bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of C2N Diagnostics’ Aβ40, 42, and 42/40 ratio in Plasma Stored in Micronic and Sarstedt Tubes
Authors: Edler Michael C. , Russ Kristen A , Mitchell Colleen M. , Holubasch Mary S. , Kirmess Kris , Meyer Matthew R. , Yarasheski Kevin E. , Foroud Tatiana M. , Dage Jeffrey L.
Published: December 2022

Background

Variation in biospecimen collection, processing, and storage parameters can introduce pre‐analytical variables that may confound interpretation of biomarker results. Samples collected under different study protocols or over a long period of time may require different labware, such as storage tubes. Comparability of storage tubes is necessary to better interpretate data collected both longitudinally within studies and across studies that may utilize various labware. The focus of this experiment was to perform comparability studies between plasma biomarkers measured in two polypropylene tube types: Sarstedt tube (72.694.006) and an automation friendly Micronic tube (MP52755).

Methods

Blood was collected from healthy controls (N=23) and Alzheimer’s Disease (AD) subjects (N=16) by the Indiana Biobank. Participants’ brain amyloid status was unknown. Plasma from the same subjects was aliquoted (0.5 mL) into both Micronic and Sarstedt polypropylene tubes following standard NCRAD protocols and then frozen and stored at ‐80 °C for <7 months prior to analysis. Blinded samples were thawed once and analyzed for ApoE proteotype, Aβ40 and Aβ42 using liquid chromatography‐high resolution tandem mass spectrometry (LC‐MS/MS; C2N Diagnostics, St. Louis, MO). Data was analyzed in JMP 16.0.0 with the method comparison add‐in and GraphPad PRISM 9.3.1 to determine comparability of the measurements made in the two sample tube types.

Results

Comparability analysis found a high correlation of measured Aβ40, Aβ42 and the Aβ42/Aβ40 ratio in plasma stored in Micronic and Sarstedt tubes. Correlation analysis revealed slopes and intercepts within 95% confidence limits of 1 or 0 respectively. Bland Altman analysis showed low measurement bias (4‐7%) between the two tube types. ApoE isoform specific proteotypes were identical between tube types for all subjects.

Conclusion

Results of the tube type study were within the validated performance range of the measurements. Plasma stored in Micronic and Sarstedt tubes can be used interchangeably when detecting ApoE proteotype and quantifying Aβ40 and Aβ42 concentrations using C2N’s LC‐MS/MS analytical platform. These results support the efforts of large biorepositories, like NCRAD to transition the storage of biospecimens from the larger, less automation friendly Sarstedt tube to the more automation friendly, freezer‐space saving Micronic tube. Supported by U24 AG021886 and UL1TR002529.
Identification TDP‐43 fragments specific for frontotemporal lobar degeneration with TDP‐43 inclusions
Authors: Forgrave Lauren M , Li Yun , Moon Kyung‐Mee , Mackenzie Ian R , Foster Leonard J , DeMarco Mari L.
Published: December 2022

Background

Ante‐mortem biomarkers specific for TDP‐43 pathology are highly desired given the challenge in distinguishing frontotemporal lobar degeneration with TDP‐43 pathology (FTLD‐TDP) from phenotypically related disorders. TDP‐43 post‐translational modifications, like C‐terminal fragments, are regarded as disease‐specific TDP‐43 proteoforms; however, the exact structure of these proteoforms remains unclear. This lack of clarity is due in part to the use of instrumentation and techniques with low structural resolution and the study of small sample sizes. With this in mind, we performed high resolution mass spectrometry (HRMS) analysis of brain tissue from cases with and without TDP‐43 proteinopathy to identify TDP‐43 proteoforms unique to FTLD‐TDP.

Method

HRMS was used to determine TDP‐43 proteoform composition in insoluble frontal lobe brain tissue from immunohistochemically‐confirmed FTLD‐TDP (n=13), related dementias (i.e., Alzheimer’s disease and FTLD‐tau without TDP‐43 deposits; n=10) and neuropathologically‐unaffected controls (n=3). Brain tissue was fractioned by gel electrophoresis, with HRMS analysis performed on molecular weight regions corresponding to <28 kDa (low molecular weight TDP; L‐TDP), 28‐38 kDa (mid molecular weight TDP; M‐TDP), and 38‐55 kDa (intact TDP; I‐TDP).

Result

In all samples tested, the greatest TDP‐43 sequence coverage was observed for I‐TDP, followed by L‐TDP and then M‐TDP. TDP‐43 peptides from L‐TDP were more frequently detected in the FTLD‐TDP cases compared to both sets of controls, whereas no frequency differences were observed for I‐TDP and M‐TDP. Quantitative analysis revealed peptide concentrations from M‐ and L‐TDP were significantly increased in FTLD‐TDP cases compared to controls. The L‐TDP peptides concentrations differentiated FTLD‐TDP cases from related dementias and unaffected controls with 78% sensitivity and 100% specificity. Further, three in vivo cleavage sites of TDP‐43 were identified, which were unique to FTLD‐TDP cases.

