Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease

BackgroundIt is unknown whether driving difficulty in Parkinson disease (PD) is attributable to nigrostriatal dopaminergic or extranigral non-dopaminergic neurodegeneration.ObjectiveTo investigate in vivo imaging differences in dopaminergic and cholinergic innervation between PD patients with and without a history of risky driving.MethodsThirty non-demented PD subjects (10 women/20 men) completed a driving survey. These subjects had previously undergone (+)-[¹¹C] dihydrotetrabenazine vesicular monoamine transporter 2 and [¹¹C] methyl-4-piperidinyl propionate acetylcholinesterase PET imaging. Acetylcholinesterase PET imaging assesses cholinergic terminal integrity with cortical uptake largely reflecting basal forebrain and thalamic uptake principally reflecting pedunculopontine nucleus integrity.ResultsEight of thirty subjects reported a history of risky driving (been pulled over, had a traffic citation, or been in an accident since PD onset) while 22 had no such history (safe drivers). There was no difference in striatal dihydrotetrabenazine vesicular monoamine transporter uptake between risky and safe drivers. There was significantly less thalamic acetylcholinesterase activity in the risky drivers compared to safe drivers (0.0513 ± 0.006 vs. 0.0570 ± 0.006, p = 0.022) but no difference in neocortical acetylcholinesterase activity. Using multivariable logistic regression, decreased thalamic acetylcholinesterase activity remained an independent predictor of risky driving in PD even after controlling for age and disease duration.ConclusionsRisky driving is related to pedunculopontine nucleus-thalamic but not neocortical cholinergic denervation or nigrostriatal dopaminergic denervation in PD. This suggests that degeneration of the pedunculopontine nucleus, a brainstem center responsible for postural and gait control, plays a role in the ability of PD patients to drive.     

Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease

BackgroundThere is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.ObjectiveTo investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.MethodsCross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [¹¹C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.ResultsThere were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98 ± 1.01) compared to the non-diabetics (−0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).ConclusionDiabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.     

Diabetes is associated with postural instability and gait difficulty in Parkinson disease

BackgroundComorbid diabetes may be associated with more severe motor impairment in Parkinson disease. In normal elderly individuals, diabetes is associated with parkinsonian features, including gait difficulty and rigidity, though not tremor. Whether diabetes contributes to increased motor dysfunction in Parkinson disease by exacerbating nigrostriatal dopaminergic denervation or through intensification of extranigral pathology is unknown.MethodsWe performed a case–control study (n = 39) involving 13 Parkinson disease subjects (age 66.4yrs ± 5.5; duration of disease 6.9yrs ± 4.4) with diabetes and 26 age, gender, and duration-of-disease-matched Parkinson disease controls without diabetes. All subjects underwent [¹¹C]dihydrotetrabenazine vesicular monoamine transporter type-2 positron emission tomography imaging to assess striatal dihydrotetrabenazine distribution volume ratio and Unified Parkinson disease rating scale motor examination to determine rigidity, bradykinesia, tremor, and postural instability and gait difficulty subscores. Magnetic resonance imaging scans were analyzed to assess leukoaraiosis burden.ResultsAfter controlling for nigrostriatal dopaminergic denervation, Parkinson disease subjects with diabetes displayed greater postural instability and gait difficulty subscores (t = 3.81, p = 0.0005). There were no differences in bradykinesia, rigidity, or tremor subscores between cases and controls. The association between diabetes and postural instability and gait difficulty persisted after controlling for comorbid hypertension and body mass index. Leukoaraiosis, distal vibratory sense, and levodopa dose equivalents did not differ significantly between cases and controls.ConclusionsDiabetes may contribute to postural instability and gait difficulty in Parkinson disease through mechanisms other than nigrostriatal dopaminergic denervation.     

