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1.  Activity enhances dopaminergic long-duration response in Parkinson disease 
Jung Kang, Un | Auinger, Peggy | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Mendis, Tilak
Neurology  2012;78(15):1146-1149.
Objective:
We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
Methods:
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
Results:
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Conclusions:
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
doi:10.1212/WNL.0b013e31824f8056
PMCID: PMC3466780  PMID: 22459675
2.  Clinical Phenotype Predicts Early Staged Bilateral Deep Brain Stimulation in Parkinson’s Disease 
Journal of neurosurgery  2013;119(6):1530-1536.
Object
While many centers place bilateral DBS systems simultaneously, unilateral STN DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite subthalamic nucleus will be required. We aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second subthalamic deep brain stimulation (DBS) electrode in patients who undergo unilateral subthalamic DBS for Parkinson's disease (PD).
Methods
Eighty-two consecutive patients with advanced PD underwent unilateral subthalamic DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression determined preoperative characteristics that predicted staged placement of a second electrode in the opposite subthalamic nucleus. Preoperative measurements included aspects of the Unified Parkinson Disease Rating Scale (UPDRS), motor asymmetry index, and body weight.
Results
At 2 years follow-up, 28 of the 82 patients (34%) had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and part 3 scores were retained at the end of the 2 year follow-up period in both subsets of patients. Multivariate logistic regression showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (odds ratio 13.4; 95% confidence interval 2.8, 64.9), high tremor subscore (OR 7.2; CI 1.5, 35.0), and low body weight (OR 5.5; CI 1.4, 22.3).
Conclusions
This single center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral subthalamic DBS. These data may aid in the management of patients with advanced PD who undergo subthalamic DBS.
doi:10.3171/2013.8.JNS122025
PMCID: PMC3992872  PMID: 24074493
deep brain stimulation; predictors; Parkinson’s disease
3.  Reliability of a new scale for essential tremor 
Objective
To determine the reliability of a new scale for the clinical assessment of essential tremor.
Background
The Essential Tremor Rating Assessment Scale contains nine performance items that rate action tremor in the head, face, voice, limbs and trunk 0–4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters.
Design/Methods
Videos of 44 patients and 6 controls were rated by 10 specialists on two occasions, 1–2 months apart. Inter- and intra-rater reliabilities were assessed with a two-way random effects intraclass correlation, using an absolute agreement definition.
Results
The inter- and intra-rater intraclass correlations for head and upper limb tremor ranged from 0.86 to 0.96, and the intraclass correlations for the total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk and leg were less robust.
Conclusions
This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.
doi:10.1002/mds.25162
PMCID: PMC4157921  PMID: 23032792
essential tremor; rating scale; reliability
4.  High-Frequency Deep Brain Stimulation of the Putamen Improves Bradykinesia in Parkinson’s Disease 
Deep brain stimulation is effective for a wide range of neurological disorders; however, its mechanisms of action remain unclear. With respect to Parkinson’s disease, the existence of multiple effective targets suggests that putamen stimulation also may be effective and raises questions as to the mechanisms of action. Are there as many mechanisms of action as there are effective targets or some single or small set of mechanisms common to all effective targets? During the course of routine surgery of the globus pallidus interna in patients with Parkinson’s disease, the deep brain stimulation lead was placed in the putamen en route to the globus pallidus interna. Recordings of hand opening and closing during high-frequency and no stimulation were made. Speed of the movements, based on the amplitude and frequency of the repetitive hand movements as well as the decay in amplitude, were studied. Hand speed in 6 subjects was statistically significantly faster during active deep brain stimulation than the no-stimulation condition. There were no statistically significant differences in decay in the amplitude of hand movements. High-frequency deep brain stimulation of the putamen improves bradykinesia in a hand-opening and -closing task in patients with Parkinson’s disease. Consequently, high-frequency deep brain stimulation of virtually every structure in the basal ganglia-thalamic-cortical system improves bradykinesia. These observations, together with microelectrode recordings reported in the literature, argue that deep brain stimulation effects may be system specific and not structure specific.
doi:10.1002/mds.23842
PMCID: PMC4151533  PMID: 21714010
putamen; deep brain stimulation; bradykinesia; physiology; pathophysiology
5.  Association of Single-Nucleotide Polymorphisms of the Tau Gene With Late-Onset Parkinson Disease 
Context
The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.
