Side and type of motor symptom influence cognition in Parkinson's disease.

It is well known that many patients with Parkinson's disease experience neuropsychological decline. However, the nature and extent of mental status change varies widely, with some patients showing mild or no cognitive impairments and others exhibiting frank dementia. Research has shown that several clinical disease parameters may differentially correlate with patterns of neuropsychological dysfunction. The present study examined side and type of motor symptom at disease onset and their relationship to cognition in idiopathic Parkinson's disease (PD). We identified 58 patients who initially presented with one of the following symptom profiles: right-side tremor onset (RSO-T; n = 15), right-side bradykinesia/rigidity onset (n = 12), left-side tremor onset (n = 19), and left-side bradykinesia/rigidity onset (n = 12). There were no differences between groups in disease duration, overall mental status, education, or depression severity. We administered a battery of neuropsychological measures to the four PD subgroups and a group of matched control subjects (n = 40). MANCOVAs controlling for age revealed patients with RSO-T performed significantly better than the other three PD subgroups across the entire neuropsychological battery. Further, the RSO-T subgroup performed comparably to controls. In contrast, the other three PD subgroups showed widespread cognitive deficits. These findings suggest an intricate relationship between motor symptom and side of disease onset and it is the combination of these factors that may influence the disease course and extent of cognitive deterioration. Furthermore, patients who develop tremor on the right side of their body represent a distinct subgroup of PD patients who exhibit relative sparing of cognitive function.     

Cognitive impairment is associated with Hoehn and Yahr stages in early,de novo Parkinson disease patients

IntroductionThe relationship between motor impairment and cognitive deterioration has long been described in Parkinson's disease (PD). The aim of the study was to compare cognitive performance of de novo PD patients in relation to the motor impairment severity according to Hoehn and Yahr (HY) stages.MethodsForty de novo PD patients at HY stage I and 40 patients at HY stage II completed a standardized neuropsychological battery. A multivariate analysis of covariance was used to compare cognitive performance between HY groups. Odds ratios (ORs) were employed to explore the risk of cognitive impairment between HY stages. Finally, the prevalence of mild cognitive impairment (MCI) was estimated for patients in HY stage I and II.ResultsPatients at HY stage I obtained better scores on neuropsychological tests than patients at HY stage II (p = 0.001). Univariate analysis of covariance revealed significant differences between HY stages on Rey's auditory verbal learning test -immediate recall (p < 0.0001), 10 points Clock Drawing Test (p = 0.002), and Rey-Osterrieth Complex Figure Test -copy (p < 0.0001). ORs of having cognitive impairment were greater for HY stage II than stage I group. MCI occurred in 7.5% of patients in HY stage I, and in 42.5% of patients in HY stage II.ConclusionIn de novo PD patients, the severity of motor impairment at the diagnosis is associated to cognitive deficits and higher risk of MCI.     

Predictors of onset of psychosis in patients with Parkinson's disease: Who gets it early?

IntroductionPsychosis is one of the common non-motor symptoms of PD, which substantially worsens the quality of life. Hence, it is important to identify factors that are associated with early onset of psychosis in PD. In order to identify those factors, the current study aims to compare various demographic and clinical features of PD patients with early and late onset psychosis.MethodologyIn this prospective case-control study, 51 consecutive patients with PD having psychosis (PDP) were recruited. Median of the latency of onset of psychotic symptoms from the onset of motor symptoms was calculated (5.5 years) and after doing a median split, the cohort of PDP was divided into early onset PDP (EOP, n = 25) and late onset PDP (LOP, n = 26). Both the groups were compared for several demographic and clinical characteristics.ResultsCompared to those with LOP, patients with EOP had poor scores on frontal assessment battery (13.8 ± 2.0 vs 15.3 ± 1.8, p = 0.007), more frequently had Rapid Eye movement sleep Behavior Disorder (RBD) (80% vs 46.2%, p = 0.02), Postural Instability with Gait Difficulty (PIGD) phenotype (72% vs 26.9%, p = 0.002), and excessive daytime sleepiness (Epworth Sleepiness Scale: 8.04 ± 3.7 vs 3.9 ± 3.1). Patients with LOP were older (63.4 ± 7.0 years vs 56.5 ± 8.1 years, p = 0.002) and had higher Levodopa equivalent dose/day (LEDD: 819.1 ± 365.8 vs 608.5 ± 356.3, p = 0.04) compared to those with EOP.ConclusionPresence of RBD, excessive daytime sleepiness, frontal lobe dysfunction, and PIGD phenotype of PD may be associated with early onset of psychosis in PD. Higher LEDD may not trigger early occurrence of psychosis in PD.     

