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1.  Genetic impact on cognition and brain function in newly diagnosed Parkinson’s disease: ICICLE-PD study 
Brain  2014;137(10):2743-2758.
See Dujardin (doi:10.1093/brain/awu218) for a scientific commentary on this article. Nombela et al. present data from the ICICLE-PD study of cognition in newly diagnosed Parkinson’s disease. Consistent with the ‘Dual Syndrome’ hypothesis, impairments in executive function reflect a frontal dopaminergic syndrome modulated by COMT genotype, while visuospatial and memory deficits reflect disruption of temporo-parietal systems modulated by MAPT and APOE.
Parkinson’s disease is associated with multiple cognitive impairments and increased risk of dementia, but the extent of these deficits varies widely among patients. The ICICLE-PD study was established to define the characteristics and prevalence of cognitive change soon after diagnosis, in a representative cohort of patients, using a multimodal approach. Specifically, we tested the ‘Dual Syndrome’ hypothesis for cognitive impairment in Parkinson’s disease, which distinguishes an executive syndrome (affecting the frontostriatal regions due to dopaminergic deficits) from a posterior cortical syndrome (affecting visuospatial, mnemonic and semantic functions related to Lewy body pathology and secondary cholinergic loss). An incident Parkinson’s disease cohort (n = 168, median 8 months from diagnosis to participation) and matched control group (n = 85) were recruited to a neuroimaging study at two sites in the UK. All participants underwent clinical, neuropsychological and functional magnetic resonance imaging assessments. The three neuroimaging tasks (Tower of London, Spatial Rotations and Memory Encoding Tasks) were designed to probe executive, visuospatial and memory encoding domains, respectively. Patients were also genotyped for three polymorphisms associated with cognitive change in Parkinson’s disease and related disorders: (i) rs4680 for COMT Val158Met polymorphism; (ii) rs9468 for MAPT H1 versus H2 haplotype; and (iii) rs429358 for APOE-ε2, 3, 4. We identified performance deficits in all three cognitive domains, which were associated with regionally specific changes in cortical activation. Task-specific regional activations in Parkinson’s disease were linked with genetic variation: the rs4680 polymorphism modulated the effect of levodopa therapy on planning-related activations in the frontoparietal network; the MAPT haplotype modulated parietal activations associated with spatial rotations; and APOE allelic variation influenced the magnitude of activation associated with memory encoding. This study demonstrates that neurocognitive deficits are common even in recently diagnosed patients with Parkinson’s disease, and that the associated regional brain activations are influenced by genotype. These data further support the dual syndrome hypothesis of cognitive change in Parkinson’s disease. Longitudinal data will confirm the extent to which these early neurocognitive changes, and their genetic factors, influence the long-term risk of dementia in Parkinson’s disease. The combination of genetics and functional neuroimaging provides a potentially useful method for stratification and identification of candidate markers, in future clinical trials against cognitive decline in Parkinson’s disease.
doi:10.1093/brain/awu201
PMCID: PMC4163033  PMID: 25080285
Parkinson’s disease; cognition; functional MRI; genetics
2.  The spectrum of nonmotor symptoms in early Parkinson disease 
Neurology  2013;80(3):276-281.
Objective:
Nonmotor symptoms (NMS) are common in patients with established Parkinson disease (PD) but their frequency in early PD has not been extensively studied. Our aim was to determine the frequency of NMS in a cohort of patients with newly diagnosed PD.
Methods:
A total of 159 patients with early PD and 99 healthy controls participated in this study. NMS were screened for using the Nonmotor Symptom Questionnaire. Other assessments included measures of motor disability (Movement Disorders Society–revised Unified Parkinson's Disease Rating Scale [MDS-UPDRS]), disease severity (Hoehn & Yahr staging), depression (Geriatric Depression Scale), and global cognitive function (Mini-Mental State Examination and Montreal Cognitive Assessment).