Conclusion

This is the largest reported proteomics study to date of histology‐confirmed FTLD‐TDP. This is also the first study to include a large number and range of control tissues, and to provide supporting evidence for in vivo cleavage sites including corroboration of the proteolytic fragment recently found in TDP‐43 fibrils. Clarity and consensus on the sequence of TDP‐43 disease‐specific proteoforms will be helpful in advancing biomarker and drug discovery efforts for TDP‐43 proteopathies.
Examining Alzheimer’s Disease Blood‐Based Biomarkers and Cognition Among Non‐Hispanic White and Mexican Americans After Traumatic Brain Injury
Authors: Garcia Joshua M , Lopez Andrea P Ochoa , Medina Luis D
Published: December 2022

Background

There is limited evidence on the relationship of traumatic brain injury with loss of consciousness (TBI‐LOC) and Alzheimer’s disease (AD) blood‐based biomarkers in relation to cognition. This research has predominantly examined associations among non‐Hispanic White (NHW) male service members and veterans, which limits generalizability to ethnically diverse community‐dwelling individuals. This study evaluated cognition in relation to TBI‐LOC in a NHW and Mexican American (MA) sample from Dallas‐Fort Worth, Texas in the United States.

Method

Data were obtained from the Health and Aging Brain Study – Health Disparities. Excluding participants with failed performance validity testing, evidence of alcohol use disorder, severe anxiety/depression, and a history of stroke or seizures, we estimated a cognitive composite using principal component analysis of the cognitive test battery. The remaining sample (n = 899) enabled baseline comparison of those with and without TBI‐LOC, before examining cognition within the TBI‐LOC group (n = 134, mean age(range) = 66.69±7.10(50‐87), mean education = 12.96±4.74, 41% female, 24.6% MA Spanish‐speaking). Multiple regression model comparisons explained variance in cognition by sociodemographic factors (age, gender, education, ethnicity/language), AD blood‐based biomarkers (Aβ42/Aβ40, Tau, Neurofilament light), and TBI‐LOC variables. TBI‐LOC variables included TBIs with loss of consciousness >30 minutes, age at first TBI‐LOC, and longest period of unconsciousness after TBI, scored by the Ohio State University TBI Identification Method.

Result

The TBI‐LOC group did not differ from the non‐TBI‐LOC group across age, education, ethnicity/language, CDR status, or cognition (ps > 0.05); they did differ by gender where the TBI‐LOC group was 59% male compared to 42.4% in the non‐TBI‐LOC group (p <0.001). Within the TBI‐LOC group, sociodemographic factors explained 49.6% of variance in cognition, and the inclusion of AD biomarkers accounted for an additional 0.4% of variance (p = 0.241). The final model including the TBI‐LOC variables explained an additional 2.5% of variance (p = 0.038) in cognition.

Conclusion

Cognitive differences between participants with and without history of TBI‐LOC were not demonstrated. Among those with TBI‐LOC, higher severity of injury was associated with lower cognition, while AD blood‐based biomarkers had non‐significant associations with cognition. Further investigation of alternative biomarkers and specific cognitive domains among ethnically diverse individuals with TBI is warranted.
Association between tau uptake and verbal fluency converge in language centers
Authors: Stevenson Alyssa , Rahmouni Nesrine , Therriault Joseph , Stevenson Jenna , Tissot Cécile , Lussier Firoza Z , Bezgin Gleb , Chamoun Mira , Pascoal Tharick A , Gauthier Serge , Benedet Andréa Lessa , Vitali Paolo , Rosa‐Neto Pedro
Published: December 2022

Background

Recent studies have shown that pathological tau accumulation, a hallmark of Alzheimer’s disease (AD), is closely related to cognitive deficits in older populations. Semantic deficits, measured using tests of category verbal fluency, are among the features of early clinical stages of AD presentations. While the association between semantic decline and AD biomarkers have been evaluated, the use of a novel tau positron emission tomography (PET) tracer [18F]MK6240, remains relatively unexplored. The present study aims to evaluate whether tau accumulation is associated with participants’ performance on both category and letter fluency neuropsychological tests and whether category fluency performance is disproportionately impaired in AD in comparison to letter fluency.

Method

The study was conducted in a population of 298 individuals (188 cognitively unimpaired, 110 cognitively impaired). The D‐KEFS Category Fluency test was used to assess semantic knowledge while Letter Fluency was used to measure lexical speed access. Participants also underwent the Mini‐Mental State Examination (MMSE) to assess overall global cognitive functioning. Accumulation of tau was assessed with [18F]MK6240 PET and standardized uptake value ratio (SUVRs) were calculated between 90 to 110 min post‐injection, using cerebellum grey matter as the reference region. A voxel‐based regression model evaluated the relationship between the cognitive scoring and the PET marker [18F]MK6240, correcting for age, sex, education, diagnosis and RFT was used to account for multiple comparisons.

Result

This study found negative associations between Category and Letter Fluency scores and tau accumulation. Notably, stronger associations were found in the Category Fluency grouping. The associated regions are mainly in the left hemisphere in language related regions and the temporal lobe. Letter Fluency scores demonstrated the strongest association in the frontal regions. Comparatively, the MMSE scores were strongly associated with tau accumulation in both right and left hemispheres.

Conclusion

Tau accumulation is associated with language dysfunction and is a major driver of domain‐specific cognitive impairment across the AD spectrum. Associations were more pronounced in the left hemisphere for both semantic knowledge and lexical speed. These results also suggest that tau accumulation is more strongly associated with semantic knowledge as indicated by uptake in language related areas.
Amyloid duration and entorhinal tau interact to influence cognition in preclinical Alzheimer’s disease
Authors: Cody Karly Alex , Koscik Rebecca Langhough , Jonaitis Erin M. , Hermann Bruce P , Chin Nathaniel A. , Asthana Sanjay , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C.
Published: December 2022

Background

The degree of involvement of amyloid and tau on cognitive decline in the pre‐symptomatic phase of AD remains unresolved. This study examines whether duration of amyloid positivity and entorhinal tau individually contribute or interact to influence longitudinal cognitive decline in initially unimpaired older individuals.