Reduced cholinergic olfactory centrifugal inputs in patients with neurodegenerative disorders and MPTP-treated monkeys

Olfactory impairment is a common feature of neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Olfactory bulb (OB) pathology in these diseases shows an increased number of olfactory dopaminergic cells, protein aggregates and dysfunction of neurotransmitter systems. Since cholinergic denervation might be a common underlying pathophysiological feature, the objective of this study was to determine cholinergic innervation of the OB in 27 patients with histological diagnosis of PD (n = 5), AD (n = 14), DLB (n = 8) and 8 healthy control subjects. Cholinergic centrifugal inputs to the OB were clearly reduced in all patients, the most significant decrease being in the DLB group. We also studied cholinergic innervation of the OB in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys (n = 7) and 7 intact animals. In MPTP-monkeys, we found that cholinergic innervation of the OB was reduced compared to control animals (n = 7). Interestingly, in MPTP-monkeys, we also detected a loss of cholinergic neurons and decreased dopaminergic innervation in the horizontal limb of the diagonal band, which is the origin of the centrifugal cholinergic input to the OB. All these data suggest that cholinergic damage in the OB might contribute, at least in part, to the olfactory dysfunction usually exhibited by these patients. Moreover, decreased cholinergic input to the OB found in MPTP-monkeys suggests that dopamine depletion in itself might reduce the cholinergic tone of basal forebrain cholinergic neurons.     

Effect of dopaminergic medication on adenosine 2A receptor availability in patients with Parkinson's disease

ObjectiveTo assess the necessity of withdrawing dopaminergic medication in Parkinson's disease (PD) patients for accurate estimation of adenosine 2A receptor (A_2AR) availability using [¹¹C]TMSX PET imaging. This was accomplished by studying the short-term effect of the cessation of dopaminergic medication on A_2AR availability in non-dyskinetic patients with PD treated with dopaminergic medication.MethodsEight PD patients (age 67.9 ± 5.6 years; 6 men, 2 women) without dyskinesia were enrolled in this study. A_2AR availability was measured using PET imaging with a [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX) radioligand after a short term cessation of dopaminergic medication (12hrs for levodopa, 24hrs for dopamine agonists and MAO-B inhibitors). Repeated PET imaging was performed while the patients were back ‘on’ their regular dopaminergic medication (median 13 days after first imaging). Conventional MRI was acquired for anatomical reference. Specific binding of [¹¹C]TMSX was quantified as distribution volume ratios (DVR) for caudate, pallidum and putamen using Logan graphical method with clustered gray matter reference region.ResultsNo significant differences were observed for the DVRs in all three striatal regions between ‘on’ and ‘off’ medication states. Strong correlations were also observed between the two states. Statistical equivalence was found in pallidum (TOST equivalence test, p = 0.045) and putamen (TOST equivalence test, p = 0.022), but not in caudate DVR (TOST equivalence test, p = 0.201) between the two medication states.ConclusionsOur results show that dopaminergic medication has no significant short-term effect on the availability of A_2A receptors in putamen and pallidum of patients with PD. However, relatively poor repeatability was demonstrated in the caudate.     

Extra‐nigral pathological conditions are common in Parkinson's disease with freezing of gait: An in vivo positron emission tomography study

Cholinergic denervation has been associated with falls and slower gait speed and β‐amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra‐nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [¹¹C]methyl‐4‐piperidinyl propionate acetylcholinesterase and [¹¹C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic “off” state. A subset of subjects (n = 61) underwent [¹¹C]Pittsburgh compound‐B β‐amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal β‐amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non‐freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ² = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ² = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical β‐amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra‐nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran‐Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra‐nigral pathological conditions studied. Extra‐nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society     

Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases

BackgroundPure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation.MethodThe University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[¹⁸F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation.ResultsThe PAF group had a low mean UPSIT score (22 ± 3), similar to that in PD (20 ± 2) and lower than in MSA (31 ± 2, p = 0.004). Individual UPSIT scores correlated positively with cardiac 6-[¹⁸F]fluorodopamine-derived radioactivity (r = 0.63 in the septum, p < 0.0001; r = 0.64 in the free wall, p < 0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity.DiscussionIn synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.     

