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Parkinsonism & Related Disorders 01/2013; · 3.80 Impact Factor
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ABSTRACT: Some reports suggest cerebellar dysfunction as the basis of essential tremor (ET). Several drugs with the action of gamma-aminobutyric acid (GABA) are known to improve ET. Autopsy studies were performed on brains from nine former patients followed at the Movement Disorders Clinic Saskatchewan, Canada, and compared with five normal control brains. We aimed to measure the concentration of GABA B receptor 1 (GBR1) in the brains of patients who had had ET and to compare them to the GABA concentration in brains of controls. Western blot was used to determine the expression of GBR1 in cerebellar cortex tissue. We found that compared to the controls, the ET brains had three different patterns of GBR1 protein concentration--two with high, four comparable, and three with marginally low levels. There was no association between the age of onset, severity or duration of tremor, the response to alcohol or other drugs and GBR1 level. Thus, we conclude that our study does not support that GBR1 is involved in ET. Further studies are needed to verify these results.
Journal of Clinical Neuroscience 02/2012; 19(6):920-1. · 1.25 Impact Factor
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ABSTRACT: The pathophysiology of essential tremor (ET) is unknown but recent studies report that the majority of ET cases has cerebellar Purkinje cell (PC) degeneration and its sequelae.
To perform PC counts in ET, and normal and Parkinson's disease (PD) controls to determine the relationship of PC loss to ET.
All ET cases and PD controls were followed at our clinic. Normal controls had no history of neurological disease and had normal standard neuropathological studies. The PC counts were done by a neuropathologist who was blinded to the clinical diagnosis. Three different methods were used for counting PC; section through any part of the PC, through any part of the PC nucleus, and through any part of PC nucleolus. The counts were done in five non-contiguous microscopic fields.
59 brains were studied. These included 12 ET, 41 PD controls, and six normal controls. The mean age at death was 82.7 in ET, 79.1 in PD, and 75.7 years in the normal controls. The mean duration of symptoms was 34 years in ET and 15.7 years in the PD cases. The mean PC counts through any part of the neuron were 64.8 in ET, 56.2 in PD, and 58.0 in normal controls. Differences were not significant.
Cerebellar PC loss does not distinguish ET from controls. It is concluded that PC loss is neither a pathological basis for, nor the distinctive feature of ET.
Parkinsonism & Related Disorders 02/2012; 18(5):626-8. · 3.80 Impact Factor
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J C Dachsel,
C Wider,
C Vilariño-Güell,
J O Aasly,
A Rajput, A H Rajput,
T Lynch,
D Craig,
A Krygowska-Wajs,
B Jasinska-Myga,
G Opala,
M Barcikowska,
K Czyzewski,
R-M Wu,
M G Heckman,
R J Uitti,
Z K Wszolek,
M J Farrer,
O A Ross
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ABSTRACT: Mutations of the LRRK2 gene are now recognized as major risk factors for Parkinson's disease. The Lrrk2 protein is a member of the ROCO family, which also includes Lrrk1 and Dapk1. Functional genetic variants of the DAPK1 gene (rs4877365 and rs4878104) have been previously associated with Alzheimer's disease.
Herein, we assessed the role of DAPK1 variants (rs4877365 and rs4878104) in risk of Parkinson's disease with Sequenom iPLEX genotyping, employing one Taiwanese series (391 patients with Parkinson's disease, 344 controls) and five separate Caucasian series' (combined sample size 1962 Parkinson's disease patients, 1900 controls).
We observed no evidence of association for rs4877365 and rs4878104 and risk of Parkinson's disease in any of the individual series or in the combined Caucasian series under either an additive or recessive model.
These specific DAPK1 intronic variants do not increase the risk of Parkinson's disease. However, further functional studies are required to elucidate the potential therapeutic implications with the dimerization of the Dapk1 and Lrrk2 proteins.
European Journal of Neurology 08/2011; 18(8):1090-3. · 3.69 Impact Factor
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ABSTRACT: Some recent studies indicate that most essential tremor (ET) cases have cerebellar pathology characterized by Purkinje cell (PC) loss and its sequelae.
To assess the role of PC degeneration in ET symptomatology.
We studied seven ET, six tremor dominant Parkinson's disease controls and two normal control brains. Cerebellar PC counts were done in all cases by a neuropathologist using three different methods to identify PC.