Method

Data were from 358 initially unimpaired individuals from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center who underwent amyloid and tau PET imaging and longitudinal cognitive assessment (Baseline age: 59.7 ±6.7 years; 67% female; follow‐up years, Median(IQR)=8.0 (6.1‐9.8); Table 1). Amyloid burden was quantified from cortical 11C‐PiB DVR, and amyloid duration, quantified as years from PiB positivity (A+/‐; global PiB DVR1.16), was estimated using a sampled iterative local approximation algorithm. Tau burden was quantified using 18F‐MK‐6240 standard uptake value ratios (SUVRs; 70‐90min, inferior cerebellar grey matter reference region). Linear mixed effects (LME) models (random intercept and age‐related slope; unstructured covariance) investigated contributions of amyloid duration (at MK‐6240 scan) and entorhinal cortex (EC) MK‐6240 uptake to retrospective cognitive decline represented by a modified three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3).

Result

Among initially unimpaired individuals, faster PACC‐3 decline was associated with both longer amyloid duration and higher EC tau. LME models showed significant linear and non‐linear interactions of amyloid duration and EC tau on cognitive decline, suggesting a synergistic effect whereby amyloid duration together with a higher tau burden increases the likelihood of cognitive decline beyond their separable effects (Table 2). To further characterize these interactions, we compared cognitive trajectories of groups based on amyloid duration and EC tau positivity (Figure 1A‐C). Post‐hoc analyses revealed significantly greater decline in the group with 10+ years of amyloid duration and high EC tau compared with all other groups over the study duration (Figure 1C).

Conclusion

These results suggest that in this pre‐symptomatic sample, amyloid duration and EC tau were not redundant contributors to decline, but rather interacted to influence decline during the retrospective period of observation. Prospective follow‐up and mediation analyses will be essential to fully elucidate the influence of amyloid duration and early tau on cognitive decline in preclinical Alzheimer’s disease.
Translational potential of JAX humanized APOE mice: Metabolism and body composition in very old mice
Authors: Bhattrai Avnish , McLean John W. , Raikes Adam C. , Wiegand Jean‐Paul L. , Skopp Stacy M , Brinton Roberta Diaz
Published: December 2022

Background

Apolipoprotein (APOE) is the strongest genetic risk factor for the development of late‐onset Alzheimer’s disease (LOAD). Clinically, LOAD exhibits strong sex effects with females being twice at the risk of developing AD than males. Models exhibiting strong AD etiology are used in preclinical settings, however lack of translatability necessitates model development with a reverse translational approach. This study explores metabolic hallmarks of LOAD assessing the clinical translatability of the JAX humanized APOE (hAPOE) mouse model.

Method

hAPOE mice (M/F, n = 65, mean age = 23.35 +/‐ 0.90 months) with e3/3, e3/4 or e4/4 genotype underwent a metabolic and body composition screening assay including fasting blood glucose (FBG) and ketone (FKB) measurement, EchoMRI, and 18F‐FDG‐PET brain imaging, prior to being sacrificed. Blood plasma was analyzed for triglyceride levels. Cerebral FDG‐PET standardized uptake values were normalized to cerebellum. All data were analyzed with genotype x sex analysis of variance. P ≤ 0.05 was considered statistically significant and post‐hoc pairwise analyses were conducted for interaction effects with p ≤ 0.1 (FKB, adipose index) for future study planning.

Result

Females had significantly lower lean mass (p < 0.0001) and FBG (p=0.05), with a trend toward lower glucose uptake on FDG‐PET compared to males (p=0.072). Post‐hoc interaction analyses of FKB (interaction p=0.105) demonstrated lower ketone body levels in male e4/4s compared to female e4/4s (uncorrected p=0.0685) and male e3/4s (p=0.034). Post‐hoc interaction analyses of adipose index (interaction p=0.093) demonstrated greater adiposity in female e4/4s compared to male e4/4s (uncorrected p=0.005) and female e3/3s (uncorrected p=0.035). No effects of APOE genotype were observed.

Conclusion

In a mouse cohort at a comparable human age of ∼ 70 years, lower lean mass, fasting blood glucose, and glucose uptake in the brain for female mice indicates ongoing bioenergetic deficits and is corroborated by observations within clinical populations. Greater adiposity in female e4/4s suggests that brain bioenergetic demand is not being met through fat reserves. However, the overall lack of genotypic effects suggests this bioenergetic crisis is not driven by hAPOE in this animal model, limiting clinical translatability.

NIA R01AG057931; University of Arizona TBIR (NIH S10 OD025016).
BDNF expression partially mediates greater verbal learning and memory ability in a cohort enriched with risk for Alzheimer’s disease
Authors: Edmunds Kyle J , Rogers Christine C , Pandos Alyssa A , Mamlouk Gabriella M , Motovylyak Alice , Johnson Sterling C. , Okonkwo Ozioma C.
Published: December 2022

Background

In cognitively normal adults, women score higher than men in verbal learning ability (VLM)—a cognitive domain sensitive to decline in Alzheimer’s disease (AD). Sex‐specific mechanisms of action in brain‐derived neurotrophic factor (BDNF), a growth factor important for modulating memory and long‐term brain health, may explain this observed sex difference. Therefore, this study examines whether circulating BDNF expression mediates sex differences in VLM scores in a cohort enriched with risk for AD.