Results:
The PD group reported a significantly greater number of NMS compared with controls (8.4 [4.3] vs 2.8 [2.6]). In the PD group, the most commonly experienced NMS were excessive saliva, forgetfulness, urinary urgency, hyposmia, and constipation. Patients with higher MDS-UPDRS III scores and those with the postural instability gait subtype experienced a greater number of NMS.
Conclusion:
NMS are common in early PD and reflect the multisystem nature of the disorder. Even in the earliest stages of PD, NMS may be detrimental to patients' functional status and sense of well-being.
doi:10.1212/WNL.0b013e31827deb74
PMCID: PMC3589180  PMID: 23319473
3.  Characterizing mild cognitive impairment in incident Parkinson disease 
Neurology  2014;82(4):308-316.
Objective:
To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers.
Methods:
Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria.
Results:
The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1–42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1–42 and 1–40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold.
Conclusions:
In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1–42 and 1–40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.
doi:10.1212/WNL.0000000000000066
PMCID: PMC3929202  PMID: 24363137
4.  Severity of mild cognitive impairment in early Parkinson's disease contributes to poorer quality of life 
Parkinsonism & Related Disorders  2014;20(10):1071-1075.
Background
Poor quality of life (QoL) is a feature of people with Parkinson's disease (PD) who develop dementia. The relationship between mild cognitive impairment in PD (PD-MCI) and QoL is less clear. To address this, we studied the impact of varying severities of cognitive impairment on QoL in a cohort of non-demented patients with early PD.
Method
Patients with newly diagnosed PD (n = 219) and age and sex matched healthy controls (n = 99) completed a schedule of neuropsychological tests, in addition to scales assessing QoL (PDQ-39), depression, sleep, neuropsychiatric symptoms and a clinical examination. The Movement Disorder Society criteria were used to define and classify PD-MCI.
Results
Participants with PD-MCI were significantly older than those with normal cognition, had more severe motor symptoms, scored higher for depression and had poorer quality of life. Logistic regression showed that mild cognitive impairment, independent of other factors, was an indicator of poorer QoL. Using cognitive performance 2.0 standard deviations (SD) below normative data as a cut-off to define PD-MCI, there was a significant difference in QoL scores between patients with PD-MCI and those classified as having normal cognition. Subjects with less severe mild cognitive impairment did not exhibit significant differences in QoL.
Conclusions
PD-MCI is a significant, independent factor contributing to poorer QoL in patients with newly diagnosed PD. Those classified with greatest impairment (2.0 SD below normal values) have lower QoL. This has implications for clinical practice and future interventions targeting cognitive impairments.
Highlights
•Quality of life declines with increased severity of cognitive impairment in PD.•Mild cognitive impairment in PD (PD-MCI) independently contributes to poorer QoL.•PD-MCI at 2 standard deviations below controls had the greatest impact on QoL.•The optimal operational cut-off for PD-MCI may be 2 standard deviations.
doi:10.1016/j.parkreldis.2014.07.004
PMCID: PMC4194347  PMID: 25074728
Parkinson's disease; Mild cognitive impairment; Quality of life
5.  Genetic variation of CHRNA4 does not modulate attention in Parkinson’s disease 
Neuroscience letters  2010;479(2):123-125.
Parkinson’s disease (PD) is a neurodegenerative disorder, characterised by cognitive decline and attentional impairment. Recently, variation in CHRNA4 (rs1044396) has been shown to affect visual and auditory function, affecting speed and attention, in healthy adults. An association between CHRNA4 variation and PD has not been shown. To determine the link between CHRNA4 variation and attentional deficit in PD. A genotype-phenotype correlation between the common CHRNA4:rs1044396 variant and several baseline parameters of attention was carried out in a large cohort of PD cases (n = 222) and controls (n = 159). We identified significant associations to measures of attention in PD patients compared to controls. However, we found no significant link to CHRNA4:rs1044396 genotypes to baseline attention variables in PD or in controls. We conclude that CHRNA4:rs1044396 genotypes do not significantly influence the attentional deficit found in PD patients. Contrary to previous studies, we also found no significant influence in healthy age-matched controls.
doi:10.1016/j.neulet.2010.05.041
PMCID: PMC4038490  PMID: 20493238
Parkinson’s disease; Ageing; Cholinergic receptor; Attention
6.  Fall in circulating mononuclear cell mitochondrial DNA content in human sepsis 
Intensive care medicine  2010;36(6):956-962.