Plasma NfL,clinical subtypes and motor progression in Parkinson's disease

Introductionneurofilament light chain (NfL) levels have been proposed as reliable biomarkers of neurodegeneration in Parkinson's disease (PD) but the relationship between plasma NfL, clinical subtypes of PD and motor progression is still debated.Methodsplasma NfL concentration was measured in 45 healthy controls and consecutive 92 PD patients who underwent an extensive motor and non-motor assessment at baseline and after 2 years of follow-up. PD malignant phenotype was defined as the combination of at least two out of cognitive impairment, orthostatic hypotension and REM sleep behavior disorder. PD patients were divided according to the age-adjusted cut-offs of plasma NfL levels into high and normal NfL (H-NfL and N-NfL, respectively). A multivariable linear regression model was used to assess the value of plasma NfL as predictor of 2-years progression in PD.ResultsNfL was higher in PD patients than in controls (p = 0.037). H-NfL (n = 16) group exhibited more severe motor and non-motor symptoms, higher prevalence of malignant phenotype and worse motor progression (MDS-UPDRS-III 11.3 vs 0.7 points, p = 0.003) compared to N-NfL group (n = 76). In linear regression analyses plasma NfL emerged as the best predictor of 2-year motor progression compared to age, sex, disease duration, baseline motor/non-motor variables.Conclusionincreased plasma NfL concentration is associated with malignant PD phenotype and faster motor progression. These findings support the role of NfL assessment as a useful measure for stratifying patients with different baseline slopes of decline in future clinical trials of putative disease-modifying treatments.     

Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson’s disease

IntroductionParkinson’s disease (PD) is characterized by loss of dopaminergic neurons. Neuroinflammation may represent an important factor in the pathophysiology of PD and recent findings indicate that PD patients present a pro-inflammatory peripheral profile of CD4+ T lymphocytes, which may correlate with motor disability. However, no data are currently available on the relationship between CD4+ T lymphocytes and cognitive function in PD.The aim of our study is to evaluate the relationship between cognitive profile and circulating CD4+ T lymphocyte subsets in PD patients.MethodsPD patients underwent blood withdrawal and CD4+ T lymphocyte subpopulations, including CD4+ T naïve and memory cells, Th1, Th2, Th17, Th1/17 and T regulatory (Treg) cells were evaluated by flow cytometry. Cognitive evaluation was performed using Addenbrooke Cognitive Examination (ACE-R).Results43 consecutive PD patients (31 males; age [mean ± SD]: 68.9 ± 8.4 years) were enrolled. 14/43 (32.6%) were drug naïve. Based on the ACE-R score, patients were divided in two groups using defined cutoff values. In comparison to patients with normal cognitive profile, patients with cognitive impairment had a higher number of circulating lymphocytes. Moreover, drug naïve patients with a worse cognitive outcome had a lower number of resting Treg and higher number of activated Treg. Furthermore, we found a correlation between pro-inflammatory peripheral immune phenotype and worse cognitive outcome in the ACE-R total and sub-items scores.ConclusionsIn our cohort of PD patients, cognitive impairment was associated with higher number of circulating lymphocytes, and – at least in drug naïve patients – with dysregulation of the Treg compartment. Further studies are needed to assess whether and to what extent peripheral immunity mechanistically contributes to cognitive decline in PD.     

Severity of mild cognitive impairment in early Parkinson's disease contributes to poorer quality of life

BackgroundPoor 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.MethodPatients 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.ResultsParticipants 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.ConclusionsPD-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.     