Method

Cognitively unimpaired participants in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; n=201, age 63.81±6.04y, 66.2% women, 65.7% family history of AD, 38% APOE‐ε4 carriers) underwent the Rey Auditory Verbal Learning Test (RAVLT). Scores from the delayed recall test and trials 3‐5 and were aggregated as a VLM performance index. Serum BDNF levels were measured using a Human BDNF Quatikine Immunoassay (R&D Systems). Mediation analysis and bootstrapping were performed using the Hayes and Preacher macro for SPSS, first using the full participant sample. Stratified models were then assembled to test the conditional dependence of BDNF mediation on APOE‐ε4 allele carriage.

Result

From the full sample, women had significantly higher VLM scores [β=‐0.68; p<0.01] and serum BDNF levels [β=‐0.61; p<0.01] than men; BDNF expression was likewise positively correlated with VLM [β=0.17; p=0.014]. Bootstrapping indicated that BDNF was indeed a significant partial mediator of the association between sex and VLM [β=‐0.07; 95% CI: ‐0.164, ‐0.005]. Models stratified by APOE‐ε4 carriage showed no significant association between sex and BDNF in APOE‐ε4+ individuals [β=‐0.13; p=0.63], but women in this group again had significantly higher VLM scores than men [β=‐0.57; p=0.02]. By comparison, in the APOE‐ε4‐ group, women had significantly higher BDNF levels [β=‐0.65; p<0.01] and VLM scores [β=‐1.01; p<0.01], and bootstrapping again showed BDNF to be a significant mediator [β=‐0.16; 95% CI: ‐0.324, ‐0.037].

Conclusion

Our findings indicate that higher circulating BDNF levels in women might be an important factor in building resilience against verbal memory decline, but this relationship may be attenuated by the deleterious effects of APOE‐ε4 allele carriage.
Construct validity of cognitive intraindividual variability: A replication study
Authors: Scott Bonnie M. , Royall Donald R. , O'Bryant Sid E. , Hilsabeck Robin C.
Published: December 2022

Background

We previously found intraindividual variability (IIV) in performance between cognitive domains to predict subsequent declines in cognitive and functional status over a 5‐year period in the Texas Alzheimer’s Research and Care Consortium (TARCC) Hispanic Longitudinal Cohort. However, we later examined the construct validity and predictive utility of this metric in a follow‐up study and found that IIV‐between domains was driven primarily by IIV‐within the executive function domain in the non‐Hispanic cohort and by IIV‐within the language domain in the Hispanic cohort. The present study aimed to replicate these findings in two independent samples: (1) FRONTIER, and (2) HABLE.

Methods

Baseline data for cognitively normal participants in the TARCC (N = 651), HABLE (N = 1199), and FRONTIER (N = 197) studies were included for analysis in the present study. All participants ranged from 50–95 years of age with 0–22 years of education. Although cognitive measures varied across studies, mean composite and standard deviation z‐scores were calculated from similar tasks for an Attention/Processing Speed, Language, Delayed Verbal Memory, and Executive Functioning domain. Measures of functional independence also varied across studies.

Results

Across studies, non‐Hispanic individuals were generally older with higher levels of education, fewer depressive symptoms, and higher cognitive and functional status. Only variability in the executive domain was found to consistently differ between Hispanic and non‐Hispanic individuals across studies and no consistent between‐group differences were observed in the relationship between cognitive IIV scores with each other and with clinical characteristics and measures of general cognitive and functional status.

Conclusions

Findings suggest that the construct validity and predictive utility of cognitive IIV scores varies across studies differing in methodology and clinical characteristics.
Neuroinflammatory profiles of the human female brain in midlife resembles the human male late‐life Alzheimer's brain
Authors: Delatorre Nicole , Van Rossum Hannah , Mishra Aarti , Padilla‐Rodriguez Marco , Rodgers Kathleen E. , Brinton Roberta Diaz
Published: December 2022

Nicole Delatorre & Hannah Van Rossum are co‐first authors

Background

Neuroinflammation is a well‐documented feature of Alzheimer’s Disease (AD). Two important questions in defining the role of the neuroimmune system in AD remain unaddressed: 1) the initiation phase of inflammation and 2) sex differences in the inflammatory cascade. Previous preclinical findings from our group demonstrated elevated inflammatory and immune transcripts including CD3, CD4, and MHCII. With this work, we extend and translate our preclinical discoveries to test the hypotheses that the inflammatory phenotype of LOAD is initiated in midlife of the human aging process and sex differences are prevalent.

Method

Both fixed and frozen human tissue samples were obtained from NIH NeuroBioBank (University of Maryland, University of Miami, and Mt. Sinai) that included the corpus callosum, hippocampus, and hypothalamus of 40 brain donors that were sex and age matched. For the purposes of this study, samples were sub‐classified into 3 groups: healthy aging 40‐49 years‐old, healthy aging 50‐59 years‐old, and AD age 60‐80 years‐old. Transcriptomic analyses were conducted to determine neuroinflammatory gene expression and to identify common signaling profiles. Neuroinflammatory markers were visualized using 3,3’‐diaminobenzidine immunohistochemistry and included microglia (IBA‐1), activated microglia (HLA), and T‐cells (CD3, CD4, CD8).

Result

Gene expression change was determined by comparing each group to the young male. The profiles were compared using fisher exact tests and revealed region‐specific and sex‐specific transcript regulation. Midlife females exhibited significant differences in genes involved in hypothalamic adaptive immune response (p=0.0054), hippocampal astrocyte function p=0.007, and hypothalamic inflammatory signaling p=0.028). AD males exhibited altered gene expression in corpus callosum neurotransmission (p=0.0355), hippocampal innate immune response, and hypothalamic adaptive and innate immune response (p=0.0496, p=0.0208). Both midlife female and AD male showed hippocampal upregulation of innate immune transcripts and hypothalamic upregulation of adaptive and innate immune response genes.