Sex differences in cerebral energy metabolism in Parkinson's disease: A phosphorus magnetic resonance spectroscopic imaging study

ObjectiveTo test the hypothesis that there are sex differences in cerebral energy metabolism in Parkinson's disease (PD).MethodsPhosphorus magnetic resonance spectroscopy (³¹P MRS) was used to determine high-energy phosphate (phosphocreatine and ATP) and low-energy phosphate (free phosphate) levels in the striatum and temporoparietal cortical gray matter (GM) in 10 men and 10 women with PD, matched for age at onset, disease duration, and UPDRS scores.ResultsIn the hemisphere more affected by PD, both ATP and high energy phosphate (HEP: phosphocreatine + ATP) content in striatum was 15% lower in men versus women with PD (p = .050 and p = .048, respectively). Similar decreases by 16% in ATP (p = .023) and 12% in HEP (p = .046) were observed in GM in men versus women with PD. In contrast, there were no detectable sex differences in ATP or HEP in healthy age-matched controls.ConclusionsMen with PD have lower levels of ATP and high energy phosphate than women in brain regions affected by PD. These findings suggest that there may be a greater burden of mitochondrial dysfunction in PD in men versus women with PD.     

Substantia nigra echogenicity is correlated with nigrostriatal impairment in Machado-Joseph disease

BackgroundSeveral studies have demonstrated increased substantia nigra (SN) echogenicity in Parkinson's disease (PD) and Machado-Joseph disease (MJD). Pathological substrate of PD is characterized by dopaminergic nigrostriatal cell loss, also found in MJD. Also, SN hyperechogenicity might be associated with nigrostriatal dysfunction in PD, when comparing dopamine transporter binding with SN echogenicity. The present study aimed to correlate the SN echogenic size and striatal dopamine transporter density in MJD patients.MethodsWe performed TCS in 30 subjects and SPECT with [^99mTc]-TRODAT-1 in 18 subjects with MJD. Fifteen healthy subjects matched for age and gender formed a control group. TCS and [^99mTc]-TRODAT-1 SPECT findings from both MJD patients and control subjects were compared.ResultsThere were no differences regarding age (p = 0.358) or gender (p = 0.566) between groups (MJD versus control group). Mean DAT binding potentials and SN echogenicity were significantly different between groups. There was a significant negative correlation with regard to the SN echogenic size and the ipsilateral striatal TRODAT-1 uptake: the higher the SN echogenicity, the lower the DAT uptake in the ipsilateral cerebral hemisphere.ConclusionIncrease in SN echogenic size likely correlates with presynaptic dopaminergic nigrostriatal dysfunction in MJD, suggesting a concurrent in vivo pathophysiological mechanism.     

Impulse control behaviors and subthalamic deep brain stimulation in Parkinson disease

To determine the clinical and demographic correlates of persistent, remitting, and new-onset impulse control behaviors (ICBs) before and after subthalamic deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). We compared the pre- and post-surgical prevalence of ICBs, classified as impulse control disorders (ICD), dopamine dysregulation syndrome (DDS), and punding in 150 consecutive PD STN-DBS-treated patients and determined the association with motor, cognitive, neuropsychological, and neuropsychiatric endpoints. At baseline (before STN-DBS), ICBs were associated with younger age (p = 0.045) and male gender (85 %; p = 0.001). Over an average follow-up of 4.3 ± 2.1 years of chronic STN-DBS there was an overall trend for reduction in ICBs (from 17.3 to 12.7 %; p = 0.095) with significant improvement in hypersexuality (12–8.0 %; p = 0.047), gambling (10.7–5.3 %; p = 0.033), and DDS (4.7–0 %; p < 0.001). ICB remitted in 18/26 patients (69 %) and persisted in 8/26 (31 %); the latter group was characterized by higher levodopa equivalent daily dose. Patients who developed a new-onset ICB during follow-up (n = 11/150) were characterized by younger age (p = 0.042), lower dyskinesia improvement (p ≤ 0.035), and a gender distribution with higher prevalence of women (p = 0.018). In addition, new-onset ICB was more common among patients with borderline, schizoid, and/or schizotypal traits of personality disorders; persistent ICB in those with obsessive–compulsive traits. PD-related ICBs exhibit a complex outcome after STN-DBS, with a tendency for overall reduction but with age, gender, dopaminergic therapy, and neuropsychiatric features exerting independent effects.     