Cognitive decline and quality of life in incident Parkinson's disease: The role of attention

IntroductionParkinson's disease dementia (PDD) is associated with poorer quality of life (QoL). Prior to the onset of PDD, many patients experience progressive cognitive impairment. There is a paucity of longitudinal studies investigating the effects of cognitive decline on QoL. This study aimed to determine the longitudinal impact of cognitive change on QoL in an incident PD cohort.MethodsRecently diagnosed patients with PD (n = 212) completed a schedule of neuropsychological assessments and QoL measures; these were repeated after 18 (n = 190) and 36 months (n = 158). Mild cognitive impairment (PD-MCI) was classified with reference to the Movement Disorder Society criteria. Principal component analysis was used to reduce 10 neuropsychological tests to three cognitive factors: attention, memory/executive function, and global cognition.ResultsBaseline PD-MCI was a significant contributor to QoL (β = 0.2, p < 0.01). For those subjects (9%) who developed dementia, cognitive function had a much greater impact on QoL (β = 10.3, p < 0.05). Multivariate modelling showed attentional deficits had the strongest predictive power (β = −2.3, p < 0.01); brief global tests only modestly predicted decline in QoL (β = −0.4, p < 0.01).ConclusionsPD-MCI was associated with poorer QoL over three years follow up. Cognitive impairment had a greater impact on QoL in individuals who developed dementia over follow-up. Impaired attention was a significant determinant of QoL in PD. Interventions which improve concentration and attention in those with PD could potentially improve QoL.     

Frontal functional connectivity and disease duration interactively predict cognitive decline in Parkinson's disease

ObjectiveCognitive decline does not always follow a predictable course in Parkinson’s disease (PD), with some patients remaining stable while others meet criteria for dementia from early stages. Functional connectivity has been proposed as a good correlate of cognitive decline in PD, although it has not been explored whether the association between this connectivity and cognitive ability is influenced by disease duration, which was our objective.MethodsWe included 30 patients with PD and 15 healthy controls (HC). Six cognitive domains were estimated based on neuropsychological assessment. Phase-based connectivity at frontal and posterior cortical regions was estimated from a resting EEG.ResultsThe PD group showed significant impairment for the executive, visuospatial, and language domains compared with HC. Increased connectivity at frontal regions was also found in the PD group. Frontal delta and theta connectivity negatively influenced general cognition and visuospatial performance, but this association was moderated by disease duration, with increased connectivity predicting worse performance after 8 years of disease duration.ConclusionSubtle neurophysiological changes underlie cognitive decline along PD progression, especially around a decade after motor symptoms onset.SignificanceConnectivity of EEG slow waves at frontal regions might be used as a predictor of cognitive decline in PD.     

Cognitive profiling in relation to short latency afferent inhibition of frontal cortex in multiple system atrophy

BackgroundCognitive dysfunction occurs in multiple system atrophy (MSA) more frequently than previously known. As a type of synucleinopathy, pathology spreads widely in cortical and subcortical areas as the disease advances. The exact anatomical and imaging substrates, and electrophysiological or biochemical indicators of cognitive impairment in MSA are not yet clear. Diminished short-latency afferent inhibition (SAI) of motor cortex was shown to be an electrophysiological correlate of dementia and mild cognitive impairment associated to Parkinson's disease (PD). We hypothesize that it can also be electrophysiological correlate of cognitive impairment in MSA.MethodsWe studied SAI and a neuropsychological test battery in 19 non-demented MSA patients (11 MSA-P and 8 MSA-C), 10 non-demented PD patients and 10 healthy controls. Neuropsychological test scores were grouped in four main cognitive domains (attention, memory, executive and visuo-spatial functions) and were analyzed by factor analysis.ResultsAll subject groups were matched for age. Moreover, the MSA-P, MSA-C, and PD groups were matched for disease duration. Scores of cognitive domains were similar in MSA and PD cases, while scores in attention, executive and visuo-spatial domains were worse in MSA than controls (p < 0.05). SAI was normal in PD but decreased in MSA patients by reaching statistical significance in MSA-C subtype. SAI response was correlated with cognitive performances measured by factor scores of neuropsychological test battery in all study subjects.ConclusionsThese results show that cognitive functions are impaired in MSA patients compared to controls as well as a parallel reduction in SAI response.     

