MED: Neurology Scholarly Works

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COVID-19 shines a light on health inequities in communities of color: a youth-driven photovoice inquiry
(Wiley, 2022-09) Augsberger, Astraea; Toraif, Noor; Young, Adrienne; Dimitri, Noelle C.; Bautista, Rosaylin; Pierre, Ja'Karri; Le, Catherine; Idahor, Osasenaga; Jusme, Calvin; Gergen Barnett, Katherine A.
This manuscript reports on a youth-driven health assessment engaging youth of color in identifying community health priorities during the coronavirus disease 2019 (COVID-19) pandemic. Photovoice, a participatory visual ethnographic health assessment strategy, was used to explore the question: What does health or healthiness mean to you and/or your community? Youth captured images that represented their priorities. The photos were discussed using the SHOWed framework and analyzed thematically. Four themes related to community health were identified. Additionally, youth captured their narrative of COVID-19 as "a revealing force that highlights systemic inequities, driving individuals and communities to both cultivate their resilience and take healthcare into their own hands in response to government and policy level failures." Youth are acutely aware of the historical and structural inequities that create multi-level barriers to healthcare access. Health inequities existed long before the pandemic, but the current crisis requires us to examine ways to transform the healthcare landscape moving forward.
Dissecting the mechanism of the nonheme iron endoperoxidase FtmOx1 using substrate analogues
(American Chemical Society (ACS), 2022-07-25) Zhu, Guoliang; Yan, Wupeng; Wang, Xinye; Cheng, Ronghai; Naowarojna, Nathchar; Wang, Kun; Wang, Jun; Song, Heng; Wang, Yuyang; Liu, Hairong; Xia, Xuekui; Costello, Catherine E.; Liu, Xueting; Zhang, Lixin; Liu, Pinghua
FtmOx1 is a nonheme iron (NHFe) endoperoxidase, catalyzing three disparate reactions, endoperoxidation, alcohol dehydrogenation, and dealkylation, under in vitro conditions; the diversity complicates its mechanistic studies. In this study, we use two substrate analogues to simplify the FtmOx1-catalyzed reaction to either a dealkylation or an alcohol dehydrogenation reaction for structure-function relationship analysis to address two key FtmOx1 mechanistic questions: (1) Y224 flipping in the proposed COX-like model vs α-ketoglutarate (αKG) rotation proposed in the CarC-like mechanistic model and (2) the involvement of a Y224 radical (COX-like model) or a Y68 radical (CarC-like model) in FtmOx1-catalysis. When 13-oxo-fumitremorgin B (7) is used as the substrate, FtmOx1-catalysis changes from the endoperoxidation to a hydroxylation reaction and leads to dealkylation. In addition, consistent with the dealkylation side-reaction in the COX-like model prediction, the X-ray structure of the FtmOx1•CoII•αKG•7 ternary complex reveals a flip of Y224 to an alternative conformation relative to the FtmOx1•FeII•αKG binary complex. Verruculogen (2) was used as a second substrate analogue to study the alcohol dehydrogenation reaction to examine the involvement of the Y224 radical or Y68 radical in FtmOx1-catalysis, and again, the results from the verruculogen reaction are more consistent with the COX-like model.