Conclusion

These results provide evidence of early activation of the immune response in brain as a potential sex‐dependent risk factor for AD. Outcomes of these analyses support future studies that identify neuroimmune biomarkers of the AD prodrome and present an early opportunity for intervention in order to reduce risk and/or delay AD.

NIH: R01AG057931, R01AG057931‐02S1, T32AG061897, R01AG057931‐01A1
Translational potential of JAX humanized APOE mice: Hippocampal volume decline in very old mice
Authors: Raikes Adam C. , Bhattrai Avnish , McLean John W. , Wiegand Jean‐Paul L. , Brinton Roberta Diaz
Published: December 2022

Background

Whole brain and hippocampal atrophy are the most prominent structural features of late‐onset Alzheimer’s disease (LOAD) and are accepted endpoints in many clinical trials. The APOE ε4 allele is the strongest genetic risk factor for LOAD, with the ε4/ε4 genotype associated with the greatest atrophy rates. To date, there is limited hippocampal volume reporting in preclinical APOE models. To assess the translational potential of a humanized APOE (hAPOE) mouse model, we report age, sex, and genotype effects on total brain and hippocampal volume.

Method

High resolution ex‐vivo MRIs were obtained from two separate cohorts of male and female hAPOE mice (Cohort 1: n=53, 18.47±0.99 months; Cohort 2: n=33, 24.24±0.58 months). A validated mouse brain atlas was used for volumetric analysis. Cohorts were analyzed separately with genotype by sex analyses of variance for total brain volume (sum of all regions in atlas) as well as left and right hippocampal volume as percent of total brain volume.

Result

In Cohort 1, hAPOEε4/ε4 mice had significantly larger brains than hAPOEε3/ε3s or hAPOEε3/ε4s, with female hAPOEε4/ε4s having the largest brains (p<0.001). Regardless of genotype, females had smaller left (p=0.006) and right (p<0.001) hippocampi relative to males. In Cohort 2, there were no genotype or sex differences in total brain volume. However, left (p=0.044) and right (p=0.034) hippocampal volumes were smaller for hAPOEε4/ε4 mice compared to hAPOEε3/ε4 mice without sex effects.

Conclusion

Our findings capitalize on a large dataset (n=88) of high‐resolution MRIs. At 18‐20 months old (∼60 human years), hAPOEε4/ε4 mice had greater total brain volume than comparably aged hAPOEε3/ε3 or hAPOEε3/ε4 mice without hippocampal atrophy. However, hippocampal atrophy was evident when mice were aged to 24‐25 months (∼70 human years). These findings of larger brain volume and greater hippocampal atrophy in hAPOEε4/ε4 carriers are consistent with large‐scale AD imaging datasets. The timing of evident hippocampal atrophy in these mice also coincides with the global average age of clinical diagnosis. Based on these findings, the translational potential of this model requires utilizing very old mice, limiting the window for therapeutic testing.

Acknowledgements

NIA R01AG057931, RF1AG059093; University of Arizona TBIR (NIH S10 OD025016)
Regional Differences of the Impact of Healthy Aging on Myeloarchitecture at 7T
Authors: Mueller Susanne G
Published: December 2022

Background

Cortical gray matter (cGM) loss in healthy aging has been well documented by volumetric MRI. Less well known though is if this age‐related cGM loss is layer‐specific or diffuse. Benefiting from the higher resolution at 7T and the close relationship between cortical cyto‐ and myeloarchitecture (1) this project used a newly developed technique for the differentiation between heavily (layers IV‐VI) and sparsely (layers I‐III) myelinated cortical layers to investigate this question.

Method

The 7T MP2Rage images (TR/TE/TI1/TI2=5000/2.45/900/2750 ms, 0.7x0.7x0.7mm) of 45 healthy controls (age: 19‐75, f/m=23/22) from the ATAG data repository (http://doi.org/10.5061/dryad.fb41s) were used for this project and the following contrasts generated: 1. T1 weighted image (UNI). 2. T1 relaxation image (T1map). 3. Inv1/Inv2 ratio map (In1/In2 ratio). After skull‐stripping and intensity calibration a fourth contrast (UNI/T1map ratio) was calculated. The UNI was segmented in SPM and a binary cortical rim mask calculated. With these four contrasts as input K‐means clustering was used to identify 6 clusters within this mask: CSF cluster, CSF/cGM transition cluster, WM cluster, WM/cGM transition cluster, heavily myelinated cGM cluster (hcGM) and sparsely myelinated cGM cluster (scGM) (Figure 1). The hGM and scGM maps were warped into a common space with SPM’s DARTEL. SPM was used to compare hcGM and scGM differences of young adults (n=27, 19‐27 years) with that of older adults (n=18, 42‐75 years).

Result

Figure 2 shows that hcGM loss was restricted to the mid‐posterior cingulate and parahippocampal gyrus. Age‐related scGM loss was more diffuse and affected mesial prefrontal, opercular cortex and superior temporal gyrus.

Conclusion

Age related cGM loss affects sparsely and heavily myelinated layers differently. The heavily myelinated posterior cingulate belongs to the late myelinating structures. The hcGM loss there is consistent with the “last in, first out” hypothesis. The scGM loss in the mesial prefrontal, opercular, superior temporal region affects sparsely myelinated layers I‐III that are known to have a high synaptic density (1) indicating that it is probably mostly driven by dendritic loss. Although preliminary, the data presented here indicate that this new technique might provide a better insight into the nature of GM loss in healthy and abnormal aging.

