Browsing by Author "Department of Neurology, School of Medicine"
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Item Active Aβ immunotherapy CAD106 in Alzheimer's disease: A phase 2b study(Elsevier, 2017-01) Vandenberghe, Rik; Riviere, Marie-Emmanuelle; Caputo, Angelika; Sovago, Judit; Maguire, R. Paul; Farlow, Martin; Marotta, Giovanni; Sanchez-Valle, Raquel; Scheltens, Philip; Ryan, J. Michael; Graf, Ana; Department of Neurology, School of MedicineIntroduction This randomized, double-blind, placebo-controlled, 90-week study assessed safety, tolerability, and immunogenicity of CAD106 with/without adjuvant in patients with mild Alzheimer's disease. Methods One hundred twenty-one patients received up to seven intramuscular injections of CAD106 (150 μg or 450 μg) or placebo ± adjuvant over 60 weeks. An amyloid positron emission tomography (PET) substudy was also conducted. Results CAD106 induced strong serological responses (amyloid-beta [Aβ]–Immunoglobuline G[IgG]) in 55.1% (150 μg) and 81.1% (450 μg) of patients (strong serological responders [SSRs]). Serious adverse events (SAEs) were reported in 24.5% (95% confidence interval [CI] 16.7–33.8) of the patients in the active treatment group and in 6.7% (95% CI 0.2–31.9) in the placebo group. Three of the SAEs were classified as possibly related to study drug by the investigators. No evidence of central nervous system inflammation was found. Amyloid-related imaging abnormalities (ARIAs) occurred in six cases, all of them were strong serological responders. None of the ARIAs were symptomatic. Serum Aβ-IgG titer area under the curves correlated negatively with amyloid PET standardized uptake value ratio percentage change from baseline to week 78 within the CAD106-treated patients (r = −0.84, P = .0004). Decrease in cortical gray-matter volume from baseline to week 78 was larger in SSRs than in controls (P = .0077). Discussion Repeated CAD106 administration was generally well tolerated. CAD106 450 μg with alum adjuvant demonstrated the best balance between antibody response and tolerability.Item American Clinical Neurophysiology Society Guideline 1: Minimum Technical Requirements for Performing Clinical Electroencephalography(Taylor & Francis, 2016) Sinha, Saurabh R.; Sullivan, Lucy; Sabau, Dragos; San-Juan, Daniel; Dombrowski, Keith; Halford, Jonathan J.; Hani, Abeer; Drislane, Frank W.; Stecker, Mark; Department of Neurology, School of MedicineItem Associations between hippocampal morphometry and neuropathologic markers of Alzheimer's disease using 7 T MRI(Elsevier, 2017-04-21) Blanken, Anna E.; Hurtz, Sona; Zarow, Chris; Biado, Kristina; Honarpisheh, Hedieh; Somme, Johanne; Brook, Jenny; Tung, Spencer; Kraft, Emily; Lo, Darrick; Ng, Denise W.; Vinters, Harry V.; Apostolova, Liana G.; Department of Neurology, School of MedicineHippocampal atrophy, amyloid plaques, and neurofibrillary tangles are established pathologic markers of Alzheimer's disease. We analyzed the temporal lobes of 9 Alzheimer's dementia (AD) and 7 cognitively normal (NC) subjects. Brains were scanned post-mortem at 7 Tesla. We extracted hippocampal volumes and radial distances using automated segmentation techniques. Hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet to evaluate neuronal counts. The hippocampal subfields, CA1, CA2, CA3, CA4, and subiculum were manually traced so that the neuronal counts, Aβ, and tau burden could be obtained for each region. We used linear regression to detect associations between hippocampal atrophy in 3D, clinical diagnosis and total as well as subfield pathology burden measures. As expected, we found significant correlations between hippocampal radial distance and mean neuronal count, as well as diagnosis. There were subfield specific associations between hippocampal radial distance and tau in CA2, and cresyl violet neuronal counts in CA1 and subiculum. These results provide further validation for the European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).Item GDNF secreted from adipose-derived stem cells stimulates VEGF-independent angiogenesis(Impact Journals, LLC, 