Illicit drug use and cerebral microbleeds in stroke and transient ischemic attack patients
(Stroke, 2019-01-30) Petrie, Benjamin; Lau, Helena; Cajiga-Pena, Fe Maria; Abbas, Saleh; Finn, Brandon; Dam, Katie; Cervantes-Arslanian, Anna; Nguyen, Thanh; Aparicio, Hugo; Greer, David; Romero, Jose Rafael
Background: Cerebral microbleeds (CMB) signal cerebral small vessel disease and are associated with ischemic stroke (IS) incidence, recurrence, and complications. While illicit drug use (IDU) is associated with cerebral small vessel disease, the association between CMB and IDU is understudied. We sought to delineate differences in vascular risk factors between IDU and CMB and determine the effect of this relationship on outcomes in IS/transient ischemic attack (TIA) patients. Methods: We included 2001 consecutive IS and TIA patients (years 2009-2018) with a readable T2*gradient-echo MRI sequence. CMB rating followed standardized guidelines and CMB were grouped topographically into lobar, deep or infratentorial. IDU data (history and/or urine toxicology) was available for 1746 patients. The adverse composite outcome included pneumonia, urinary tract infection, deep venous thrombosis or death during hospitalization. Good functional outcome was defined as modified Rankin scale score < 3 and ambulatory on discharge. Univariate analysis was used to assess vascular risk factors and multivariable logistic regression was used to characterize the IDU/CMB relationship on outcomes. Results: We observed IDU in 13.8 % (n=241), and CMB in 32.9% (n=575, 53.8% lobar, 27.3% deep and 18.8% infratentorial). Patients with IDU and at least one CMB were older (53.6±10.5 vs. 56.9±11.5, p=0.04), had a lower BMI (28.1±5.9 vs. 26.6±4.4, p=0.04), and were more likely to have had a previous IS/TIA (25.1% vs. 41.9%, p=0.01). IDU trended higher for those with severe CMB (10+) compared with those without CMB and 1-9 CMB (25% [n=9] vs 14.3% [n=1171] and 12.1% [n=65] respectively; p=0.07) without individual drug deviations from this pattern. Adverse and good functional outcomes were observed in 177 and 905 total patients, respectively. No significant interaction was observed between IDU and CMB with either adverse or functional composite outcomes. Conclusion: IDU prevalence was high in our urban study population, and showed a borderline association with increasing CMB burden. Patients with CMB and IDU history were older and more likely to have had a previous IS/TIA. Further studies are required to clarify the clinical consequences related to the relationship between IDU and CMB.
Activation instead of Blocking Mesolimbic Dopaminergic Reward Circuitry Is a Preferred Modality in the Long Term Treatment of Reward Deficiency Syndrome (RDS): A Commentary
(BioMed Central, 2008-11-12) Blum, Kenneth; Chen, Amanda Lih-Chuan; Chen, Thomas J.H.; Braverman, Eric R.; Reinking, Jeffrey; Blum, Seth H.; Cassel, Kimberly; Downs, Bernard W.; Waite, Roger L.; Williams, Lonna; Prihoda, Thomas J.; Kerner, Mallory M.; Palomo, Tomas; Comings, David E.; Tung, Howard; Rhoades, Patrick; Oscar-Berman, Marlene
BACKGROUND AND HYPOTHESIS. Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors. PROPOSAL AND CONCLUSION. The authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine™, a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system.
Tar DNA binding Protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue
(Public Library of Science, 2010-10-11) Liu-Yesucevitz, Liqun; Bilgutay, Aylin; Zhang, Yong-Jie; Vanderwyde, Tara; Citro, Allison; Mehta, Tapan; Zaarur, Nava; McKee, Ann; Bowser, Robert; Sherman, Michael; Petrucelli, Leonard; Wolozin, Benjamin
Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein - RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway.
Modulators of Cytoskeletal Reorganization in CA1 Hippocampal Neurons Show Increased Expression in Patients at Mid-Stage Alzheimer's Disease
(Public Library of Science, 2010-10-13) Kao, Patricia F.; Davis, David A.; Banigan, Meredith G.; Vanderburg, Charles R.; Seshadri, Sudha; Delalle, Ivana
During the progression of Alzheimer's disease (AD), hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB) III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF) receptor tyrosine kinase B (TrkB), mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression.
The Parkinson's Disease Associated LRRK2 Exhibits Weaker In Vitro Phosphorylation of 4E-BP Compared to Autophosphorylation
(Public Library of Science, 2010-1-15) Kumar, Azad; Greggio, Elisa; Beilina, Alexandra; Kaganovich, Alice; Chan, Diane; Taymans, Jean-Marc; Wolozin, Benjamin; Cookson, Mark R.
Mutations in the gene encoding Leucine-rich repeat kinase 2 (LRRK2) are the most common cause of inherited Parkinson's disease (PD). LRRK2 is a multi-domain protein kinase containing a central catalytic core and a number of protein-protein interaction domains. An important step forward in the understanding of both the biology and the pathology of LRRK2 would be achieved by identification of its authentic physiological substrates. In the present study we examined phosphorylation of 4E-BP (eukaryotic initiation factor 4E (eIF4E)-binding protein), a recently proposed substrate for LRRKs. We found that LRRK2 is capable of phosphorylating 4E-BP in vitro. The PD related LRRK2-G2019S mutant was ~2 fold more active than wild type protein. However, LRRK2 autophosphorylation was stronger than 4E-BP phosphorylation under conditions of molar excess of 4E-BP to LRRK2. We also tested three other kinases (STK3, MAPK14/p38a and DAPK2) and found that MAPK14/p38a could efficiently phosphorylate 4E-BP at the same site as LRRK2 in vitro. Finally, we did not see changes in 4E-BP phosphorylation levels using inducible expression of LRRK2 in HEK cell lines. We also found that MAPK14/p38a phosphorylates 4E-BP in transient overexpression experiments whereas LRRK2 did not. We suggest that increased 4E-BP phosphorylation reported in some systems may be related to p38-mediated cell stress rather than direct LRRK2 activity. Overall, our results suggest that 4E-BP is a relatively poor direct substrate for LRRK2.