Purpose
Loss of mitochondrial DNA (mtDNA) has been described in whole blood samples from a small number of patients with sepsis, but the underlying mechanism and clinical implications of this observation are not clear. We have investigated the cellular basis of the mtDNA depletion in sepsis, and determined clinical correlates with mtDNA depletion.
Methods
Whole blood samples were obtained from 147 consecutive patients with severe sepsis admitted to a General Critical Care Unit in a University Hospital and 83 healthy controls. In a separate study of 13 patients with severe sepsis, blood was obtained for immediate cell sorting by flow cytometry. MtDNA content was determined in whole blood DNA by PCR methods, and subsequently in the 13 samples where white cell subtypes were separated.
Results
The mtDNA content of peripheral blood in human subjects was lower in patients with sepsis than controls (P < 0.0001). By studying leukocyte subsets in a subgroup of 13 patients, we showed that this was largely due to an increase in the proportion of circulating neutrophils, which contained ~3-fold less mtDNA than mononuclear leukocytes. However, isolated monocytes (P = 0.041) and lymphocytes (P = 0.021) from septic patients showed clear evidence of mtDNA depletion, which correlated with the APACHE II score (P = 0.015).
Conclusions
In severe sepsis much of the apparent whole blood mtDNA depletion is due to a change in the differential leukocyte count. However mtDNA depletion in mononuclear cells occurs in patients with sepsis and correlates with disease severity.
doi:10.1007/s00134-010-1823-7
PMCID: PMC4034433  PMID: 20224905
Sepsis; Mitochondria; Copy number; Neutrophil; Monocyte; Lymphocyte
7.  No evidence of substantia nigra telomere shortening in Parkinson’s disease 
Neurobiology of aging  2011;32(11):2107.e3-2107.e5.
Telomeres are repetitive tracts of DNA which protect chromosomal integrity. Increased oxidative stress leads to shorter telomeres, which have been associated with several late-onset human diseases. Given independent evidence of oxidative stress and Parkinson’s disease (PD), and conflicting reports of the role of telomere length in PD, we measured telomere length in both PD peripheral blood monocytes and in substantia nigra from affected individuals and controls. We confirmed previous findings of a paradoxically longer telomere length in blood from PD patients, but found no difference in telomere length in substantia nigra. Confounding factors provide a likely explanation for the findings in blood, and possibly the reduced frequency of cigarette smoking in PD patients. We conclude that telomere shortening is unlikely to be involved in the pathogenesis of PD.
doi:10.1016/j.neurobiolaging.2011.05.022
PMCID: PMC4034165  PMID: 21794951
8.  Single-Cell Expression Profiling of Dopaminergic Neurons Combined with Association Analysis Identifies Pyridoxal Kinase as Parkinson’s Disease Gene 
Annals of neurology  2009;66(6):792-798.
Objective
The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined.
Methods
We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts.
Results
We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44).
Interpretation
We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.
doi:10.1002/ana.21780
PMCID: PMC4034432  PMID: 20035503
9.  Subthalamic deep brain stimulation in Parkinson׳s disease has no significant effect on perceptual timing in the hundreds of milliseconds range 
Neuropsychologia  2014;57(100):29-37.
Bilateral, high-frequency stimulation of the basal ganglia (STN-DBS) is in widespread use for the treatment of the motor symptoms of Parkinson׳s disease (PD). We present here the first psychophysical investigation of the effect of STN-DBS upon perceptual timing in the hundreds of milliseconds range, with both duration-based (absolute) and beat-based (relative) tasks; 13 patients with PD were assessed with their STN-DBS ‘on’, ‘off’, and then ‘on’ again.
