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Biomedical subjects

Sid Gilman

Publications and source records attributed to Sid Gilman.

At least 19 recordsLinked to original sources
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2007

G2019S mutation in the leucine-rich repeat kinase 2 gene is not associated with multiple system atrophy.

Multiple system atrophy (MSA) is characterized clinically by Parkinsonism, cerebellar dysfunction, and autonomic impairment. Multiple mutations in the LRRK2 gene are associated with parkinsonian disorders, and the most common one, the G2019S mutation, has been found in approximately 1% of sporadic cases of Parkinsonism. In a well-characterized cohort of 136 subjects with probable MSA and 110 neurologically evaluated control subjects, none carried the G2019S mutation. We conclude that the G2019S mutation in the LRRK2 gene is unlikely to be associated with MSA.

Cerebellum↗
PubMed2006

Rosuvastatin: an independent analysis of risks and benefits.

BACKGROUND: Although the effectiveness of statins is well established, analyses of spontaneous adverse event reports have recently questioned the safety of rosuvastatin. METHODS AND RESULTS: We evaluated the risks and benefits of rosuvastatin and compared it with other statins presently on the market. Information was obtained from a search of medical and scientific literature that produced 3001 entries, of which 591 publications containing particularly relevant data were identified, and from the US Food and Drug Administration (FDA) Adverse Events Reporting System (AERS) and Spontaneous Reporting System through June 30, 2004. For the AERS data and to control for overreporting in the first postmarketing year and the effect on reporting due to the withdrawal of cerivastatin in 2001, we used the rate of a given adverse event among all adverse events as a measure of risk. We found that adverse effects of rosuvastatin in skeletal muscle, liver, and kidney function did not substantially differ in frequency from those reported for those of other statins in the market in 2004, except for the uncommon development of a mild form of presumably "tubular" proteinuria at doses of 40 mg/day or greater. In contrast, cerivastatin had significantly higher rates of myopathy and rhabdomyolysis than rosuvastatin's, but there was no additional effect on renal failure beyond that mediated through rhabdomyolysis. From our literature review, we found that rosuvastatin reduces abnormal lipids on a milligram-per-milligram comparison more than atorvastatin. CONCLUSION: We conclude that rosuvastatin at approved doses incurs no greater risk for adverse events than other marketed statins, except for a mild form of tubular proteinuria when doses at or above the maximum recommended levels (> or = 40 mg/day) were administered. Its risk-benefit ratio is acceptable when compared with other statins on the market in 2006.

Fluorobenzenes↗
PubMed2006

Pharmacologic management of ischemic stroke: relevance to stem cell therapy.

Pharmacologic management of the acute phase of the ischemic stroke includes treating the physical and medical conditions that can worsen cerebral injury; administering intravenous thrombolytic therapy (recombinant tissue plasminogen activator) in those who meet current guidelines; instituting prophylactic measures to prevent medical complications; and initiating passive rehabilitation measures. New approaches under investigation include intra-arterial thrombolytic therapy; endovascular embolectomy and clot disruption; and neuroprotective treatments to preserve surviving ischemic tissue. One neuroprotective agent given within 6 h after stroke onset, NXY059, recently met the primary outcome measure in a phase III clinical trial. Pharmacologic management of the subacute and chronic phases involves treatment of risk factors for recurrent stroke and other forms of cardiovascular disease, including hypercholesterolemia, hypertension, and diabetes mellitus. In this phase, antiplatelet therapy can be initiated or continued; smoking, obesity and alcohol intake can be managed; and active rehabilitation can begin through physical, occupational, and speech therapy. A few medications to augment rehabilitation have shown promising results in small clinical trials, but none have been tested in large phase III trials or approved by the US or European regulatory agencies. Thus, there are no pharmacologic measures available to enhance central nervous system restorative processes after acute stroke, and implantation of stem cells provides one promising approach, not only for cell replacement but also for the provision of therapeutic molecules.

Brain Ischemia↗
PubMed2006

Time course and outcome of recovery from stroke: relevance to stem cell treatment.