Longitudinal and Age Trends of Metabolic Syndrome and Its Risk Factors: The Family Heart Study
(BioMed Central, 2006-12-5) Kraja, Aldi T.; Borecki, Ingrid B.; North, Kari; Tang, Weihong; Myers, Richard H.; Hopkins, Paul N.; Arnett, Donna K.; Corbett, Jonathan; Adelman, Avril; Province, Michael A.
BACKGROUND. We report longitudinal changes in the metabolic syndrome (MetS) in 2,458 participants from 480 families in the Family Heart Study. Participants were examined between 1994–96 (FHS-T1) and 2002–03 (FHS-T2), about 7.4 years apart. Additionally, the impact of medication on estimates of MetS prevalence, and associations of MetS with prevalent coronary heart disease (CHD) and type 2 diabetes (T2D) were studied. METHODS. Three definitions for MetS prevalence were considered. One represented the original (o) National Cholesterol Education Program (NCEP) MetS criteria. Two others considered the confounding of medications effects, respectively (m) lipid medications constituted a categorical diagnostic criterion for lipids variables, and (c) lipids and blood pressure variables were corrected with average clinical trials medications effects. Logistic regression of MetS on CHD and T2D, as well as the trend analysis of MetS by age, were performed. RESULTS. MetS increased from 17.1% in FHS-T1(o) to 28.8% in FHS-T2(o); from 19.7% in FHS-T1(m) to 42.5% in FHS-T2(m); and from 18.4% in FHS-T1(c) to 33.6% in FHS-T2(c). While we observed adverse changes in all risk factors, the greatest increase was for waist circumference (25%). The percentages of MetS were about 2 to almost 3 times higher in ages 50 years and older than in younger ages. The odds of having prevalent CHD were about 2.5 times higher in the subjects classified with MetS than without. CONCLUSION. MetS percentages increased noticeably longitudinally and cross-sectionally with older age. These conclusions were reached with and without considering medication use, but correcting risk factors for medications use affects the MetS prevalence estimates. As found in other studies, MetS was associated with increased odds for prevalent CHD.
Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease
(Public Library of Science, 2009-8-12) Mastroeni, Diego; McKee, Ann; Grover, Andrew; Rogers, Joseph; Coleman, Paul D.
DNA methylation [1], [2] is capable of modulating coordinate expression of large numbers of genes across many different pathways, and may therefore warrant investigation for their potential role between genes and disease phenotype. In a rare set of monozygotic twins discordant for Alzheimer's disease (AD), significantly reduced levels of DNA methylation were observed in temporal neocortex neuronal nuclei of the AD twin. These findings are consistent with the hypothesis that epigenetic mechanisms may mediate at the molecular level the effects of life events on AD risk, and provide, for the first time, a potential explanation for AD discordance despite genetic similarities.
On the Analysis of Genome-Wide Association Studies in Family-Based Designs: A Universal, Robust Analysis Approach and an Application to Four Genome-Wide Association Studies
(Public Library of Science, 2009-11-26) Won, Sungho; Wilk, Jemma B.; Mathias, Rasika A.; O'Donnell, Christopher J.; Silverman, Edwin K.; Barnes, Kathleen; O'Connor, George T.; Weiss, Scott T.; Lange, Christoph
For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1) in 4 genome-wide association studies. Author Summary In genome-wide association studies, the multiple testing problem and confounding due to population stratification have been intractable issues. Family-based designs have considered only the transmission of genotypes from founder to nonfounder to prevent sensitivity to the population stratification, which leads to the loss of information. Here we propose a novel analysis approach that combines mutually independent FBAT and screening statistics in a robust way. The proposed method is more powerful than any other, while it preserves the complete robustness of family-based association tests, which only achieves much smaller power level. Furthermore, the proposed method is virtually as powerful as population-based approaches/designs, even in the absence of population stratification. By nature of the proposed method, it is always robust as long as FBAT is valid, and the proposed method achieves the optimal efficiency if our linear model for screening test reasonably explains the observed data in terms of covariance structure and population admixture. We illustrate the practical relevance of the approach by an application in 4 genome-wide association studies.
