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1.  Increased reflection impulsivity in patients with ephedrone induced Parkinsonism 
Addiction (Abingdon, England)  2013;108(4):771-779.
To examine a syndrome of chronic manganism that occurs in drug addicts in Eastern Europe who use intravenous methcathinone (ephedrone) contaminated with potassium permanganate. The basal ganglia, especially the globus pallidus and the putamen, are damaged irreversibly in many cases. Routine neuropsychological assessment has revealed no cognitive deficits despite widespread abnormalities on brain imaging studies and severe extrapyramidal motor handicap on clinical examination.
Case control study.
Ephedrone patients and patients with opioid dependence were recruited from Lviv, Ukraine.
We tested 15 patients with ephedrone induced toxicity, 13 opiate dependent patients, who were receiving opioid replacement therapy and 18 matched healthy volunteers.
The ‘beads task’, an information gathering task to assess reflection impulsivity was used and feedback learning, working memory and risk taking were also assessed.
Opiate dependent patients differed from controls on three out of four tasks, whereas ephedrone patients differed from controls on only one task. More specifically both patient groups were more impulsive and made more irrational choices on the beads task than controls (p<0.001). However, ephedrone patients had no deficits in working memory (p>0.1) or risk taking (p>0.1) compared with controls. Opioid dependent patients had significantly worse working memory (p<0.001) and were significantly more risk prone than controls (p=0.002).
Ephedrone patients may have similar deficits in information gathering and decision making to opiate dependent patients, with preservation of working memory and risk taking. This may reflect specific damage to anterior cingulate- basal ganglia loops.
PMCID: PMC3938292  PMID: 23228208
2.  Uncertainty about mapping future actions into rewards may underlie performance on multiple measures of impulsivity in behavioral addiction: Evidence from Parkinson’s disease 
Behavioral neuroscience  2013;127(2):245-255.
A subset of patients with Parkinson disease (PD) develops behavioral addictions, which may be due to their dopamine replacement therapy. Recently, several groups have been comparing PD patients with and without behavioral addictions on tasks that are thought to measure aspects of impulsivity. Several of these experiments, including information sampling, a bias towards novel stimuli and temporal discounting, have shown differences between PD patients with and without behavioral addictions. We have developed a unifying theoretical framework which allows us to model behavior in all three of these tasks. By exploring the performance of the patient groups on the three tasks with a single framework we can ask questions about common mechanisms that underlie all three. Our results suggest that the effects seen in all three tasks can be accounted for by uncertainty about the ability to map future actions into rewards. More specifically, the modeling is consistent with the hypothesis that the group with behavioral addictions behaves as if they cannot use information provided within the experimental context to improve future reward guided actions. Future studies will be necessary to more firmly establish (or refute) this hypothesis. We discuss this result in light of what is known about the pathology that underlies the behavioral addictions in the Parkinson patients.
PMCID: PMC3935250  PMID: 23565936
3.  Decision-making, impulsivity and addictions: Do Parkinson’s disease patients jump to conclusions? 
Links between impulsive compulsive behaviors in treated Parkinson’s disease, behavioral addictions and substance abuse have been postulated, but no direct comparisons have been carried out so far.
We directly compared patients with Parkinson’s disease with and without impulsive compulsive behaviors with illicit drug abusers, pathological gamblers and age-matched healthy controls using the beads task, a test of reflection impulsivity and a working memory task.
We found that all patients with Parkinson’s disease made more impulsive and irrational choices than the control group. Parkinson’s disease patients who had an impulsive compulsive behavior showed similar behavior to illicit substance abusers whereas patients without impulsive compulsive behaviors more closely resembled pathological gamblers. In contrast we found no difference in working memory performance within the Parkinson’s disease groups. However Parkinson’s disease patients without impulsive compulsive behaviors remembered distractors significantly less than all other patients during working memory tests.
We were able to correctly classify 96% of the Parkinson’s disease patients with respect to whether or not they had an impulsive compulsive behavior by analyzing 3 trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3% and we propose that this task may prove to be a powerful screening tool to detect an impulsive compulsive behavior in Parkinson’s disease. Our results also suggest that intact cortical processing and less distractibility in Parkinson’s disease patients without impulsive compulsive behaviors may protect them from developing behavioral addictions.
