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Item Associations of Health and Financial Literacy with Mortality in Advanced Age(SpringerLink, 2020-05) Stewart, Christopher C.; Yu, Lei; Lamar, Melissa; Wilson, Robert S.; Bennett, David A.; Neurology, School of MedicineBackground: Health and financial literacy are central to older adults' well-being and financial standing, but the relation of literacy with mortality in advanced age remains unclear. Aims: To determine whether lower literacy, as reflected in measures of total literacy and subscales of health and financial literacy, was associated with an increased risk of mortality. Methods: Participants were 931 community-based older adults from the Rush Memory and Aging Project [age: mean (SD) = 80.9 (7.6), range 58.8-100.8], an ongoing, prospective observational cohort study of aging. Participants were without dementia at the time literacy was assessed. Proportional hazards models were used to determine whether literacy measures were associated with mortality. Results: During up to 8 years of follow-up, 224 (24.1% of 931) participants died. In models that adjusted for age, sex, and education, lower total, health, and financial literacy were each associated with an increased risk of mortality (total literacy: HR = 1.020, 95% CI 1.010-1.031, p < 0.001; health literacy: HR = 1.015, 95% CI 1.008-1.023, p < 0.001; financial literacy: HR = 1.013, 95% CI 1.003-1.023, p = 0.014). These associations persisted after additionally adjusting for income and indices of health status; however, only the association of lower health literacy with mortality persisted after further adjusting for a robust measure of global cognition. Discussion: We suspect that the current associations of lower literacy with mortality reflect the detrimental effect of early pathologic brain aging on literacy. Conclusions: Lower literacy, particularly lower health literacy, is associated with mortality in advanced age.Item Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity(Wiley, 2019-10-23) Cheng, Hanyin; Capponi, Simona; Wakeling, Emma; Marchi, Elaine; Li, Quan; Zhao, Mengge; Weng, Chunhua; Piatek, Stefan G.; Ahlfors, Helena; Kleyner, Robert; Rope, Alan; Lumaka, Aimé; Lukusa, Prosper; Devriendt, Koenraad; Vermeesch, Joris; Posey, Jennifer E.; Palmer, Elizabeth E.; Murray, Lucinda; Leon, Eyby; Diaz, Jullianne; Worgan, Lisa; Mallawaarachchi, Amali; Vogt, Julie; de Munnik, Sonja A.; Dreyer, Lauren; Baynam, Gareth; Ewans, Lisa; Stark, Zornitza; Lunke, Sebastian; Gonçalves, Ana R.; Soares, Gabriela; Oliveira, Jorge; Fassi, Emily; Willing, Marcia; Waugh, Jeff L.; Faivre, Laurence; Riviere, Jean-Baptiste; Moutton, Sebastien; Mohammed, Shehla; Payne, Katelyn; Walsh, Laurence; Begtrup, Amber; Guillen Sacoto, Maria J.; Douglas, Ganka; Alexander, Nora; Buckley, Michael F.; Mark, Paul R.; Adès, Lesley C.; Sandaradura, Sarah A.; Lupski, James R.; Roscioli, Tony; Agrawal, Pankaj B.; Kline, Antonie D.; Wang, Kai; Timmers, T. Marc; Lyon, Gholson J.; Neurology, School of MedicineWe recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X.Item Temporal Trends in Stroke Incidence over Time by Sex and Age in the Greater Cincinnati Northern Kentucky Stroke Study(American Heart Association, 2020-04) Madsen, Tracy E.; Khoury, Jane C.; Leppert, Michelle; Alwell, Kathleen; Moomaw, Charles J.; Sucharew, Heidi; Woo, Daniel; Ferioli, Simona; Martini, Sharyl; Adeoye, Opeolu; Khatri, Pooja; Flaherty, Matthew; De Los Rios La Rosa, Felipe; Mackey, Jason; Mistry, Eva; Demel, Stacie L.; Coleman, Elisheva; Jasne, Adam; Slavin, Sabreena J.; Walsh, Kyle; Star, Michael; Broderick, Joseph P.; Kissela, Brett M.; Kleindorfer, Dawn O.; Neurology, School of MedicineBackground and Purpose- Sex differences in stroke incidence over time were previously reported from the GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study). We aimed to determine whether these differences continued through 2015 and whether they were driven by particular age groups. Methods- Within the GCNKSS population of 1.3 million, incident (first ever) strokes among residents ≥20 years of age were ascertained at all local hospitals during 5 periods: July 1993 to June 1994 and calendar years 1999, 2005, 2010, and 2015. Out-of-hospital cases were sampled. Sex-specific incidence rates per 100 000 were adjusted for age and race and standardized to the 2010 US Census. Trends over time by sex were compared (overall and age stratified). Sex-specific case fatality rates were also reported. Bonferroni corrections were applied for multiple comparisons. Results- Over the 5 study periods, there were 9733 incident strokes (56.3% women). For women, there were 229 (95% CI, 215-242) per 100 000 incident strokes in 1993/1994 and 174 (95% CI, 163-185) in 2015 (P<0.05), compared with 282 (95% CI, 263-301) in 1993/1994 to 211 (95% CI, 198-225) in 2015 (P<0.05) in men. Incidence rates decreased between the first and last study periods in both sexes for IS but not for intracerebral hemorrhage or subarachnoid hemorrhage. Significant decreases in stroke incidence occurred between the first and last study periods for both sexes in the 65- to 84-year age group and men only in the ≥85-year age group; stroke incidence increased for men only in the 20- to 44-year