Paired parametric analyses revealed no statistically significant differences for any task according to DBS status. We demonstrate, from the examination of confidence intervals, that any functionally relevant effect of STN-DBS on relative perceptual timing is statistically unlikely. For absolute, duration-based timing, we demonstrate that the activation of STN-DBS may either worsen performance or have no effect, but that it is unlikely to lead to significant improvement.
Although these results are negative they have important implications for our understanding of perceptual timing and its relationship to motor functions within the timing network of the brain. They imply that the mechanisms involved in the perceptual processing of temporal information are likely to be functionally independent from those that underpin movement. Further, they suggest that the connections between STN and the subtantia nigra and globus pallidus are unlikely to be critical to beat-based perceptual timing.
Graphical abstract
Paired difference in performance thresholds according to DBS status. The first and third measures within each triplet show performance for that run with DBS ‘on’ compared to that with DBS ‘off’; values greater than zero denote poorer performance with DBS ‘on’, while those less than zero denote poorer performance with DBS ‘off’. The middle measure shows the difference in performance between the two runs with DBS ‘on’. Error bars denote confidence intervals.
Highlights
•We assessed the effect of STN-DBS on both duration- and beat-based perceptual timing.•DBS activation did not profoundly affect beat-based perceptual timing.•An effect of DBS on duration-based timing was not demonstrated but cannot be excluded.•Connections between STN and cerebellum are unlikely to be critical to perceptual timing.
doi:10.1016/j.neuropsychologia.2014.02.021
PMCID: PMC4022837  PMID: 24613477
Perceptual timing; Parkinson׳s disease; Subthalamic nucleus; Deep brain stimulation
10.  A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease 
Holmans, Peter | Moskvina, Valentina | Jones, Lesley | Sharma, Manu | Vedernikov, Alexey | Buchel, Finja | Sadd, Mohamad | Bras, Jose M. | Bettella, Francesco | Nicolaou, Nayia | Simón-Sánchez, Javier | Mittag, Florian | Gibbs, J. Raphael | Schulte, Claudia | Durr, Alexandra | Guerreiro, Rita | Hernandez, Dena | Brice, Alexis | Stefánsson, Hreinn | Majamaa, Kari | Gasser, Thomas | Heutink, Peter | Wood, Nicholas W. | Martinez, Maria | Singleton, Andrew B. | Nalls, Michael A. | Hardy, John | Morris, Huw R. | Williams, Nigel M. | Arepalli, Sampath | Barker, Roger | Barrett, Jeffrey | Ben-Shlomo, Yoav | Berendse, Henk W. | Berg, Daniela | Bhatia, Kailash | de Bie, Rob M.A. | Biffi, Alessandro | Bloem, Bas | Brice, Alexis | Bochdanovits, Zoltan | Bonin, Michael | Bras, Jose M. | Brockmann, Kathrin | Brooks, Janet | Burn, David J. | Charlesworth, Gavin | Chen, Honglei | Chinnery, Patrick F. | Chong, Sean | Clarke, Carl E. | Cookson, Mark R. | Cooper, Jonathan M. | Corvol, Jen-Christophe | Counsell, Carl | Damier, Philippe | Dartigues, Jean Francois | Deloukas, Panagiotis | Deuschl, Günther | Dexter, David T. | van Dijk, Karin D. | Dillman, Allissa | Durif, Frank | Durr, Alexandra | Edkins, Sarah | Evans, Jonathan R. | Foltynie, Thomas | Gao, Jianjun | Gardner, Michelle | Gasser, Thomas | Gibbs, J. Raphael | Goate, Alison | Gray, Emma | Guerreiro, Rita | Gústafsson, Ómar | Hardy, John | Harris, Clare | Hernandez, Dena G. | Heutink, Peter | van Hilten, Jacobus J. | Hofman, Albert | Hollenbeck, Albert | Holmans, Peter | Holton, Janice | Hu, Michele | Huber, Heiko | Hudson, Gavin | Hunt, Sarah E. | Huttenlocher, Johanna | Illig, Thomas | Langford, Cordelia | Lees, Andrew | Lesage, Suzanne | Lichtner, Peter | Limousin, Patricia | Lopez, Grisel | Lorenz, Delia | Martinez, Maria | McNeill, Alisdair | Moorby, Catriona | Moore, Matthew | Morris, Huw | Morrison, Karen E. | Moskvina, Valentina | Mudanohwo, Ese | Nalls, Michael A. | Pearson, Justin | Perlmutter, Joel