PMCID: PMC3412901  PMID: 22821557
Impulsive compulsive behavior; Parkinson’s disease; reflection impulsivity; pathological gambling; substance abuse; beads task
4.  Somatic mitochondrial DNA mutations in early Parkinson's and incidental Lewy body disease 
Annals of Neurology  2012;71(6):850-854.
Somatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late-stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra (SN) neurons are significantly elevated in this group of early PD and ILBD cases.
PMCID: PMC3383820  PMID: 22718549
5.  Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease 
Brain  2012;135(4):1141-1153.
Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as ‘slowness of initiation with progressive reduction in speed and amplitude of repetitive action’. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n = 15), progressive supranuclear palsy (n = 9) and healthy age- and gender-matched controls (n = 16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P < 0.001 in both cases). Change in tap amplitude over consecutive taps was computed by linear regression. The average amplitude slope in progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (−0.20°/cycle, P = 0.002). ‘Hypokinesia’, defined as <50% of control group's mean amplitude, combined with ‘absence of decrement’, defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P = 0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of ‘hypokinesia without decrement’ and they do not have criteria-defined limb bradykinesia. Similarly, ‘micrographia’ and ‘lack of decrement in script size’ are also more common in progressive supranuclear palsy than in Parkinson's disease.
PMCID: PMC3326257  PMID: 22396397
hypokinesia; bradykinesia; repetitive finger tap; micrographia; progressive supranuclear palsy
6.  α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? 
Acta Neuropathologica  2013;125(5):753-769.
We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1096-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3681325  PMID: 23404372
Parkinson’s disease; Multiple system atrophy; α-Synuclein; SNCA
7.  Shell shock at Queen Square: Lewis Yealland 100 years on 
Brain  2013;136(6):1976-1988.
This article reviews the treatment of functional neurological symptoms during World War I by Lewis Yealland at the National Hospital for the Paralysed and Epileptic in London. Yealland was among the first doctors in Britain to incorporate electricity in the systematic treatment of shell shock. Our analysis is based on the original case records of his treatment of 196 soldiers with functional motor and sensory symptoms, functional seizures and somatoform disorders. Yealland’s treatment approach integrated peripheral and central electrical stimulation with a variety of other—psychological and physical—interventions. A combination of electrical stimulation of affected muscles with suggestion of imminent improvement was the hallmark of his approach. Although his reported success rates were high, Yealland conducted no formal follow-up. Many of the principles of his treatment, including the emphasis on suggestion, demonstration of preserved function and the communication of a physiological illness model, are encountered in current therapeutic approaches to functional motor and sensory symptoms. Yealland has been attacked for his use of electrical stimulation and harsh disciplinary procedures in popular and scientific literature during and after World War I. This criticism reflects changing views on patient autonomy and the social role of doctors and directly impacts on current debates on ethical justification of suggestive therapies. We argue that knowledge of the historical approaches to diagnosis and management of functional neurological syndromes can inform both aetiological models and treatment concepts for these challenging conditions.
PMCID: PMC3673538  PMID: 23384604
war; electrotherapy; history; psychogenic; movement disorders
8.  Olfactory Impairment in Familial Ataxias 
The main clinical manifestations of the spinocerebellar ataxias (SCAs) result from the involvement of the cerebellum and its connections. Cerebellar activity has been consistently observed in functional imaging studies of olfaction, but the anatomical pathways responsible for this connection have not yet been elucidated. Previous studies have demonstrated olfactory deficit in SCA2, Friedreich’s ataxia (FA) and in small groups of ataxia of diverse etiology. We used a validated version of the 16 item smell identification test from Sniffin’ Sticks (SS-16) was used to evaluate 37 patients with genetically determined autosomal dominant ataxia, and 31 with familial ataxia of unknown genetic basis .This data was also compared to results in 106 Parkinson’s disease (PD) patients and 218 healthy controls. The SS-16 score was significantly lower in ataxia than in the control group (p<0.001, 95%CI for β = 0.55 to 1.90) and significantly higher in ataxia than in PD (p<0.001, 95%CI for β = −4.58 to −3.00) when adjusted for age (p=0.001, 95%CI for β = −0.05 to −0.01), gender (p=0.19) and history of tobacco use (p=0.41). When adjusted for general cognitive function we found no significant difference between the ataxia and control group. Our study confirms previous findings of mild hyposmia in ataxia, and further suggests this may be due to general cognitive deficits rather than specific olfactory problems.