There were individual differences in PC counts in all subgroups. There was no difference between ET and controls of the same age. The PC count in ET was not related to: onset site of ET, severity of symptoms, or any other clinical features that we studied but there was a trend to a reduced number of PC with age in all groups.
There is no evidence in our study or in the literature to date indicating that PC loss is the pathological basis of ET. Further studies are needed to determine the pathophysiology of ET.
Parkinsonism & Related Disorders 07/2011; 17(6):410-2. · 3.80 Impact Factor
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C Vilariño-Güell,
A I Soto-Ortolaza, A Rajput,
D C Mash,
S Papapetropoulos,
R Pahwa,
K E Lyons,
R J Uitti,
Z K Wszolek,
D W Dickson,
M J Farrer,
O A Ross
Neurology 02/2011; 76(7):670-2. · 8.31 Impact Factor
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ABSTRACT: Most of the literature on pathology of essential tremor (ET) has reported no consistent abnormalities. Some recent studies however indicate that cerebellar Purkinje cell (PC) loss is the pathological basis of ET in most patients.
To compare cerebellar PC loss in ET, with normal and tremor dominant Parkinson's disease [PD] control brains.
Cerebellar PC counts were performed in seven ET, six PD and two normal control brains. Three different counting methods - sectioned through nucleolus, through nucleus and through any part of PC body, were used to count the PC.
There were individual differences in the PC counts both in the ET and the PD cases. In all three subgroups, there was a reduction in the number of PC with advancing age. When the individuals of comparable age in the three subgroups were considered, there was no clear distinction between ET, PD and normal control subjects. There was no association between the degree of PC loss and the severity or the duration of ET.
Our study militates against the hypothesis that PC loss is pathognomonic of ET.
Parkinsonism & Related Disorders 01/2011; 17(1):16-21. · 3.80 Impact Factor
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C Vilariño-Güell,
O A Ross,
J O Aasly,
L R White,
A Rajput, A H Rajput,
T Lynch,
A Krygowska-Wajs,
B Jasinska-Myga,
G Opala,
M Barcikowska,
M-C Lee,
F Hentati,
R J Uitti,
Z K Wszolek,
M J Farrer,
R-M Wu
Neurology 12/2010; 75(24):2248-9. · 8.31 Impact Factor
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ABSTRACT: Individual variations in the course of Lewy body Parkinson disease (PD) are well known. Patients have been classified into different clinical subtypes to identify differences in the course among the subgroups. Several studies indicate that the outcome is more favorable in tremor dominant (TD) cases but others report no difference. A majority of progression studies are based on cross-sectional single point data or short-term clinical observations. The lack of longitudinally followed autopsy-confirmed PD cohort remains a major weakness in the literature. Biochemical studies of brain indicate most pronounced abnormalities in akinetic/rigid (AR) and the least in TD cases. We postulate that PD course in these subtypes is concordant with the biochemical findings.
To compare the course in TD, mixed (MX), and AR subtypes of PD.
Longitudinal clinical follow-up and autopsy studies were performed on 166 patients with PD over 39 years (1968-2006). Patients were classified into TD, AR, and MX based on the entire clinical course. Only the pathologically confirmed PD cases were included.
Sixty-six percent of cases had MX, 26% AR, and 8% TD profile. The age at onset was younger (p < 0.001) and progression to Hoehn & Yahr stage 4 was slower (p = 0.016) in the TD cases. Dementia was most common in AR (p = 0.039) and the least common in TD. In general, the course was most favorable in TD, followed by MX and AR subgroups.
The three subtypes of Parkinson disease have different courses which are concordant with the differences in brain biochemical abnormalities.
Neurology 08/2009; 73(3):206-12. · 8.31 Impact Factor
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C Vilariño-Güell,
H Chai,
B H Keeling,
J E Young, A Rajput,
T Lynch,
J O Aasly,
R J Uitti,
Z K Wszolek,
M J Farrer,
S-C Lin
Neurology 08/2009; 73(3):243-5. · 8.31 Impact Factor
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ABSTRACT: Patients with Parkinson disease (PD) may be akinetic/rigid, be tremor dominant, or have comparable severity of these motor symptoms (classic). The pathophysiologic basis of different PD phenotypes is unknown. This study assessed pallidal and striatal dopamine level patterns in different motor subgroups of PD and normal control brains.