2016-06-14) Zhong, Zhaohui; Gu, Huiying; Peng, Jirun; Wang, Wenzheng; Johnstone, Brian H.; March, Keith L.; Farlow, Martin R.; Du, Yansheng; Department of Neurology, School of MedicineAdipose tissue stroma contains a population of mesenchymal stem cells (MSC) promote new blood vessel formation and stabilization. These adipose-derived stem cells (ASC) promote de novo formation of vascular structures in vitro. We investigated the angiogenic factors secreted by ASC and discovered that glial-derived neurotrophic factor (GDNF) is a key mediator for endothelial cell network formation. It was found that both GDNF alone or present in ASC-conditioned medium (ASC-CM) stimulated capillary network formation by using human umbilical vein endothelial cells (HUVECs) and such an effect was totally independent of vascular endothelial growth factor (VEGF) activity. Additionally, we showed stimulation of capillary network formation by GDNF, but not VEGF, could be blocked by the Ret (rearranged during transfection) receptor antagonist RPI-1, a GDNF signaling inhibitor. Furthermore, GDNF were found to be overexpressed in cancer cells that were resistant to the anti-angiogenic treatment using the VEGF antibody. Cancer cells in the liver hepatocellular carcinoma (HCC), a non-nervous related cancer, highly overexpressed GDNF as compared to normal liver cells. Our data strongly suggest that, in addition to VEGF, GDNF secreted by ASC and HCC cells, may be another important factor promoting pathological neovascularization. Thus, GDNF may be a potential therapeutic target for HCC and obesity treatments.Item Mapping the functional connectome traits of levels of consciousness(Elsevier, 2017-03) Amico, Enrico; Marinazzo, Daniele; DiPerri, Carol; Heine, Lizette; Annen, Jitka; Martial, Charlotte; Dzemidzic, Mario; Laureys, Steven; Goñi, Joaquín; Department of Neurology, School of MedicineExamining task-free functional connectivity (FC) in the human brain offers insights on how spontaneous integration and segregation of information relate to human cognition, and how this organization may be altered in different conditions, and neurological disorders. This is particularly relevant for patients in disorders of consciousness (DOC) following severe acquired brain damage and coma, one of the most devastating conditions in modern medical care. We present a novel data-driven methodology, connICA, which implements Independent Component Analysis (ICA) for the extraction of robust independent FC patterns (FC-traits) from a set of individual functional connectomes, without imposing any a priori data stratification into groups. We here apply connICA to investigate associations between network traits derived from task-free FC and cognitive/clinical features that define levels of consciousness. Three main independent FC-traits were identified and linked to consciousness-related clinical features. The first one represents the functional configuration of a “resting” human brain, and it is associated to a sedative (sevoflurane), the overall effect of the pathology and the level of arousal. The second FC-trait reflects the disconnection of the visual and sensory-motor connectivity patterns. It also relates to the time since the insult and to the ability of communicating with the external environment. The third FC-trait isolates the connectivity pattern encompassing the fronto-parietal and the default-mode network areas as well as the interaction between left and right hemispheres, which are also associated to the awareness of the self and its surroundings. Each FC-trait represents a distinct functional process with a role in the degradation of conscious states of functional brain networks, shedding further light on the functional sub-circuits that get disrupted in severe brain-damage.Item Medication for Alzheimer’s Disease and Associated Fall Hazard: a Retrospective Cohort Study from the Alzheimer’s Disease Neuro-Imaging Initiative(Springer, 2014-02) Epstein, Noam U.; Guo, Rong; Farlow, Martin R.; Singh, Jaswinder P.; Fisher, Morris; Department of Neurology, School of MedicineBACKGROUND: Falls are common in the elderly, especially in those with cognitive impairment. The