bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and longitudinal clinical outcomes of negative, moderate, and advanced 18F‐flortaucipir PET visual patterns in aging and Alzheimer’s disease
Authors: Moscoso Alexis , Heeman Fiona , Camacho Valle , van Essen Martijn , Grothe Michel J. , Lin Li , Mainta Isminni , Ribaldi Federica , Devous Michael D. , Pontecorvo Michael J. , Frisoni Giovanni B , Garibotto Valentina , Schöll Michael
Published: December 2022

Background

The advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.

Method

We included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.

Result

A total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.

Conclusion

Our large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.
Utility of online cognitive test in cognitive neurology unit
Authors: Curnin Charlotte B , Hayashi Takuji , Smith Mauice A , Press Daniel Z.
Published: December 2022

Background

Delirium is one of the most common complications in hospitalized elders and corresponds with a higher risk of cognitive decline and death. Numerous test batteries exist to assist clinicians in detecting delirium, but it continues to be undiagnosed in up to 88% of patients, particularly those with AD where “confusion” is mistakenly attributed to impaired baseline (1). This pilot study investigated the utility of a digital cognitive assessment (D‐Cog), in the form of an iPad game, which would allow for rapid and routine baseline testing in patients with AD so that delirium‐induced changes can be easily detected.

Method

While collecting traditional vital signs, medical assistants in the Beth Israel Deaconess Center (BIDMC) Cognitive Neurology Unit (CNU) prompted 67 willing patients to complete the D‐Cog assessment, an adaptive visuospatial span task, on an iPad. We then retrospectively reviewed the medical records of each patient to collect diagnosis, demographics, and pen‐and‐paper neuropsychological scores (e.g., MoCA or MMSE). Of the 67 patients (mean age 67, 29 female), 22 were clinically diagnosed with mild cognitive impairment (MCI) or varying severities of AD.

Result

The assessment was successfully completed by 52 participants. 15 participants, including 5 participants with moderate AD, experienced great difficulty during the task and were subsequently excluded. The 17 included participants with AD (mean age 75, 6 female) averaged a D‐Cog score of 4.1 and a MMSE score of 23.1. In comparison, a control group with no cognitive concerns (n = 16, mean age 60, 9 female) garnered a 6.7 average D‐Cog score and 29.3 MMSE score. The difference in D‐Cog scores was significantly different at p = 0.001.

Conclusion

The D‐Cog assessment is feasible in clinical practice for patients with a wide range of cognitive impairments. These scores can act as an attentional baseline to compare against later testing in the event of suspected delirium. While the D‐Cog is derived from traditional pen‐and‐paper testing, its digital framework offers new opportunities for adaptive and remote testing.

Reference

Fong TG, Davis D, Grodon ME, Albuquerque A, Inouye SK. The interface between delirium and dementia in elderly adults. Lancet Neruol. 2015; 14(8): 823–32
Tau and amyloid PET imaging with 18F‐PI‐2620 and 18F‐Florbetaben in patients with early‐onset dementia and healthy controls
Authors: Santibanez Rodrigo A , Mendez‐Orellana Carolina , Escobar Sebastian , Bustamante Gabriel , Juri Carlos , Haeger Arlette , Amaral Horacio , Kramer Vasko
Published: December 2022

Background

Abnormal deposits of tau protein and beta‐amyloid are the two fundamental pathological features of Alzheimer's disease (AD). The research framework for AD diagnosis proposes categorizing subjects based on biomarker evidence of pathology using the ATN classification system (amyloid, tau, neurodegeneration). In‐vivo detection of amyloid pathology using positron emission tomography (PET) is well established and new generation tau PET tracers like 18F‐PI‐2620 have shown a high binding affinity for aggregated tau without significant off‐target binding. The purpose of this study is to describe the ability of 18F‐PI‐2620 to detect tau pathology in patients with early‐onset dementia (EOD) with proven amyloid pathology.

Method

Ten patients with EOD and positive 18F‐Florbetaben amyloid PET (age range 54‐64y, 8 with suspected early‐onset AD (EOAD) and 2 with logopenic variant primary progressive aphasia (lvPPA)), along with 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans for 75 minutes after injection of 18F‐PI‐2620 to examine the presence of tau‐pathology in cortical and deep brain regions. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.

Result

In 9 out of 10 EOD patients, 18F‐PI‐2620 uptake was robust and extensive predominantly in cortical regions with relative sparing of deep brain regions. In the remaining EOD case, binding was low but with the same distribution pattern described for other EOD patients. In one HC, significant, specific uptake was observed predominantly in deep brain regions. 18F‐PI‐2620 administration was safe and well‐tolerated.

Conclusion

Our preliminary results suggest an excellent performance of the tracer 18F‐PI‐2620 to detect tau deposits in EOAD and lvPPA. Tau PET imaging with 18F‐PI‐2620, in conjunction with 18F‐Florbetaben amyloid PET, distinctly discriminates between early‐onset dementias due to AD pathology from HC. These results also support the usefulness of 18F‐PI‐2620 for visualizing tau aggregation in EOD. Finally, 18F‐Florbetaben and 18F‐PI‐2620 appear to be reliable tools for establishing the ATN biomarker status in EOD patients. Nevertheless, further studies are needed to confirm these preliminary results.
A telemedical interface for at‐home cognitive testing
Authors: Pebler Peter , Blank Michael , Geraci Kristin , Williams Garrett , Hall Kathleen , Baldo Juliana , Schendel Krista , Lwi Sandy J. , Chok Jas M. , Herron Tim , Wyma‐Hughes John , Woods David L.
Published: December 2022

Background

The COVID‐19 pandemic has limited in‐lab cognitive testing. While at‐home alternatives exist (testing over the phone), differences in test design and delivery complicate direct comparison of most in‐lab and at‐home tests.