β‐amyloid and postural instability and gait difficulty in Parkinson's disease at risk for dementia

Although motor impairments in Parkinson's disease (PD) are attributed to nigrostriatal dopaminergic denervation, postural instability and gait difficulty (PIGD) features are less responsive to dopaminergic medications. PIGD features are a risk factor also for the development of dementia in PD (PDD). These observations suggest that nondopaminergic mechanisms may contribute to axial motor impairments. The aim was to perform a correlative PET study to examine the relationship between neocortical β‐amyloid deposition ([¹¹C]‐Pittsburgh Compound B), nigrostriatal dopaminergic denervation ([¹¹C]‐dihydrotetrabenazine), and PIGD feature severity in PD patients at risk for dementia. This was a cross‐sectional study of 44 PD patients (11 female and 33 male; 69.5 ± 6.6 years of age; 7.0 ± 4.8 years motor disease duration; mean H & Y stage: 2.7 ± 0.5) who underwent PET, motor feature severity assessment using the Movement Disorder Society revised UPDRS, and the Dementia Rating Scale (DRS). Linear regression (R²_adj = 0.147; F_4,39 = 2.85; P = 0.036) showed that increased PIGD feature severity was associated with increased neocortical [¹¹C]‐Pittsburgh Compound B binding (β = 0.346; t₃₉ = 2.13; P = 0.039) while controlling for striatal [¹¹C]‐dihydrotetrabenazine binding, age, and DRS total score. Increased neocortical β‐amyloid deposition, even at low‐range levels, is associated with higher PIGD feature severity in PD patients at risk for dementia. This finding may explain why the PIGD motor phenotype is a risk factor for the development of PDD. © 2012 Movement Disorder Society     

Drivers with Parkinson’s disease: are the symptoms of PD associated with restricted driving practices?

This study examined whether symptoms (motor, cognitive, vision, sleepiness, depression) of Parkinson’s disease (PD) were associated with restricted driving practices. To quantify driving practices, electronic devices were installed in the vehicles of 27 drivers with PD (78 % men; M = 71.6, SD = 6.6; Unified Parkinson’s Disease Rating Scale (UPDRS) motor score M = 30.1, SD = 8.6; disease duration M = 3.9, SD = 2.8 years) and 20 controls (80 % men; M = 70.6, SD = 7.9) for 2 weeks. Participants completed measures of sleepiness, depression, quality of life, and assessments of motor, cognitive and visual functions. The PD group had significantly slower brake response times (p < 0.05), poorer cognitive and quality of life scores (p < 0.01) and greater depression (p < 0.05) compared to controls. Slower reaction time was significantly related to reduced driving; specifically, fewer trips (r = ?0.46; p < 0.05), distance (r = ?0.54, p < 0.01) and duration at night (r = ?0.58, p < 0.01). Better cognitive scores were associated with driving less often in difficult situations such as bad weather and rush hour (p < 0.05), as well as reduced speed on city streets, but only for the control group. While most drivers with PD rated their overall health as good or excellent, the five PD drivers who rated their health more poorly had significantly worse clinical symptoms (UPDRS motor scores, contrast sensitivity, depression, brake response time) and more restricted driving patterns. These findings show that drivers with PD who perceive their health poorly have greater symptomatology and were more likely to restrict their driving, possibly due to noticeable declines in multiple driving-related abilities.     