Stroke is the third leading cause of death in the United States after heart disease and cancer; it has an incidence of approximately 750,000 cases per year, and it is a leading cause of disability in adults. The factors predicting a poor outcome from stroke include severe initial neurological dysfunction, hypertension, cardiac arrhythmias, myocardial infarction, hypercholesterolemia, and diabetes mellitus. The armamentarium available for improvement of neurological function after stroke is currently limited to placement in specialized stroke units, optimal therapy for medical complications, and intense physical, occupational and speech rehabilitation. Despite many trials, no pharmacological intervention has been shown convincingly to improve neurological outcome. This review was undertaken to determine the appropriate time for new approaches to the therapy of stroke such as the infusion of stem cells into the central nervous system. The literature shows in large case series that functional recovery from stroke reaches a maximum level by 3-6 months after onset, and no further recovery occurs beyond this time. Nevertheless, about 80% of these patients reach their maximum function for activities of daily living within 6 weeks from onset. Initiation of a clinical trial of stem cell therapy would require demonstration of optimal clinical improvement by neurological evaluations, with no change over at least 4 weeks of observation. Accordingly, in subjects with first-ever ischemic stroke who remained neurologically unchanged from the second until the third month after the acute event, implementation of stem cell therapy would be appropriate at approximately 3 months after the stroke.

Humans↗
PubMed2006

Unexpected abundance of pathological tau in progressive supranuclear palsy white matter.

OBJECTIVE: To investigate whether biochemical insoluble tau with 4 (4R) and/or 3 (3R) microtubule-binding repeats accumulate in white as well as gray matter in progressive supranuclear palsy (PSP), a neurodegenerative tauopathy. METHODS: To assess tau pathology in PSP white matter, we combined Western blot (WB) and immunohistochemical methods to analyze 23 autopsy-confirmed PSP brains. RESULTS: WBs showed an unexpected abundance of insoluble tau in white and gray matter of PSP brains, but biochemical tau pathology in white matter was not correlated with immunohistochemistry using the same panel of epitope-specific anti-tau antibodies used for WB. Despite heterogeneity in the representation of pathological 3R and 4R tau isoforms in cortical versus subcortical regions, biochemically detectable white matter tau pathology is a constant feature of PSP. INTERPRETATION: These studies show additional similarities between PSP and corticobasal degeneration, but unlike corticobasal degeneration, more abundant white matter tau pathology in PSP is detectable by WB than by immunohistochemistry. The differential detection of abnormal tau by biochemistry versus microscopy in PSP may reflect distinct pathological mechanisms, and elucidation of these processes will augment efforts to develop better strategies for the diagnosis and treatment of PSP and related neurodegenerative tauopathies.

Aged↗
PubMed2006

Movement disorders associated with encephalitis lethargica: a video compilation.

Encephalitis lethargica (EL; epidemic encephalitis; von Economo's disease) often presented with a movement disorder, and the motor consequences of postencephalitic parkinsonism (PEP) were characteristic of the chronic sequelae of this condition. PEP was similar to Parkinson's disease but was more variable and had some distinct features such as oculogyric crises. Although two previous publications have included video images of the movement disorders associated with EL and PEP, the sequences presented were typically short, showed only a few patients, and did not include the work of several neurologists who had the foresight to preserve filmed images of their patients. We describe the most complete record of EL and PEP moving images that have been preserved and make them available in edited form.

Disease Outbreaks↗
PubMed2006

Parkinsonian syndromes.

The term parkinsonian syndromes refers to a group of disorders whose clinical features overlap those of idiopathic Parkinson's disease. The four major entities include three important neurodegenerations, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration, and a lacunar cerebrovascular disorder, vascular parkinsonism. This article reviews the epidemiology, pathology, clinical features, diagnosis, and management of these disorders.

Cerebrovascular Disorders↗
PubMed2006

PET measurement of cardiac and nigrostriatal denervation in Parkinsonian syndromes.

UNLABELLED: Scintigraphic imaging with (123)I-metaiodobenzylguanidine ((123)I-MIBG) has demonstrated extensive losses of cardiac sympathetic neurons in idiopathic Parkinson's disease (IPD). In contrast, normal cardiac innervation has been observed in (123)I-MIBG studies of multiple-system atrophy (MSA) and progressive supranuclear palsy (PSP). Consequently, it has been hypothesized that cardiac denervation can be used to differentiate IPD from MSA and PSP. We sought to test this hypothesis by mapping the distribution of cardiac sympathetic neurons in patients with IPD, MSA, and PSP by using PET and (11)C-meta-hydroxyephedrine ((11)C-HED). Also, the relationship between cardiac denervation and nigrostriatal denervation was investigated by measuring striatal presynaptic monoaminergic nerve density with PET and (11)C-dihydrotetrabenazine ((11)C-DTBZ). METHODS: (11)C-HED and (11)C-DTBZ scans were obtained for patients with IPD (n = 9), MSA (n = 10), and PSP (n = 8) and for age-matched control subjects (n = 10). Global and regional measurements of (11)C-HED retention were obtained to assess the extent of cardiac sympathetic denervation. (11)C-DTBZ binding was measured in the caudate nucleus, anterior putamen, and posterior putamen. RESULTS: As expected, extensive cardiac denervation was observed in several of the patients with IPD. However, substantial cardiac denervation was also seen in some patients with MSA and PSP. (11)C-DTBZ studies demonstrated striatal denervation in all patients with IPD and in most patients with MSA and PSP. No correlation was found between cardiac (11)C-HED retention and striatal (11)C-DTBZ binding. CONCLUSION: Cardiac sympathetic denervation was found to occur not only in IPD but also in other movement disorders, such as MSA and PSP. This finding implies that scintigraphic detection of cardiac sympathetic denervation cannot be used independently to discriminate IPD from other movement disorders, such as MSA and PSP. Cardiac sympathetic denervation was not correlated with striatal denervation, suggesting that the pathophysiologic processes underlying cardiac denervation and striatal denervation occur independently in patients with parkinsonian syndromes. These findings provide novel information about central and peripheral denervation in patients with neurodegenerative disorders.