Here we describe the design, infrastructure, and implementation of the California Cognitive Assessment Battery (CCAB), a cognitive test battery and administration system. Using automated remote administration over cellular networks, identical computerized cognitive tests can be administered at‐home or in the lab.

Method

The CCAB comprises 30+ computerized cognitive tests. Test delivery is automated through text, text‐to‐speech, and graphical instructions; test scoring is also automated, using automatic speech recognition for verbal responses.

The test delivery infrastructure consists of two components: the test kit (MS Surface Pro tablet computer with mouse, headset, and cellular dongle) , and a web‐browser application “CCAB Examiner,” used by the test administrator to control test delivery, view real‐time progress and scores, and monitor/chat with the participant via AV feeds.

The system is coordinated by a cloud‐based server which also delivers the CCAB Examiner application to any browser. Once connected, the “CCAB Test Station” application and CCAB Examiner communicate over a commercial Communication as a Service (CAAS) provider, which transmits AV streams and a text messaging protocol. CCAB Test Station is designed to isolate control, communications, and testing functions for maximal fault tolerance. For example, test administration continues automatically even if Examiner and Test Station lose connection. Test data is uploaded to the server during sessions and re‐synced when the test kit returns.

Result

442 participants underwent three 90‐minute CCAB test sessions on successive days (72 total tests per participant). More than 98% of participants finished all three sessions, and >99% of tests were completed. Cellular connection failures occurred occasionally, but >98% resulted only in the loss of A/V feeds for the examiner, while tests continued automatically and examiners were able to monitor real‐time performance data.

Conclusion

The CCAB permits identical tests to be administered at home or in the laboratory, while cellular‐network based remote administration allows for nationwide access for all socioeconomic groups, even for people in remote areas without Wi‐Fi, or those with limited technical expertise.
Characterization of tau PET according to amyloid chronicity
Authors: Cody Karly Alex , Koscik Rebecca Langhough , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C.
Published: December 2022

Background

This work examined tau PET (MK‐6240 SUVR) relative to amyloid chronicity (duration of amyloid positivity (A+)) to better understand neurofibrillary tangle (NFT) spatial burden across the time course of Alzheimer’s disease (AD).

Method

Individuals (N=457, 68.3±7.1 years, 417 CU, 30 MCI, 10 dementia) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin AD Research Center underwent amyloid and tau PET and neuropsychological assessment. Cortical 11C‐PiB DVR and sampled iterative local approximation was used to estimate A+ onset age and years of A+ duration at tau PET. Tau burden was quantified using 18F‐MK‐6240 SUVR (70‐90 min, inferior cerebellar GM reference region). MK‐6240 SUVR was assessed for relationships with A+ duration (continuous and grouped by decade) and clinical diagnosis as well as spatial patterns corresponding to Braak NFT stages. Regional and voxelwise analyses were performed.

Result

MK‐6240 SUVR was positively associated with A+ duration in regions associated with Braak NFT stages I‐VI while age was not associated after accounting for A+ duration (Figure 1A). In the CU subset, the MK‐6240/A+ duration association was spatially restricted to regions associated with NFT stages I‐IV(Figure 1B). Voxelwise MK‐6240 analyses revealed that with each decade of A+ duration, the spatial extent of measurable tau “spread”(ie .progressed) from regions associated with early to late Braak NFT stages (Figure 2A). Similar patterns were observed in the CU subset, but with lower SUVR and signal spatially restricted to the medial temporal lobe (MTL; Figure 2B). Regional analyses of MK‐6240 SUVR Z‐scores indicated significant stepwise increases across A+ duration groups (A‐ < A+ 0‐10 years < A+ 10‐20 years <A+ 20+ years; Figure 3A) and across clinical groups (CN A‐ < CN A+ < MCI A+ < AD A+; Figures 3B). Between group differences were largest in the entorhinal cortex and MTL Meta‐ROI for both A+ duration and clinical diagnosis groups (Figure 4A‐B).

Conclusion

Results suggest that entorhinal and MTL regions were most sensitive to early amyloid pathology and cognitive changes in AD. Applying the amyloid chronicity framework to tau PET data enables 'pseudo'spatiotemporal characterization of tau deposition patterns in the AD continuum. Longitudinal assessment of spatiotemporal tau deposition patterns is ongoing.
Associations of pathway‐specific polygenic risk scores with clinical status and Alzheimer’s‐related biomarkers
Authors: Elman Jeremy A. , Schork Nicholas J. , Kremen William S.
Published: December 2022

Background

The APOE gene represents the largest genetic risk factor in sporadic Alzheimer’s disease (AD), but there is a substantial polygenic component as well. Polygenic risk scores (PRS) represent a useful approach to summarize small effects across the genome but may obscure which pathways are affected. Variability across individuals at the genetic level may contribute to the extensive phenotypic heterogeneity of AD. Therefore, we calculated polygenic risk in multiple pathways associated with AD and examined its relationship with clinical status and AD biomarkers.

