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1.  Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers 
Neurology  2013;81(15):1322-1331.
Objective:
In this prospective cohort study, we investigated cerebral glucose metabolism reductions on [18F]-fluorodeoxyglucose (FDG)-PET in progranulin (GRN) mutation carriers prior to frontotemporal dementia (FTD) onset.
Methods:
Nine mutation carriers (age 51.5 ± 13.5 years) and 11 noncarriers (age 52.7 ± 9.5 years) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions of interest (ROI) and statistical parametric mapping (SPM) approaches.
Results:
Compared with noncarriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86 ± 0.09 vs 0.92 ± 0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed clinically symptomatic no dementia or asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula, and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri, and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (modified Mini-Mental State Examination r = 0.74; Functional Rating Scale r = −0.73) but not age and years to estimated onset in mutation carriers.
Conclusion:
The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age at FTD onset (late 50s–early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated.
doi:10.1212/WNL.0b013e3182a8237e
PMCID: PMC3806924  PMID: 24005336
2.  The effects of exercise on cognition in Parkinson’s disease: a systematic review 
Cognitive impairments are highly prevalent in Parkinson’s disease (PD) and can substantially affect a patient’s quality of life. These impairments remain difficult to manage with current clinical therapies, but exercise has been identified as a possible treatment. The objective of this systematic review was to accumulate and analyze evidence for the effects of exercise on cognition in both animal models of PD and human disease. This systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Fourteen original reports were identified, including six pre-clinical animal studies and eight human clinical studies. These studies used various exercise interventions and evaluated many different outcome measures; therefore, only a qualitative synthesis was performed. The evidence from animal studies supports the role of exercise to improve cognition in humans through the promotion of neuronal proliferation, neuroprotection and neurogenesis. These findings warrant more research to determine what roles these neural mechanisms play in clinical populations. The reports on cognitive changes in clinical studies demonstrate that a range of exercise programs can improve cognition in humans. While each clinical study demonstrated improvements in a marker of cognition, there were limitations in each study, including non-randomized designs and risk of bias. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used and the quality of the evidence for human studies were rated from “low” to “moderate” and the strength of the recommendations were rated from “weak” to “strong”. Studies that assessed executive function, compared to general cognitive abilities, received a higher GRADE rating. Overall, this systematic review found that in animal models exercise results in behavioral and corresponding neurobiological changes in the basal ganglia related to cognition. The clinical studies showed that various types of exercise, including aerobic, resistance and dance can improve cognitive function, although the optimal type, amount, mechanisms, and duration of exercise are unclear. With growing support for exercise to improve not only motor symptoms, but also cognitive impairments in PD, health care providers and policy makers should recommend exercise as part of routine management and neurorehabilitation for this disorder.
doi:10.1186/2047-9158-3-5
PMCID: PMC3936925  PMID: 24559472
Parkinson’s disease; Exercise; Cognition; Humans; Animals
3.  In-vivo measurement of LDOPA uptake, dopamine reserve and turnover in the rat brain using [18F]FDOPA PET 
Longitudinal measurements of dopamine (DA) uptake and turnover in transgenic rodents may be critical when developing disease-modifying therapies for Parkinson's disease (PD). We demonstrate methodology for such measurements using [18F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18F]FDOPA) positron emission tomography (PET). The method was applied to 6-hydroxydopamine lesioned rats, providing the first PET-derived estimates of DA turnover for this species. Control (n=4) and unilaterally lesioned (n=11) rats were imaged multiple times. Kinetic modeling was performed using extended Patlak, incorporating a kloss term for metabolite washout, and modified Logan methods. Dopaminergic terminal loss was measured via [11C]-(+)-dihydrotetrabenazine (DTBZ) PET. Clear striatal [18F]FDOPA uptake was observed. In the lesioned striatum the effective DA turnover increased, shown by a reduced effective distribution volume ratio (EDVR) for [18F]FDOPA. Effective distribution volume ratio correlated (r>0.9) with the [11C]DTBZ binding potential (BPND). The uptake and trapping rate (kref) decreased after lesioning, but relatively less so than [11C]DTBZ BPND. For normal controls, striatal estimates were kref=0.037±0.005 per minute, EDVR=1.07±0.22 and kloss=0.024±0.003 per minute (30 minutes turnover half-time), with repeatability (coefficient of variation) ≤11%. [18F]fluoro-3,4-dihydroxyphenyl-L-alanine PET enables measurements of DA turnover in the rat, which is useful for developing novel therapies for PD.
doi:10.1038/jcbfm.2012.120
PMCID: PMC3597374  PMID: 22929441
dopamine synthesis; FDOPA; 6-OHDA lesion; Parkinson's disease; PET
4.  The Nature of Progression in Parkinson’s Disease: An Application of Non-Linear, Multivariate, Longitudinal Random Effects Modelling 
PLoS ONE  2013;8(10):e76595.