Cerebral white matter hyperintensity in Parkinson's disease: A major risk factor for mild cognitive impairment

BackgroundMild cognitive impairment (MCI) and dementia contribute to a poor quality of life among patients with PD. The influence of cerebral ischemia as a risk factor for MCI in PD has not been adequately investigated. To address this issue, we examined the influence of the volume and distribution of white matter hyperintensity (WMH) as a risk factor for MCI in early PD.MethodsProspective study of patients with early idiopathic PD. All patients had baseline MRI-FLAIR, clinical assessment and detailed neuropsychological evaluation. Data on demographics, vascular risk factors, cognitive performance and WMH volumes were analyzed.Results91 patients; mean age 64.9 years, mean education of 10.5 years. 24 patients fulfilled the Movement Disorder Society criteria for MCI and were classified as PD-MCI while the rest were classified as PD with no cognitive impairment (PD-NCI). Patients with PD-MCI and PD-NCI did not differ in Hoehn & Yahr staging. PD-MCI patients had a higher prevalence of diabetes mellitus, hypertension and hyperlipidemia. PD-MCI patients had significantly greater volume of periventricular (6.04 ml vs. 2.66 ml, p = 0.001) and deep subcortical WMH (2.16 vs.1.44, p = 0.002). Regional WMH was significantly greater among PD-MCI in the frontal, parietal and occipital regions. Logistic regression analyses demonstrated WMH to be associated with PD-MCI independent of age, education, and vascular risk factors. Increasing WMH volume was associated with lower performance on executive function, memory and language.ConclusionsWMH is an important risk factor for PD-MCI independent of vascular risk factors. PD patients with WMH should be regularly screened for MCI.     

Dissociations among daytime sleepiness,nighttime sleep,and cognitive status in Parkinson's disease

BackgroundDaytime and nighttime sleep disturbances and cognitive impairment occur frequently in Parkinson's disease (PD), but little is known about the interdependence of these non-motor complications. Thus, we examined the relationships among excessive daytime sleepiness, nighttime sleep quality and cognitive impairment in PD, including severity and specific cognitive deficits.MethodsNinety-three PD patients underwent clinical and neuropsychological evaluations including the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Patients were classified as having normal cognition (PD-NC), mild cognitive impairment (PD-MCI), or dementia (PDD) using recently proposed Movement Disorder Society PD-MCI and PDD criteria. Relationships between the sleep and cognitive measures and PD cognitive groups were examined.ResultsThe PD cohort included PD-NC (n = 28), PD-MCI (n = 40), and PDD (n = 25) patients. ESS scores, as a measure of daytime sleepiness, were significantly worse (p = 0.005) in cognitively impaired PD patients, particularly PDD patients. ESS scores correlated significantly with Mini-Mental State Examination scores and also with cognitive domain scores for attention/working memory, executive function, memory, and visuospatial function. In contrast, PSQI scores, as a measure of nighttime sleep quality, neither differed among cognitive groups nor correlated with any cognitive measures.ConclusionsDaytime sleepiness in PD, but not nighttime sleep problems, is associated with cognitive impairment in PD, especially in the setting of dementia, and attention/working memory, executive function, memory, and visuospatial deficits. The presence of nighttime sleep problems is pervasive across the PD cognitive spectrum, from normal cognition to dementia, and is not independently associated with cognitive impairment or deficits in cognitive domains.     

