Apathy in drug-naïve patients with incident Parkinson’s disease: the Norwegian ParkWest study

Apathy is a common behavioural problem in Parkinson’s disease (PD), with important clinical consequences for patients and their families. However, little is known about apathy in early PD. We examined the frequency and clinical characteristics of apathy in 175 nondemented, drug-naïve patients with newly diagnosed PD and 165 control subjects matched for age, sex and education level in Western and Southern Norway. All participants underwent a comprehensive neurological, psychiatric and neuropsychological evaluation. Apathy was diagnosed based on Neuropsychiatric Inventory assessment and recently proposed consensus criteria. Apathy was found in 22.9% of the PD patients, of whom 37.5% had significant depressive symptoms, whereas none of the control subjects were apathetic. Apathy was significantly associated with male gender, higher depression scores and more severe motor symptoms, but was not associated with greater cognitive impairment. When excluding patients with significant depressive symptoms, apathy remained significantly associated with motor severity. Approximately 50% of the caregivers of patients with apathy reported the apathetic behaviour to be at least moderately distressing. The association between apathy and motor severity in our PD cohort suggests a common underlying pathophysiological mechanism. Future studies should explore the longitudinal effect of dopamine replacement therapy on apathetic behaviour in early PD. The relationship between apathy and male gender needs further study to be fully evaluated.     

Restless legs syndrome in Korean patients with drug-naïve Parkinson's disease: A nation-wide study

BackgroundRestless legs syndrome is a common neurologic disorder, and there is increasing evidence for a dopaminergic link between Parkinson's disease and restless legs syndrome. However, most previous studies did not take into account the effects of dopaminergic medication. We conducted a nation-wide, cross-sectional study to determine the prevalence and clinical characteristics of restless legs syndrome in Korean drug-naïve Parkinson's disease patients.MethodsOne hundred and fifty-one drug-naïve patients with Parkinson's disease were enrolled from 18 centers in South Korea over the course of one year. Clinical profiles of parkinsonism, restless legs syndrome, psychiatric symptoms, and laboratory data were collected. The findings of subjects with and without restless legs syndrome were compared.ResultsThe prevalence of restless legs syndrome in drug-naïve patients with Parkinson's disease was 16.5%. Subjects with restless legs syndrome had a higher mean Hoehn and Yahr stage and more severe limb parkinsonism, especially tremor. There was, however, no difference in iron metabolism between patients with and without restless legs syndrome. Analysis demonstrated that Beck's depression inventory score was associated with the severity of restless legs syndrome.ConclusionOur study demonstrated an increased prevalence of restless leg syndrome in drug-naïve patients with Parkinson's disease than in the general population. Based on the association between parkinsonism and restless legs syndrome, and the unique characteristics of restless legs syndrome in patients with Parkinson's disease, we suggest that the pathophysiology of restless legs syndrome in Parkinson's disease differs from that in patients without Parkinson's disease.     

Functional connectomes of akinetic-rigid and tremor within drug-naïve Parkinson's disease

Aims

To detect functional connectomes of akinetic-rigid (AR) and tremor and compare their connection pattern.

Methods

Resting-state functional MRI data of 78 drug-naïve PD patients were enrolled to construct connectomes of AR and tremor via connectome-based predictive modeling (CPM). The connectomes were further validated with 17 drug-naïve patients to verify their replication.

Results

The connectomes related to AR and tremor were identified via CPM method and successfully validated in the independent set. Additional regional-based CPM demonstrated neither AR nor tremor could be simplified to functional changes within a single brain region. Computational lesion version of CPM revealed that parietal lobe and limbic system were the most important regions among AR-related connectome, and motor strip and cerebellum were the most important regions among tremor-related connectome. Comparing two connectomes found that the patterns of connection between them were largely distinct, with only four overlapped connections identified.

Conclusion

AR and tremor were found to be associated with functional changes in multiple brain regions. Distinct connection patterns of AR-related and tremor-related connectomes suggest different neural mechanisms underlying the two symptoms.     