Clinical characteristics of acute lacunar stroke in women: emphasis on gender differences

There are few studies analyzing features of ischemic stroke subtypes in women. We assessed gender differences in lacunar stroke subtype based on data collected from a prospective stroke registry in Barcelona, Spain. Lacunar ischemic stroke was diagnosed in 310 (8.1 %) women and 423 (11.1 %) men of a total of 3,808 consecutive stroke patients included in a prospective hospital-based stroke registry, in Barcelona, Catalonia (Spain), over a period of 19 years. Independent factors for lacunar stroke in women were assessed by multivariate analysis. Women accounted for 42 % of all lacunar stroke patients (n = 733) in the registry and 11.4 % of all patients with ischemic stroke (n = 2,704). Very old age (85 years or older) was found in 20.3 % in women versus 11.1 % in men (P < 0.0001). In the logistic regression analysis, obesity [odds ratio (OR) = 4.24], prolonged hospital stay (>12 days) (OR = 1.59), arterial hypertension (OR = 1.50), and age (OR = 1.06) were significant variables independently associated with lacunar stoke in women, whereas peripheral vascular disease (OR = 0.51), chronic obstructive pulmonary disease (OR = 0.46), renal dysfunction (OR = 0.13), and heavy smoking (OR = 0.04) were independent variables for lacunar stroke in men. Women with lacunar stroke were remarkably older and presented with obesity and hypertension more frequently than did men. Lacunar stroke severity was similar in men and women. These findings in lacunar stroke patients could be explained by differences in gender for ischemic stroke in general.     

REM sleep behavior disorder in Parkinson's disease – Is there a gender difference?

BackgroundREM sleep behavior disorder (RBD) is common in Parkinson's disease (PD). While previous studies of idiopathic RBD have reported a striking male preponderance, little information exists about potential gender differences of RBD in PD.MethodsWe performed a cross sectional study of 107 PD patients. Probable RBD (pRBD) was diagnosed using the RBD Screening Questionnaire.ResultsMen had more fights (96% versus 54%, p < 0.001), violent behavior (71% versus 39%, p = 0.04) and awakening by own movements (89% versus 62%, p = 0.04). More women experienced disturbed sleep (85% versus 32%, p = 0.02). The frequency of pRBD was 31% in women and 43% in men (p = 0.2), total frequency 38%.ConclusionsWe found no clear differences in the frequency of pRBD among men and women with PD, but demonstrated significant gender differences in its clinical expression. Female PD patients reported significantly less fights and aggressive behavior during dreams, but had more disturbed sleep.     

Serum epidermal growth factor predicts cognitive functions in early, drug-naive Parkinson’s disease patients

Epidermal growth factor (EGF) has been proposed as a candidate biomarker for cognitive impairment in Parkinson’s disease (PD). We aimed to assess the relationship between serum EGF and cognitive functions in early, drug-naive PD patients and evaluate the predictive value of EGF on cognitive functions in a 2-year follow-up study. Serum EGF was measured in 65 early, drug-naive PD patients, that underwent a comprehensive neuropsychological battery. Motor symptoms were assessed by means of the Unified Parkinson’s Disease Rating Scale, Part III (UPDRS-III). Neuropsychological evaluation was repeated after 2 years. Spearman’s rank correlation was used to assess the relationship between serum EGF levels and neuropsychological variables. Linear regression analysis was used to evaluate the relationship between EGF and neuropsychological scores as well as other variables (age, gender, UPDRS-III, levodopa equivalent dose, and type of treatment at follow-up) potentially affecting cognitive performance. Variation over time in cognitive scores was analyzed using repeated-measures ANOVA. At baseline, EGF was the only significant variable associated with performance on semantic fluency (R ² = 0.131; p = 0.005). EGF levels (p = 0.025), together with UPDRS-III (p = 0.009) and age (p = 0.011), were associated with performance on frontal assessment battery (R ² = 0.260). At 2-year follow-up, EGF was the only significant variable to predict performance on semantic fluency (R ² = 0.147; p = 0.025) and color naming task of Stroop color-word test (R ² = 0.121; p = 0.044). Serum EGF levels are related to frontal and temporal cognitive functions in early, drug-naive PD patients and predict performance on frontal and posterior cognitive functions at 2-year follow-up. EGF is proposed as a potential serum biomarker for early cognitive impairment in PD.     

Generalized tonic–clonic seizures and antiepileptic drugs during pregnancy—a matter of importance for the baby?