S. | Pétursson, Hjörvar | Plagnol, Vincent | Pollak, Pierre | Post, Bart | Potter, Simon | Ravina, Bernard | Revesz, Tamas | Riess, Olaf | Rivadeneira, Fernando | Rizzu, Patrizia | Ryten, Mina | Saad, Mohamad | Sawcer, Stephen | Schapira, Anthony | Scheffer, Hans | Sharma, Manu | Shaw, Karen | Sheerin, Una-Marie | Shoulson, Ira | Schulte, Claudia | Sidransky, Ellen | Simón-Sánchez, Javier | Singleton, Andrew B. | Smith, Colin | Stefánsson, Hreinn | Stefánsson, Kári | Steinberg, Stacy | Stockton, Joanna D. | Sveinbjornsdottir, Sigurlaug | Talbot, Kevin | Tanner, Carlie M. | Tashakkori-Ghanbaria, Avazeh | Tison, François | Trabzuni, Daniah | Traynor, Bryan J. | Uitterlinden, André G. | Velseboer, Daan | Vidailhet, Marie | Walker, Robert | van de Warrenburg, Bart | Wickremaratchi, Mirdhu | Williams, Nigel | Williams-Gray, Caroline H. | Winder-Rhodes, Sophie | Wood, Nicholas
Human Molecular Genetics  2012;22(5):1039-1049.
Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people >60 and 3–4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10−16) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the ‘regulation of leucocyte/lymphocyte activity’ and also ‘cytokine-mediated signalling’ as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
doi:10.1093/hmg/dds492
PMCID: PMC3561909  PMID: 23223016
11.  The basal ganglia in perceptual timing: Timing performance in Multiple System Atrophy and Huntington's disease☆ 
Neuropsychologia  2014;52(100):73-81.
The timing of perceptual events depends on an anatomically and functionally connected network comprising basal ganglia, cerebellum, pre-frontal cortex and supplementary motor area. Recent studies demonstrate the cerebellum to be involved in absolute, duration-based timing, but not in relative timing based on a regular beat. Conversely, functional involvement of the striatum is observed in relative timing, but its role in absolute timing is unclear.
This work tests the specific role of the basal ganglia in the perceptual timing of auditory events. It aims to distinguish the hypothesised unified model of time perception (Teki, Grube, & Griffiths, 2012), in which the striatum is a mandatory component for all timing tasks, from a modular system in which they subserve relative timing, with absolute timing processed by the cerebellum.
Test groups comprised individuals with Multiple System Atrophy, a disorder in which similar pathology can produce clinical deficits associated with dysfunction of the cerebellum (MSA-C, n=8) or striatum (MSA-P, n=10), and early symptomatic Huntington's disease (HD, n=14). Individuals with chronic autoimmune peripheral neuropathy (n=11) acted as controls.
Six adaptive tasks were carried out to assess perceptual thresholds for absolute timing through duration discrimination for sub- and supra-second time intervals, and relative timing through the detection of beat-based regularity and irregularity, detection of a delay within an isochronous sequence, and the discrimination of sequences with metrical structure.
All three patient groups exhibited impairments in performance in comparison with the control group for all tasks, and severity of impairment was significantly correlated with disease progression. No differences were demonstrated between MSA-C and MSA-P, and the most severe impairments were observed in those with HD.
The data support an obligatory role for the basal ganglia in all tested timing tasks, both absolute and relative, as predicted by the unified model. The results are not compatible with models of a brain timing network based upon independent modules.
Graphical abstract
Ninety five percent confidence intervals for mean group performance by task. Var: sub-second variable-interval discrimination. Sup: supra-second variable-interval discrimination. Pul: detection of regularity (pulse or beat) within an irregular sequence. Iso: detection of deviation from isochrony. Irr: detection of irregularity within a regular sequence. Met: detection of distortion of a sequence with strong metrical structure.