Default-mode network connectivity in cognitively unimpaired drug-naïve patients with rigidity-dominant Parkinson’s disease

Parkinson’s disease (PD) with akinetic rigidity (PD_AR) is more likely to develop cognitive deficits compared to PD with tremor-dominant symptoms (PD_TD). The default mode network (DMN) is highly relevant for cognitive processes, so this study tested the functional connectivity (FC) of DMN in cognitively unimpaired PD_AR patients. Resting-state fMRI data were collected in 21 cognitively unimpaired early stage drug-naïve patients with PD_AR and 21 healthy controls (HC). PD patients were matched closely to HCs for demographic and cognitive variables. FC of DMN was evaluated by seed-based correlation approach. Compared to HCs, despite comparable cognitive performance and no statistically discernible GM volume differences, a disruption in the DMN of PD_AR subjects was detected. A decreased FC of DMN was found, specifically prominent in the posterior DMN. We also found a significantly increased FC of the anterior DMN. Three parts of left medial prefrontal regions (anterior, ventral, and dorsal) had significantly increased FC with the cerebellum. In addition, increased FC values of the anterior and ventral parts were negatively correlated with cognitive scores. An evident decline of FC of posterior DMN and enhanced compensatory FC of anterior DMN suggested an early functional disruption of DMN in PD_AR prior to clinical evidence of cognitive impairment. It could be hypothesized that the dysfunction of DMN connectivity may have a role in the development of cognitive decline in PD. However, further longitudinal studies are warranted to understand the underlying neural mechanisms and their relevance to clinical and cognitive outcomes in PD_AR subtype.     

Prolactin levels in drug-naïve patients with schizophrenia and other psychotic disorders

Objective: Hyperprolactinaemia as a side effect of dopamine receptor blockers is common in patients with schizophrenia and other psychotic disorders and may lead to amenorrhoea, galactorrhoea, hypogonadism, subfertility and osteoporosis. The aim of our study was to determine whether hyperprolactinaemia occurs also in patients with schizophrenia and other psychotic disorders prior to any antipsychotic treatment.

Methods: Serum prolactin, thyroid-stimulating hormone (TSH), triiodothyronine (T3), free tetraiodothyronine (FT4) and cortisol levels were measured in 40 newly diagnosed, drug naïve, patients with schizophrenia and other psychotic disorders and in 40 age and gender matched healthy subjects.

Results: The median prolactin value was 12.5?ng/ml (range: 2–38?ng/ml) for patients and 8.6?ng/ml (range: 4–17.6?ng/ml) for healthy subjects (p?=?0.011). Patients had lower levels of T3 compared to healthy controls (mean: 1.08?ng/ml, SD: 0.16 vs. 1.18?ng/ml, 0.18, respectively; p?=?0.008). Serum TSH, FT4 and cortisol levels were similar between the two groups. Multiple regression analysis revealed that the difference in serum prolactin values was independent of thyroid function (TSH, FT4, T3) and serum cortisol levels.

Conclusions: A higher serum prolactin level was found in drug naïve, newly diagnosed patients with schizophrenia and other psychotic disorders compared to healthy controls, prior to starting any antipsychotic treatment.     

Topography of sensory symptoms in patients with drug-naïve restless legs syndrome

ObjectivesWe aimed to describe the sensory topography of restless legs syndrome (RLS) sensory symptoms and to identify the relationship between topography and clinical variables.MethodsEighty adult patients with drug-naïve RLS who had symptoms for more than 1 year were consecutively recruited. During face-to-face interviews using a structured paper and pencil questionnaire with all participants, we obtained clinical information and also marked the topography of RLS sensory symptoms on a specified body template, all of which were subsequently inputted into our in-house software. The RLS sensory topography patterns were classified according to localization, lateralization, and symmetry. We investigated if these sensory topography patterns differed according to various clinical variables.ResultsThe lower extremities only (LE) were the most common location (72.5%), and 76.3% of participants exhibited symmetric sensory topography. Late-onset RLS showed more asymmetric sensory distribution compared with early-onset RLS (P = .024). Patients whose sensory symptoms involved the lower extremities in addition to other body parts (LE-PLUS) showed more severe RLS compared with those involving the LE (P = .037).ConclusionRLS sensory symptoms typically were symmetrically located in the lower extremities. LE-PLUS or an asymmetric distribution more often occurred in patients with more severe RLS symptoms or late-onset RLS.     

Gait in drug naïve patients with de novo Parkinson's disease – altered but symmetric

Abstract

Background:

Motor symptoms in Parkinson's disease (PD) are typically asymmetrical. Early stage of PD is characterised with a predominantly unilateral appearance of tremor, rigidity and bradykinesia, with or without axial involvement. Also, studies have demonstrated gait asymmetry in de novo drug naïve PD patients. Aim of this study was to investigate gait pattern, gait symmetry and gait variability in early phases of PD.

Methods:

The gait was measured in 40 de novo, drug naïve PD patients and 43 healthy control subjects (HC) while performing a simple walking task. Calculated parameters were cycle time (CT), stride length (SL) and swing time (ST), and their coefficients of variation (CV).