elderly are often treated with several medications, which may have both beneficial and deleterious effects. The use and type of medication in Alzheimer's disease (AD) patients and association with falls is limited. OBJECTIVE: We examined the association between falls and medication use in the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: Diagnosis, demographics, medication use, apolipoprotein E4 allele status and functional activity level at baseline were gathered for 810 participants enrolled in the ADNI, including healthy controls and subjects with mild cognitive impairment or Alzheimer's. Reports detailing adverse event falls were tabulated. Baseline characteristics were compared between subjects with and without one or more falls. Cox proportional hazards models were conducted to evaluate the association between subject characteristics and hazard of the first fall. RESULTS: Age (p < 0.0001), Functional Activities Questionnaire (p = 0.035), Beers List (p = 0.0477) and medications for treating cognitive symptoms of Alzheimer's (p = 0.0019) were associated with hazard of fall in the univariate model. In the final multivariate model, after adjusting for covariates, Alzheimer's medication use (p = 0.0005) was associated with hazard of fall. Medication was changed by the clinician after an adverse fall event in 9% of the falls. About 7% of the falls were reported as serious adverse events and 6% were reported to be severe. CONCLUSION: We found a significant association between the use of symptomatic medication treating cognitive symptoms in AD and hazard of fall after adjusting for age and Beers List medication use. Additional pharmacovigilance of the association between falls and Alzheimer's medication use is warranted.Item A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease(2017-01) McGarry, Andrew; McDermott, Michael; Kieburtz, Karl; de Blieck, Elisabeth A.; Beal, Flint; Marder, Karen; Ross, Christopher; Shoulson, Ira; Gibert, Peter; Mallonee, William M.; Guttman, Mark; Wojcieszek, Joanne; Kumar, Rajeev; LeDoux, Mark S.; Jenkins, Mary; Rosas, H. Diana; Nance, Martha; Biglan, Kevin; Como, Peter; Dubinsky, Richard M.; Shannon, Kathleen M.; O'Suilleabhain, Padraig; Chou, Kelvin; Walker, Francis; Martin, Wayne; Wheelock, Vicki L.; McCusker, Elizabeth; Jankovic, Joseph; Singer, Carlos; Sanchez-Ramos, Juan; Scott, Burton; Suchowersky, Oksana; Factor, Stewart A.; Higgins, Donald S., Jr.; Molho, Eric; Revilla, Fredy; Caviness, John N.; Friedman, Joseph H.; Perlmutter, Joel S.; Feigin, Andrew; Anderson, Karen; Rodriguez, Ramon; McFarland, Nikolaus R.; Margolis, Russell L.; Farbman, Eric S.; Raymond, Lynn A.; Suski, Valerie; Kostyk, Sandra; Colcher, Amy; Seeberger, Lauren; Epping, Eric; Esmail, Sherali; Diaz, Nancy; Fung, Wai Lun Alan; Diamond, Alan; Frank, Samuel; Hanna, Philip; Hermanowicz, Neal; Dure, Leon S.; Cudkowicz, Merit; Department of Neurology, School of MedicineObjective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD.Item Sex differences in cardiovascular risk profiles of ischemic stroke patients with diabetes in the Greater Cincinnati/Northern Kentucky Stroke Study(Wiley, 2017) Madsen, Tracy E.; Khoury, Jane C.; Alwell, Kathleen A.; Moomaw, Charles J.; Demel, Stacie L.; Flaherty, Matthew L.; Woo, Daniel; Mackey, Jason; De Los Rios La Rosa, Felipe; Martini, Sharyl; Ferioli, Simona; Adeoye, Opeolu; Khatri, Pooja; Kissela, Brett M.; Kleindorfer, Dawn O.; Department of Neurology, School of MedicineBackground The aim of the present study was to compare sex-specific associations between cardiovascular risk factors and diabetes mellitus (DM) among patients with acute ischemic stroke (AIS) in the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS). Methods The GCNKSS ascertained AIS cases in 2005 and 2010 among adult (age ≥ 20 years) residents of a biracial population of 1.3 million. Past and current stroke risk factors were compared between those with and without DM using Chi-squared tests and multiple logistic regression analysis to examine sex-specific profiles. Results There were 3515 patients with incident AIS; 1919 (55%) were female, 697 (20%) were