PMCID: PMC3521149  PMID: 22791905
Movement disorders; Smell; Cerebellar ataxia; Cerebellar degeneration; Cognition
9.  Vascular endothelial growth factor is upregulated by l-dopa in the parkinsonian brain: implications for the development of dyskinesia 
Brain  2011;134(8):2339-2357.
Angiogenesis and increased permeability of the blood–brain barrier have been reported to occur in animal models of Parkinson’s disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood–brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson’s disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson’s disease.
PMCID: PMC3155708  PMID: 21771855
Parkinson’s disease; levodopa; D1 receptors; neuroplasticity; angiogenesis; blood–brain barrier
10.  Novelty seeking behaviour in Parkinson’s disease 
Neuropsychologia  2011;49(9):2483-2488.
Novelty seeking can be a positive trait leading to creativity and innovation, but it is also related to increased risk of damaging addictive behaviour. We have assessed novelty seeking with a three armed bandit task, in which novel stimuli were occasionally introduced, replacing choice options from which the participants had been choosing. This allowed us to assess whether or not they would be prone to selecting novel stimuli. We tested 25 non impulsive patients with Parkinson s disease (PD) and 27 PD patients with impulsive compulsive behaviours (ICB). Both patient groups were examined “on” and “off” dopaminergic medication in a counterbalanced order and their behaviour was compared with 24 healthy controls. We found that PD patients with ICBs were significantly more prone to choose novel options than either non impulsive PD patients or controls, regardless of medication status. Our findings suggest that attraction to novelty is a personality trait in all PD patients with ICBs which is independent of medication status.
PMCID: PMC3137690  PMID: 21565210
11.  Altruistic punishment in patients with Parkinson's disease with and without impulsive behaviour 
Neuropsychologia  2010;49(1):103-107.
Punishing violators of social norms when there is personal cost is known as altruistic punishment. We tested patients with Parkinson's disease (PD) with and without impulsive-compulsive behaviours (ICBs) and matched control subjects, on and off their regular dopamine replacement therapy on a task, in which the patients decided whether or not to invest a sum of money with a trustee. The sum was then quadrupled and the trustee could decide whether or not to return a portion of the investment. Participants could punish the trustee after they were informed of the trustee's decision. We found that PD patients without ICBs on or off medication punished more often than controls, whereas PD patients with ICBs punished more than controls on medication, but similar to controls off medication. These results suggest a role for dopamine in altruistic punishment decisions in PD patients with impulsive compulsive behaviour.
PMCID: PMC3005080  PMID: 20965203
12.  Intact Reward Learning but Elevated Delay Discounting in Parkinson's Disease Patients With Impulsive-Compulsive Spectrum Behaviors 
Neuropsychopharmacology  2010;35(11):2155-2164.
It has been postulated that impulsive-compulsive spectrum behaviors (ICBs) in Parkinson's disease (PD) reflect overvaluation of rewards, resulting from excessive dopaminergic transmission in the ventral striatum. However, as the ventral striatum is also strongly implicated in delay discounting, an alternative explanation would be that, similar to stimulant-dependent individuals, PD patients with ICBs impulsively discount future rewards. To test these hypotheses, we investigated whether 36 medicated PD patients with and without ICBs differed from controls on measures of stimulus-reinforcement learning and delay discounting. There was a clear double dissociation between reward learning and impulsivity in PD patients with and without ICBs. Although PD patients without ICBs were impaired at learning stimulus–reward associations for high-probability stimuli, PD patients with ICBs were able to learn such associations equally as well as controls. By contrast, PD patients with ICBs showed highly elevated delay discounting, whereas PD patients without ICBs did not differ from controls on this measure. These results contradict the hypothesis that ICBs in PD result from overvaluation of rewards. Instead, our data are more consistent with a model in which excessive dopaminergic transmission induces a strong preference for immediate over future rewards, driving maladaptive behavior in PD patients with ICBs.
