher brain copper levels in the vulnerable region of Alzheimer’s disease, such as the inferior temporal region with slower cognitive decline, supports the role of copper dyshomeostasis in the disease process.
Precision Functional Assessment for Alzheimer’s disease (PFA‐AD): A pilot study framework
Authors: Lopez Claudia M. , Hernandez Gerson D. , Wang Yiwei , Wershiner Dana , Gisler Trang , Seyfert‐Margolis Vicki , Brinton Roberta Diaz
Published: December 2020

Background

Current clinical trial assessments of cognitive function and activities of daily living are based on periodic assessments conducted under controlled clinical conditions using standardized measures. This approach is highly correlated with diagnosis of Alzheimer’s disease (AD) but has varied relevance to the real‐life challenges of those living with the disease and their caregivers. The use of digital technologies in clinical trials is actively encouraged. The opportunity to embed these tools in clinical trials in parallel with traditional measures is needed to move the field forward. This pilot study provides a framework to build on this approach and expand its use in research and patient care management. PFA‐AD will enable: 1) identification of key behavioral challenges that are relevant to the person with AD and their caregivers; 2) assessment of therapeutic effect in real time across multiple domains of behavioral function; and 3) innovate clinical trial measures of daily activities that are personalized and relevant to the patient and caregiver.

Method

PFA‐AD proof‐of‐concept development was embedded as part of a clinical trial (Clinicaltrials.gov: NCT03748303) to further develop allopregnanolone, a first‐in‐class regenerative therapeutic for AD. This study is enrolling 12 persons with AD to assess the intramuscular formulation of allopregnanolone. Participants are being asked to download the “Allo IM app” and interact with it daily during 12‐weeks. The platform/app created by MyOwnMed,Inc supports simple digital measures of lifestyle and daily function defined by the team interacting with patients. Content is personalized for each patient/caregiver based on their input. Wearable technologies have been integrated to capture physical activity and sleep, using available interfaces that will be seamlessly integrate into the app.

Result

Analysis of PFA‐AD data will include: 1) App usability; 2) Fidelity of personalized measures; 3) Correlation of personalized measures with standardized assessments; 4) Feasibility for inclusion in clinical trials.

Conclusion

AD is personal and assessment of functional capacity can be too. The PFA‐AD application brings the power of precision analytics to those living with AD and their caregivers. Outcomes of this research will advance the development of a technology‐based tool to enable assessments of real‐life function that really matters, in real‐time.
Reported chronic high glycemic diet intake predicts amyloid deposition in the precuneus of cognitively normal older adults over one year
Authors: Taylor Matthew K , Sullivan Debra K , Vidoni Eric D , Burns Jeffrey M
Published: December 2020

Background

We previously reported that high glycemic diet (HGD) was related to cerebral amyloid deposits, a pathologic hallmark of Alzheimer’s disease (AD), in multiple highly metabolic regions of interest (ROI). The purpose of this study was to test high glycemic diet’s relationship with longitudinal change in cerebral amyloid deposition in older adults.

Methods

This longitudinal study included 106 cognitively normal older adults with elevated (n=72) and non‐elevated (n=34) amyloid participating in a one‐year exercise intervention trial. Habitual dietary intake was collected at baseline using the National Cancer Institute’s Diet History Questionnaire (DHQ II) and intake was quantified using Diet*Calc software. We derived a HGD pattern using principal covariates regression (PCovR). Amyloid PET (Florbetapir F18) scans were obtained on a GE Discovery ST‐16PET/CT scanner at baseline and 52‐weeks. MIMNuero software was used to standardize the PET images to the whole cerebellum and calculate tracer standard uptake value ratios (SUVR) in 6 ROIs. One‐year regional SUVR delta scores were calculated. We constructed ordinary least squares regression models to assess HGD’s relationship with continuous regional delta SUVR scores controlling for age, sex, and intervention group assignment. Statistical analyses were performed using R (v. 3.6.2; R Foundation, Vienna, Austria). Statistical significance was set at p < 0.05.

Results

The participants were 68% female with a mean age of 71.1 ± 5.2 years. In the precuneus, higher intake of the derived HGD pattern (β=0.23, p=0.02), sugar (β=0.24, p=0.01), and total carbohydrate (β=0.22, p=0.03) correlated with more amyloid accumulation. Higher reported intake of carbohydrate as a percentage of total energy was related to more amyloid accumulation in the inferior medial frontal gyrus (β=0.20, p=0.04), posterior cingulate gyrus (β=0.20, p=0.04), precuneus (β=0.21, p=0.04), and superior parietal lobule (β=0.21, p=0.03).

Conclusion

The results of this study corroborate our previous findings and suggest a physiological role for HGD in amyloid pathology prior to onset of AD‐related symptoms.
A time‐embedding network model captures dynamic longitudinal pathology changes in a dominantly inherited Alzheimer disease population
Authors: McCullough Austin A , Gordon Brian A , McDade Eric , Bateman Randall J , Morris John C , Benzinger Tammie LS ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2020

Background

Population‐level analyses of autosomal dominant Alzheimer disease (ADAD) cohorts have revealed a roadmap of neuropathological and volumetric changes that increase over disease‐time and culminate in severe cognitive impairment. Traditional statistical analysis approaches struggle to integrate these cohort‐level dynamics with patient data to inform disease trajectory predictions at the individual level. Current machine learning approaches excel at this integration of population and individual level information, but require much larger sample sizes than current Alzheimer disease research cohorts can provide. The current work introduces a time‐embedding neural network in order to accurately represent known disease‐time dependent patterns among neuroimaging variables. The network is trained to predict ADAD carrier status to demonstrate the ability of this framework to make actionable predictions within ADAD populations.

Method

468 participants from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer Network (DIAN) were selected for analysis. Structural MRI, [11C] Pittsburgh Compound B (PiB) PET, and [18F] Fluorodeoxyglucose (FDG) PET region of interest imaging data was utilized (Table 1). DIAN estimated years to symptom onset (EYO) was used as disease‐time. The time‐embedding network learns EYO‐dependent representations of all imaging data in both mutation carrier and non‐carrier groups. These representations are combined with control variables and passed to a decoder network trained to output carrier status predictions (Figure 1).

Result

The time‐embedding network captures three main longitudinal pathology dynamics that correspond to known longitudinal PiB PET, FDG PET, and volumetric pathology changes in ADAD populations (Figure 2A). The network was successfully trained to predict ADAD carrier status in individual participants (Figure 2B). Prediction accuracy increases as the time of prediction moves closer to onset of clinical symptoms (Figure 2C).

Conclusion

The time‐embedding network model is able to accurately represent nonlinear time‐dependent processes in a low‐dimensional, sparsely sampled embedding. This embedding provides an interpretable framework that is consistent with known longitudinal pathology changes when applied to an ADAD population, and can be trained to make accurate longitudinal predictions with currently available data sets.