Method

A total of 1,411 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with genotyping data were included. Top gene sets from a pathway analysis of AD GWAS summary statistics were combined into clusters based on proportion of overlapping genes. Pathway‐specific PRSs (ps‐PRS) were calculated for each participant by restricting to SNPs annotated to genes in each cluster. We tested associations of ps‐PRSs with diagnostic status (AD vs cognitively normal, MCI vs cognitively normal) and rate of progression to AD among those with no dementia at baseline. Additional analyses examined associations with amyloid and tau positivity, and hippocampal volume. The APOE region was excluded from all ps‐PRSs and the number of APOE‐ε4 alleles was included as a covariate along with age, gender, and the first 3 principal components. All analyses were FDR‐corrected.

Result

Thirteen pathway clusters were identified relating to categories such as immune response, amyloid precursor processing, protein localization, lipid transport and binding, tyrosine kinase, and endocytosis. Nine ps‐PRSs were significantly higher in AD and MCI compared to controls. A large subset of these were associated with both faster progression to AD and hippocampal volume. Amyloid and tau‐positivity were both related to endocytosis ps‐PRSs. Amyloid‐positivity was additionally related to microglial activation, lipid processing, fibril formation and amyloid precursor processing, whereas tau‐positivity was related to protein localization.

Conclusion

Although genetic risk for AD is widely distributed, AD‐phenotypes may be preferentially associated with risk in specific pathways. Defining genetic risk along multiple dimensions at the individual level may help clarify the etiology of heterogeneity in AD.
Brain morphometric and metabolic changes in Subjective Cognitive Decline individuals
Authors: Bieger Andrei , Souza Laura Willers , Borelli Wyllians Vendramini , Negrini Guilherme Bauer , Povala Guilherme , De Bastiani Marco Antônio , Tissot Cécile , Ferrari‐Souza João Pedro , Castilhos Raphael Machado , Souza Diogo O. , Rosa‐Neto Pedro , Pascoal Tharick A , Schumacher‐Schuh Artur Francisco , DuBois Jonathan M , Zimmer Eduardo R
Published: December 2022

Background

Subjective cognitive decline (SCD) is defined as a memory complaint in individuals without an objective measure of cognitive impairment. In this study, we investigated the morphometric and metabolic brain changes in individuals presenting with SCD.

Method

Age and sex matched structural MRI and [18F]FDG PET images from SCD and CU (n = 101, per group) were extracted from the ADNI database. We built general linear models corrected for multiple comparisons with 10,000 Monte‐Carlo simulations to verify differences in cortical thickness between groups, using age as a covariate (Freesurfer’s v7.1.1). Metabolic analysis was performed using voxel‐wise general linear models comparing the SUVR of the FDG signal, correcting for age and APOE4 allele carrying status, using the MINC toolkit and the R statistical program.

Result

SCD and CU groups presented similar age, sex, years of education, CSF AD‐related protein levels (amyloid beta 1‐42, p‐tau and tau), and Clinical Dementia Rating – Sum of Boxes score (Table 1). Compared to CU individuals, SCD subjects showed increased cortical thickness in the right hemisphere rostral middle frontal gyrus (Figure 1), while glucose metabolism was increased in the right medial temporal lobe, including the hippocampus, and right occipital cortex (Figure 2).

Conclusion

Individuals with SCD present cortical hypertrophy in the rostral middle frontal gyrus and glucose hypermetabolism in the medial temporal lobe and occipital cortex, all in the right hemisphere. Previous studies suggest that these areas play a role in personality and humor, and may be altering self‐perception of cognitive decline. At the biological level, given the high concentration of astrocytes in these areas, such changes may suggest a scenario of astrocyte reactivity. More specifically, astrocyte hypertrophy may account for increased cortical thickness and glucose uptake. In summary, we provide neuroimaging evidence of structural and functional changes in individuals with SCD, suggesting early astrocyte reactivity.
APOE3 Christchurch mutation carriers from the Colombian kindred with autosomal dominant Alzheimer’s disease due to PSEN1 E280A
Authors: Aguillon David , Lopera Francisco , Vasquez Daniel , Baena Ana Y. , Hincapie Liliana , Zuluaga‐Castaño Yesica , Vila‐Castelar Clara , Ramirez‐Gomez Liliana A. , Aduen Paula , Acosta‐Uribe Juliana , Kosik Kenneth S. , Reiman Eric M. , Arboleda‐Velasquez Joseph F , Quiroz Yakeel T.
Published: December 2022

Background

Our understanding of the mechanisms of protection mediated by APOE has advanced significantly in the past years. Our group previously showed that APOE3 Christchurch (APOE3ch) homozygosity was associated with the protection against Alzheimer’s disease dementia in an individual who carried the Presenilin‐1 (PSEN1)‐E280A variant for autosomal dominant AD (ADAD) (Arboleda‐Velasquez et al., 2019). Here we present the initial characterization of individuals from the PSEN1‐E280A kindred with the APOE3ch variant.

Methods

1,000 PSEN1‐E280A variant carriers and 1,000 non‐carriers from the Colombian ADAD kindred were characterized in terms of their common APOE variants and the rare APOEch variant. Participants had previously completed a comprehensive neurological and neuropsychological evaluation. Those who were alive were re‐contacted in 2021 to undergo comprehensive clinical assessments, including the CERAD‐Colombia neuropsychological battery, and MRI and FDG PET imaging as part of the Resist Alzheimer’s Project.