1. Neuroimage 2019;197:716‐741
Alpha‐synuclein co‐pathology in Alzheimer’s disease identified by RT‐QUIC identification
Authors: Pilotto Andrea
Published: December 2022

Background

alpha‐synuclein co‐pathology may influence Alzheimer’s disease (AD) phenotype but its presence has never been tested in large series of patients. Real‐time quaking‐induced conversion (RT‐QuIC) recently provided evidence of alpha‐synuclein seeding activity in CSF and olfactory mucosa of patients with alpha‐synucleinopathies

Method

a preliminary set of 82 AD patients (mean age 70,3 + 7.3 years) underwent CSF analyses for Tau, P‐tau and A‐beta amyloid and an extensive cognitive, behavioral and motor assessment. RT‐QuiC for alpha‐synuclein was performed on CSF samples.

Result

alpha synuclein RT‐QuIC resulted positive in thirty‐nine out of 82 AD patients (47.6%). AD patients with positive alpha‐synuclein were comparable for age and disease severity those negative to RT‐QuIC assay including Tau/P‐Tau and A‐beta CSF markers in cross‐sectional analyses but exhibited higher prevalence of parkinsonism (p=0.02).

Conclusion

these preliminary findings indicate that alpha‐synuclein co‐pathology might be detected in more than one third of Alzheimer’s disease patients. These findings might potentially explain the clinical variability of AD including age at onset, progression and response to treatment observed in clinical series. Larger longitudinal studies are warranted to confirm and extend these findings.
Analyzing Medical Claims Data to Identify Health Care Provider Specialties Diagnosing Frontotemporal Dementia
Authors: Chenette Devon , McCaughey Stella , Wolfus Charles , Fisher Daniel
Published: December 2022

Background

Frontotemporal dementia (FTD) is a rare, early‐onset form of dementia presenting with changes in personality, speech, executive function, and movement. Early diagnosis of FTD is challenging due to lack of definitive clinical tests and biomarkers. FTD patients are misdiagnosed with Alzheimer’s disease, vascular dementia, Parkinson’s disease, or psychiatric disorders. Analysis of medical claims data can help better understand the journey to FTD diagnosis.

Method

An analytical model was developed using deidentified medical claims data from 2008−2021 to determine those patients recently diagnosed with FTD through diagnosis codes. To achieve greater confidence in the FTD diagnosis, patients may not have had coding for non‐FTD forms of dementia subsequent to their most recent FTD diagnosis. All patients were attributed to the health care provider (HCP) on the medical claim in which the patient was diagnosed with FTD.

Result

26,155 HCPs were identified based on their unique National Provider Identifier (NPI); provider specialty was sourced from the National Plan and Provider Enumeration System (NPPES) registry. Attributed to each HCP was the distinct number of FTD patients diagnosed in the most recent 12 months with International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM) codes for Frontotemporal dementia, Other frontotemporal dementia, Pick’s disease, or Corticobasal degeneration. Data were sorted by provider specialty. Combined, Family Medicine and Internal Medicine providers comprised 48% of diagnosing HCPs; followed by Neurologists (10%), Emergency Medicine (3%), Psychiatry (3%), and Geriatric Medicine (3%). To further analyze this data, HCPs were divided into quartiles based on the relative volume of FTD patients diagnosed in the most recent 12‐month time period. The top quartile averaged 12 FTD patients diagnosed annually with Neurologists comprising the greatest percentage (40%) of HCP specialties. The bottom quartile averaged 1 FTD patient diagnosed annually with Primary Care Providers comprising the greatest percentage (49%) of HCP specialties.

Conclusion

HCPs across several specialties diagnosed FTD patients; including Family Medicine and Internal Medicine, Neurologists, Emergency Medicine, Psychiatry, and Geriatric Medicine. Neurologists comprised the greatest percentage (40%) of top quartile diagnosing HCP specialties.
Construct Validity Indicators from the ARMADA STUDY for the Tablet Computer‐Based NIH Toolbox Cognition Battery
Authors: Giordani Bruno , Goldstein Felicia C , Rigby Taylor , Gregoire Allyson , Reader Jonathan M , Fisher Jordan , Gurecki Sydney , Bhaumik Arijit K , Ho Emily , Ustsinovich Vitali , Gershon Richard C. , Weintraub Sandra
Published: December 2022

Background

The Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study was designed to validate and further develop the full tablet‐based NIH Toolbox Assessment of Neurological and Behavioral Function within an older, racially diverse sample. This ARMADA cohort study of the Toolbox Cognition Battery (NIHTB‐CB) reports construct validity, assessed through its two components: convergent (high correlations to related constructs) and discriminant (low correlations with dissimilar constructs) validity.

Methods

Participants (age range 65–99 years, 142 aged 85+) were consensus conference‐diagnosed with normal cognition (N = 367), amnestic mild cognitive impairment (N = 136), and Alzheimer’s disease (N = 68). NIHTB‐CB assesses domains of Fluid Executive, including Set Shifting (Dimensional Card Sort/DCCS), Inhibitory Control and Attention, (Flanker) and Working Memory (List Sort Working Memory/LSWM); Fluid Processing Speed (Pattern Comparison/PCPS), Fluid Episodic Memory (Picture Sequence Memory/PSM) and Crystalized Language (Oral Reading/ORR, Vocabulary/TPVT). Participants were also given the National Alzheimer’s Disease Coordinating Center Unified Data Set (UDS3) cognitive measures: Memory Composite (Benson Figure and Craft Stories Delayed Recall); Executive Composite (Trail Making, Semantic Fluency), Auditory Attention (Digit Span Forward), Figure Copy (Benson), and Language (Multi‐lingual Naming Test). Unadjusted, (uncorrected) standard scores were created based on the full Toolbox and UDS populations.

