Department of Neurology Works

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15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN
(medRxiv, 2024-08-09) Daniels, Alisha J.; McDade, Eric; Llibre-Guerra, Jorge J.; Xiong, Chengjie; Perrin, Richard J.; Ibanez, Laura; Supnet-Bell, Charlene; Cruchaga, Carlos; Goate, Alison; Renton, Alan E.; Benzinger, Tammie L. S.; Gordon, Brian A.; Hassenstab, Jason; Karch, Celeste; Popp, Brent; Levey, Allan; Morris, John; Buckles, Virginia; Allegri, Ricardo F.; Chrem, Patricio; Berman, Sarah B.; Chhatwal, Jasmeer P.; Farlow, Martin R.; Fox, Nick C.; Day, Gregory S.; Ikeuchi, Takeshi; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Lopera, Francisco; Takada, Leonel; Sosa, Ana Luisa; Martins, Ralph; Mori, Hiroshi; Noble, James M.; Salloway, Stephen; Huey, Edward; Rosa-Neto, Pedro; Sánchez-Valle, Raquel; Schofield, Peter R.; Roh, Jee Hoon; Bateman, Randall J.; Dominantly Inherited Alzheimer Network; Neurology, School of Medicine
This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.
2023 Inaugural Healthcare Delivery Science: Innovation and Partnerships for Health Equity Research (DESCIPHER) Symposium
(Wiley, 2024-07-04) Orechwa, Allison Z.; Abhat, Anshu; Amezcua, Lilyana; Boden-Albala, Bernadette; Buchanan, Thomas A.; Chen, Steve; Daskivich, Lauren P.; Feldman, Brett; Gould, Michael K.; Lee, Wei-an; Lynch, Christopher; Meltzer, Carolyn C.; Mittman, Brian S.; Pereyda, Margarita; Raff, Evan; Robinson, Jehni; Saluja, Sonali; Turner, Barbara J.; Taira, Breena R.; Trotzky-Sirr, Rebecca; Williams, Linda; Wu, Shinyi; Yee, Hal, Jr.; Towfighi, Amytis; Neurology, School of Medicine
Introduction: This article provides an overview of presentations and discussions from the inaugural Healthcare Delivery Science: Innovation and Partnerships for Health Equity Research (DESCIPHER) Symposium. Methods: The symposium brought together esteemed experts from various disciplines to explore models for translating evidence-based interventions into practice. Results: The symposium highlighted the importance of disruptive innovation in healthcare, the need for multi-stakeholder engagement, and the significance of family and community involvement in healthcare interventions. Conclusions: The article concluded with a call to action for advancing healthcare delivery science to achieve health equity.
A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease
(Lippincott Williams & Wilkins, 2015-04) Farlow, Martin R.; Grossberg, George T.; Sadowsky, Carl H.; Meng, Xiangyi; Velting, Drew M.; Department of Neurology, IU School of Medicine
The long-term safety, tolerability, and efficacy of high-dose 13.3 mg/24 h rivastigmine patch in severe Alzheimer disease was evaluated in a 24-week, open-label extension to the double-blind ACTION study. Safety and tolerability, and efficacy on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV), Severe Impairment Battery (SIB), and ADCS-Clinical Global Impression of Change (ADCS-CGIC) were assessed. Overall, 197 patients continued on 13.3 mg/24 h patch; 199 uptitrated from 4.6 mg/24 h to 13.3 mg/24 h patch. The incidence of adverse events (AEs), serious AEs and discontinuations due to AEs was similar in patients who continued on, and patients who uptitrated to, 13.3 mg/24 h patch (AEs: 57.9% and 59.8%; serious AEs: 16.2% and 16.1%; discontinuations: 11.2% and 12.1%, respectively). Larger mean changes from double-blind baseline were observed in patients uptitrated on the ADCS-ADL-SIV (−4.6; SD=8.7) and SIB (−7.0; SD=16.6), than those who continued on 13.3 mg/24 h patch (−3.9; SD=8.0 and −4.7; SD=16.8, respectively). ADCS-CGIC scores were comparable. There were no clinically relevant between-group differences in safety and tolerability. Greater decline was observed in patients with delayed uptitration to high-dose 13.3 mg/24 h patch than patients who continued on high-dose patch.