Treating sleep apnea in Parkinson's disease with C-PAP: feasibility concerns and effects on cognition and alertness

BackgroundObstructive sleep apnea (OSA) is highly prevalent in Parkinson disease (PD) and is known to contribute to cognitive impairment and daytime sleepiness. We investigated feasibility of continuous positive airway pressure treatment (CPAP) and its effects on subjective daytime sleepiness and cognitive profile in PD plus OSA subjects in a longitudinal three months follow up study.MethodsSeventy (age 71.7 ± 7.6, disease duration 9.9 ± 12.3, UPDRS-III 33.7 ± 12.5, MMSE 25.3 ± 3.6; years of education 7.7 ± 3.2) out of 228 consecutive PD patients undergoing in-lab video-polysomnography were found to have obstructive sleep apnea. Thirty-six subjects accepted to titrate therapeutic CPAP. Video-polysomnography, neuropsychological battery evaluating different cognitive domains and subjective scales for daytime sleepiness were scheduled at baseline and after three months. All the patients were given educational informations relative to diagnosis of OSA and benefits of OSA treatment, and an individualized training with CPAP.ResultsTwenty-seven (75%) subjects dropped out of the study due to CPAP intolerance. No demographic or disease-related variables (in particular, severity of OSA), could be found between subjects who completed the study versus those who dropped out. Nine subjects completed the three-month follow up, and there were no significant changes in subjective sleepiness, neuropsychological scores and sleep structure (except for reduction in apnea/hypopnea index and a trend toward increase in stage N3 sleep).ConclusionOur data show that feasibility of CPAP treatment can be significantly threatened by overall attrition rates. Further studies should consider well-structured adherence promoting interventions. The actual role of OSA as a determinant of the profile of subjective daytime sleepiness and cognition in PD, and the effects of CPAP in PD need to be further studied.     

Functional neuroimaging and clinical features of drug naive patients with de novo Parkinson’s disease and probable RBD

IntroductionThe association between Parkinson Disease (PD) and REM sleep behavior disorder (RBD) has been related to a specific, malignant clinical phenotype. Definite RBD diagnosis requires video-polysomnography that is often unfeasible. A malignant clinical PD-RBD phenotype could be expected also in PD patients with probable RBD. Aim of this cross-sectional study was to evaluate whether a more severe neuropsychological and functional neuroimaging phenotype can be identified in PD patients with probable RBD.MethodsThirty-eight de novo, drug naïve PD patients underwent a first-line clinical assessment and a second-line multimodal assessment, including neuropsychological evaluation, ¹²³I-FP-CIT-SPECT and ¹⁸F-FDG-PET, which were compared between PD patients with (PD + RBD+) and without (PD + RBD-) probable RBD.ResultsOn first-line assessment, PD + RBD + patients had significantly more constipation (p = 0.02) and showed worse olfaction (p = 0.01) compared with PD + RBD-while the two groups were similar as for age, presence of orthostatic hypotension, UPDRS-III and MMSE scores. On second-line assessment, PD + RBD + patients showed a worse neuropsychological test profile, more severe nigro-striatal dopaminergic impairment, mainly at caudate level in the less affected hemisphere (p = 0.004) and impaired brain glucose metabolism, with relative hypometabolism in posterior cortical regions and relative hypermetabolism mainly in anterior regions of the more affected hemisphere (p = 0.015).ConclusionsPD patients with probable RBD are likely to have a more severe neuropsychological and functional brain-imaging phenotype already at the time of diagnosis.     

Motor,behavioural, and cognitive correlates of fatigue in early,de novo Parkinson disease patients

IntroductionFatigue is one of the most common and disabling non-motor symptoms in Parkinson's disease (PD). The objective of this study was to determine prevalence and motor, behavioural, and cognitive correlates of distressing fatigue in early, de novo PD patients.MethodsEighty-one consecutive de novo PD patients (64% men; mean age 65.73 ± 8.26 years) underwent a comprehensive examination, including Parkinson's disease Fatigue Scale (PFS), Epworth Sleepiness Scale (ESS), Parkinson's Disease Sleep Scale (PDSS), Beck Depression Inventory (BDI), Parkinson's Anxiety Scale (PAS), and Apathy Evaluation Scale (AES). Moreover, all patients underwent a detailed neuropsychological evaluation exploring attention and working memory, executive functions, memory, visuospatial abilities and language. Score of patients with or without distressing fatigue (defined as a PFS score ≥ 8) were compared by Student's t-test or Pearson's chi-square test. Logistic regression analyses were performed to search for motor and non-motor features independently associated with presence of distressing fatigue.ResultsTwelve (15%) patients presented distressing fatigue. Logistic regression identified sleepiness (p = 0.04), “episodic anxiety” subscale of PAS (p = 0.005), and “cognitive apathy” subscale of AES (p = 0.017) as the main factors associated with distressing fatigue. No significant association was found between diagnosis of Mild Cognitive Impairment and distressing fatigue (p = 0.745).ConclusionIn a sample of consecutive de novo PD patients, distressing fatigue is associated with episodic anxiety, cognitive apathy and sleepiness, but not with cognitive impairment. Our findings suggest possible shared pathogenic mechanisms underlying these non-motor symptoms and foster development of early combined therapeutic approaches.     