PMCID: PMC3055316  PMID: 20631686
reward learning; dopamine agonist; delay discounting; impulsivity; Parkinson's disease (PD); impulsive-compulsive spectrum behaviors (ICBs); dopamine; psychopharmacology; movement disorders; cognition; Parkinson's Disease; implusitivity
13.  The midbrain to pons ratio 
Neurology  2013;80(20):1856-1861.
MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP.
Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21).
The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm.
We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.
PMCID: PMC3908351  PMID: 23616165
14.  Adult onset asymmetric upper limb tremor misdiagnosed as Parkinson’s disease: A clinical and electrophysiological study 
Approximately 10% of subjects thought clinically to have early Parkinson’s disease (PD) have normal dopaminergic functional imaging (SWEDDs – Scans Without Evidence of Dopaminergic Deficit). SWEDDs are a heterogeneous group. Here we aimed to delineate clinical and electrophysiological characteristics of a distinct subgroup of SWEDDs patients from PD and to clarify the underlying pathophysiology of this subgroup as a form of parkinsonism or dystonia. Therefore we compared clinical details of 25 patients referred with a diagnosis of tremor-dominant PD but with normal DaT SPECT scans (SWEDDs) with 12 tremor-dominant PD patients with abnormal DaT SPECT scans. We performed tremor analysis using accelerometry in the following patients with 1) SWEDDs, 2) PD, 3) primary segmental dystonia with dystonic limb tremor and 4) essential tremor (ET). We used transcranial magnetic stimulation with a facilitatory paired associative stimulation (PAS) paradigm to test if sensorimotor plasticity in SWEDDs resembled the pattern seen in PD, dystonia or ET. Although PD and SWEDDs patients shared several clinical features, the lack of true bradykinesia, occurrence of dystonia, and position- and task-specificity of tremor favoured a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs as well as presence of nonmotor symptoms made PD more likely. Basic tremor parameters overlapped between SWEDDs, PD, segmental dystonia and ET. However, a combination of re-emergent tremor and highest tremor amplitude in the resting condition was characteristic of PD tremor, while SWEDDs, dystonia and ET subjects had the highest tremor amplitude during action. Both SWEDDs and segmental dystonia patients exhibited an exaggerated pattern of sensorimotor plasticity in response to the PAS paradigm, with spread of excitation to an adjacent hand muscle. In contrast, PD patients showed no response to PAS, and the response of ET patients was no different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adult-onset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs.
PMCID: PMC2996567  PMID: 20131394
SWEDDs; benign tremulous Parkinson’s disease; dystonic tremor; accelerometry; paired associative stimulation
16.  Meta-Analysis of Early Nonmotor Features and Risk Factors for Parkinson Disease 
Annals of Neurology  2012;72(6):893-901.
To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population-based screening.
A systematic review and meta-analysis of risk factors for PD.
The strongest associations with later diagnosis of PD were found for having a first-degree or any relative with PD (odds ratio [OR], 3.23; 95% confidence interval [CI], 2.65–3.93 and OR, 4.45; 95% CI, 3.39–5.83) or any relative with tremor (OR, 2.74; 95% CI, 2.10–3.57), constipation (relative risk [RR], 2.34; 95% CI, 1.55–3.53), or lack of smoking history (current vs never: RR, 0.44; 95% CI, 0.39–0.50), each at least doubling the risk of PD. Further positive significant associations were found for history of anxiety or depression, pesticide exposure, head injury, rural living, beta-blockers, farming occupation, and well-water drinking, and negative significant associations were found for coffee drinking, hypertension, nonsteroidal anti-inflammatory drugs, calcium channel blockers, and alcohol, but not for diabetes mellitus, cancer, oral contraceptive pill use, surgical menopause, hormone replacement therapy, statins, acetaminophen/paracetamol, aspirin, tea drinking, history of general anesthesia, or gastric ulcers. In the systematic review, additional associations included negative associations with raised serum urate, and single studies or studies with conflicting results.