Highlights
•Patients with basal ganglia disease undertook a battery of perceptual timing tasks.•All patients displayed poorer performance than neurological control participants.•Performance in Huntington's disease was worse than Multiple System Atrophy.•Poorer performance was significantly correlated with disease progression.•These findings support the hypothesised unified model of time perception.
doi:10.1016/j.neuropsychologia.2013.09.039
PMCID: PMC3905186  PMID: 24135486
Perceptual timing; Beat; Basal ganglia; Multiple System Atrophy; Huntington's disease
12.  Cholinergic dysfunction contributes to gait disturbance in early Parkinson’s disease 
Brain  2012;135(9):2779-2788.
Gait disturbance is an early feature in Parkinson’s disease. Its pathophysiology is poorly understood; however, cholinergic dysfunction may be a non-dopaminergic contributor to gait. Short-latency afferent inhibition is a surrogate measure of cholinergic activity, allowing the contribution of cholinergic dysfunction to gait to be evaluated. We hypothesized that short-latency afferent inhibition would be an independent predictor of gait dysfunction in early Parkinson’s disease. Twenty-two participants with Parkinson’s disease and 22 age-matched control subjects took part in the study. Gait was measured objectively using an instrumented walkway (GAITRite), and subjects were asked to walk at their preferred speed for 2 min around a 25-m circuit. Spatiotemporal characteristics (speed, stride length, stride time and step width) and gait dynamics (variability described as the within subject standard deviation of: speed, stride time, stride length and step width) were determined. Short-latency afferent inhibition was measured by conditioning motor evoked potentials, elicited by transcranial magnetic stimulation of the motor cortex, with electrical stimuli delivered to the contralateral median nerve at intervals ranging from N20 (predetermined) to N20 + 4 ms. Short-latency afferent inhibition was determined as the percentage difference between test and conditioned response for all intervals and was described as the group mean. Participants were optimally medicated at the time of testing. Participants with Parkinson’s disease had significantly reduced gait speed (P = 0.002), stride length (P = 0.008) and stride time standard deviation (P = 0.001). Short-latency afferent inhibition was also significantly reduced in participants with Parkinson’s disease (P = 0.004). In participants with Parkinson’s disease, but not control subjects, significant associations were found between gait speed, short-latency afferent inhibition, age and postural instability and gait disorder score (Movement Disorders Society Unified Parkinson’s Disease Rating Scale) and attention, whereas global cognition and depression were marginally significant. No other gait variables were associated with short-latency afferent inhibition. A multiple hierarchical regression model explored the contribution of short-latency afferent inhibition to gait speed, controlling for age, posture and gait symptoms (Postural Instability and Gait Disorder score—Movement Disorders Society Unified Parkinson’s Disease Rating Scale), attention and depression. Regression analysis in participants with Parkinson’s disease showed that reduced short-latency afferent inhibition was an independent predictor of slower gait speed, explaining 37% of variability. The final model explained 72% of variability in gait speed with only short-latency afferent inhibition and attention emerging as independent determinants. The results suggest that cholinergic dysfunction may be an important and early contributor to gait dysfunction in Parkinson’s disease. The findings also point to the contribution of non-motor mechanisms to gait dysfunction. Our study provides new insights into underlying mechanisms of non-dopaminergic gait dysfunction, and may help to direct future therapeutic approaches.
doi:10.1093/brain/aws207
PMCID: PMC3437031  PMID: 22961550
Parkinson’s disease; gait; short-latency afferent inhibition; cholinergic dysfunction; attention
13.  Prevalence and pattern of perceived intelligibility changes in Parkinson's disease 
Background
Changes to spoken communication are inevitable in Parkinson's disease (PD). It remains unclear what consequences changes have for intelligibility of speech.
Aims
To establish the prevalence of impaired speech intelligibility in people with PD and the relationship of intelligibility decline to indicators of disease progression.