Objective
To investigate whether the tau gene is involved in idiopathic PD.
Design, Setting, and Participants
Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.
Main Outcome Measure
Family-based tests of association, calculated using asymptotic distributions.
Results
Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,9i, 9ii, and 11).
Conclusions
This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
PMCID: PMC3973175  PMID: 11710889
6.  Short latency activation of cortex by clinically effective thalamic brain stimulation for tremor 
Deep brain stimulation relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate nucleus stimulation for essential tremor activates cortex at short latencies and that this potential is related to suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (7 brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event related potential in ipsilateral sensorimotor cortex with peaks at discrete latencies beginning less than one millisecond after stimulus onset (mean latencies 0.9±0.2, 5.6±0.7, and 13.9±1.4 milliseconds, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (p<0.0001, Levene’s test), and R1 amplitude and frequency were both closely associated with tremor suppression (p<0.0001, respectively). These findings demonstrate that effective ventral intermediate nucleus thalamic stimulation for essential tremor activates cerebral cortex at approximately one millisecond after the stimulus pulse. The association between this short latency potential and tremor suppression suggests that deep brain stimulation may improve tremor by synchronizing the precise timing of discharges in nearby axons, and by extension the distributed motor network, to the stimulation frequency or one of its subharmonics.
doi:10.1002/mds.25137
PMCID: PMC3691999  PMID: 22926754
ventral intermediate nucleus; deep brain stimulation; essential tremor; thalamus; cerebral cortex; event related potential
7.  Short latency activation of cortex during clinically effective subthalamic DBS for Parkinson disease 
Background
Subthalamic deep brain stimulation is superior to medical therapy for the motor symptoms of advanced Parkinson’s disease, and additional evidence suggests that it improves refractory symptoms of essential tremor, primary generalized dystonia, and obsessive-compulsive disorder. Despite this, its therapeutic mechanism is unknown. We hypothesized that subthalamic stimulation activates cerebral cortex at short latencies after stimulus onset during clinically effective stimulation for Parkinson disease.
Methods
In 5 subjects (6 hemispheres) electroencephalography measured the response of cortex to subthalamic stimulation across a range of stimulation voltages and frequencies. Novel analytical techniques reversed the anode and cathode electrode contacts and summed the resulting pair of event related potentials to suppress the stimulation artifact.
Results
Subthalamic brain stimulation at 20 Hertz activates somatosensory cortex at discrete latencies (mean latencies 1.0 ± 0.4, 5.7 ± 1.1, and 22.2 ± 1.8 milliseconds, denoted R1, R2, and R3, respectively). The amplitude of the short latency peak (R1) during clinically effective high frequency stimulation is nonlinearly dependent on stimulation voltage (p < 0.001, repeated measures analysis of variance), and its latency is less variable than that of R3 (1.02 versus 19.46 milliseconds, p < 0.001, Levene’s test).
Conclusions
Clinically effective subthalamic brain stimulation in humans with Parkinson disease activates cerebral cortex at one millisecond after stimulus onset, most likely by antidromic activation. Our findings suggest that alteration of the precise timing of action potentials in cortical neurons with axonal projections to the subthalamic region is an important component of the therapeutic mechanism of subthalamic brain stimulation.
doi:10.1002/mds.25025
PMCID: PMC3636546  PMID: 22648508
8.  Unilateral subthalamic nucleus deep brain stimulation improves sleep quality in Parkinson’s disease 
Background
Sleep disturbances are common in Parkinson’s disease (PD). Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is superior to best medical therapy in the treatment of motor symptoms in advanced PD, and observational studies suggest that bilateral STN DBS improves sleep in these patients as well. Unilateral STN DBS also improves motor function in PD, but its effects on sleep have not been extensively investigated.