Black, and 1146 (33%) had DM. Among both women and men with DM, significantly more were obese and had hypertension, high cholesterol, and coronary artery disease (CAD) compared with those without DM. For women with AIS, multivariable sex-specific adjusted analyses revealed that older age was associated with decreased odds of having DM (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI] 0.80–0.98). For women with CAD, the odds of DM were increased (aOR 1.76, 95% CI 1.33–2.32). Age and CAD were not significant factors in differentiating the profiles of men with and without DM. Conclusions Women with DM had strokes at a younger age, whereas no such age difference existed in men. Compared with men, women with DM were also more likely to have CAD than those without DM, suggesting a sex difference in the association between DM and vascular disease. These findings may suggest a need for more aggressive risk factor management in diabetic women.Item Social Comparisons, Social Support, and Self-Perceptions in Group Exercise for People With Parkinson's Disease(Taylor & Francis, 2017) Sheehy, Tammy L.; McDonough, Meghan H.; Zauber, S. Elizabeth; Department of Neurology, School of MedicinePeople with Parkinson's disease (PD) may experience declining function and limited interaction with others with PD. Group exercise provides opportunities for physical accomplishment and social support, as well as potential social challenges. We used interpretative phenomenological analysis to examine experiences of social comparison, social support, and self-perceptions of 20 people with PD in group exercise. Participants experienced (a) reticence evolving to inspiration, (b) anxiety relief through camaraderie and breaking taboos, and (c) maintaining athletic identity through participating and helping others. Practical implications include facilitating a safe space and support to alleviate anxiety and sustain participation.Item Thalamic GABA levels and Occupational Manganese Neurotoxicity: Association with Exposure Levels and Brain MRI(Elsevier, 2017) Ma, Ruoyun E.; Ward, Eric J.; Yeh, Chien-Lin; Snyder, Sandy; Long, Zaiyang; Yavuz, Fulya Gokalp; Zauber, S. Elizabeth; Dydak, Ulrike; Department of Neurology, School of MedicineExcessive occupational exposure to Manganese (Mn) has been associated with clinical symptoms resembling idiopathic Parkinson’s disease (IPD), impairing cognitive and motor functions. Several studies point towards an involvement of the brain neurotransmitter system in Mn intoxication, which is hypothesized to be disturbed prior to onset of symptoms. Edited Magnetic Resonance Spectroscopy (MRS) offers the unique possibility to measure γ-amminobutyric acid (GABA) and other neurometabolites in vivo non-invasively in workers exposed to Mn. In addition, the property of Mn as Magnetic Resonance Imaging (MRI) contrast agent may be used to study Mn deposition in the human brain. In this study, using MRI, MRS, personal air sampling at the working place, work history questionnaires, and neurological assessment (UPDRS-III), the effects of chronic Mn exposure on the thalamic GABAergic system was studied in a group of welders (N = 39) with exposure to Mn fumes in a typical occupational setting. Two subgroups of welders with different exposure levels (Low: N = 26; mean air Mn = 0.13 ± 0.1 mg/m3; High: N = 13; mean air Mn = 0.23 ± 0.18 mg/m3), as well as unexposed control workers (N = 22, mean air Mn = 0.002 ± 0.001 mg/m3) were recruited. The group of welders with higher exposure showed a significant increase of thalamic GABA levels by 45% (p < 0.01, F(1,33) = 9.55), as well as significantly worse performance in general motor function (p < 0.01, F(1,33) = 11.35). However, welders with lower exposure did not differ from the controls in GABA levels or motor performance. Further, in welders the thalamic GABA levels were best predicted by past-12-months exposure levels and were influenced by the Mn deposition in the substantia nigra and globus pallidus. Importantly, both thalamic GABA levels and motor function displayed a non-linear pattern of response to Mn exposure, suggesting a threshold effect.