Background
To date, statistical methods that take into account fully the non-linear, longitudinal and multivariate aspects of clinical data have not been applied to the study of progression in Parkinson’s disease (PD). In this paper, we demonstrate the usefulness of such methodology for studying the temporal and spatial aspects of the progression of PD. Extending this methodology further, we also explore the presymptomatic course of this disease.
Methods
Longitudinal Positron Emission Tomography (PET) measurements were collected on 78 PD patients, from 4 subregions on each side of the brain, using 3 different radiotracers. Non-linear, multivariate, longitudinal random effects modelling was applied to analyze and interpret these data.
Results
The data showed a non-linear decline in PET measurements, which we modelled successfully by an exponential function depending on two patient-related covariates duration since symptom onset and age at symptom onset. We found that the degree of damage was significantly greater in the posterior putamen than in the anterior putamen throughout the disease. We also found that over the course of the illness, the difference between the less affected and more affected sides of the brain decreased in the anterior putamen. Younger patients had significantly poorer measurements than older patients at the time of symptom onset suggesting more effective compensatory mechanisms delaying the onset of symptoms. Cautious extrapolation showed that disease onset had occurred some 8 to 17 years prior to symptom onset.
Conclusions
Our model provides important biological insights into the pathogenesis of PD, as well as its preclinical aspects. Our methodology can be applied widely to study many other chronic progressive diseases.
doi:10.1371/journal.pone.0076595
PMCID: PMC3799835  PMID: 24204641
5.  Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis 
EJNMMI Research  2013;3:69.
Background
[18 F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [18 F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques.
Methods
[18 F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [11C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity.
Results
The different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BPND; r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BPND) but not with the contralateral PET measures. EDVR and BPND in the contralateral striatum were not different from controls and were not correlated with the denervation severity.
Conclusions
The demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [18 F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control.
doi:10.1186/2191-219X-3-69
PMCID: PMC3875899  PMID: 24088510
Dopamine synthesis; FDOPA; Parkinson's disease; PET; Microdialysis; 6-OHDA lesion
6.  Neurology in Canada: History of the Canadian Neurological Society 
Neurology  2013;80(4):406-408.
In the 19th and early 20th century, Canadian physicians interested in neurology focused on this area as part of their broader clinical practices. The most renowned was William Osler, often called Canada's first neurologist because one-third of his writing was devoted to neurology. Until the mid-20th century, most Canadian neurologists trained at the National Hospital, Queen Square, London, and in Paris. The majority returned to academic centers and after World War II every Canadian medical school and major center had consultant neurologists.
doi:10.1212/WNL.0b013e31827f0788
PMCID: PMC3589243  PMID: 23339206
7.  DJ-1 and αSYN in LRRK2 CSF do not correlate with striatal dopaminergic function 
Neurobiology of Aging  2011;33(4):836.e5-836.e7.
Previous studies demonstrated decreased levels of DJ-1 and α-synuclein (αSYN) in human cerebrospinal fluid (CSF) in patients with Parkinson’s disease (PD), but neither marker correlated with PD severity, raising the possibility that they may be excellent progression markers during early or preclinical phases of PD. Individuals carrying the leucine-rich repeat kinase 2 (LRRK2) gene mutation are at increased risk for PD, and the phenotype of LRRK2 patients is almost identical to sporadic PD. To determine whether dopaminergic dysfunction in the basal ganglia, as determined by positron emission tomography (PET) scans, correlates with CSF levels of DJ-1 and αSYN during preclinical stages, Luminex assays were used to analyze CSF samples from asymptomatic LRRK2 mutation carriers, along with carriers who presented with a clinical diagnosis of PD. The data revealed no statistically significant relationship between PET scan evidence of loss of striatal dopaminergic function and the CSF biomarkers DJ-1 and αSYN, except for a weak correlation between DJ-1 and MP binding, suggesting that the use of these potential biomarkers on their own to screen LRRK2 gene mutation carriers for PD is not appropriate.
doi:10.1016/j.neurobiolaging.2011.09.015
PMCID: PMC3279603  PMID: 22019052
Parkinson’s Disease; LRRK2; gene mutation; biomarker; DJ-1; α-synuclein
8.  Leg muscle strength is reduced in PD and relates to the ability to rise from a chair 
Individuals with Parkinson’s disease (PD) have difficulties rising from a chair; however, factors contributing to this inability have never been investigated. This study compared lower extremity strength between individuals with PD and healthy controls and quantified the relationships between strength and the ability to rise from a chair. Ten males with mild PD and ten male age-matched controls performed maximal concentric, isokinetic knee and hip extensor torque on an isokinetic dynamometer to quantify muscle strength. Subjects also rose from a chair at their comfortable pace without the use of their arms and the duration of this task provided a measure of sit-to-stand (STS) ability. Subjects with PD were tested in an on- and off-medication state on different days. Mean hip and knee extensor torques were less in subjects with PD, with greater deficits found at the hip. Greater hip strength was related to better STS ability in subjects with PD while greater knee strength was related to better STS ability in controls. These results show that individuals with mild PD generate smaller extremity forces compared to controls. Reduced strength, particularly at the hip, may be one factor that contributes to the difficulty of persons with PD to rise from a chair.