Results

We discovered 97 ADAD kindred members with the APOE3ch variant (95 heterozygotes), including 84 who are living and 13 who are deceased (7 who were brain donors). 29 of the APOE3ch carriers also had the PSEN1‐E280A variant, including 18 who are living and 11 who are deceased. The age range for all APOE3ch variant carriers was from 17 to 72 years, including 11 APOE3ch + PSEN1‐E280A carriers who were 50‐72 years old (i.e., older than the PSEN1‐E280A variant carriers’ median age at dementia onset). Overall, global cognition and memory performances of the first three APOE3ch + PSEN1‐E280A carriers (older than 50 years of age) assessed fell within the normal range, compared to age‐matched individuals from this kindred.

Conclusions

The prevalence rate of APOE3 Christchurch heterozygosity in the Colombian kindred with ADAD (4.85%) is very high compared to the general population (e.g., gnomAD database reports an allele frequency of 0.00001283; Karczewski et al., 2019). Preliminary clinical and cognitive data from APOE3ch variant carriers are consistent with the hypothesis that heterozygosity may have a mild‐to‐moderate protective effect against cognitive decline. We plan to compare longitudinal clinical, cognitive, biomarker, and post‐mortem neuropathological changes in PSEN1‐E280A carriers with and without the APOE3ch variant to clarify the role of APOE3ch heterozygosity in the protection from ADAD.
Seeding human tau knock‐in neurons with human derived pathological tau results in the formation of pathogenic conformations of tau
Authors: Mueller Rebecca L , Kanaan Nicholas M
Published: December 2022

Background

One of the pathological hallmarks of Alzheimer’s disease (AD) is the accumulation of pathological tau inclusions. Conformational exposure of an N‐terminal motif in tau known as the phosphatase‐activating domain (PAD) occurs early in AD and other tauopathies and aberrant exposure of this motif disrupts axonal transport. Tau is capable of seeding aggregation in cells; however, the extent to which disease‐associated pathogenic conformations can be effectively seeded remains an area of active investigation. To help address this gap, we seeded aggregation in primary neurons and assessed known pathogenic tau conformations.

Method

Primary hippocampal neurons from human tau knock‐in mice were treated with pathological tau aggregates from human AD‐brain (AD‐tau) according to methods described in Narasimhan and Lee, 2017. The same purification protocol was used with non‐demented human brain tissue (CO) as a control. The AD‐tau and CO samples were characterized by transmission electron microscopy and biochemical assays that measure total tau and pathological modifications, such as phosphorylation (PHF1) and a conformation specific antibody (TNT1) that labels display of PAD. Neurons treated at 5 days in vitro were maintained for up to 28 days post‐treatment. Markers of pathological species of tau (PAD exposed and phospho‐tau) were used to assess the formation of disease‐associated forms of tau and changes in the numbers of neurons (MAP2) and astrocytes (GFAP) were measured.

Result

The AD‐derived material showed morphologies consistent with small pieces of the characteristic paired helical filaments of AD, phosphorylation at the PHF1 site, and the presence of oligomeric tau and PAD‐exposed tau species. We observed a robust dose and time‐dependent increase in TNT1 in AD‐tau‐treated neurons and ongoing studies are evaluating the presence of other pathological tau species. There were no significant effects on cell number in seeded cultures out to 28 days post‐treatment.

Conclusion

Our results suggest that primary neurons seeded with AD‐tau form inclusions consisting of PAD‐exposed tau, but overt degeneration does not occur within 28 days of seeding. The presence of PAD‐exposed tau but lack of cell loss could indicate that more time is needed and/or that the consequences of these tau species are more subtle.
Comparing the longitudinal progression of CSF biomarkers with PET Amyloid biomarkers for Alzheimer’s disease
Authors: Cox Timothy , Bourgeat Pierrick , Dore Vincent , Doecke James D , Fripp Jurgen , Chatterjee Pratishtha , Schindler Elizabeth E. , Benzinger Tammie L.S. , Rowe Christopher , Villemagne Victor L , Weiner Michael W. , Morris John C. , Masters Colin L.
Published: December 2022

Background

Cerebrospinal fluid (CSF) soluble biomarkers are useful at detecting pre‐clinical levels of Alzheimer’s disease (AD) biomarkers of b‐amyloid (Ab) and tau. Disease progression times for participants in longitudinal studies can be estimated for different biomarkers. Utilizing a new technique, this work compared the disease progression times between CSF and PET biomarkers.

Methods

Four hundred and ten participants from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) including participants form ACS/OASIS, ADNI and AIBL with three or more data points of longitudinal CSF Ab42 and pTau181 (pTau) and Ab PET were selected. PET results were expressed in Centiloid (CL), (299 cognitively unimpaired, 107 mild cognitively impaired, 4 AD dementia; aged 69±9; 216 females (NAIBL=30, NADNI=252, NOASIS=128). Disease trajectory curves for individual biomarkers and the pTau/Ab42 ratio were created by: 1) Fitting a function to the rates of change of the variable of interest versus its mean value), 2) integrating the fit to obtain longitudinal trajectory curves as a function of disease progression time for each of the variables. The participants’ disease progression time along each curve were estimated. Threshold values for Ab PET and pTau/Ab42 ratios were calculated using a gaussian mixture model. Estimates of age of onset were calculated using the progression times. The participants’ disease progression times for each of the different variables were compared using rank correlations.