Result

Based on the large sample size, most all correlations between NIHTB‐CD and UDS3 were significant, though patterns were clear. NIHTB‐CB/Fluid Executive tests had highest correlations with the related UDS3 Executive factor composite (r = 0.53‐0.60), approaching threshold for a “good” designation (>0.6), and “low” designation correlations (r<0.3) for Auditory Attention. PSM correlated highest with UDS Episodic Memory (r = 0.55), and lowest with Auditory Attention (r = 0.23). PCPS was highest with the Executive Composite (r = 0.53) and lowest with Language (r = 0.26). Crystalized NIHTB‐CB correlated highest with UDS Language (r = 0.41‐0.50) versus ORR with Memory (r = 0.22) and TPVT with Copy (r = 0.26).

Conclusion

Results demonstrated that the highest correlations between NIHTB‐CD and UDS3 measures were between related constructs and lowest correlations were between dissimilar constructs. Thus, convergent/discriminant expectations were supported across NIHTB‐CB measures, reinforcing NIHTB‐CB construct validity. Consistent results across diagnoses and other analytic approaches are also presented, supporting these findings.
Hippocampal inflammation is associated with vascular dysfunction in middle aged Non‐Latinx Black APOE‐ε4 carriers
Authors: Igwe Kay C , Lao Patrick J. , Seblova Dominika , Swanberg Kelley , Rivera Andres M. , Giudicessi Averi , Tejeda Emely , Juchem Christoph , Mayeux Richard , Manly Jennifer J , Brickman Adam M.
Published: December 2022

Background

Neuroinflammation may be associated with global vascular dysfunction and damage. APOE‐ε4, a major genetic risk factor for late onset AD, is expressed in neuroinflammatory cells and may lead to increased pro‐inflammatory cytokine and nitric oxide production in response to injury. We examined the relationship of vascular dysfunction and damage with a magnetic resonance spectroscopy (MRS) marker of neuroinflammation in APOE‐ε4 carriers and non‐carriers.

Method

Single proton MRS, pulsed arterial spin labeling (PASL), and T2 fluid attenuated inversion recovery (FLAIR) were collected in a sample of racially/ethnically diverse, middle‐aged adults (n=313, women=67%, age=55±11, years of education=13±3, 72% Latinx/22% Non‐Latinx Black/6% Non‐Latinx White) and used to derive hippocampal Inositol/creatine ratios (Ins/Cr) as a measure of neuroinflammation. Global cerebral blood flow (CBF) was used as a measure of vascular function, and white matter hyperintensity (WMH) volume as a measure of small vessel cerebrovascular damage. APOE genotype was categorized as the presence or absence of at least one ε4 alleles. We estimated general linear models to test main effects and the interaction of APOE‐ε4 and Ins/Cr on WMH or CBF, adjusting for age and stratified by race/ethnicity due to differential prevalence and effects of APOE ε4.

Results

In the whole sample, being an ε4 non‐carrier (β=‐12.0 95%CI: [‐24.8, 0.83], p=0.067) and having greater Ins/Cr (β=‐1.1[‐2.2, 0.1], p=0.062) were associated with lower CBF. Within Non‐Latinx Black participants, being an APOE‐ε4 non‐carrier (β=‐40.2[‐73.3, ‐7.1], p=0.02) and having greater Ins/Cr (β=‐3.7[‐73.3, ‐7.1], p=0.007) were associated with lower CBF. The negative association with Ins/Cr was stronger in APOE‐ε4 carriers compared to non‐carriers (β=3.9[0.65, 7.1], p=0.02). No associations of Ins/Cr were observed with WMH.

Conclusion

Global vascular dysfunction, but not vascular damage, was related to hippocampal inflammation in APOE‐ε4 carriers among Non‐Latinx Black middle‐aged adults. Neuroinflammation may be linked to vascular brain health which is particularly important for groups with higher APOE‐ε4 prevalence or with greater exposure to social determinants of health that can lead to greater inflammation.
The Neurologist’s Role in Patients with Mild Cognitive Impairment and Mild Alzheimer’s Disease Dementia
Authors: Pruzin Jeremy J. , Brunton Stephen , Alford Susan , Hamersky Carol , Sabharwal Anup , Gopalakrishna Ganesh
Published: December 2022

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Mild cognitive impairment (MCI) affects >10% of US adults over the age of 70 and represents a transitional stage between healthy aging and dementia. Multiple factors influence the path to care through the health system. This study sought to better understand the medical journey of patients with all‐cause MCI and mild AD dementia (ADD) to identify opportunities for improvement.

Method

An anonymous online survey was conducted in a cross‐sectional US‐population of 103 patients with self‐reported diagnosis of MCI/mild ADD, 150 care partners of patients with MCI/mild ADD, and 75 neurologists.

Result

In the most common medical journey for patients (73% of patients), half of patients/care partners (51%) reported they received their diagnosis from a neurologist. The most common reasons patients/care partners initiated discussions with a healthcare provider were symptoms interfering with activities of daily life (51%), symptoms not resolving (46%), encouragement from family or friends (44%), and symptoms worsening in degree of discomfort/frequency (43%). Most patients/care partners (23%) reported receiving a misdiagnosis prior to receiving a formal diagnosis of MCI/mild ADD. Half of neurologists (52%) view themselves as the coordinator of care for patients with MCI/mild ADD; whereas 35% of patients/care partners view them as such.