Does Sleep Play a Role in Memory Consolidation? A Comparative Test
(Public Library of Science, 2009-2-25) Capellini, Isabella; McNamara, Patrick; Preston, Brian T.; Nunn, Charles L.; Barton, Robert A.
Sleep is a pervasive characteristic of mammalian species, yet its purpose remains obscure. It is often proposed that 'sleep is for the brain', a view that is supported by experimental studies showing that sleep improves cognitive processes such as memory consolidation. Some comparative studies have also reported that mammalian sleep durations are higher among more encephalized species. However, no study has assessed the relationship between sleep and the brain structures that are implicated in specific cognitive processes across species. The hippocampus, neocortex and amygdala are important for memory consolidation and learning and are also in a highly actived state during sleep. We therefore investigated the evolutionary relationship between mammalian sleep and the size of these brain structures using phylogenetic comparative methods. We found that evolutionary increases in the size of the amygdala are associated with corresponding increases in NREM sleep durations. These results are consistent with the hypothesis that NREM sleep is functionally linked with specializations of the amygdala, including perhaps memory processing.
Test of Variables of Attention (TOVA) as a Predictor of Early Attention Complaints, an Antecedent to Dementia
(Dove Medical Press, 2010-10-15) Braverman, Eric R.; Chen, Amanda Lih-Chuan; Chen, Thomas J.H.; Schoolfield, John D.; Notaro, Alison; Braverman, Dasha; Kerner, Mallory; Blum, Seth H.; Arcuri, Vanessa; Varshavskiy, Michael; Damle, Uma; Downs, B. William; Waite, Roger L.; Oscar-Berman, Marlene; Giordano, John; Blum, Kenneth
The goal of this study was to determine if impairments detected by the test of variables of attention (TOVA) may be used to predict early attention complaints and memory impairments accurately in a clinical setting. We performed a statistical analysis of outcomes in a patient population screened for attention deficit hyperactivity disorder or attention complaints, processing errors as measured by TOVA and the Wechsler Memory Scale (WMS-III) results. Attention deficit disorder (ADD) checklists, constructed using the Diagnostic and Statistical Manual of Mental Disorders 4th Edition criteria, which were completed by patients at PATH Medical, revealed that 72.8% of the patients had more than one attention complaint out of a total of 16 complaints, and 41.5% had more than five complaints. For the 128 males with a significant number of ADD complaints, individuals whose scores were significantly deviant or borderline (SDB) on TOVA, had a significantly greater number of attention complaints compared with normals for omissions (P > 0.02), response time (P > 0.015), and variability (P > 0.005), but not commissions (P < 0.50). For males, the mean scores for auditory, visual, immediate, and working memory scores as measured by the WMS-III were significantly greater for normals versus SDBs on the TOVA subtest, ie, omission (P > 0.01) and response time (P > 0.05), but not variability or commissions. The means for auditory, visual, and immediate memory scores were significantly greater for normals versus SDBs for variability (P > 0.045) only. In females, the mean scores for visual and working memory scores were significantly greater for normals versus SDBs for omissions (P > 0.025). The number of SDB TOVA quarters was a significant predictor for "impaired" or "normal" group membership for visual memory (P > 0.015), but not for the other three WMS-III components. For males, the partial correlation between the number of attention complaints and the number of SDB TOVA quarters was also significant (r = 0.251, P > 0.005). For the 152 females with a significant number of attention complaints, no significant differences between SDBs and normals were observed (P < 0.15). This is the first report, to our knowledge, which provides evidence that TOVA is an accurate predictor of early attention complaints and memory impairments in a clinical setting. This finding is more robust for males than for females between the ages of 40 and 90 years.
Attention-Deficit-Hyperactivity Disorder and Reward Deficiency Syndrome
(Dove Medical Press, 2008) Blum, Kenneth; Chen, Amanda Lih-Chuan; Braverman, Eric R.; Comings, David E.; Chen, Thomas J.H.; Arcuri, Vanessa; Blum, Seth H.; Downs, Bernard W.; Waite, Roger L.; Notaro, Alison; Lubar, Joel; Williams, Lonna; Prihoda, Thomas J.; Palomo, Tomas; Oscar-Berman, Marlene
Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the "brain reward cascade," especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD2 A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other "reward genes" are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.