age group. Conclusions- Overall stroke incidence decreased from the early 1990s to 2015 for both sexes. Future studies should continue close surveillance of sex differences in the 20- to 44-year and ≥85-year age groups, and future stroke prevention strategies should target strokes in the young- and middle-age groups, as well as intracerebral hemorrhage.Item A morphospace of functional configuration to assess configural breadth based on brain functional networks(MIT Press, 2021-09) Duong-Tran, Duy; Abbas, Kausar; Amico, Enrico; Corominas-Murtra, Bernat; Dzemidzic, Mario; Kareken, David; Ventresca, Mario; Goñi, Joaquín; Neurology, School of MedicineThe quantification of human brain functional (re)configurations across varying cognitive demands remains an unresolved topic. We propose that such functional configurations may be categorized into three different types: (a) network configural breadth, (b) task-to task transitional reconfiguration, and (c) within-task reconfiguration. Such functional reconfigurations are rather subtle at the whole-brain level. Hence, we propose a mesoscopic framework focused on functional networks (FNs) or communities to quantify functional (re)configurations. To do so, we introduce a 2D network morphospace that relies on two novel mesoscopic metrics, trapping efficiency (TE) and exit entropy (EE), which capture topology and integration of information within and between a reference set of FNs. We use this framework to quantify the network configural breadth across different tasks. We show that the metrics defining this morphospace can differentiate FNs, cognitive tasks, and subjects. We also show that network configural breadth significantly predicts behavioral measures, such as episodic memory, verbal episodic memory, fluid intelligence, and general intelligence. In essence, we put forth a framework to explore the cognitive space in a comprehensive manner, for each individual separately, and at different levels of granularity. This tool that can also quantify the FN reconfigurations that result from the brain switching between mental states.Item Patients With Extreme Early Onset Juvenile Huntington Disease Can Have Delays in Diagnosis: A Case Report and Literature Review(SAGE, 2021-01-01) Moeller, Ashley A.; Felker, Marcia V.; Brault, Jennifer A.; Duncan, Laura C.; Hamid, Rizwan; Golomb, Meredith R.; Neurology, School of MedicineHuntington disease (HD) is caused by a pathologic cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the HTT gene. Typical adult-onset disease occurs with a minimum of 40 repeats. With more than 60 CAG repeats, patients can have juvenile-onset disease (jHD), with symptom onset by the age of 20 years. We report a case of a boy with extreme early onset, paternally inherited jHD, with symptom onset between 18 and 24 months. He was found to have 250 to 350 CAG repeats, one of the largest repeat expansions published to date. At initial presentation, he had an ataxic gait, truncal titubation, and speech delay. Magnetic resonance imaging showed cerebellar atrophy. Over time, he continued to regress and became nonverbal, wheelchair-bound, gastrostomy-tube dependent, and increasingly rigid. His young age at presentation and the ethical concerns regarding HD testing in minors delayed his diagnosis.Item Deep multiple instance learning for foreground speech localization in ambient audio from wearable devices(Springer, 2021) Hebbar, Rajat; Papadopoulos, Pavlos; Reyes, Ramon; Danvers, Alexander F.; Polsinelli, Angelina J.; Moseley, Suzanne A.; Sbarra, David A.; Mehl, Matthias R.; Narayanan, Shrikanth; Neurology, School of MedicineOver the recent years, machine learning techniques have been employed to produce state-of-the-art results in several audio related tasks. The success of these approaches has been largely due to access to large amounts of open-source datasets and enhancement of computational resources. However, a shortcoming of these methods is that they often fail to generalize well to tasks from real life scenarios, due to domain mismatch. One such task is foreground speech detection from wearable audio devices. Several interfering factors such as dynamically varying environmental conditions, including background speakers, TV, or radio audio, render foreground speech detection to be a challenging task. Moreover, obtaining precise moment-to-moment annotations of audio streams for analysis and model training is also time-consuming and costly. In this work, we use multiple instance learning (MIL) to facilitate development of such models using annotations available at a lower time-resolution (coarsely labeled). We show how MIL can be applied to localize foreground speech in coarsely labeled audio and show both bag-level and instance-level results. We also study different pooling methods and how they can be adapted to densely distributed events as observed in our application. Finally, we show improvements using speech activity detection embeddings as features for foreground detection.Item A novel SNCA E83Q mutation in a case of dementia with Lewy bodies and atypical frontotemporal lobar degeneration(Wiley, 2020-12) Kapasi, Alifiya; Brosch, Jared R.; Nudelman, Kelly N.; Agrawal, Sonal; Foroud, Tatiana M.; Schneider, Julie A.; Neurology, School