A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer's dementia
(Wiley Blackwell (Blackwell Publishing), 2013-10) Farlow, Martin R.; Grossberg, George T.; Sadowsky, Carl H.; Meng, Xiangyi; Somogyi, Monique; Department of Neurology, IU School of Medicine
AIMS: The 24-week, prospective, randomized, double-blind ACTION study investigated the efficacy, safety, and tolerability of 13.3 versus 4.6 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease (AD). METHODS: Patients had probable AD and Mini-Mental State Examination scores ≥3-≤12. Primary outcome measures were as follows: Severe Impairment Battery (SIB) and AD Cooperative Study-Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Secondary outcomes were as follows: ADCS-Clinical Global Impression of Change (ADCS-CGIC), 12-item Neuropsychiatric Inventory (NPI-12), and safety/tolerability. RESULTS: Of 1014 patients screened, 716 were randomized to 13.3 mg/24 h (N = 356) or 4.6 mg/24 h (N = 360) patch. Baseline characteristics/demographics were comparable. Completion rates were as follows: 64.3% (N = 229) with 13.3 mg/24 h and 65.0% (N = 234) with 4.6 mg/24 h patch. The 13.3 mg/24 h patch was significantly superior to 4.6 mg/24 h patch on cognition (SIB) and function (ADCS-ADL-SIV) at Week 16 (P < 0.0001 and P = 0.049, respectively) and 24 (primary endpoint; P < 0.0001 and P = 0.025). Significant between-group differences (Week 24) were observed on the ADCS-CGIC (P = 0.0023), not NPI-12 (P = 0.1437). A similar proportion of the 13.3 mg/24 h and 4.6 mg/24 h patch groups reported adverse events (AEs; 74.6% and 73.3%, respectively) and serious AEs (14.9% and 13.6%). CONCLUSIONS: The 13.3 mg/24 h patch demonstrated superior efficacy to 4.6 mg/24 h patch on SIB and ADCS-ADL-SIV, without marked increase in AEs, suggesting higher-dose patch has a favorable benefit-to-risk profile in severe AD.
3,4-Diaminopyridine Base Effectively Treats the Weakness of Lambert-Eaton Myasthenia
(Wiley, 2018) Sanders, Donald B.; Juel, Vern C.; Harati, Yadollah; Smith, A. Gordon; Peltier, Amanda C.; Marburger, Tessa; Lou, Jau-Shin; Pascuzzi, Robert M.; Richman, David P.; Xie, Tai; Demmel, Valentin; Jacobus, Laura R.; Aleš, Kathy L.; Jacobus, David P.; Neurology, School of Medicine
Introduction: 3,4-diaminopyridine has been used to treat Lambert Eaton myasthenia (LEM) for thirty years despite the lack of conclusive evidence of efficacy. Methods: We conducted a randomized double-blind placebo-controlled withdrawal study in LEM patients who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in Triple Timed Up-and-Go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM–related weakness (W-SAS). Results: 32 participants were randomized to continuous 3,4-DAP or placebo. None of the 14 receiving continuous 3,4-DAP had >30% deterioration in 3TUG time vs 72% of the 18 who tapered to placebo (p<0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (p<0.0001). Need for rescue and adverse events were more common in the placebo group. Discussion: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM.
A comparison of techniques for deriving clustering and switching scores from verbal fluency word lists
(Frontiers Media, 2022-09-14) Bushnell, Justin; Svaldi, Diana; Ayers, Matthew R.; Gao, Sujuan; Unverzagt, Frederick; Del Gaizo, John; Wadley, Virginia G.; Kennedy, Richard; Goñi, Joaquín; Clark, David Glenn; Neurology, School of Medicine
Objective: To compare techniques for computing clustering and switching scores in terms of agreement, correlation, and empirical value as predictors of incident cognitive impairment (ICI). Methods: We transcribed animal and letter F fluency recordings on 640 cases of ICI and matched controls from a national epidemiological study, amending each transcription with word timings. We then calculated clustering and switching scores, as well as scores indexing speed of responses, using techniques described in the literature. We evaluated agreement among the techniques with Cohen's κ and calculated correlations among the scores. After fitting a base model with raw scores, repetitions, and intrusions, we fit a series of Bayesian logistic regression models adding either clustering and switching scores or speed scores, comparing the models in terms of several metrics. We partitioned the ICI cases into acute and progressive cases and repeated the regression analysis for each group. Results: For animal fluency, we found that models with speed scores derived using the slope difference algorithm achieved the best values of the Watanabe-Akaike Information Criterion (WAIC), but with good net reclassification improvement (NRI) only for the progressive group (8.2%). For letter fluency, different models excelled for prediction of acute and progressive cases. For acute cases, NRI was best for speed scores derived from a network model (3.4%), while for progressive cases, the best model used clustering and switching scores derived from the same network model (5.1%). Combining variables from the best animal and letter F models led to marginal improvements in model fit and NRI only for the all-cases and acute-cases analyses. Conclusion: Speed scores improve a base model for predicting progressive cognitive impairment from animal fluency. Letter fluency scores may provide complementary information.