The strongest risk factors associated with later PD diagnosis are having a family history of PD or tremor, a history of constipation, and lack of smoking history. Further factors also but less strongly contribute to risk of PD diagnosis or, as some premotor symptoms, require further standardized studies to demonstrate the magnitude of risk associated with them. ANN NEUROL 2012
PMCID: PMC3556649  PMID: 23071076
17.  Is Transcranial Sonography Useful to Distinguish Scans Without Evidence of Dopaminergic Deficit Patients From Parkinson's Disease? 
Movement Disorders  2012;27(9):1182-1185.
Approximately 10% of patients clinically diagnosed with early Parkinson's disease (PD) subsequently have normal dopaminergic functional imaging. Transcranial sonography (TCS) has been shown to detect midbrain hyperechogenicity in approximately 90% of Parkinson's disease (PD) patients and 10% of the healthy population. The aim of this study was to investigate the prevalence of midbrain hyperechogenicity in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDD), in comparison to PD patients.
TCS was performed in 14 patients with SWEDD and 19 PD patients.
There was a significantly increased area of echogenicity in the PD group (0.24 ± 0.06 cm2), compared to the group of patients with SWEDD (0.13 ± 0.06 cm2; P < 0.001). One (9.1%) of these patients, compared to 14 (82.5%) of the PD patients, was found to have hyperechogenicity (P < 0.001).
We conclude that TCS is useful to distinguish PD patients from patients with suspected parkinsonism and SWEDD. © 2012 Movement Disorder Society
PMCID: PMC3660780  PMID: 22744819
transcranial sonography; SWEDD; Parkinson's disease; hyperechogenicity
18.  THAP1 Mutations and Dystonia Phenotypes: Genotype Phenotype Correlations 
Movement Disorders  2012;27(10):1290-1294.
THAP1 mutations have been shown to be the cause of DYT6. A number of different mutation types and locations in the THAP1 gene have been associated with a range of severity and dystonia phenotypes, but, as yet, it has been difficult to identify clear genotype phenotype patterns. Here, we screened the THAP1 gene in a further series of dystonia cases and evaluated the mutation pathogenicity in this series as well as previously reported mutations to investigate possible phenotype-genotype correlations. THAP1 mutations have been identified throughout the coding region of the gene, with the greatest concentration of variants localized to the THAP1 domain. In the additional cases analyzed here, a further two mutations were found. No obvious, indisputable genotype-phenotype correlation emerged from these data. However, we managed to find a correlation between the pathogenicity of mutations, distribution, and age of onset of dystonia. THAP1 mutations are an important cause of dystonia, but, as yet, no clear genotype-phenotype correlations have been identified. Greater mutation numbers in different populations will be important and mutation-specific functional studies will be essential to identify the pathogenicity of the various THAP1 mutations. © 2012 Movement Disorder Society
PMCID: PMC3664430  PMID: 22903657
THAP1; dystonia; DYT6; mutations; phenotype; genotype
19.  Primary Progressive Aphasia With Parkinsonism 
Movement Disorders  2013;28(6):741-746.
A 65-year-old man presented with word-finding difficulty and gait disturbance. His speech was nonfluent with word retrieval impairment and difficulties with sentence repetition. Other cognitive domains were intact initially. He developed asymmetrical bradykinesia, rigidity and a rest tremor. Over the following 8 years, his speech production impairment slowly deteriorated with the development of a motor speech disorder, anomia, impaired repetition of single words as well as sentences, and impaired comprehension of initially sentences then single words. His parkinsonian syndrome also deteriorated with limited response to levodopa. Serial brain MRI revealed progressive asymmetric perisylvian atrophy. He died after a disease duration of 12 years. The clinical syndrome is discussed by an expert, the pathology is described, and important clinical points from the case are highlighted. © 2013 Movement Disorder Society
PMCID: PMC3748791  PMID: 23401267
aphasia; parkinsonism; Lewy body; Alzheimer's disease; Parkinson's disease
20.  Pisa syndrome in Parkinson's disease: a mobile or fixed deformity? 
Although Pisa syndrome and scoliosis are sometimes used interchangeably to describe a laterally flexed postural deviation in Parkinson's disease (PD), the imaging findings of Pisa syndrome in PD have not been previously studied in detail.