Results

Rank correlations for the progression times were: r(Ab42, Ab PET) = 0.75, r(pTau, Ab PET)=0.62, and r(pTau/Ab42, Ab PET)=0.83. The estimated ages at which participants’ reach Ab PET and the pTau/Ab42 ratio thresholds are compared in Fig 1, the average age at which were estimated to reach the threshold values were 55 yr for pTau/Ab42 (threshold of 0.021) and 61 yr for Ab PET (threshold of 22 CL).

Conclusions

The high correlation between pTau/Ab42 and Ab PET, indicates that pTau/Ab42 captures the progression of AD pathology better than the individual CSF biomarkers. On average participants’ reach abnormal levels of pTau/Ab42 earlier than Ab PET. Further work is required to understand individual variations in progression times.
Handgrip Strength is Related to Regional Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden
Authors: Meysami Somayeh , Raji Cyrus A. , Popa Emily S. , Ganapathi Aarthi S. , Bookheimer Tess , Slyapich Colby B. , Pierce Kyron P. , Richards Casey J. , Gill Jaya M. , Lampa Melanie G. , Rapozo Molly K. , Hodes John F. , Glatt Ryan M. , Tongson Ynez M. , Wong Claudia L. , Kim Mihae , Porter Verna R. , Kaiser Scott A. , Panos Stella E. , Dye Richelin V. , Miller Karen J. , Bookheimer Susan Y. , Martin Neil A. , Kesari Santosh , Kelly Daniel F. , Siddarth Prabha , Bramen Jennifer E. , Merrill David A.
Published: December 2022

Background

Handgrip strength is important for performing activities of daily living[1]. In older adults, weaker handgrip strength and asymmetry are associated with poorer cognition. o better understand mechanisms, we sought to quantify the relationship between handgrip strength and regional volumes quantified on brain MR imaging.

Method

We selected 32 participants (mean age=70.8±7.3 [range 57‐89] years, 53.1% female, 90.6% right‐handed, mean body mass index BMI=23.9±4.1) from the Pacific Brain Health Center at Providence St. John’s Health Center, with Alzheimer dementia biomarker evidence of amyloidosis[2]. Mean Montreal Cognitive Assessment score for all participants was 21.3±3.8 points. Handgrip strength on dominant and non‐dominant hands was measured using the NIH Motor Toolbox[3] as part of a cognitive fitness assessment using a hydraulic hand dynamometer. The resulting scores included handgrip strength and percentile comparisons to normative data. Asymmetry scores were calculated. Regional brain volumes, including lobar structures and the hippocampus, were measured from T1‐weighted MR images using Neuroreader[4]. Partial correlations (rp), adjusting for age, sex, BMI and total intracranial volume modeled handgrip strength, asymmetry, and brain volumes with a significance threshold of p<0.05.

Result

In the dominant hand, higher handgrip strength scores and percentiles were associated with larger volumes in the left frontal lobe (rp=+0.51, p=0.007; rp =+0.47, p=0.01) and right parietal lobe (rp=+0.40, p=0.03; rp=+0.39, p=0.04). In the non‐dominant hand, higher handgrip strength score and percentiles were associated with smaller total cerebral spinal fluid (CSF) volume (rp =‐0.55, p=0.004; rp =‐0.52, p =0.006) and larger volumes within the left hippocampus (rp=+0.45, p=0.01; rp=+.43, p=0.02), right hippocampus (rp=+0.47, p=0.01; rp=+0.43, p=0.02), and right parietal lobe (rp=+0.39, p=0.04; rp=+0.44, p=0.02). Handgrip strength asymmetry was inversely related to right hippocampal volume (rp=‐0.58, p=0.002) and positively correlated to CSF volume (rp=+0.39, p=0.04).

Conclusion

Greater handgrip strength was related to larger regional brain volumes. A higher number of brain regions were related to the non‐dominant hand. Asymmetry was associated with lower right hippocampal volume and higher CSF volume. Interventions focused on improving handgrip strength may seek to include quantified brain volumes on MR imaging as endpoints.
A longitudinal analysis of depressive symptoms in relation to repeated measurements of regional tau
Authors: Munro Catherine E , Buckley Rachel F. , Vannini Patrizia , Hanseeuw Bernard , Quiroz Yakeel T. , Farrell Michelle E. , Rentz Dorene M. , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Amariglio Rebecca E. , Marshall Gad A , Gatchel Jennifer R
Published: December 2022

Background

Depressive symptoms are commonly observed early in Alzheimer’s disease (AD), but their temporal association with progression along the AD continuum is less clear. We sought to determine if initial measurements of regional tau were predictive of increasing depressive symptoms, and if changes in depressive symptoms predicted later tau levels. We examined these relationships in a region of early tau accumulation (i.e., entorhinal cortex (EC)), and in regions of later neocortical tau spread commonly involved in affective regulation (amygdala and medial and lateral orbitofrontal cortex (mOFC, lOFC)).

Method

Participants (n=257; mean age=70.7; 61% female) came from the Harvard Aging Brain Study, a longitudinal observational cohort of cognitively unimpaired adults with no/low depression at baseline (mean years of follow‐up=7.2). All participants completed the self‐reported 30‐item Geriatric Depression Scale (GDS) annually and tau PET imaging (Flortaucipir‐FTP) every 3 years. On average, initial tau PET scans occurred 2.3 years after enrollment and the latest available scan occurred 5.1 years after enrollment. Separate linear mixed effects models investigated relationships between longitudinal GDS and cross‐sectional regional tau (FTP PET SUVr), at initial scan and at the latest scan available, in the following regions of interest: EC, amygdala, mOFC, and lOFC. Covariates included age, sex, and education.