This study investigates the impact of generalized tonic–clonic seizures (GTCS) and antiepileptic drugs (AED) during pregnancy on gestational age (GA) and anthropometric data of newborns. One hundred twenty-nine singleton pregnancies resulting in live births from September 1999 to October 2010 in 106 women with epilepsy on AED therapy, recorded within the framework of the EURAP (International Registry of Antiepileptic Drugs and Pregnancy) program at the Department of Neurology, Medical University Innsbruck, Austria, were studied. Occurrence of ≥1 GTCS during pregnancy was associated with a shorter GA [median (range) 37.5 [35.1–41.6] vs. 39.7 [29.1–46.3] weeks; p ≤ 0.001], an overall five times higher preterm risk (p = 0.042) and a reduced birth weight in boys (2,900 [2,050–3,870] vs. 3,205 [1,575–4,355] g; p = 0.040). In primipara, when compared to multipara, GTCS ≥1 significantly reduced the GA (37.9 [35.1–41.6] vs. 39.7 [29.4–44.9] weeks; p = 0.020) and raised the incidence of low birth weight (LBW) (p = 0.022) in neonates. Antiepileptic drug polytherapy significantly increased the risk for small-for-gestational-age regarding weight (SGA^W; p = 0.035) and regarding weight and/or length (SGA^W/L; p = 0.046) when compared to monotherapy. GTCS during pregnancy was associated with diverse negative effects comprising shorter GA, an increased incidence of prematurity and LBW in primiparous women. Furthermore, AED polytherapy was correlated with an enhanced risk for SGA delivery. Re-evaluating the need for drug therapy (in particular polytherapy), maintaining seizure control for a given period before pregnancy and counseling about the importance of preventing GTCS might improve pregnancy outcome in women with epilepsy.     

Rhinorrhea: A common nondopaminergic feature of Parkinson's disease

We compared the frequency of rhinorrhea between 34 Parkinson's disease (PD) subjects and 15 normal controls (NC) and explored relationships between rhinorrhea and clinical functions, and degree of nigrostriatal dopaminergic denervation using [¹¹C]dihydrotetrabenazine (DTBZ) brain positron emission tomography imaging. Sixty‐eight percent (23 of 34) of PD subjects reported rhinorrhea of any cause compared with 27% (4 of 15) of NC (χ² = 7.07, P = 0.008). Rhinorrhea frequency remained higher in the PD group after excluding possible rhinitic etiologies: 35% (12 of 34) of PD versus 7% (1 of 15) of NC (χ² = 4.38, P = 0.04). There were no differences in demographics, nigrostriatal dopaminergic denervation, and clinical motor or nonmotor variables between PD subjects with and without rhinorrhea, except that more PD subjects with rhinorrhea complained of lightheadedness (52% vs. 9%, χ² = 5.85, P = 0.02). Rhinorrhea is a common nondopaminergic feature of PD, unrelated to olfactory or motor deficits. Further investigations are needed to determine if rhinorrhea correlates with sympathetic denervation or other autonomic symptoms in PD. © 2010 Movement Disorder Society     

Abnormal MoCA and normal range MMSE scores in Parkinson disease without dementia: Cognitive and neurochemical correlates

BackgroundThe Montreal Cognitive Assessment (MoCA) is increasingly being used as a cognitive screening test in Parkinson disease (PD). The MoCA's popularity likely reflects its ability to detect executive dysfunction, a relative deficiency of the Mini-Mental State Examination (MMSE).ObjectiveTo compare neurochemical and neuropsychological functions in non-demented PD patients with mild cognitive impairment (PD-MCI) and without, as defined by MoCA (PD-MCI = MoCA<26).MethodsNon-demented PD subjects underwent combined MoCA and MMSE, detailed cognitive testing and [¹¹C]methyl-4-piperidinyl propionate acetylcholinesterase and [¹¹C]dihydrotetrabenazine monoaminergic PET imaging.ResultsEighteen subjects met MoCA PD-MCI criteria but had MMSE scores in the normal range, compared to 29 subjects with normal MoCA and MMSE scores. The MoCA-defined PD-MCI group had reduced performance in global cognition (t = 2.91, P = 0.0056), most significantly in executive function (t = 3.18, P = 0.002), as well as significant reduction in dorsal caudate nucleus dopaminergic innervation (t = 2.72, P = 0.009) compared to the PD without MCI group. Both MoCA and MMSE had poor diagnostic accuracy for PD-MCI (65.3%) when using the Level 2 Movement Disorder Society Task Force definition.ConclusionPD subjects with normal range MMSE but abnormal MoCA scores had evidence of caudate nucleus dopaminergic denervation and mild cognitive changes, predominantly in executive function. The MoCA may be able to preferentially detect executive dysfunction compared to the MMSE, but the MoCA has limited diagnostic accuracy for PD-MCI, and should not be used alone to make this diagnosis.     

