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Toft M.,University of Oslo | Ross O.A.,Mayo Clinic Jacksonville
Genome Medicine | Year: 2010

A central theme of human genetic studies is to understand genomic variation and how this underlies the inherited basis of disease. Genomic variation can provide increased biological understanding of disease processes, which is necessary to develop future treatments. Recent technological advances have highlighted the role of copy number variants in normal and pathological phenotypic expression. These applications have been used in studies of Parkinson's disease, a common, late-onset, progressive neurodegenerative disorder. At present the main therapeutic approach is administration of symptom-alleviating drugs, which neither reverses the disease process nor halts its progression. However, the generation of in vivo model systems and development of novel disease intervention strategies for Parkinson's disease have come from research on monogenic forms of the disorder, including those caused by copy number variants. Here, we review the role of copy number variants and the mechanistic insights they have provided on the pathogenesis of Parkinson's disease. © 2010 BioMed Central Ltd.


Whaley N.R.,Tri State Mountain Neurology | Fujioka S.,Mayo Clinic Jacksonville | Wszolek Z.K.,Mayo Clinic Jacksonville
Orphanet Journal of Rare Diseases | Year: 2011

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds. © 2011 Whaley et al; licensee BioMed Central Ltd.


Mesleh M.G.,Mayo Clinic Jacksonville | Stauffer J.A.,Mayo Clinic Jacksonville | Bowers S.P.,Mayo Clinic Jacksonville | Asbun H.J.,Mayo Clinic Jacksonville
Surgical Endoscopy and Other Interventional Techniques | Year: 2013

Introduction: The laparoscopic approach to pancreaticoduodenectomy has been recently more frequently reported and is now being performed at multiple centers across the US. While laparoscopic pancreaticoduodenectomy (LPD) has been shown to be safe and feasible, comparing its cost in relation to open pancreaticoduodenectomy (OPD) has not been examined. The aim of this study is to examine the cost of LPD compared with OPD at a single institution over a 3-year time period. Methods: An institutional database was analyzed to compare patients who underwent OPD and LPD (including Whipple resections and total pancreatectomy) between May 2009 and June 2012. A cost analysis was performed, which included the use the hospital billing database to assess surgical costs, hospital admission costs, and overall cost of the patient's care during the index admission. The operative costs were further analyzed with respect to OR time and surgical supplies. Standard statistical analysis was performed to assess for significance. Results: In the study time period, 123 patients underwent pancreaticoduodenectomy, including 48 OPD (39 %) and 75 LPD (61 %). The groups were similar with respect to age, gender, ASA, vein resection, and indication for surgery. In the LPD group, the use of hand assist or conversion to OPD occurred in 3 (4 %) and 10 (13 %) patients, respectively. Additionally, 10 % of the OPD group underwent total pancreatectomy (n = 5), compared to 21 % of the LPD (n = 16). Mean operative time for OPD and LPD was 355 min (range 199-681) and 551 min (range 390-819) respectively (p < 0.0001). Median hospital stay for OPD and LPD was 8 days (range 5-63), and 7 days (range 4-68) respectively (p = 0.5). Morbidity rates were equal at 31 % for the two groups. The LPD group was associated with significantly higher surgical cost due to both increased time and supply cost. However, mean hospital admission cost associated with OPD was greater in comparison to the LPD group, though not significant. The overall total cost of care was similar between the two groups. Conclusions: LPD is associated with equivalent overall cost compared with OPD. While operating time and supply costs were higher for LPD, this was balanced by decreased cost of the postoperative admission. © 2013 Springer Science+Business Media New York.


Boylan K.,Mayo Clinic Jacksonville
Neurologic Clinics | Year: 2015

Genes linked to amyotrophic lateral sclerosis (ALS) susceptibility are being identified at an increasing rate owing to advances in molecular genetic technology. Genetic mechanisms in ALS pathogenesis seem to exert major effects in about 10% of patients, but genetic factors at some level may be important components of disease risk in most patients with ALS. Identification of gene variants associated with ALS has informed concepts of the pathogenesis of ALS, aided the identification of therapeutic targets, facilitated research to develop new ALS biomarkers, and supported the establishment of clinical diagnostic tests for ALS-linked genes. © 2015 Elsevier Inc.


McLean P.J.,Mayo Clinic Jacksonville
Molecular neurodegeneration | Year: 2014

The accumulation of α-synuclein aggregates is the hallmark of Parkinson's disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases α-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, α-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and α-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and α-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and α-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between α-synuclein and tau.


Melrose H.L.,Mayo Clinic Jacksonville
Biochemical Journal | Year: 2015

Pathogenic mutations and risk variants in LRRK2 (leucine-rich repeat kinase 2) represent the most common genetic cause of familial and sporadic PD (Parkinson's disease). LRRK2 protein is widely expressed throughout the brain and the periphery. Structurally, LRRK2 contains several functional domains, including a dual enzymatic core consisting of a kinase and GTPase domain. Disease-linked variants are found in both these enzymatic domains as well as in the COR [C-terminal of ROC (Ras of complex proteins)] and WD40 protein-protein binding domain. The kinase domain is widely believed to be linked to toxicity, and thus the thrust of pharmaceutical effort has focused on developing LRRK2 kinase inhibitors. However, recent data have suggested that inhibition of LRRK2 activity results in reduced LRRK2 levels and peripheral side effects, which are similar to those observed in homozygous LRRK2-knockout and LRRK2 kinase-dead rodent models. In a recent issue of the Biochemical Journal, a study led by Nichols reveals that dephosphorylation of LRRK2 cellular phosphorylation sites (Ser910/Ser935/Ser955/Ser973) triggers its ubiquitination and subsequent degradation and thus may account for the loss of function phenotypes observed in peripheral tissues in LRRK2-knockout/kinase-dead or inhibitor-treated rodents and primates. Albeit negative from a kinase inhibitor standpoint, the data open new avenues for LRRK2 biology and therapeutic approaches to counteract LRRK2 toxicity. © 2015 Authors.