Patients with PD and Pisa syndrome (lateral flexion >10° in the standing position) were examined clinically and underwent radiological assessment using standing radiograph and supine CT scan of the whole spine.
Fifteen patients were included in this observational study. All patients had scoliosis on standing radiographs, and 12 had scoliosis persisting in the supine position. Scoliotic curves improved by a mean of 44% when patients moved from standing to supine. Only a quarter of patients with structural scoliosis had evidence of bony fusion on the side of their lateral deviation rendering their deformity fixed.
Pisa syndrome describes a patient who lists to the side whereas scoliosis is defined by spinal curvature and rotation and may not be associated with lateral flexion. The finding of ‘structural scoliosis’ in Pisa syndrome should not preclude intervening to improve posture as most patients had little or no evidence of structural bony changes even when the deformity had been present for a number of years.
PMCID: PMC3841793  PMID: 23532719
21.  PREDICT-PD: Identifying risk of Parkinson's disease in the community: methods and baseline results 
To present methods and baseline results for an online screening tool to identify increased risk for Parkinson's disease (PD) in the UK population.
Risk estimates for future PD were derived from the results of a systematic review of risk factors and early features of PD. Participants aged 60–80 years without PD were recruited by self-referral. They completed an online survey (including family history, non-motor symptoms and lifestyle factors), a keyboard-tapping task and the University of Pennsylvania Smell Identification Test. Risk scores were calculated based on survey answers. Preliminary support for the validity of this algorithm was assessed by comparing those estimated to be higher risk for PD with those at lower risk using proxies, including smell loss, REM-sleep behaviour disorder and reduced tapping speed, and by assessing associations in the whole group.
1324 eligible participants completed the survey and 1146 undertook the keyboard-tapping task. Smell tests were sent to 1065 participants. Comparing the 100 highest-risk participants and 100 lowest-risk participants, median University of Pennsylvania Smell Identification Test scores were 30/40 versus 33/40 (p<0.001), mean number of key taps in 30 s were 55 versus 58 (p=0.045), and 24% versus 10% scored above cut-off for REM-sleep behaviour disorder (p=0.008). Regression analyses showed increasing risk scores were associated with worse scores in the three proxies across the whole group (p≤0.001).
PREDICT-PD is the first study to systematically combine risk factors for PD in the general population. Validity to predict risk of PD will be tested through longitudinal follow-up of incident PD diagnosis.
PMCID: PMC3888633  PMID: 23828833
Parkinson×s Disease; Smell; Sleep Disorders; Scales; Epidemiology
22.  A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies 
Brain  2011;134(9):2548-2564.
Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often ‘Pick body-like’ in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.
PMCID: PMC3170529  PMID: 21752791
frontotemporal lobar degeneration; FUS; clinical presentation; neuropathology; biochemistry
23.  Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy 
Nature genetics  2011;43(7):699-705.
Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component.
PMCID: PMC3125476  PMID: 21685912
24.  Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21 
Human Molecular Genetics  2010;20(2):345-353.
We performed a genome-wide association study (GWAS) in 1705 Parkinson's disease (PD) UK patients and 5175 UK controls, the largest sample size so far for a PD GWAS. Replication was attempted in an additional cohort of 1039 French PD cases and 1984 controls for the 27 regions showing the strongest evidence of association (P< 10−4). We replicated published associations in the 4q22/SNCA and 17q21/MAPT chromosome regions (P< 10−10) and found evidence for an additional independent association in 4q22/SNCA. A detailed analysis of the haplotype structure at 17q21 showed that there are three separate risk groups within this region. We found weak but consistent evidence of association for common variants located in three previously published associated regions (4p15/BST1, 4p16/GAK and 1q32/PARK16). We found no support for the previously reported SNP association in 12q12/LRRK2. We also found an association of the two SNPs in 4q22/SNCA with the age of onset of the disease.
PMCID: PMC3005904  PMID: 21044948
25.  Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study 
Lancet Neurology  2008;7(7):583-590.
Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2?
Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD.
Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD.
Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients.
UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.
PMCID: PMC2832754  PMID: 18539534

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