Methods
We report the effects of unilateral STN DBS on subjective sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) in 53 consecutive PD patients. These subjects completed the PSQI prior to surgery and at 3 and 6 months post-operatively. The primary outcome measure was the change in the global PSQI at 6 months post-operatively versus the preoperative baseline, measured with repeated measures analysis of variance (ANOVA).
Results
Patients with PD who underwent unilateral STN DBS had a significant improvement in PSQI at 6 months post-operatively (baseline 9.30 ± 0.56 (mean ± SEM), 6 months: 7.93 ± 0.56, p=0.013). Supplemental analyses showed that subjects selected for STN DBS placed on the right had worse baseline subjective sleep quality and more improvement in PSQI at 6 months compared to patients who received left STN DBS.
Conclusion
This prospective case series study provides evidence that unilateral STN DBS improves subjective sleep quality in patients with PD at up to 6 months postoperatively as measured by the PSQI.
doi:10.1016/j.parkreldis.2011.09.001
PMCID: PMC3249526  PMID: 21924664
Parkinson’s disease; sleep; subthalamic nucleus; deep brain stimulation; non-motor symptom
9.  Comparison of weight changes following unilateral and staged bilateral STN DBS for advanced PD 
Brain and Behavior  2011;1(1):12-18.
Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case–control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode.
doi:10.1002/brb3.9
PMCID: PMC3217670  PMID: 22398977
Bilateral; deep brain stimulation; Parkinson's disease; subthalamic; unilateral; weight
10.  The effects of deep brain stimulation on sleep in Parkinson’s disease 
Sleep dysfunction is a common nonmotor symptom experienced by patients with Parkinson’s disease (PD). Symptoms, including excessive daytime sleepiness, sleep fragmentation, rapid eye movement (REM) sleep behavior disorder and others, can significantly affect quality of life and daytime functioning in these patients. Recent studies have evaluated the effects of deep brain stimulation (DBS) at various targets on sleep in patients with advanced PD. Several of these studies have provided evidence that subthalamic nucleus DBS improves subjective and objective measures of sleep, including sleep efficiency, nocturnal mobility, and wake after sleep onset (minutes spent awake after initial sleep onset). Although fewer studies have investigated the effects of bilateral internal globus pallidus and thalamic ventral intermedius DBS on sleep, pallidal stimulation does appear to improve subjective sleep quality. Stimulation of the pedunculopontine nucleus has recently been proposed for selected patients with advanced PD to treat severe gait and postural dysfunction. Owing to the role of the pedunculopontine nucleus in modulating behavioral state, the impact of stimulation at this target on sleep has also been evaluated in a small number of patients, showing that pedunculopontine nucleus DBS increases REM sleep. In this review, we discuss the effects of stimulation at these various targets on sleep in patients with PD. Studying the effects of DBS on sleep can enhance our understanding of the pathophysiology of sleep disorders, provide strategies for optimizing clinical benefit from DBS, and may eventually guide novel therapies for sleep dysfunction.
doi:10.1177/1756285610392446
PMCID: PMC3036959  PMID: 21339905
deep brain stimulation; globus pallidus; Parkinson’s disease; pedunculopontine nucleus; sleep; subthalamic nucleus; ventral intermediate nucleus of the thalamus
11.  Striatal overexpression of ΔFosB reproduces chronic levodopa-induced involuntary movements 
Long-term dopamine replacement therapy in Parkinson’s disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor ΔFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of ΔFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV viral vectors, high levels of ΔFosB expression were induced in the striatum of dopamine-denervated rats naïve of chronic drug administration. Transgenic ΔFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of ΔFosB binding to AP-1 sites of genes, remained unchanged in rats with high ΔFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal ΔFosB in the evolution of chronically treated Parkinson’s disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.