A harmonized memory composite score for cross‐cohort Alzheimer’s disease and related dementia research: development and validation
(Wiley, 2025-01-03) Sanderson-Cimino, Mark E.; Gross, Alden L.; Gaynor, Leslie S.; Paolillo, Emily W.; Casaletto, Kaitlin B.; Chatterjee, Ankita; Albert, Marilyn S.; Apostolova, Liana G.; Boersema, Brooke; Boxer, Adam L.; Boeve, Brad F.; Clark, Lindsay R.; La Joie, Renaud; Eloyan, Ani; Tomaszewski Farias, Sarah; Gonzales, Mitzi M.; Hammers, Dustin B.; Wise, Amy B.; Cobigo, Yann; Yballa, Claire; Schonhaut, Daniel R.; Hampstead, Benjamin M.; Mechanic-Hamilton, Dawn; Miller, Bruce L.; Rabinovici, Gil D.; Rascovsky, Katya; Ringman, John M.; Rosen, Howard J.; Ryman, Sephira; Salmon, David P.; Smith, Glenn E.; Decarli, Charles; Kramer, Joel H.; Staffaroni, Adam M.; Neurology, School of Medicine
Background: The Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list‐learning paradigm. ADCs often supplement the UDS with their own preferred list‐learning task. Given the importance of list‐learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list‐learning tasks. Method: We applied item‐banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking‐items) and one of five list‐learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list‐learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD‐biomarker+ MCI (n = 26), and AD‐biomarker+ dementia (n = 98). In a subsample with amyloid‐ and tau‐PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs. Result: Model fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43‐0.93). Differences in list‐learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly (p’s<.001) correlated with younger age (β = ‐0.18), lower CDR Box Scores (β = ‐0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid‐PET positivity was associated with lower composite scores, but was not statistically significant (β = ‐0.34; p = 0.25; d = 0.40). Tau‐PET positivity was associated with worse performance, demonstrating a large effect size (β = ‐0.75; p<0.002; d = 0.91). Conclusion: The harmonized memory score developed in a large national sample was stable regardless of contributing list‐learning task and its validity for cross‐cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross‐cohort ADRD research.
A high-throughput single-cell RNA expression profiling method identifies human pericyte markers
(Wiley, 2023) Sziraki, Andras; Zhong, Yu; Neltner, Allison M.; Niedowicz, Dana; Rogers, Colin B.; Wilcock, Donna M.; Nehra, Geetika; Neltner, Janna H.; Smith, Rebecca R.; Hartz, Anika M.; Cao, Junyue; Nelson, Peter T.; Neurology, School of Medicine
Aims: We sought to identify and optimise a universally available histological marker for pericytes in the human brain. Such a marker could be a useful tool for researchers. Further, identifying a gene expressed relatively specifically in human pericytes could provide new insights into the biological functions of this fascinating cell type. Methods: We analysed single-cell RNA expression profiles derived from different human and mouse brain regions using a high-throughput and low-cost single-cell transcriptome sequencing method called EasySci. Through this analysis, we were able to identify specific gene markers for pericytes, some of which had not been previously characterised. We then used commercially (and therefore universally) available antibodies to immunolabel the pericyte-specific gene products in formalin-fixed paraffin-embedded (FFPE) human brains and also performed immunoblots to determine whether appropriately sized proteins were recognised. Results: In the EasySci data sets, highly pericyte-enriched expression was notable for SLC6A12 and SLC19A1. Antibodies against these proteins recognised bands of approximately the correct size in immunoblots of human brain extracts. Following optimisation of the immunohistochemical technique, staining for both antibodies was strongly positive in small blood vessels and was far more effective than a PDGFRB antibody at staining pericyte-like cells in FFPE human brain sections. In an exploratory sample of other human organs (kidney, lung, liver, muscle), immunohistochemistry did not show the same pericyte-like pattern of staining. Conclusions: The SLC6A12 antibody was well suited for labelling pericytes in human FFPE brain sections, based on the combined results of single-cell RNA-seq analyses, immunoblots and immunohistochemical studies.