Subclinical neurological involvement does not develop if Wilson's disease is treated early

Background & aimsWilson's disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset.MethodsThirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests.ResultsPatients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement.ConclusionsThis study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.     

Thalamic volume and related visual recognition are associated with freezing of gait in non-demented patients with Parkinson's disease

BackgroundThe pathophysiology of freezing of gait (FOG) in non-demented Parkinson's disease (PD) patients remains poorly understood. Recent studies have suggested that neurochemical alterations in the cholinergic systems play a role in the development of FOG. Here, we evaluated the association between subcortical cholinergic structures and FOG in patients with non-demented PD.MethodsWe recruited 46 non-demented patients with PD, categorized into PD with (n = 16) and without FOG (n = 30) groups. We performed neuropsychological test, region-of-interest-based volumetric analysis of the substantia innominata (SI) and automatic analysis of subcortical brain structures using a computerized segmentation procedure.ResultsThe comprehensive neuropsychological assessment showed that PD patients with FOG had lower cognitive performance in the frontal executive and visual-related functions compared with those without freezing of gait. The normalized SI volume did not differ significantly between the two groups (1.65 ± 0.18 vs. 1.68 ± 0.31). The automatic analysis of subcortical structures revealed that the thalamic volumes were significantly reduced in PD patients with FOG compared with those without FOG after adjusting for age, sex, disease duration, the Unified PD Rating Scale scores and total intracranial volume (left: 6.71 vs. 7.16 cm³, p = 0.029, right: 6.47 vs. 6.91 cm³, p = 0.026). Multiple linear regression analysis revealed that thalamic volume showed significant positive correlations with visual recognition memory (left: β = 0.441, p = 0.037, right: β = 0.498, p = 0.04).ConclusionsThese data suggest that thalamic volume and related visual recognition, rather than the cortical cholinergic system arising from the SI, may be a major contributor to the development of freezing of gait in non-demented patients with PD.     

Interhemispheric Balance in Parkinson's Disease: A Transcranial Magnetic Stimulation Study

BackgroundParkinson's disease (PD) is characterized by various changes in motor excitability.ObjectiveTo examine through Transcranial Magnetic Stimulation (TMS) cortical excitability, specifically addressing interhemispheric connections in PD.MethodsNineteen PD patients with a predominant involvement of the left hemibody (7 females, age 61.7 years,) and 13 controls (6 females, age 61.5 years) entered the study. Patients were subdivided into two groups (early and advanced) according to the time from PD diagnosis. Participants underwent evaluation of Resting Motor Threshold (RMT) and ipsilateral Silent Period (iSP), induced by suprathreshold TMS on the ipsilateral-M1, measured as suppression of voluntary EMG activity. Mirror Movements (MM) were EMG-recorded and scored, in three upper limb muscles, during unilateral voluntary hand movement. Patients were studied at baseline (OFF drug) and after acute levodopa challenge (ON).ResultsPD patients showed a general reduction in RMT vs controls (P < 0.01 for right and left hemisphere) in both drug conditions. Early PD had a significantly lower RMT over the right vs the left hemisphere (P = 0.027); this difference was no longer significant after levodopa. In early PD patients, MM were mainly observed in the right arm during voluntary activation of the left, more affected side both in OFF (P = 0.033) and in ON (P = 0.046). In PD, RMT of the left, less affected M1 was significantly correlated with the right lateralized motor score (P = 0.011; Spearman's coefficient = ?0.585), as well as with disease duration. In PD patients, a shorter (P = 0.039) and smaller (P = 0.037) iSP was detected when the stimulus was applied to the worse M1 (right) compared with the contralateral side. This asymmetry was significant only OFF drug. In the PD group iSP-duration from the right, less affected APB was negatively correlated with the MM recorded from the same side during the voluntary movement of the worse side (Spearman's coefficient = ?0.498; P = 0.035).ConclusionsIncreased cortical motor excitability in PD, consistent with previous findings, is more evident in the worse hemisphere, particularly in early PD. Asymmetric motor involvement is also associated with excessive involuntary mirroring and defective interhemispheric inhibition, both unfavoring the more affected side. Altogether, these findings suggest that asymmetric motor involvement in PD, particularly in the earlier phases of the disease, affects the interhemispheric balance of cortical excitability, movement lateralization and transcallosal inhibition.     