Neuroimaging and clinical predictors of fatigue in Parkinson disease

BackgroundFatigue is disabling in Parkinson disease. It is often associated with other non-motor symptoms, but little is known about its underlying pathophysiology.ObjectiveTo investigate neuroimaging (using dopaminergic and cholinergic PET) and clinical factors associated with fatigue severity in PD.Methods133 PD subjects (96M/37F) completed the Fatigue Severity Scale, Movement Disorders Society-Sponsored Revision of the Unified PD Rating Scale (MDS-UPDRS), Hoehn-Yahr staging, validated scales for depression, anxiety, apathy, sleep, and cognition, and underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [¹¹C]dihydrotetrabenazine (DTBZ) monoaminergic PET imaging. We explored contributions to PD fatigue using separate regression models based either on neuroimaging parameters or clinicometric scales.ResultsIn a neuroimaging regression model, neither striatal DTBZ uptake nor AChE PMP uptake were predictors of fatigue in PD. In a post-hoc neuroimaging regression model, stratifying the total cohort into mild vs. moderate-to-severe PD, striatal DTBZ uptake was a significant predictor of fatigue in mild but not moderate-to-severe PD. In a clinicometric regression model, higher Beck Depression Inventory-somatic subscore, higher levodopa dose equivalents and younger age were all significant predictors of fatigue in PD, but the MDS-UPDRS non-motor experiences of daily living score was the best predictor overall.ConclusionsCholinergic uptake was not a predictor of fatigue in PD, but nigrostriatal dopaminergic denervation predicted fatigue in mild disease. Total non-motor symptom burden, somatic affective symptoms, levodopa dose equivalents, and younger age were independent clinical predictors of fatigue.     

Sequence Variants in SLC6A3, DRD2, and BDNF Genes and Time to Levodopa-Induced Dyskinesias in Parkinson’s Disease

Levodopa-induced dyskinesias (LID) present a common but elusive complication of levodopa therapy in Parkinson’s disease (PD). In order to identify genetic factors associated with LID, 352 (213 males) levodopa-treated Israeli PD patients were genotyped for 34 polymorphisms within three candidate genes affecting dopaminergic activity and synaptic plasticity: dopamine transporter gene (DAT1 or SLC6A3) [14 single nucleotide polymorphisms (SNPs) and 40-bp variable number tandem repeat (VNTR)], DRD2 [11 SNPs and dinucleotide CA short tandem repeat (STR)], and BDNF (7 SNPs). A comparison of patients with and without LID was performed by applying a time-oriented approach, with survival analyses evaluating LID development hazard rate over time [Cox proportional hazards and accelerated failure time (AFT) lognormal models]. Overall, 192 (54.5 %) participants developed LID, with a mean latency of 5.0 (±4.5) years. After adjusting for gender, age at PD onset, duration of symptoms prior to levodopa exposure, and multiple testing correction, one SNP in SLC6A3 (with 81 % genotyping success) was significantly associated with LID latency: the C allele of the rs393795 extended the time to LID onset, time ratio?=?4.96 (95 % CI, 2.3–10.9; p?=?4.1?×?10^?5). This finding should be validated in larger, ethnically diverse PD populations, and the biological mechanism should be explored.