of MedicineIn this case report, we discuss a patient presenting with parkinsonism followed by a non-amnestic dementia with aphasic clinical features, as well as frontal dysexecutive syndrome. There was a family history of dementia with an autopsy diagnosis of "Pick's disease" in the proband's father. Neuroimaging of the patient revealed focal and severe temporal lobe and lesser frontoparietal lobe atrophy. At autopsy, there was severe frontotemporal lobar degeneration. Histologic evaluation revealed an absence of tau or transactivation response DNA-binding protein of 43 kDa (TDP) pathology but rather severe Lewy body deposition in the affected cortices. Genetic phenotyping revealed a novel missense mutation (p.E83Q) in exon 4 of the gene encoding α-synuclein (SNCA). This case study presents a patient with a novel SNCA E83Q mutation associated with widespread Lewy body pathology with prominent severe atrophy of the frontotemporal lobes and corresponding cognitive impairment.Item Technology intervention to support caregiving for Alzheimer’s disease (I-CARE): study protocol for a randomized controlled pilot trial(BMC, 2021-01) Braly, Tyler; Muriathiri, Doris; Brown, Janetta C.; Taylor, Britain M.; Boustani, Malaz A.; Holden, Richard J.; Neurology, School of MedicineBackground: Informal caregivers of patients with Alzheimer's disease and related dementias (ADRD) manage a complex spectrum of patient behavioral and psychological symptoms of dementia (BPSD). Mobile health information technologies have quickly become sources for modern social support and chronic disease management. These technologies can improve our understanding of how to care for patients with ADRD and their informal caregivers. A mobile telehealth intervention could help reduce caregiver burden and BPSD. Methods: This is a pilot randomized controlled trial of 60 dyads of patients living with ADRD and their caregivers, to test the feasibility and estimate the potential effect of the Brain CareNotes (BCN) mobile telehealth system. Participants will be recruited from two health systems. Participants will be randomly assigned to either the BCN intervention arm or usual care comparator. Data will be collected at baseline, 3- and 6-month follow-up. The primary objectives of this trial are to assess feasibility outcomes: (a) recruitment rate, (b) data completion, (c) BCN usability, (d) BCN acceptance, and (e) BCN use and assessed either on an ongoing basis or at 3- and 6-month post-intervention. A secondary objective was to estimate the intervention's effects on caregiver burden and patient BPSD outcomes at 3 and 6 months, assessed by the Neuropsychiatric Inventory. Discussion: The study will assess the intervention feasibility and potential effect size of the BCN telehealth system as a potentially scalable and lower-cost solution for addressing the ADRD public health crisis.Item Awareness of Genetic Risk in the Dominantly Inherited Alzheimer Network (DIAN)(Wiley, 2020-01) Aschenbrenner, Andrew J.; James, Bryan D.; McDade, Eric; Wang, Guoqiao; Lim, Yen Ying; Benzinger, Tammie L.S.; Cruchaga, Carlos; Goate, Alison; Xiong, Chengjie; Perrin, Richard; Buckles, Virginia; Allegri, Ricardo; Berman, Sarah B.; Chhatwal, Jasmeer P.; Fagan, Anne; Farlow, Martin; O'Connor, Antoinette; Ghetti, Bernardino; Graff-Radford, Neill; Goldman, Jill; Gräber, Susanne; Karch, Celeste M.; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Masters, Colin; Mori, Hiroshi; Noble, James; Salloway, Stephen; Schofield, Peter; Morris, John C.; Bateman, Randall J.; Hassenstab, Jason; Neurology, School of MedicineIntroduction: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. Methods: Mutation carriers and non-carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. Results: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non-carriers. Carriers who learned their status mid-study had slightly higher levels of depression and lower cognitive scores. Discussion: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid-study may confer short-term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.Item The Impact of Pediatric Basal Ganglia Stroke on Mental Health in Children: Report of 2 Cases(Sage, 2020-12-15) Badar, Sidrah A.; Radhakrishnan, Rupa; Golomb, Meredith R.; Neurology, School of MedicineBackground: The impact of basal ganglia stroke on mental health is better described in adults than in children. We report 2 children with significant mental health issues after basal ganglia stroke. Case reports: Patient 1, an 8-year-old boy, had mild anxiety before his left basal ganglia stroke. Post-stroke, he developed severe anxiety, obsessions, depression, and attention deficit hyperactivity disorder, in addition to a right hemiplegia and some mild chorea. He gradually improved over 3 years with psychiatric care and medication but continued to have residual symptoms. Patient 2, a 10-year-old boy, had no history of mental health issues before his right basal ganglia stroke. Post-stroke, he developed significant anxiety and mild depression, along with a left hemiplegia. He improved over 9 months and returned to his mental health baseline. Conclusions: Mental health issues after basal ganglia stroke in children can be significant, and recovery can take months to years.