Frontal Brain Dysfunction in Alcoholism with and without Antisocial Personality Disorder
(Dove Medical Press, 2009-06-10) Oscar-Berman, Marlene; Valmas, Mary M.; Sawyer, Kayle S.; Kirkley, Shalene M.; Gansler, David A.; Merritt, Diane; Couture, Ashley
Alcoholism and antisocial personality disorder (ASPD) often are comorbid conditions. Alcoholics, as well as nonalcoholic individuals with ASPD, exhibit behaviors associated with prefrontal brain dysfunction such as increased impulsivity and emotional dysregulation. These behaviors can influence drinking motives and patterns of consumption. Because few studies have investigated the combined association between ASPD and alcoholism on neuropsychological functioning, this study examined the influence of ASPD symptoms and alcoholism on tests sensitive to frontal brain deficits. The participants were 345 men and women. Of them, 144 were abstinent alcoholics (66 with ASPD symptoms), and 201 were nonalcoholic control participants (24 with ASPD symptoms). Performances among the groups were examined with Trails A and B tests, the Wisconsin Card Sorting Test, the Controlled Oral Word Association Test, the Ruff Figural Fluency Test, and Performance subtests of the Wechsler Adult Intelligence Scale. Measures of affect also were obtained. Multiple regression analyses showed that alcoholism, specific drinking variables (amount and duration of heavy drinking), and ASPD were significant predictors of frontal system and affective abnormalities. These effects were different for men and women. The findings suggested that the combination of alcoholism and ASPD leads to greater deficits than the sum of each.
Tetrabenazine: The First Approved Drug for the Treatment of Chorea in US Patients with Huntington Disease
(Dove Medical Press, 2010-10-05) Frank, Samuel
Huntington disease (HD) is a dominantly inherited progressive neurological disease characterized by chorea, an involuntary brief movement that tends to flow between body regions. HD is typically diagnosed based on clinical findings in the setting of a family history and may be confirmed with genetic testing. Predictive testing is available to those at risk, but only experienced clinicians should perform the counseling and testing. Multiple areas of the brain degenerate mainly involving the neurotransmitters dopamine, glutamate, and γ-aminobutyric acid. Although pharmacotherapies theoretically target these neurotransmitters, few well-conducted trials for symptomatic or neuroprotective interventions yielded positive results. Tetrabenazine (TBZ) is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. Some newer antipsychotic agents, such as olanzapine and aripiprazole, may have adequate efficacy with a more favorable adverse-effect profile than older antipsychotic agents for treating chorea and psychosis. This review will address the epidemiology and diagnosis of HD as background for understanding potential pharmacological treatment options. Because TBZ is the only US Food and Drug Administration-approved medication in the United States for HD, the focus of this review will be on its pharmacology, efficacy, safety, and practical uses. There are no current treatments to change the course of HD, but education and symptomatic therapies can be effective tools for clinicians to use with patients and families affected by HD.
Rule Knowledge Aids Performance on Spatial and Object Alternation Tasks by Alcoholic Patients with and Without Korsakoff's Amnesia
(Dove Medical Press, 2007) Bardenhagen, Fiona J.; Oscar-Berman, Marlene; Bowden, Stephen C.
Delayed alternation (DA) and object alternation (OA) tasks traditionally have been used to measure defective response inhibition associated with dysfunction of frontal brain systems. However, these tasks are also sensitive to nonfrontal lesions, and cognitive processes such as the induction of rule-learning strategies also are needed in order to perform well on these tasks. Performance on DA and OA tasks was explored in 10 patients with alcohol-induced persisting amnestic disorder (Korsakoff's syndrome), 11 abstinent long-term alcoholics, and 13 healthy non-alcoholic controls under each of two rule provision conditions: Alternation Rule and Correction Rule. Results confirmed that rule knowledge is a crucial cognitive component for solving problems such as DA and OA, and therefore, that errors on these tasks are not due to defective response inhibition alone. Further, rule-induction strategies were helpful to Korsakoff patients, despite their poorer performance on the tasks. These results stress the role of multiple cognitive abilities in successful performance on rule induction tasks. Evidence that these cognitive abilities are served by diffusely distributed neural networks should be considered when interpreting behavioral impairments on these tasks.