Methods
125 speakers with PD and age matched unaffected controls completed a diagnostic intelligibility test and described how to carry out a common daily activity in an “off drug” state. Listeners unfamiliar with dysarthric speech evaluated responses.
Results
69.6% (n = 87) of people with PD fell below the control mean of unaffected speakers (n = 40), 51.2% (n = 64) by more than −1 SD below. 48% (n = 60) were perceived as worse than the lowest unaffected speaker for how disordered speech sounded. 38% (n = 47) placed speech changes among their top four concerns regarding their PD. Intelligibility level did not correlate significantly with age or disease duration and only weakly with stage and severity of PD. There were no significant differences between participants with tremor dominant versus postural instability/gait disorder motor phenotypes of PD.
Conclusions
Speech intelligibility is significantly reduced in PD; it can be among the main concerns of people with PD, but it is not dependent on disease severity, duration or motor phenotype. Patients' own perceptions of the extent of change do not necessarily reflect objective measures.
doi:10.1136/jnnp.2006.110171
PMCID: PMC2117612  PMID: 17400592
14.  Parkinson's Disease: The Quintessential Neuropsychiatric Disorder 
Although diagnosed by characteristic motor features, Parkinson's disease may be preceded, and is frequently accompanied by, a wide range of cognitive and neuropsychiatric features. In addition to the most commonly studied disorders of dementia, depression, and psychosis, other relatively common and clinically significant psychiatric complications include impulse control disorders, anxiety symptoms, disorders of sleep and wakefulness, and apathy. These problems may be underrecognized and are frequently undertreated. The emergent focus on nonmotor aspects of Parkinson's disease over the past quarter of a century is highlighted by a nonlinear increase in the number of articles published devoted to this topic. Although the development of newer antidepressants, atypical antipsychotics, and cholinesterase inhibitors in recent years has had a positive benefit on the management of these troublesome and distressing symptoms, responses are frequently suboptimal, and this remains an area of major unmet therapeutic need.
doi:10.1002/mds.23664
PMCID: PMC3513835  PMID: 21626547
Parkinson's; dementia; neuropsychiatric; depression; psychosis
15.  Cholinesterase inhibitor use does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish Alzheimer's disease from dementia with Lewy bodies 
Background
123I‐labelled 2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane (123I‐FP‐CIT) imaging is a diagnostic tool to help differentiate dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, in animals, cholinesterase inhibitors (ChEi) have been reported to reduce radioligand binding to the striatal dopamine transporter. As ChEi are frequently used in people with dementia, it is important to determine whether their use affects 123I‐FP‐CIT uptake in the striatum.
Objective
To clarify whether chronic ChEi therapy modulates striatal dopamine transporter binding measured by 123I‐FP‐CIT in patients with AD, DLB and Parkinson's disease with dementia (PDD).
Design
Cross sectional study in 99 patients with AD (nine on ChEi, 25 not on ChEi), DLB (nine on ChEi, 19 not on ChEi) and PDD (six on ChEi, 31 not on ChEi) comparing 123I‐FP‐CIT striatal binding (caudate, anterior and posterior putamen) in patients receiving compared with those not receiving ChEi, correcting for key clinical variables including diagnosis, age, sex, Mini‐Mental State Examination score, severity of parkinsonism and concurrent antidepressant use.
Results
As previously described, 123I‐FP‐CIT striatal uptake was lower in DLB and PDD subjects compared with those with AD. Median duration of ChEi use was 180 days. 123I‐FP‐CIT uptake was not significantly reduced in subjects receiving ChEi compared those not receiving ChEi (mean percentage reduction: AD 4.3%; DLB 0.7%; PDD 6.1%; p = 0.40). ChEi use did not differentially affect striatal 123FP‐CIT uptake between patient groups (p = 0.83).
Conclusions
Use of ChEi does not significantly influence the ability of 123I‐FP‐CIT imaging to distinguish AD from DLB.
doi:10.1136/jnnp.2006.111666
PMCID: PMC2117542  PMID: 17299017
16.  Sex and Parkinson's disease: a world of difference? 
Do women with Parkinson's disease have a more benign phenotype?
doi:10.1136/jnnp.2006.109991
PMCID: PMC2117743  PMID: 17635975
17.  Tau acts as an independent genetic risk factor in pathologically proven PD 
Neurobiology of Aging  2012;33(4):838.e7-838.e11.
MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.
doi:10.1016/j.neurobiolaging.2011.11.001
PMCID: PMC3629571  PMID: 22221882
Genetics; Association study; Parkinson's disease; MAPT; Tau; Progressive supranuclear palsy; PD; PSP
19.  Huntington CAG repeat size does not modify onset age in familial Parkinson’s disease: The GenePD Study 
The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson’s disease (PD) and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n=495) with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range 15 to 34) below the clinical range for HD, although 5.2 percent of the sample (n=25) had repeats in the intermediate range (the intermediate range lower limit=27; upper limit=35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD.
doi:10.1002/mds.22186
PMCID: PMC2655323  PMID: 18649400
Parkinson’s disease; Huntington’s disease; CAG repeat; onset age; genetics; mitochondria
20.  Replication of association between ELAVL4 and Parkinson disease: the GenePD study 
Human genetics  2008;124(1):95-99.
Genetic variants in embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) have been reported to be associated with onset age of Parkinson disease (PD) or risk for PD affection in Caucasian populations. In the current study we genotyped three single nucleotide polymorphisms in ELAVL4 in a Caucasian study sample consisting of 712 PD patients and 312 unrelated controls from the GenePD study. The minor allele of rs967582 was associated with increased risk of PD (odds ratio = 1.46, nominal P value = 0.011) in the GenePD population. The minor allele of rs967582 was also the risk allele for PD affection or earlier onset age in the previously studied populations. This replication of association with rs967582 in a third cohort further implicates ELAVL4 as a PD susceptibility gene.
doi:10.1007/s00439-008-0526-4
PMCID: PMC2716559  PMID: 18587682
21.  Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease 
Neurology  2013;80(22):2042-2048.
Objectives:
Previous associations between mitochondrial DNA (mtDNA) and idiopathic Parkinson disease (PD) have been inconsistent and contradictory. Our aim was to resolve these inconsistencies and determine whether mtDNA has a significant role in the risk of developing PD.
Methods:
Two-stage genetic association study of 138 common mtDNA variants in 3,074 PD cases and 5,659 ethnically matched controls followed by meta-analysis of 6,140 PD cases and 13,280 controls.
Results:
In the association study, m.2158T>C and m.11251A>G were associated with a reduced risk of PD in both the discovery and replication cohorts. None of the common European mtDNA haplogroups were consistently associated with PD, but pooling of discovery and replication cohorts revealed a protective association with “super-haplogroup” JT. In the meta-analysis, there was a reduced risk of PD with haplogroups J, K, and T and super-haplogroup JT, and an increase in the risk of PD with super-haplogroup H.
Conclusions:
In a 2-stage association study of mtDNA variants and PD, we confirm the reduced risk of PD with super-haplogroup JT and resolve this at the J1b level. Meta-analysis explains the previous inconsistent associations that likely arise through sampling effects. The reduced risk of PD with haplogroups J, K, and T is mirrored by an increased risk of PD in super-haplogroup HV, which increases survival after sepsis. Antagonistic pleiotropy between mtDNA haplogroups may thus be shaping the genetic landscape in humans, leading to an increased risk of PD in later life.
doi:10.1212/WNL.0b013e318294b434
PMCID: PMC3716399  PMID: 23645593
22.  The Gly2019Ser mutation in LRRK2 is not fully penetrant in familial Parkinson's disease: the GenePD study 
BMC Medicine  2008;6:32.
Background
We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson's disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.
Methods
A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.
Results
Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.
Conclusion
Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.
doi:10.1186/1741-7015-6-32
PMCID: PMC2596771  PMID: 18986508
23.  The midbrain to pons ratio 
Neurology  2013;80(20):1856-1861.
Objectives:
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.
Methods:
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).
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0b013e318292a2d2
PMCID: PMC3908351  PMID: 23616165

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