Result

Higher initial FTP levels were associated with significant increases in GDS score over time in temporal cortex (amygdala: b=0.29,p=0.0002; EC: b=0.21,p=0.0006) and mOFC (b=0.30,p=0.004), with marginal significance in lOFC (b=0.21,p=0.07). However, the reverse temporal sequence was only observed between GDS scores over all time points and later measurement of amygdala FTP, such that increasing depressive symptoms over time preceded higher final amygdala tau levels (b=0.15,p=0.02).

Conclusion

Higher tau in EC, amygdala and OFC regions predicted increasing depressive symptoms over time in older adults. Only for the amygdala did we also observe the converse relationship: increasing depressive symptoms predicting higher final tau. These results suggest early tau proliferation in affective regions is associated with increased depressive symptoms, though the question of causality is still unclear. Further work is needed to dissect possible temporal relationships across whole brain voxels to better understand depressive symptoms in AD progression.
The effects of age and sex on plasma p‐tau181 concentrations in Alzheimer’s Disease
Authors: Kumar Pankaj , Vanbrabant Jeroen , Encarnacion Mary , Mousavi Ali , Hsiung Ging‐Yuek Robin , Stoops Erik , Vanmechelen Eugeen , Frykman Hans
Published: December 2022

Background

Quantifying levels of phosphorylated tau in plasma is a highly promising and specific marker for Alzheimer’s disease (AD), but limited data are available on the effect of age on plasma p‐tau181 concentrations in specific clinical groups and especially control subjects. Similarly, the effect of sex on concentration of plasma ptau‐181 levels are unclear.

Method

A total of 343 samples of EDTA plasma from patients examined at the UBC Hospital Alzheimer Clinic between 2008 – 2018 included.

The patients had been referred with complaint of cognitive impairment and were assessed for dementia and they sorted into four diagnostic groups: Non‐Cognitive Impairment (NCI), non‐ AD neurodegenerative diseases, possible AD, and probable AD, according to US National Institute on Aging (NIA) and the Alzheimer’s Association (AA) criteria diagnosis. The concentrations of their plasma p‐tau181 was measured by a homebrew ADX assay on SIMOA HD‐X platform. We analysed the effect of age and sex on the concentrations of plasma p‐tau181 among and within clinically defined groups. We also assessed p‐tau181 levels in a separate group of healthy individuals (n=60).

Result

There was no significant sex difference in p‐tau181 levels across and between the diagnostic categories (p=0.426). We also confirmed there was not any correlation between age and p‐tau181 levels in healthy controls. Moreover, we did not find any correlation between the age and plasma concentrations of p‐tau181 within each diagnostic group separately. Further with two model linear regression, age was not found to be a significant contributor of plasma p‐tau181 variations (F (3, 429) = 109.04, B=.16, t= 1.42, p<0.16).

Interestingly, there was a correlation between average of plasma p‐tau181 with age among the spectrum from NCI to AD.

Conclusion

We did not detect any sex difference in plasma p‐tau181 levels. Our findings about the age‐effect of plasma p‐tau181 levels especially within and among diagnostic groups might be described by the intricate dynamics, and kinetics of p‐tau181 in brain and plasma and it needs to investigate with larger healthy control population and multicenter clinical studies.
CSF proteomics analysis to investigate the pharmacodynamic response of the S2R modulator CT1812 in Alzheimer’s disease patients from the SPARC clinical trial
Authors: Pandey Kiran , Waybright Lora , Duong Duc M. , Malagise Evi , Blennow Kaj , Zetterberg Henrik , Mecca Adam P , van Dyck Christopher H , Caggiano Anthony O , Seyfried Nicholas T. , Hamby Mary E
Published: December 2022

Background

CT1812 is an investigational therapeutic that can displace toxic amyloid‐beta oligomers from neuronal receptors and is currently in development for Alzheimer’s disease (AD). SPARC (COG0105; NCT03493282), was a randomized double‐blinded placebo‐controlled clinical trial designed to test the impact of the small molecule sigma‐2 receptor (S2R) modulator CT1812 on safety and synaptic density. Exploratory analyses included discovery proteomics for pharmacodynamic biomarker identification and to understand the impact of CT1812 on CSF proteins detected in mild to moderate AD patients.

Method

Unbiased quantification, using tandem‐mass tag mass spectrometry (TMT‐MS), of proteomes from AD patients given the S2R modulator CT1812 or placebo (N=18) was performed on baseline and end of study CSF to test two doses (100 mg, 300 mg) of CT1812 given once daily for 6 months in participants with mild‐moderate AD. Individual CSF proteomes were compared to within‐study pooled AD and non‐demented control CSF reference standards from the Emory ADRC to benchmark protein levels in SPARC participant CSF at baseline and to assess treatment effects, via differential expression analysis (one‐way ANOVA; p<0.05) and pathway analyses.