Are there differences in cortical excitability between akinetic-rigid and tremor-dominant subtypes of Parkinson's disease?

ObjectiveTo assess by transcranial magnetic stimulation (TMS) the excitability of various cortical circuits in akinetic-rigid and tremor-dominant subtypes of Parkinson's disease (PD).MethodsThe study included 92 patients with PD according to UK Brain Bank criteria, with akinetic-rigid (n = 64) or tremor-dominant (n = 28) subtype. Cortical excitability study, including resting and active motor thresholds (rMT and aMT), input—output curve of motor evoked potentials, contralateral and ipsilateral silent periods (cSP and iSP), short and long-interval intracortical inhibition (SICI and LICI), and intracortical facilitation (ICF) were measured. The results obtained were compared to a control group of 30 age- and sex-matched healthy subjects.ResultsThe patients in the tremor group had significantly lower rMT and aMT compared to controls and akinetic-rigid patients and significantly shorter iSP duration compared to akinetic-rigid patients, while iSP latency tended to be longer in akinetic-rigid patients compared to controls. There were no significant differences between the two PD subgroups regarding other cortical excitability parameters, including paired-pulse TMS parameters.ConclusionsOnly subtle differences of cortical excitability were found between patients with akinetic-rigid vs. tremor-dominant subtype of PD.SignificanceThe clinical heterogeneity of PD patients probably has an impact on cortical excitability measures, far beyond the akinetic-rigid versus tremor-dominant profile.     

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.     

Gender may be related to the side of the motor syndrome and cognition in idiopathic Parkinson's disease

Backgroundand Sex and cognitive profile may be related to the laterality of motor symptoms in idiopathic Parkinson's disease.IntroductionParkinson's disease (PD) is well recognised as an inherently asymmetric disease with unilateral onset of motor symptoms. The laterality of motor symptoms may be linked to sex, clinical and demographic variables, and neuropsychological disorders. However, the available data are inconsistent. This study aimed to explore the potential association between the laterality of motor symptoms and clinical and demographic variables and deficits in specific cognitive domains.Material and methodsWe retrospectively recruited 97 participants with idiopathic PD without dementia; 60 presented motor symptoms on the left side and 37 on the right side. Both groups were comparable in terms of age, age at disease onset, disease duration, and severity of the neurological deficits according to the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr scale.ResultsParticipants with left-side motor symptoms scored lower on the Schwab and England Activities of Daily Living scale. Our sample included more men than women (67% vs. 33%). Both sexes were not equally represented in the 2 groups: there were significantly more men than women in the group of patients with left-side motor symptoms (77% vs. 23%), whereas the percentages of men and women in the group of patients with right-side motor symptoms were similar (51% vs. 49%). Both groups performed similarly in all neuropsychological tasks, but women, independently of laterality, performed better than men in the naming task.ConclusionWe found a clear prevalence of men in the group of patients with left-side motor symptoms; this group also scored lower on the Schwab and England Scale. Female sex was predictive of better performance in the naming task. Sex should always be considered in disorders that cause asymmetric involvement of the brain, such as PD.