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Item Verbal Memory Functioning in Adolescents and Young Adults with Costello Syndrome: Evidence for Relative Preservation in Recognition Memory(Wiley, 2013) Schwartz, David D.; Katzenstein, Jennifer M.; Hopkins, Elisabeth; Stabley, Deborah L.; Sol-Church, Katia; Gripp, Karen W.; Axelrad, Marni E.; Neurology, School of MedicineCostello syndrome (CS) is a rare genetic disorder caused by germline mutations in the HRAS proto-oncogene which belongs to the family of syndromes called rasopathies. HRAS plays a key role in synaptic long-term potentiation (LTP) and memory formation. Prior research has found impaired recall memory in CS despite enhancement in LTP that would predict memory preservation. Based on findings in other rasopathies, we hypothesized that the memory deficit in CS would be specific to recall, and that recognition memory would show relative preservation. Memory was tested using word-list learning and story memory tasks with both recall and recognition trials, a design that allowed us to examine these processes separately. Participants were 11 adolescents and young adults with molecularly confirmed CS, all of whom fell in the mild to moderate range of intellectual disability. Results indicated a clear dissociation between verbal recall, which was impaired (M = 69 ± 14), and recognition memory, which was relatively intact (M = 86 ± 14). Story recognition was highly correlated with listening comprehension (r = 0.986), which also fell in the low-average range (M = 80 ± 12.9). Performance on other measures of linguistic ability and academic skills was impaired. The findings suggest relatively preserved recognition memory that also provides some support for verbal comprehension. This is the first report of relatively normal performance in a cognitive domain in CS. Further research is needed to better understand the mechanisms by which altered RAS-MAPK signaling affects neuronal plasticity and memory processes in the brain.Item Language impairment in Alzheimer’s disease and benefits of acetylcholinesterase inhibitors(Dove Press, 2013) Ferris, Steven H.; Farlow, Martin; Neurology, School of MedicineAlzheimer’s disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer’s disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer’s disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer’s disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important.Item Young-Onset Dementia(Thieme, 2013) Kuruppu, Dulanji K.; Matthews, Brandy R.; Neurology, School of MedicineYoung-onset dementia (YOD) is an neurological syndrome that affects behavior and cognition of patients younger than 65 years of age. Although frequently misdiagnosed, a systematic approach, reliant upon attainment of detailed medical history, collateral history from an informant, neuropsychological testing, laboratory studies, and neuroimaging, may facilitate earlier and more accurate diagnosis with subsequent intervention. The differential diagnosis of YOD is extensive and includes early-onset forms of adult neurodegenerative conditions including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementias, Huntington's disease, and prion disease. Late-onset forms of childhood neurodegenerative conditions may also present as YOD and include mitochondrial disorders, lysosomal storage disorders, and leukodystrophies. Potentially reversible etiologies including inflammatory disorders, infectious diseases, toxic/metabolic abnormalities, transient epileptic amnesia, obstructive sleep apnea, and normal pressure hydrocephalus also represent important differential diagnostic considerations in YOD. This review will present etiologies, diagnostic strategies, and options for management of YOD with comprehensive summary tables for clinical reference.Item Comparing Clinical Profiles in Alzheimer's Disease and Parkinson's Disease Dementia(Karger, 2013-09-11) Farlow, Martin R.; Schmitt, Frederick; Aarsland, Dag; Grossberg, George T.; Somogyi, Monique; Meng, Xiangyi; Neurology, School of MedicineBackground: Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies. Methods: This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1]. Results: Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD. Conclusion: Differing patterns of impairment occur in AD and PDD.Item Opportunities to encourage adoption of a biomarker-enabled care pathway for Alzheimer's in primary care(Wiley, 2025-03-11) Borson, Soo; Au, Rhoda; Chodos, Anna H.; Gandy, Sam; Jain, Holly; Alagor, Amy; Cohn, Kristi; Kerwin, Diana R.; Mintzer, Jacobo; Monroe, Stephanie; Robinson, Delecia; Mielke, Michelle M.; Wilcock, Donna M.; Neurology, School of MedicineIdentification of early-stage Alzheimer's disease (AD) remains a challenge due to limited specialist availability, diagnostic access, disease awareness, and cultural factors. Blood-based biomarkers (BBBM) could play a critical role in the identification and referral of patients suspected of AD to specialty care. A multidisciplinary AD Biomarker Task Force was convened to evaluate current biomarker use cases, define an optimal biomarker-enabled AD diagnostic care pathway, and understand factors impacting adoption. The Task Force identified opportunities to support biomarker-enabled AD diagnostic care pathway adoption, including streamlining risk assessment and screening by leveraging digital tools, activating primary