At the time of diagnosis, most neurologists (83%) reported discussing with patients the potential causes of MCI/mild ADD. Most neurologists (84%) reported following American Academy of Neurology guidelines (AAN) for treatment and management of patients with MCI/mild ADD. For ongoing care, treatments most commonly prescribed/recommended by neurologists included mental exercises (84%), general improvements in lifestyle (84%), acetylcholinesterase (AChE) inhibitors (78%), social interaction (75%), and NMDA antagonists (73%).

Conclusion

Neurologists are often the healthcare provider diagnosing MCI/mild ADD however patients frequently experience misdiagnosis in their medical journey. Neurologists are not viewed as coordinators of care by most patients. Positioning neurologists as coordinators of MCI/mild ADD care and equipping them with the right resources may help patients obtain a diagnosis and treatment sooner.
Translational potential of JAX humanized APOE mice: trajectories of resilient versus susceptible aging by sex and weight
Authors: Vitali Francesca , Wiegand Jean‐Paul L. , Tucker Allan , Merlini Simona , Brinton Roberta Diaz
Published: December 2022

Background

Aging, chromosomal sex, and genetic risk factors interact to determine the trajectory of an individual’s age‐related biological changes and, in turn, may predispose individual risk or resilience to AD. To advance translational validity of the JAX humanized APOE (hAPOE) mouse model, we investigated whether a well‐documented preclinical AD symptom, inexplicable weight loss, was evident in our hAPOE mouse colony. Further we determined whether this hallmark symptom could be used to detect subpopulations of vulnerable vs resilient.

Method

We used an autoregressive hidden Markov model (AHMM) to identify trajectories of JAX humanized APOE mice based on their longitudinal weight data. We assumed 10 hidden states to estimate proper trajectories. We ran 10 AHMM models to ensure stability and each model was run with 1500 iterations to reach convergence. The AHMM with maximum trace value was selected as the main model. The key trajectories were then identified by clustering together mice ending in the same hidden state. Weight data were collected from November 2018 to September 2021 for 1196 hAPOE mice (652M, 544F) at different time points ranging from 5 to 28 months of age. Genotypes included APOEe3/3, APOEe3/4 and APOEe4/4.

Result

AHMM results identified 5 main weight trajectories for mice ending in one of the 5 most probable ending states (formally named A,B,C,D,E). Of these, three states (A,B,D) captured weight loss trajectories for 426 (36%) mice, one state (C) was characterized by an increase in weight for 152 (36%) mice and 403 (13%) mice ending in a state stable (E) with no significant weight loss or increase. Weight loss was more apparent in female mice, while weight increase was more typical of male mice.

Conclusion

This mouse cohort displays weight loss that may correspond to individuals exhibiting a hallmark inexplicable weight loss starting around 15/20 months (corresponding to human 50/55 years old) that can be symptomatic of the prodromal phase of AD.

Acknowledgements

This work was supported R01AG057931, RF1AG059093 and the Center for Innovation in Brain Science to RDB.
Allopregnanolone as a Regenerative Therapeutic for Alzheimer’s Disease: Phase 2 proof‐of‐concept clinical trial using hippocampal volume as a surrogate endpoint
Authors: Hernandez Gerson D , Lopez Claudia M , Raikes Adam C. , Rodgers Kathleen E. , Matthews Dawn C , Cutter Gary R , Schneider Lon S. , Brinton Roberta Diaz
Published: December 2022

Background

Given that hippocampal volume is a well‐established imaging biomarker predictive of cognitive decline although not itself a measure of cognition, we propose its use as a surrogate endpoint to test the efficacy of allopregnanolone as a regenerative therapeutic for mild AD.

Method

Phase 2 multi‐center, double‐blind, parallel‐group, randomized‐controlled clinical trial. A total of 20 sites will recruit 200 participants with mild AD, 100 participants per treatment arm. Eligible participants are male or female, age 55 to 80 years old, diagnosed with probable AD, with a MMSE between 20‐26 and APOE ε4 genotype (3/4 and 4/4). Participants will be randomized to 4 mg Allo (administered intravenously over 30 minutes, once per week) or matching placebo, 1:1 allocation, for a 12‐month period. After 12 months, all participants in the placebo group will be crossed‐over to receive Allo for the remainder of the study (6 month open‐label phase). Brain imaging to evaluate the primary endpoint will be conducted at baseline, 6 and 12 months. A critical component of this trial is that all imaging sites participating in the trial are capable of performing both basic and advanced MRI sequences required in the protocol.

Result

Primary Endpoint is Mean rate of change in hippocampal volume at 12 months. Secondary Endpoints include mean rate of change in cognitive outcomes (CANTAB‐PAL, ADAS‐Cog11), functional outcomes (ADCS‐iADL) and safety outcomes at 12 months. Exploratory endpoints include other imaging outcomes (regional brain volumes, white matter fiber tract diffusion measures as determined by DTI, average intrinsic connectivity as determined by resting state fMRI, and cerebral region cerebral blood flow); blood‐based biomarkers of target engagement; other cognitive and functional outcomes (CDR‐SB score, ADAS‐Cog14 score, MMSE score, NPI‐Q score, EuroQol 5‐Dimension / 5‐Level (EQ‐5D‐5L) health‐related quality of life scale scores, QoL‐AD score, Zarit Burden Interview Questionnaire score at 12 and 18 months. Additionally, change from baseline to 6, 12 and 18 months in open‐label treatment participants switching from placebo to Allo at 12 months in the above endpoints.

Conclusion

Results from this study will validate previous findings indicating that allopregnanolone may exert both regenerative and neuroprotective effects on structure and connectivity in the Alzheimer’s brain.