doi:10.1523/JNEUROSCI.0252-10.2010
PMCID: PMC2888489  PMID: 20505100
ΔFosB; Parkinson’s disease; Striatum; Involuntary Movements; Dyskinesias; AAV
12.  The Contribution of Executive Control on Verbal-Learning Impairment in Patients with Parkinson's Disease with Dementia and Alzheimer's Disease 
Deficits in learning, memory, and executive functions are common cognitive sequelae of Parkinson's disease with dementia (PDD) and Alzheimer's disease (AD); however, the pattern of deficits within these populations is distinct. Hierarchical regression was used to investigate the contribution of two measures with executive function properties (Verbal Fluency and CLOX) on list-learning performance (CVLT-II total words learned) in a sample of 25 PDD patients and 25 matched AD patients. Executive measures were predictive of list learning in the PDD group after the contribution of overall cognition and contextual verbal learning was accounted for, whereas in the AD group the addition of executive measures did not add to prediction of variance in CVLT-II learning. These findings suggest that deficits in executive functions play a vital role in learning impairments in patients with PDD; however, for AD patients, learning difficulties appear relatively independent of executive dysfunction.
doi:10.1093/arclin/acp029
PMCID: PMC2765349  PMID: 19587066
Parkinson's disease with dementia; Alzheimer's disease; Executive function; List learning; Neuropsychologic tests; Comparative studies
13.  Brain metabolism differs in Alzheimer disease and Parkinson disease dementia 
Background
Few comparative studies exist of metabolic brain changes among neurodegenerative illnesses. We compared brain metabolic abnormalities in Alzheimer’s disease (AD) and in Parkinson’s disease with dementia (PDD) as measured by proton magnetic resonance spectroscopy (MRS).
Methods
Twelve patients with idiopathic PDD, 22 patients with probable mild AD, and 61 healthy older controls underwent posterior cingulate MRS.
Results
Patients with AD showed reduced N-acetylaspartate (NAA)/creatine (Cr) (p <0.05) and increased choline (Cho)/Cr (p <0.05) and myo-Inositol (mI)/Cr (p <0.01) compared to controls. Patients with PDD showed reduced NAA/Cr (p <0.05) and glutamate (Glu)/Cr (p <0.01) compared to controls. There was reduced Glu/Cr in PDD compared to AD (p <0.01).
Conclusion
Patients with AD and patients with PDD showed distinct brain metabolic MRS profiles. Findings suggest that comparison of brain MRS profiles across dementias provides useful direction for future study.
doi:10.1016/j.jalz.2008.04.008
PMCID: PMC2600665  PMID: 19012867
Parkinson Disease; Alzheimer Disease; MR Spectroscopy; N-acetylaspartate; Gyrus Cinguli
14.  Medical Decision-Making Capacity in Cognitively Impaired Parkinson's Disease Patients Without Dementia 
Little is currently known about the higher order functional skills of patients with Parkinson disease and cognitive impairment. Medical decision-making capacity (MDC) was assessed in patients with Parkinson's disease (PD) with cognitive impairment and dementia. Participants were 16 patients with PD and cognitive impairment without dementia (PD-CIND), 16 patients with PD dementia (PDD), and 22 healthy older adults. All participants were administered the Capacity to Consent to Treatment Instrument (CCTI), a standardized capacity instrument assessing MDC under five different consent standards. Parametric and non-parametric statistical analyses were utilized to examine capacity performance on the consent standards. In addition, capacity outcomes (capable, marginally capable, or incapable outcomes) on the standards were identified for the two patient groups. Relative to controls, PD-CIND patients demonstrated significant impairment on the understanding treatment consent standard, clinically the most stringent CCTI standard. Relative to controls and PD-CIND patients, patients with PDD patients were impaired on the three clinical standards of understanding, reasoning, and appreciation. The findings suggest that impairment in decisional capacity is already present in cognitively impaired PD patients without dementia, and increases as these patients develop dementia. Clinicians and researchers should carefully assess decisional capacity in all PD patients with cognitive impairment.
doi:10.1002/mds.22170
PMCID: PMC2579319  PMID: 18759361
consent capacity; medical decision-making; cognitive impairment without dementia; functional change; Parkinson's disease
15.  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
16.  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
17.  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

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