Result

A total of 2,760 CSF proteins were detected across all CSF samples. Strong correlations (r>|0.70|) between TMT‐MS values and clinically validated ELISAs for canonical AD biomarker levels (Tau, NFL) were observed across participants and timepoints, confirming previous findings of TMT‐MS as a quantitative method. Differential expression analyses identified 327 proteins altered (one‐way ANOVA; p<0.05) in CT1812 vs placebo CSF. From a curated list of previously published AD biomarkers representing distinct pathways, a subset of proteins were found to be significantly altered by treatment with CT1812 compared to placebo (p<0.05), and included some proteins known to be genetically linked to AD. Pathway analysis identified statistically significant pathways (p<0.05) altered by CT1812, including that tied to inflammation, amyloid biology, and synaptic function.

Conclusion

This study enabled the identification of candidate pharmacodynamic biomarkers that may reflect target/pathway engagement or disease modification, and extends proteomics CSF learnings from previous clinical trials with CT1812. Overall, this data suggest CT1812 may impact key proteins and pathways in AD and provides additional support for CT1812 to be further evaluated as a promising therapy for AD.
Antemortem‐postmortem correlates of 4D‐Flow MRI in cerebral vessels
Authors: Schroeder Brooke E , Rivera Leonardo A , Romero Monica Ospina , Johnson Kevin M , Wieben Oliver , Asthana Sanjay , Johnson Sterling C. , Eisenmenger Laura , Salamat Shahriar , Betthauser Tobey J
Published: December 2022

Background

Cerebrovascular disease (CVD) is associated with increased dementia risk and often co‐occurs with Alzheimer’s disease (AD). Non‐invasive quantitative 4D‐Flow MRI can be used to characterize cerebrovascular hemodynamics and study CVD/AD interactions during life, but has not been validated against postmortem pathological assessment. This study compares antemortem 4D‐Flow metrics with postmortem pathological assessment in cerebral arteries to inform the interpretation of 4D‐Flow MRI.

Methods

Three participants from the Wisconsin ADRC underwent antemortem 4D‐Flow and postmortem pathological examination. Subjects had MCI or dementia before death with suspected AD etiology (Table 1). Antemortem 4D‐Flow was acquired on a 3.0T system (GE Healthcare). Vessel cross‐sections from 4D‐Flow angiograms of cerebral arteries were used to estimate blood flow, pulsatility index (PI), and luminal area. Upon death, brain extraction and neuropathological examination were performed according to NIA‐AA guidelines. Sampled cerebral arteries included left anterior (A1) and middle (M1) cerebral, and left internal carotid arteries, basilar artery, and left and right posterior cerebral (P1 and P2) and vertebral arteries. Mason’s trichrome stained sections of the arteries were captured using an Aperio Digital Slide Scanner. QuPath software was used to delineate the intima, media and functional luminal area of the vessels. A pixel classifier measured the area of smooth muscle cells (SMC) and fibrous tissue (Figure 1). The percentage of stenosis (%stenosis) was calculated as the area of atherosclerotic plaque divided by the area encompassed by the elastica. The percentage of media fibrosis (%fibrosis) was calculated as the area of fibrotic tissue divided by the sum of the SMC and fibrotic areas within the media. Spearman correlations were used to compare antemortem and postmortem vascular measures without correction for multiple comparisons.

Results

Imaging‐postmortem correlates were highest for PI vs. %fibrosis (ρSpearman=0.42), mean flow vs. %stenosis (ρSpearman=0.40), and comparisons of luminal area (ρSpearman=0.43) (Table 2, Figure 2). Correlations between other imaging and pathology measures were low (|ρSpearman|<0.21).

Conclusion

These data provide preliminary evidence that 4D‐Flow metrics correlate with underlying arterial vessel stenosis and fibrosis. Future work is ongoing to investigate antemortem‐postmortem associations in more cases.
Preoperative Cerebrospinal Fluid and Plasma Markers of Inflammation and Neurodegeneration Predict Mortality Eight Years Later in an Observational Cohort Study of Postoperative delirium in an Older Elective Arthroplasty Populatio
Authors: Sweeney Aoife , Passmore Anthony Peter , Beverland David , McGuinness Bernadette , McAuley Daniel F , Mawhinney Tim , O'Brien Seamus , Schott Jonathan M , Heslegrave Amanda , Zetterberg Henrik , Cunningham Emma L
Published: December 2022

Background

Between 2012‐2014, an observational cohort study of postoperative delirium (POD) in an elective arthroplasty population recruited 315 individuals aged over 65, without a diagnosis of dementia. We are now conducting a follow‐up study to determine what effect POD has on cognition years later.

Method

In the baseline study, neuropsychological testing was undertaken preoperatively, cerebrospinal fluid (CSF) was sampled at the time of spinal anaesthesia and delirium was assessed daily on days 1‐3 postoperatively. Stored CSF (n = 270) was analysed for markers of inflammation and neurodegeneration. In 2020, all surviving participants were invited to take part in the follow‐up study.

Result

The average age of the cohort at baseline was 74.4 (5.8) years. Eight years later, 84% (n=264) of the observational study participants are still alive. Mortality rates in the intervening years are higher in those who developed POD (14/44, 32%) than those who did not (37/271, 14%), but is not statistically significant (p=0.13). Significant predictors of mortality in all participants included multi‐morbidity (p=0.007), age at surgery (p<0.001), performance on Colour Trails 2, a test of executive function(p<0.001); CSF glial fibrillary acidic protein (GFAP), a marker of inflammation (p=0.01); CSF neurofilament light (NFL), a marker of axonal degeneration (p=0.019); CSF interleukin‐8 (IL‐8), a marker of inflammation (p=0.007) and CSF triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of age‐related neuroinflammation and tau‐related neurodegeneration (p=0.002).