care providers through education, generating data to expand applicability to diverse populations, and advocating for aligned policies and quality measures. Adoption of BBBMs in the primary care setting will be critical to improve early AD detection. However, challenges to pathway adoption persist and will require action from clinicians, payers, policy makers, and patients to address. Highlights: Blood-based biomarkers can streamline the identification of AD in primary care. Future biomarker-enabled diagnostic care pathways will leverage digital assessments. Education, data generation, and policy advocacy are vital to encourage BBBM use. Implementation of AD care pathways requires the activation of diverse stakeholders.Item Assessment of the Quality, Accountability, and Readability of Online Patient Education Materials for Optic Neuritis(Taylor & Francis, 2024-03-12) Patel, Prem N.; Patel, Parth A.; Ahmed, Harris; Lai, Kevin E.; Mackay, Devin D.; Mollan, Susan P.; Truong-Le, Melanie; Neurology, School of MedicineMost cases of optic neuritis (ON) occur in women and in patients between the ages of 15 and 45 years, which represents a key demographic of individuals who seek health information using the internet. As clinical providers strive to ensure patients have accessible information to understand their condition, assessing the standard of online resources is essential. To assess the quality, content, accountability, and readability of online information for optic neuritis. This cross-sectional study analyzed 11 freely available medical sites with information on optic neuritis and used PubMed as a gold standard for comparison. Twelve questions were composed to include the information most relevant to patients, and each website was independently examined by four neuro-ophthalmologists. Readability was analyzed using an online readability tool. Journal of the American Medical Association (JAMA) benchmarks, four criteria designed to assess the quality of health information further were used to evaluate the accountability of each website. Freely available online information. On average, websites scored 27.98 (SD ± 9.93, 95% CI 24.96-31.00) of 48 potential points (58.3%) for the twelve questions. There were significant differences in the comprehensiveness and accuracy of content across websites (p < .001). The mean reading grade level of websites was 11.90 (SD ± 2.52, 95% CI 8.83-15.25). Zero websites achieved all four JAMA benchmarks. Interobserver reliability was robust between three of four neuro-ophthalmologist (NO) reviewers (ρ = 0.77 between NO3 and NO2, ρ = 0.91 between NO3 and NO1, ρ = 0.74 between NO2 and NO1; all p < .05). The quality of freely available online information detailing optic neuritis varies by source, with significant room for improvement. The material presented is difficult to interpret and exceeds the recommended reading level for health information. Most websites reviewed did not provide comprehensive information regarding non-therapeutic aspects of the disease. Ophthalmology organizations should be encouraged to create content that is more accessible to the general public.Item Parosmia Is Positively Associated With Problematic Drinking, as Is Phantosmia With Depressive Symptoms(Wolters Kluwer, 2024) Agarwal, Khushbu; Luk, Jeremy W.; Stangl, Bethany L.; Schwandt, Melanie L.; Momenan, Reza; Goldman, David; Diazgranados, Nancy; Kareken, David A.; Leggio, Lorenzo; Ramchandani, Vijay A.; Joseph, Paule V.; Neurology, School of MedicineObjectives: Alcohol use disorder (AUD) is a global health problem with significant negative consequences, including preventable deaths. Although olfactory dysfunction is associated with chronic alcohol drinking, the relationship among specific types of olfactory deficits, depressive symptoms, and problematic drinking remains to be explored. Here, we examined the prevalence of olfactory distortion (parosmia) and hallucination (phantosmia) and assessed their associations with problematic drinking and depressive symptoms. Methods: In April-June 2022, 250 participants across the spectrum of AUD were recruited for assessment in the National Institute on Alcohol Abuse and Alcoholism COVID-19 Pandemic Impact on Alcohol study. Surveys covered self-reported olfactory function, depressive symptoms, and problematic drinking, with key measures assessed, including the Alcohol Use Disorders Identification Test and the Patient Health Questionnaire. Predictors in the analysis included parosmia and phantosmia, with covariates comprising age, sex, socioeconomic status, race, ethnicity, COVID-19 infection status, and smoking status. Results: Among 250 individuals, 5.2% experienced parosmia and 4.4% reported phantosmia. Parosmia was associated with higher Alcohol Use Disorders Identification Test scores (β = 7.14; 95% confidence interval = 3.31, 10.96; P < 0.001), whereas phantosmia was linked to higher Patient Health Questionnaire scores (β = 3.32; 95% confidence interval = 0.22, 6.42; P = 0.03). These associations persisted in both the full sample and the subset of participants without COVID-19. Conclusions: Our study highlights strong existing links among olfactory deficits, problem drinking, and depressive symptoms, underscoring the need to assess smell impairments in clinical settings. Future research should explore these connections further to develop new treatments for individuals with