doi:10.1002/mds.10299
PMCID: PMC3471985  PMID: 12539208 CAMSID: cams2418
Parkinson’s disease; sit-to-stand; hip torque; knee torque; strength
9.  Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research 
PLoS ONE  2012;7(8):e43099.
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
doi:10.1371/journal.pone.0043099
PMCID: PMC3428297  PMID: 22952635
10.  Neuroimaging in the early diagnosis of neurodegenerative disease 
Functional imaging may be useful for both the early diagnosis as well as preclinical detection of neurodegenerative disease. Additionally, while structural imaging has traditionally been regarded as a tool to exclude alternate diagnoses, recent advances in magnetic resonance show promise for greater diagnostic specificity. The role of MR and radionuclide imaging in early diagnosis and preclinical detection of dementia and parkinsonism are reviewed here.
doi:10.1186/2047-9158-1-5
PMCID: PMC3506998  PMID: 23211024
11.  Neuroimaging in Parkinson’s Disease 
Summary
Parkinson’s disease (PD) is a common disorder in which the primary features can be related to dopamine deficiency. Changes on structural imaging are limited, but a wealth of abnormalities can be detected using positron emission tomography, single photon emission computed tomography, or functional magnetic resonance imaging to detect changes in neurochemical pathology or functional connectivity. The changes detected on these studies may reflect the disease process itself and/or compensatory responses to the disease, or they may arise in association with disease- and/or treatment-related complications. This review will focus mainly on neurochemical and metabolic studies and reviews various approaches to the assessment of dopaminergic function as well as the function of other neurotransmitters that may be affected in PD. A number of clinical applications are highlighted, including diagnostic utility, identification of preclinical disease, changes associated with motor and nonmotor complications of PD, and the effects of various therapeutic interventions.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-010-0007-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-010-0007-z
PMCID: PMC3075732  PMID: 21274687
Positron emission tomography; single photon emission computed tomography; functional magnetic resonance imaging; dopamine; monoamines
12.  Familial Parkinsonism: Study of Original Sagamihara PARK8 (I2020T) Kindred With Variable Clinicopathologic Outcomes 
Parkinsonism & related disorders  2008;15(4):300-306.
Background
Since the causative gene linked to PARK8 parkinsonism was identified as LRRK2, LRRK2 gene mutations have been found to occur in about 4% of patients with hereditary Parkinson disease (PD); this percentage is even higher in certain populations. Moreover, no clear clinical differences between PARK8-linked parkinsonism and sporadic PD have been identified. Neuropathologic findings have been diverse in PARK8 parkinsonism, but few of the clinicopathologic examinations have been performed in the same family tree. We aimed to describe PET and neuropathologic findings in members of the same family tree with PARK8 parkinsonism.
Methods
We conducted PET of 2 subjects and neuropathologically examined 8 subjects in the same family from the Sagamihara district, the original source of PARK8-linked parkinsonism (I2020T mutation).
Results
The results of the PET scans were virtually identical to those seen in sporadic PD. The neuropathologic study results showed pure nigral degeneration with no Lewy bodies in 6 cases. One case, however, showed the presence of Lewy bodies and was similar neuropathologically to conventional PD with Lewy bodies. Another case had multiple system atrophy pathology.
Conclusions
Our study of PARK8-linked parkinsonism affecting several members of the same pedigree shows that the same gene mutation can induce diverse neuropathologies, even if the clinical picture and PET findings are virtually identical.
doi:10.1016/j.parkreldis.2008.07.010
PMCID: PMC2702757  PMID: 18804399
nigral degeneration; PARK8; PET
13.  DCTN1 mutations in Perry syndrome 
Nature genetics  2009;41(2):163-165.
Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, in which brain pathology is characterized by TDP-43 immunostaining. Through genome-wide linkage analysis we have identified five disease-segregating dynactin (DCTN1) CAP-Gly domain substitutions in 8 families that diminish microtubule binding and lead to intracytoplasmic inclusions. DCTN1 mutations were previously associated with motor neuron disease but can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.
doi:10.1038/ng.293
PMCID: PMC2813485  PMID: 19136952
Dynactin; DCTN1; Perry syndrome; parkinsonism; neurodegeneration; TDP-43

Results 1-13 (13)