Religiosity in Patients with Parkinson's Disease
(Dove Medical Press, 2006) McNamara, Patrick; Durso, Raymon; Brown, Ariel
OBJECTIVE. To study clinical correlates of religiosity in Parkinson's disease (PD). METHODS. Measures of life goals, religiosity, mood, and neuropsychologic function were assessed in 22 persons with mid-stage PD and 20 age-matched healthy controls. Levodopa dose equivalents (LDE) were also computed for the patients. RESULTS. Relative to other major life goals parkinsonian patients were significantly more likely to report that "my religion or life philosophy" was less important than were age-matched controls. Scores on a battery of religiosity scales were consistently lower for Parkinson's patients than those of age-matched controls. While Mini Mental State Exam, logical memory recall, Stroop, and selected (depression and anxiety) mood scales reliably distinguished patients from controls, only measures of prefrontal function correlated with religiosity scores. CONCLUSIONS. Patients with PD express less interest in religion and report consistently lower scores on measures of religiosity than age-matched controls. Prefrontal dopaminergic networks may support motivational aspects of religiosity.
Assessment of Neuropsychological Trajectories in Longitudinal Population-Based Studies of Children
(BMJ Publishing Group, 2008-12-5) White, R. F.; Campbell, R.; Echeverria, D.; Knox, S. S.; Janulewicz, P.
This paper provides a strategy for the assessment of brain function in longitudinal cohort studies of children. The proposed strategy invokes both domain-specific and omnibus intelligence test approaches. In order to minimise testing burden and practice effects, the cohort is divided into four groups with one-quarter tested at 6-monthly intervals in the 0–2-year age range (at ages 6 months, 1.0, 1.5 and 2.0 years) and at annual intervals from ages 3–20 (one-quarter of the children at age 3, another at age 4, etc). This strategy allows investigation of cognitive development and of the relationship between environmental influences and development at each age. It also allows introduction of new domains of function when age-appropriate. As far as possible, tests are used that will provide a rich source of both longitudinal and cross-sectional data. The testing strategy allows the introduction of novel tests and new domains as well as piloting of tests when the test burden is relatively light. In addition to the recommended tests for each age and domain, alternative tests are described. Assessment methodology and knowledge about child cognitive development will change over the next 20 years, and strategies are suggested for altering the proposed test schedule as appropriate.
MRI parameters of Alzheimer's disease in an Arab population of Wadi Ara, Israel
(Dove Medical Press, 2005) Bowirrat, Abdalla; Reider-Groswasser, Irith I.; Oscar-Berman, Marlene; Aizenstein, Orna; Levy, Gad; Korczyn, Amos D.
Magnetic resonance imaging (MRI) findings are reported from 15 individuals in an Arab–Israeli community who were diagnosed with Alzheimer's disease (AD). The quantitative parameters that were used for MRI analyses included gradings (0–3) and linear measurements of different brain structures. Generalized tissue loss was assessed by combined measurements of the ventricles (ventricular score, VS) and sulcal grading and width (SG, SW, respectively). Loss of brain tissue in specific regions of interest, eg, temporal lobes, basal ganglia, and midbrain, was evaluated by precise measurements. We observed abnormal tissue characteristics, expressed as high intensity foci in white matter on T2W sequences, as well as tissue loss, both generalized and focal. Most notable were changes involving the head of the caudate nuclei, the midbrain, and to a lesser degree, medial temporal structures.
Cognitive neuroscience of delusions in aging
(Dove Medical Press, 2006) Holt, Anna E.M.; Albert, Martin L.
Assessments and clinical understanding of late-onset delusions in the elderly are inconsistent and often incomplete. In this review, we consider the prevalence, neurobehavioral features, and neuroanatomic correlations of delusions in elderly persons – those with documented cognitive decline and those with no evidence of cognitive decline. Both groups exhibit a common phenotype: delusions are either of persecution or of misidentification. Late-onset delusions show a nearly complete absence of the grandiose, mystical, or erotomanic content typical of early onset psychoses. Absent also from both elderly populations are formal thought disorders, thought insertions, and delusions of external control. Neuroimaging and behavioral studies suggest a frontotemporal localization of delusions in the elderly, with right hemispheric lateralization in delusional misidentification and left lateralization in delusions of persecution. We propose that delusions in the elderly reflect a common neuroanatomic and functional phenotype, and we discuss applications of our proposal to diagnosis and treatment.

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