Conclusion

The majority of participants in this elective arthroplasty observational cohort are still alive eight years later. Older age at time of surgery, multimorbidity, lower neuropsychological performance and increased preoperative CSF measures of inflammation and neurodegeneration were associated with mortality in adults eight years following elective orthopaedic surgery.
Medium‐chain fatty acids in combination with a multidomain lifestyle intervention in Alzheimer’s disease prevention: Protocol design to study implementation
Authors: Hillebrandt Heidi L , Dias Cintia B , Chatterjee Pratishtha , Asih Prita Riana , Barin Edward S , Shah Tejal M , Fuller Stephanie Jane , Rainey‐Smith Stephanie , Bharadwaj Prashant , Pedrini Steve , Thota Rohith N , Castro Carolina B , Ramezani Matin , Sohrabi Hamid R , Martins Ralph N
Published: December 2022

Background

Alzheimer’s disease (AD) neuropathology begins 20 to 30 years before clinical diagnosis. Thus, there is an opportunity to implement strategies to prevent the progression of AD. Insulin resistance in the brain causes a disruption in glucose utilisation. Medium‐chain fatty acids (MCFA) are readily available substrates for the synthesis of ketone bodies (KB), which are an alternative brain fuel not controlled by insulin. A constant supply of KB may close the energy gap in the AD‐prone brain, and in doing so prevent or delay symptom onset, or protect the brain from further degeneration. There is increasing evidence that multidomain lifestyle interventions with dietary components significantly impact cognitive decline. Yet, these interventions have not considered the effects MCFA supplementation, to ensure sufficient energy for the brain.

Method

This is a phase II placebo‐controlled, randomised double‐blind 24‐month intervention trial of MCFA supplementation within the AUstralian‐multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention (AU‐ARROW) study, to investigate the additive effect of MCFA supplementation in older adults at increased risk of AD. A total of 124 participants will be recruited aged 60‐79 years, with subjective cognitive decline. Participants will be randomised 1:1 into either the intervention or placebo groups and will consume 3 daily doses at 15mL per dose of either MCFA or placebo supplement whilst continuing the AU‐ARROW protocol, which includes dietary education, physical activity, brain training, and health education.

Result

The primary outcomes involve statistical assessment of cognition, blood ketone body levels, and brain glucose utilisation. At baseline, and every 6 months, participants will have fasting blood samples collected. At baseline, 12, and 24 months, participants will undergo cognitive assessments. At baseline and 24 months, participants will undergo fluorodeoxyglucose positron emission tomography scans to determine brain glucose utilisation.

Conclusion

The final protocol is expected to maximise data collection and analyses. Combined with AU‐ARROW, it will allow for a) the implementation of MCFA supplementation guidelines in a plan to reduce cognitive decline and risk of AD, b) the determination of effects of MCFA consumption on neuroimaging and blood‐based biomarkers, and c) the comparison of between subject differences.
Allostatic load and the influence of economic adversity and neighborhood disadvantage on cognitive function in a multiethnic cohort
Authors: Longoria Anthony Joseph , Brinson Zabecca S. , Carlew Anne R , Cullum Munro , De Lemos James A , Goette William , Lacritz Laura , Rossetti Heidi
Published: December 2022

Background

Previous research has demonstrated a link between objective socio‐economic indicators and cognitive test performance. Although some studies include subjective indicators, such as perceived neighborhood environment, little is known about which specific factors are most strongly associated with cognitive performance and whether these measures are useful beyond traditional SES proxies. Further, in addition to being disproportionately at risk of experiencing neighborhood disadvantage and lower SES, racial/ethnic minorities are more likely to be diagnosed with dementia and receive less timely care compared with White individuals. This study aims to investigate how perceived neighborhood environment and neighborhood disadvantage are related to cognitive performance within a large diverse sample.

Method

A probability‐based sample of participants (N = 3858; Female = 59%; Black = 51%; Hispanic = 14%) from the Dallas Heart Study Phase 2 (DHS‐2; Mean: Age = 50, Education = 13) were administered the Montreal Cognitive Assessment (MoCA), in addition to measures of perceptions of neighborhood physical environment and violence, and perceived SES. Multiple regression was used to determine associations of these variables with MoCA scores relative to traditional SES measures (i.e., income, education), controlling for demographic and relevant health factors. Post‐hoc analyses stratified by racial/ethnic group were conducted to determine whether indicators differentially influenced test scores.

Result

After controlling for socio‐demographic and health factors, reporting lower quality neighborhood resources and difficulty paying for “very basics like food and heating” and “medical care” were associated with lower MoCA scores in the overall sample. Post‐hoc analyses revealed significant relationships between MoCA scores and quality of neighborhood resources, “food and heating,” and “medical care” only in Black participants, while “violence” was significantly associated with lower MoCA scores in Hispanics. There were no significant relationships found in Whites. Overall, subjective measures of SES and neighborhood environment contributed modest variance in the overall model, specifically for Black and Hispanic participants (R
2 = 3% to 5%).

Conclusion

Experiencing neighborhood and economic adversity was associated with lower scores on a cognitive screening measure and accounted for more variance than income or education in Black individuals and income in Hispanic individuals, while no relationship was seen in White participants. Future research is needed to determine whether these allostatic stressors influence cognitive impairment or dementia later in life.