Adult↗
PubMed2005

Validation of a polysomnographic score for REM sleep behavior disorder.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) was described more than 2 decades ago, but only 1 report on 5 patients and 5 normal subjects has tested the effectiveness of a method by which relevant polysomnographic findings can be quantified. We sought to validate this method in a larger sample of patients and control subjects. DESIGN: Cross-sectional. SETTING: Academic hospital. INTERVENTIONS: A clinician interviewed 17 patients at risk for RBD secondary to neurodegenerative disorders and 6 controls to assess whether RBD was present by history. Bed partners completed a questionnaire that quantified RBD symptom severity. From 2 consecutive nocturnal studies in each patient, 2 different polysomnographic RBD scores were generated: the percentage of 30-second REM epochs with at least 15 seconds of tonically maintained electromyographic activity, and the percentage of 3-second REM mini-epochs that contained phasic electromyographic bursts. MEASUREMENTS AND RESULTS: The tonic and phasic measures, combined together, were higher in patients with clinical determinations of probable or possible RBD (n=9) than in patients judged unlikely to have RBD (n=4, P = .023). The overall polysomnographic measure correlated with the symptom scores (rho = 0.42, P = .048). Specific polysomnographic RBD measures on night 1 correlated highly with those on night 2 (rho > 0.70, P < .0001). CONCLUSIONS: This quantitative method to assess the severity of RBD polysomnographic features appears to be both valid and reliable in patients at risk for RBD because of neurodegenerative disorders.

Aged↗
PubMed2005

Differentiation of Alzheimer's disease from dementia with Lewy bodies utilizing positron emission tomography with [18F]fluorodeoxyglucose and neuropsychological testing.

We compared the relative utility of neuropsychological testing and positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG) in differentiating Alzheimer's disease (AD) from dementia with Lewy bodies (DLB). We studied 25 patients with AD, 20 with DLB, and 19 normal elderly controls. There was no difference between patient groups for MMSE, confrontational naming, or verbal learning. The DLB group was significantly more impaired than the AD group for verbal fluency, and the AD group was significantly more impaired than the DLB group for verbal delayed recall. The DLB group had greater difficulty than the AD group on a visual discrimination task that does not require motor functioning, but the difference did not reach significance. Family ratings of motor functioning suggested significantly greater impairment in DLB patients than in AD patients. PET studies revealed significantly lower local cerebral metabolic rates for glucose (lCMRglc) for visual cortex (Brodmann areas 17, 18, and 19) in the DLB than the AD group, but no differences for other regions commonly affected in AD, including posterior cingulate, superior parietal lobe, lateral temporal lobe, and the prefrontal region. Motor ratings were significantly correlated with lCMRglc in all areas of cerebral cortex, including Brodmann areas 17, 18, and 19. The results demonstrate a similar profile of cerebral hypometabolism in the two patient groups except in the visual cortex, where the DLB group shows markedly lower lCMRglc than the AD group. Neuropsychological testing also differentiates the groups, and family ratings of motor functioning are as robust as PET in these later stages of the disorders.

Aged↗
PubMed2005

The publications of Sir Victor Horsley: a listing and an assessment.

Sir Victor Horsley is well recognized as the father of neurological surgery, publishing many articles within this discipline and on other neurologically related topics. Furthermore, he published many important articles in other areas of science and medicine, as well as on social issues (e.g., women's suffrage). Accordingly, we compiled, for the first time, a complete listing of his writings. We briefly describe here some of the characteristics of his bibliography, which is available on the Journal's web site.

History, 19th Century↗
PubMed2005

11C-DTBZ and 18F-FDG PET measures in differentiating dementias.