Nottmeier E.W.,Mayo Clinic Jacksonville
Journal of Neurosurgical Sciences | Year: 2012

Image-guided spinal surgery has evolved rapidly in recent years. This review highlights the advances in image-guided spinal surgery during this evolution. The current literature regarding image-guided spinal surgery will be discussed. In addition, several aspects of image-guided spinal surgery will be focused on, including its learning curve and influence on operating room time, as well as its effect on surgeon radiation exposure. The accuracy of instrumentation placement with this technology and current applications will also be addressed.


Nottmeier E.W.,Mayo Clinic Jacksonville | Pirris S.M.,Mayo Clinic Jacksonville
Journal of Neurosurgery: Spine | Year: 2013

Object: Transvertebral pedicle screws have successfully been used in the treatment of high-grade L5-S1 spondylolisthesis. An advantage of transvertebral pedicle screws is the purchase of multiple cortical layers across 2 vertebrae, thereby increasing the stability of the construct. At the lumbosacral junction, transvertebral pedicle screws have been shown to be biomechanically superior to pedicle screws placed in the standard fashion. The use of transvertebral pedicle screws at spinal levels other than L5-S1 has not been reported in the literature. The authors describe their technique of transvertebral pedicle screw placement in the thoracic spine using 3D image guidance. Methods: Twelve patients undergoing cervicothoracic or thoracolumbar fusion had 41 thoracic transvertebral pedicle screws placed across 26 spinal levels using this technique. Indications for placement of thoracic transvertebral pedicle screws in earlier cases included osteoporosis and pedicle screw salvage. However, in subsequent cases screws were placed in patients undergoing multilevel thoracolumbar fusion without osteoporosis, particularly near the top of the construct. Image guidance in this study was accomplished using the Medtronic StealthStation S7 image guidance system used in conjunction with the O-arm. All patients were slated to undergo postoperative CT scanning at approximately 4-6 months for fusion assessment, which also allowed for grading of the transvertebral pedicle screws. Results: No thoracic transvertebral pedicle screw placed in this study had to be replaced or repositioned after intraoperative review of the cone beam CT scans. Review of the postoperative CT scans revealed all transvertebral screws to be across the superior disc space with the tips in the superior vertebral body. Six pedicle screws were placed using the in-out-in technique in patients with narrow pedicles, leaving 35 screws that underwent breach analysis. No pedicle breach was noted in 34 of 35 screws. A Grade 1 (< 2 mm) medial breach was noted in 1 screw without clinical consequence. Solid fusion was observed across 25 of 26 spinal levels that underwent transvertebral screw placement including 7 spinal levels located at the top of a multilevel construct. Conclusions: This report describes the authors' initial in vivo experience with the 3D image-guided placement of 41 thoracic transvertebral pedicle screws. Advantages of thoracic transvertebral screws include the purchase of 2 vertebral segments across multiple cortical layers. A high fusion rate was observed across spinal levels in which transvertebral screws were placed. A formal biomechanical study is needed to assess the biomechanical advantages of this technique and is currently being planned. © 2013 AANS.


Graff-Radford N.R.,Mayo Clinic Jacksonville
Alzheimer's Research and Therapy | Year: 2011

There are more than 36 million people in the US over the age of 65, and all of them are impacted by the cognitive decline and brain atrophy associated with normal aging and dementia-causing conditions like Alzheimer's disease, Lewy body disease, and vascular dementia. Recently, moderate exercise and improved fitness have been shown to enhance cognition in cognitively normal older persons as well as in individuals who complain of memory difficulty. Additionally, fitness correlates with brain volume in persons who are cognitively normal and those with Alzheimer's disease. Exercise in mouse models causes neurogenesis in the dentate gyrus. This review will discuss animal experiments, epidemiology, limited prospective studies, and biomarker data that make the case that prospective blinded studies are urgently needed to evaluate the role of aerobic exercise in protecting against dementia. © 2011 BioMed Central Ltd.


Nicholson A.M.,Mayo Clinic Jacksonville | Rademakers R.,Mayo Clinic Jacksonville
Acta Neuropathologica | Year: 2016

Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7. In this manuscript, we review the initial discovery and replication studies describing TMEM106B variants as disease risk factors and modifiers in TDP-43 proteinopathies, such as FTLD-TDP caused by progranulin (GRN) or chromosome 9 open reading frame 72 (C9orf72) mutations, as well as Alzheimer’s disease and hippocampal sclerosis. We further summarize what is currently known about the previously uncharacterized TMEM106B protein and its role as a potential regulator of lysosomal function, and we discuss how modifying TMEM106B levels might uncover promising therapeutic strategies for individuals suffering from TDP-43 proteinopathy. © 2016 Springer-Verlag Berlin Heidelberg

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