Globus pallidus and striatum dopamine (DA) levels were measured with high performance liquid chromatography in eight autopsy confirmed PD and five control frozen brains.
DA levels in the external globus pallidus (GPe) of normal brains were nearly six times greater than in the internal pallidum (GPi). In PD, the mean loss of DA was marked (-82%) in GPe and moderate (-51%) in GPi. DA loss of variable degree was seen in different subdivisions of GPe and GPi in PD; however, DA levels were near normal in the ventral (rostral and caudal) GPi of PD cases with prominent tremor. There was marked loss of DA (-89%) in the caudate and severe loss (-98.4%) in the putamen in PD. The pattern of pallidal DA loss did not match the putaminal DA loss.
There is sufficient loss of dopamine (DA) in external globus pallidus and the internal globus pallidum (GPi) as may contribute to the motor manifestations of Parkinson disease (PD). The possible functional disequilibrium between GABAergic and DAergic influences in favor of DA in the caudoventral parts of the GPi may contribute to resting tremor in tremor dominant and classic PD cases.
Neurology 05/2008; 70(16 Pt 2):1403-10. · 8.31 Impact Factor
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ABSTRACT: Lrrk2 G2019S is predominantly associated with alpha-synuclein-immunopositive Lewy body pathology. We have identified Family SK where Lrrk2 G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology. Thus alpha-synucleinopathy and tauopathy, the predominant pathologies associated with parkinsonism, may be alternate outcomes of the same underlying genetic cause. Intriguingly, we observe no evidence of a direct interaction between either the tau or alpha-synuclein protein with Lrrk2.
Neurology 11/2006; 67(8):1506-8. · 8.31 Impact Factor
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ABSTRACT: Progressive supranuclear palsy (PSP) is a degenerative condition of unknown aetiology that produces an akinetic-rigid form of parkinsonism characterised by early falls and abnormalities of extraocular movements. Mean age of onset is approximately 63 years, and mean survival from symptom onset is 9 years. Men are much more frequently affected than women. The classic clinical finding is supranuclear ophthalmoplegia, which may not present until late in the illness, if at all. The clinical diagnosis of PSP can be difficult to make, as the sites of pathology are heterogeneous. Structural and functional neuroimaging studies, although not specific for PSP, may be of some assistance in making the diagnosis. The definitive diagnosis of PSP requires the presence of both clinical and neuropathological evidence. Multiple anatomical sites are affected in PSP. The most consistently involved are the subthalamic nucleus, globus pallidus interna and externa, pontine nuclei, periaqueductal grey matter and the substantia nigra. The location of the pathology accounts for the clinical features. The histological hallmark of PSP is the presence of globose neurofibrillary tangles in the affected subcortical nuclei. Neurofibrillary tangles are composed of abnormally phosphorylated tau, a microtubule-associated protein that is involved in maintenance of the cytoskeleton. Abnormalities near or in the gene coding for tau are implicated in the pathogenesis of PSP. The multiple neurotransmitter abnormalities, including those affecting dopamine, acetylcholine, gamma-aminobutyric acid and norepinephrine (noradrenaline) systems and pathways, as well as both pre- and post-synaptic pathology, make pharmacological therapy of PSP a challenge. Although an individual patient may respond to a drug, in general patients with PSP have a minimal response and a short duration of sustained benefit.
Drugs & Aging 02/2001; 18(12):913-25. · 2.67 Impact Factor
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ABSTRACT: Previous open-label trials have shown iron to be efficacious in the treatment of restless legs syndrome. We performed a randomized, double-blind, placebo-controlled trial of iron sulfate.
Twenty-eight patients were randomized to receive either ferrous sulfate 325 mg b.i.d. or placebo for 12 weeks. The primary outcome measure was the dichotomous variable of improvement or no improvement in average quality of sleep as recorded by a visual analog scale nightly over a 2-week period, comparing a pretreatment 2-week baseline to weeks 13-14. Secondary outcome measures included a comparison of the quality of sleep as measured by a visual analog scale, effect of restless legs syndrome on life as a whole as measured by a different visual analog scale, and the percentage of nights patients were symptomatic.
No significant differences were noted between iron and placebo groups for both primary and secondary outcome measures. Responders taking iron did have a significant increase in their iron saturation compared to nonresponders taking iron.