UNLABELLED: Accurate, early differentiation of dementias will become increasingly important as new therapies are introduced. Differential diagnosis by standard clinical criteria has limited accuracy. PET offers the potential to increase diagnostic accuracy. (18)F-FDG studies detect metabolic abnormalities in demented patients, but with limited specificity. PET also offers the ability to quantify other biochemical markers that can yield additional useful diagnostic information. We demonstrate that (+)-(11)C-dihydrotetrabenazine ((11)C-DTBZ) studies, which provide an index of nigrostriatal terminal density (distribution volume; DV), also provide a measure of transport (K(1)) that produces information comparable to the metabolic measure of (18)F-FDG. METHODS: Fifty-two patients and 19 control subjects underwent both (11)C-DTBZ and (18)F-FDG PET scans. Seven had the clinical diagnosis of frontotemporal dementia (FTD), 25 had Alzheimer's disease (AD), and 20 had dementia with Lewy bodies (DLB). DTBZ scans provided maps of K(1) and DV, whereas (18)F-FDG scans provided maps of glucose metabolism. Correlation analyses were performed between the different PET measures both within and across subjects. Discriminant analysis using logistic regression compared the performance of (11)C-DTBZ K(1) and (18)F-FDG in differentiating subject groups. Three experienced PET researchers participated in an interrater reliability study using both (11)C-DTBZ K(1) and (18)F-FDG images. RESULTS: Within-subject correspondence between (11)C-DTBZ K(1) and (18)F-FDG measures was high, with correlations averaging 0.92. Correlations between the (11)C-DTBZ DV and either K(1) or (18)F-FDG were far lower, averaging 0.37 and 0.31, respectively, indicating the much higher degree of similarity in information provided by K(1) and (18)F-FDG compared with the very different information provided by (11)C-DTBZ DV. Discriminant analysis demonstrated that (11)C-DTBZ K(1) and (18)F-FDG yielded similar levels of sensitivity and specificity for differentiating the subjects in this study. Including (11)C-DTBZ DV in addition to either K(1) or (18)F-FDG improved discrimination between groups. The raters classified PET scans nearly equivalently using K(1) and (18)F-FDG. CONCLUSION: Multiple PET measures, whether 2 parameters from a single PET study such as (11)C-DTBZ K(1) and DV, or 2 parameters from different studies such as (18)F-FDG and (11)C-DTBZ DV, offer complementary information useful for diagnosing dementias. K(1) and DV images generated from a single (11)C-DTBZ scan provide as much diagnostic information as 2-scan studies using both (11)C-DTBZ and (18)F-FDG.

Aged↗
PubMed2004

Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease.

We used positron emission tomography (PET) with (+)-[(11)C]dihydrotetrabenazine ([+]-[(11)C]DTBZ) to examine striatal monoaminergic presynaptic terminal density in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimer's disease (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at least 1 year before dementia (DLB/PD) and 14 developed dementia before parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD compared to AD and control. Binding was lower in the DLB/PD group than the DLB/AD, but the differences reached only marginal significance in the caudate nucleus. No differences were found between AD and control groups though a few AD patients had binding values below the range of the controls. Subsequent neuropathological examination in one AD patient revealed both AD and DLB changes despite the absence of clinical parkinsonism. Both DLB groups had an anterior to posterior binding deficit gradient relative to controls, largest in posterior putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD group showed significant binding asymmetry only in posterior putamen. We conclude that PET with (+)-[(11)C]DTBZ differentiates DLB from AD, and decreased binding in AD may indicate subclinical DLB pathology in addition to AD pathology.

Aged↗
PubMed2004

Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS).

We aimed to develop and validate a novel rating scale for multiple system atrophy (Unified Multiple System Atrophy Rating Scale-UMSARS). The scale comprises the following components: Part I, historical, 12 items; Part II, motor examination, 14 items; Part III, autonomic examination; and Part IV, global disability scale. For validation purposes, 40 MSA patients were assessed in four centers by 4 raters per center (2 senior and 2 junior raters). The raters applied the UMSARS, as well as a range of other scales, including the Unified Parkinson's Disease Rating Scale (UPDRS) and the International Cooperative Ataxia Rating Scale (ICARS). Internal consistency was high for both UMSARS-I (Crohnbach's alpha = 0.84) and UMSARS-II (Crohnbach's alpha = 0.90) sections. The interrater reliability of most of the UMSARS-I and -II items as well as of total UMSARS-I and -II subscores was substantial (k(w) = 0.6-0.8) to excellent (k(w) > 0.8). UMSARS-II correlated well with UPDRS-III and ICARS (rs > 0.8). Depending on the degree of the patient's disability, completion of the entire UMSARS took 30 to 45 minutes. Based on our findings, the UMSARS appears to be a multidimensional, reliable, and valid scale for semiquantitative clinical assessments of MSA patients.

Activities of Daily Living↗