A multi-channel EEG mini-cap can improve reliability for recording auditory brainstem responses in chinchillas
(Elsevier, 2023) Ginsberg, Hannah M.; Singh, Ravinderjit; Bharadwaj, Hari M.; Heinz, Michael G.; Neurology, School of Medicine
Background: Disabling hearing loss affects nearly 466 million people worldwide (World Health Organization). The auditory brainstem response (ABR) is the most common non-invasive clinical measure of evoked potentials, e.g., as an objective measure for universal newborn hearing screening. In research, the ABR is widely used for estimating hearing thresholds and cochlear synaptopathy in animal models of hearing loss. The ABR contains multiple waves representing neural activity across different peripheral auditory pathway stages, which arise within the first 10 ms after stimulus onset. Multi-channel (e.g., 32 or higher) caps provide robust measures for a wide variety of EEG applications for the study of human hearing. However, translational studies using preclinical animal models typically rely on only a few subdermal electrodes. New method: We evaluated the feasibility of a 32-channel rodent EEG mini-cap for improving the reliability of ABR measures in chinchillas, a common model of human hearing. Results: After confirming initial feasibility, a systematic experimental design tested five potential sources of variability inherent to the mini-cap methodology. We found each source of variance minimally affected mini-cap ABR waveform morphology, thresholds, and wave-1 amplitudes. Comparison with existing method: The mini-cap methodology was statistically more robust and less variable than the conventional subdermal-needle methodology, most notably when analyzing ABR thresholds. Additionally, fewer repetitions were required to produce a robust ABR response when using the mini-cap. Conclusions: These results suggest the EEG mini-cap can improve translational studies of peripheral auditory evoked responses. Future work will evaluate the potential of the mini-cap to improve the reliability of more centrally evoked (e.g., cortical) EEG responses.
A multiethnic transcriptome for Alzheimer Disease identifies cross‐ancestry and ancestry‐specific expression profiles
(Wiley, 2025-01-03) Yang, Zikun; Cieza, Basilio; Reyes-Dumeyer, Dolly; Lee, Annie J.; Dugger, Brittany N.; Jin, Lee-Way; Murray, Melissa E.; Dickson, Dennis W.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Foroud, Tatiana M.; Teich, Andrew F.; Mayeux, Richard; Tosto, Giuseppe; Neurology, School of Medicine
Background: Alzheimer’s Disease (AD) presents complex molecular heterogeneity, influenced by a variety of factors including heterogeneous phenotypic, genetic, and neuropathologic presentations. Regulation of gene expression mechanisms is a primary interest of investigations aiming to uncover the underlying disease mechanisms and progression. Method: We generated bulk RNA‐sequencing in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks, and conducted differential gene expression and enrichment analyses. We sought to identify cross‐ancestry and ancestry‐specific differentially expressed genes (DEG) and pathways across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We validated our findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Lastly, we validated top DEG using publically‐available human single‐nucleus RNA sequencing (snRNAseq) data. Result: AD‐known genes VGF (LFC = ‐0.661, padj = 3.78) and ADAMTS2 (padj = 1.21) were consistently differentially expressed across statistical models, ethnic groups, and replicated in ROS/MAP (Figure 1). Genes from the heat shock protein (HSP) family, e.g. HSPB7 (padj = 3.78), were the top DEG, also replicated in ROS/MAP. Ethnic‐stratified analyses prioritized TNFSF14 and SPOCD1 as top DEG in Hispanic samples. Gene set enrichment analysis highlighted several significantly pathways, including “TYROBP causal network in microglia” (WP3945; padj = 1.68) and “Alzheimer Disease” (WP5124; padj = 4.24). snRNAseq validated several DEG, including VGF downregulated in neurons (padj = 1.1). Conclusion: To our knowledge, this is the largest diverse transcriptome study for AD in post‐mortem tissue. We identified perturbated genes and pathways resulting in cross‐ethnic and ethnic‐specific findings, ultimately highlighting the importance of diversity in AD investigations.

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