Iron sulfate does not appear to be an effective empiric treatment for restless legs syndrome.
European Neurology 02/2000; 43(2):70-5. · 1.81 Impact Factor
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ABSTRACT: To determine the incidence of deep venous thrombosis (DVT) in patients with Parkinson disease.
Prospective study.
Outpatient neurology clinic.
Eighty-one patients with Parkinson disease.
Duplex ultrasonographic scans consisting of M mode images and compression images, Doppler flow assessment and augmentation of flow assessment.
Four patients had leg DVT; in 3 of the patients the thrombi were in calf veins, whereas in 1 patient the thrombosis was in the superficial femoral vein. Of the patients with DVT, 1 (1.23%) had stage 2 Parkinson disease, 1 (1.23%) had stage 2.5, and the other 2 (2.46%) had stage 4.
There was no statistically significant difference in the incidence of DVT among patients who were more severely disabled by Parkinson disease. However, an overall incidence of DVT of 4.9% in a group of asymptomatic patients is clinically meaningful, suggesting that patients with Parkinson disease are at risk for asymptomatic leg DVT.
Journal of psychiatry & neuroscience: JPN 10/1999; 24(4):338-40. · 5.34 Impact Factor
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Movement Disorders 10/1998; 13(5):851. · 4.51 Impact Factor
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ABSTRACT: Multicase families are frequently utilized in studies of movement disorders (MDs). We report families with two or more MD cases seen at the Movement Disorder Clinic, Saskatoon (MDCS). In 30% of the MD probands, there was either a history or documentation of at least one secondary MD case in the family. Only those MD cases that were seen at the MDCS were considered in this study. A total of 56 probands and 77 secondary MD cases were seen at the MDCS between 1968 and 1996. In 24 (31.2%) of the secondary cases, the diagnosis was different from that in the proband. In 46 families (82%), only one secondary case was seen, and the diagnosis was concordant with the proband in 71.7%. In the remaining 10 families with two or more secondary cases, the diagnosis was concordant in 64.5% of cases. The largest subgroup was Parkinson's disease (PD)--40 probands and 53 secondary cases. of these secondary cases, 73.6% had PD. The concordance rate was 91% in essential tremor, but only 12.5% if the proband had essential tremor + parkinsonism. Considering that a large proportion of secondary cases have a diagnosis discordant with the proband, we recommend that, whenever possible, MD diagnosis in secondary cases be based on clinical assessment.
Movement Disorders 10/1997; 12(5):747-51. · 4.51 Impact Factor
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Movement Disorders 06/1997; 12(3):453-6. · 4.51 Impact Factor
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ABSTRACT: To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers. These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([3H])GBR 12,935 and [3H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [3H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [3H]WIN 35,428 > [3H]DTBZ > [3H]GBR 12, 935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.
Neurology 10/1996; 47(3):718-26. · 8.31 Impact Factor
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ABSTRACT: Amantadine has been used for more than 20 years in the symptomatic treatment of Parkinson's disease (PD). Several recent discoveries suggest that amantadine could also have a neuroprotective effect in PD. We studied survival in all parkinsonism (including PD and other parkinsonian syndromes) patients attending a single clinic, employing standard survival curves and a Cox regression model, to identify independent predictive variables for survival (while taking into account factors potentially associated with both outcome and treatment selection). Amantadine-treated patients (n = 250) were similar to the patients not treated with amantadine (n = 586) in terms of age, gender, type of parkinsonism, Hoehn and Yahr stage and dementia status at initial neurological visit. Amantadine use was an independent predictor of improved survival (p < 0.01). Improved survival was also associated with a higher 10-year expected survival (based on age, gender, and birth year), absence of dementia, type of parkinsonism = PD, and low Hoehn and Yahr stage (I or II) at initial neurologic visit (all p < 0.01); these additional factors occurred in statistically similar proportions in the groups that were and were not treated with amantadine. The association of improved survival with amantadine use may stem from symptomatic benefit or may reflect a "neuroprotective" effect, mediated through N-methyl-D-aspartate (NMDA) receptor antagonism, dopamine uptake blockade activity, or other mechanisms. Our preliminary findings suggest that a prospective, controlled, randomized trial of amantadine's effects on PD progression is warranted.
Neurology 06/1996; 46(6):1551-6. · 8.31 Impact Factor