AUD and depression.Item Recent advances in Tumor Treating Fields (TTFields) therapy for glioblastoma(Oxford University Press, 2025) Khagi, Simon; Kotecha, Rupesh; Gatson, Na Tosha N.; Jeyapalan, Suriya; Abdullah, Huda Ismail; Avgeropoulos, Nicholas G.; Batzianouli, Eleni T.; Giladi, Moshe; Lustgarten, Leonardo; Goldlust, Samuel A.; Neurology, School of MedicineTumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin. Based on efficacy and safety data from global pivotal (randomized phase III) clinical studies, TTFields therapy (Optune Gio) is US Food and Drug Administration-approved for newly diagnosed (nd) and recurrent glioblastoma (GBM) and Conformité Européenne-marked for grade 4 glioma. Here we review data on the multimodal TTFields mechanism of action that includes disruption of cancer cell mitosis, inhibition of DNA replication and damage response, interference with cell motility, and enhancement of systemic antitumor immunity (adaptive immunity). We describe new data showing that TTFields therapy has efficacy in a broad range of patients, with a tolerable safety profile extending to high-risk subpopulations. New analyses of clinical study data also confirmed that overall and progression-free survival positively correlated with increased usage of the device and dose of TTFields at the tumor site. Additionally, pilot/early phase clinical studies evaluating TTFields therapy in ndGBM concomitant with immunotherapy as well as radiotherapy have shown promise, and new pivotal studies will explore TTFields therapy in these settings. Finally, we review recent and ongoing studies in patients in pediatric care, other central nervous system tumors and brain metastases, as well as other advanced-stage solid tumors (ie, lung, ovarian, pancreatic, gastric, and hepatic cancers), that highlight the broad potential of TTFields therapy as an adjuvant treatment in oncology.Item Scam susceptibility is associated with a markedly accelerated onset of Alzheimer's disease dementia(Wiley, 2025) Boyle, Patricia A.; Wang, Tianhao; Mottola, Gary; Stewart, Chris; Wilson, Robert S.; Bennett, David A.; Yu, Lei; Neurology, School of MedicineIntroduction: The association of scam susceptibility with the timing of Alzheimer's disease (AD) dementia onset is unknown. Methods: One thousand ninety-two older adults without dementia underwent assessments of scam susceptibility and annual clinical evaluations to document incident AD dementia. Accelerated failure time models examined the relation of scam susceptibility with dementia onset. Results: During a mean of 5 years of follow-up (standard deviation = 3.1), 188 individuals (17%) were diagnosed with incident AD dementia. A higher level of scam susceptibility was associated with a considerably earlier dementia onset ( β = -0.039; 95% confidence interval: -0.061, -0.017); those with a high level of susceptibility developed AD dementia at a mean age of 90.9 years compared to 98.2 for those with a low level. Results persisted after controlling for global cognition, sex, and education. Discussion: Scam susceptibility is associated with a markedly earlier onset of AD dementia. Assessment of susceptibility may facilitate early identification of individuals at risk of developing dementia. Highlights: We examined whether scam susceptibility among older adults is associated with an accelerated onset of Alzheimer's disease dementia. Participants came from a large ongoing cohort study of aging. Scam susceptibility was assessed using a validated measure. Scam susceptibility was associated with a marked acceleration in dementia onset. Assessment of susceptibility may facilitate early identification of dementia.Item Tangent space functional reconfigurations in individuals at risk for alcohol use disorder(MIT Press, 2025-03-03) Moghaddam, Mahdi; Dzemidzic, Mario; Guerrero, Daniel; Liu, Mintao; Alessi, Jonathan; Plawecki, Martin H.; Harezlak, Jaroslaw; Kareken, David A.; Goñi, Joaquín; Neurology, School of MedicineHuman brain function dynamically adjusts to ever-changing stimuli from the external environment. Studies characterizing brain functional reconfiguration are, nevertheless, scarce. Here, we present a principled mathematical framework to quantify brain functional reconfiguration when engaging and disengaging from a stop signal task (SST). We apply tangent space projection (a Riemannian geometry mapping technique) to transform the functional connectomes (FCs) of 54 participants and quantify functional reconfiguration using the correlation distance of the resulting tangent-FCs. Our goal was to compare functional reconfigurations in individuals at risk for alcohol use disorder (AUD). We hypothesized that functional reconfigurations when transitioning to/from a task would be influenced by family history of AUD (FHA) and other AUD risk factors. Multilinear regression models showed that engaging and disengaging functional reconfiguration were associated with FHA and recent drinking. When engaging in the SST after a rest condition, functional reconfiguration was negatively associated with recent drinking, while functional reconfiguration when disengaging from the SST was negatively associated with FHA. In both models, several other factors contributed to the functional reconfiguration. This study demonstrates that tangent-FCs can characterize task-induced functional reconfiguration and that it is related to AUD risk.