Results:

Considering gait parameters, PD patients and HC differed in terms of all parameters, except for the CV of CT. Analysis of gait symmetry, comparison between the gait patterns of the left and the right leg in PD patients revealed no difference for any of the assessed parameters. The majority of the gait parameters did not differ between left and right legs of HC.

Conclusions:

It can be concluded that even gait was already altered in de novo drug naive PD patients, gait symmetry remained preserved. The SL was the most prominent parameter of altered gait in initial stages of PD patients, while the ST heralded postural asymmetry.     

Apathy in patients with Parkinson’s disease

Apathy is a common feature of basal ganglia disorders such as Parkinson's disease (PD), yet it is often 'invisible' to the clinician, patient and family. Factors responsible for the lack of recognition of apathy include confusion between the presence of depression and apathy and the overlap of symptoms of apathy with the phenomenology of PD. Raising awareness of apathy in PD is important because apathy contributes to PD-related disability and has an important impact on quality of life. The neurotransmitter dopamine is central to normal motivational behavior. Therefore, PD, a disorder of primary dopamine deficiency, is an ideal model for the study of apathy and its management.     

Frequency-specific altered global signal topography in drug-naïve first-episode patients with adolescent-onset schizophrenia

Adolescent-onset schizophrenia (AOS) is a severe neuropsychiatric disease associated with frequency-specific abnormalities across distributed neural systems in a slow rhythm. Recently, functional magnetic resonance imaging (fMRI) studies have determined that the global signal. (GS) is an important source of the local neuronal activity in 0.01–0.1 Hz frequency band. However, it remains unknown whether the effects follow a specific spatially preferential pattern in different frequency bands in schizophrenia. To address this issue, resting-state fMRI data from 39 drug-naïve AOS patients and 31 healthy controls (HCs) were used to assess the changes in GS topography patterns in the slow-4 (0.027–0.073 Hz) and slow-5 bands (0.01–0.027 Hz). Results revealed that GS mainly affects the default mode network (DMN) in slow-4 and sensory regions in the slow-5 band respectively, and GS has a stronger driving effect in the slow-5 band. Moreover, significant frequency-by-group interaction was observed in the frontoparietal network. Compared with HCs, patients with AOS exhibited altered GS topography mainly located in the DMN. Our findings demonstrated that the influence of the GS on brain networks altered in a frequency-specific way in schizophrenia.

     

Prevalence and factors related to orthostatic syndromes in recently diagnosed,drug-naïve patients with Parkinson disease

Clinical Autonomic Research - The aim of this study was to explore the prevalence of and factors related to orthostatic syndromes in recently diagnosed drug-naïve patients with Parkinson...     

Hyper- and hypo-connectivity in sensorimotor network of drug-naïve patients with cervical dystonia

BackgroundCervical dystonia (CD) is the most common form of focal dystonia with involuntary movements and postures of the head. The pathogenesis and neural mechanisms underlying CD have not been fully elucidated.MethodsTwenty-seven newly drug-naïve patients with CD and 21 healthy controls (HCs) were recruited with clinical assessment and resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Severity of CD was measured by Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Tsui scores. Whole-brain voxel-wise intrinsic connectivity (IC) and seed-based functional connectivity (FC) analyses were performed for detection of changes in the CD group relative to HCs, controlling for age, gender, and global time series correlation, followed by correlation analyses of IC, seed-based FC and clinically relevant features, respectively.ResultsIn comparison with HCs, CD patients showed significantly increased IC measurement in the anterior part of the left supramarginal gyrus and extended to the inferior left postcentral gyrus (AL-SMG/IL-PCG). With this cluster as a seed, decreased FC was found in the right precentral and postcentral gyrus. Moreover, the regional IC value in the AL-SMG/IL-PCG was significantly positively correlated with TWSTRS-1 (severity) score, and significantly negatively correlated with the associated seed-based FC strength.ConclusionsOur results showed signs of both hyper- and hypo-connectivity in bilateral regions of the sensorimotor network related to CD. The imbalance of functional connectivity (both hyper- and hypo-) may hint both overloading and disrupted somatosensory or sensorimotor integration dysfunction within the sensorimotor network underlying the pathophysiology of CD, thus providing a network target for future therapies.     

Alterations in Polysomnographic (PSG) profile in drug-na?ve Parkinson's disease

Objective:

We studied the changes in Polysomnographic (PSG) profile in drug-naïve patients of Parkinson''s disease (PD) who underwent evaluation with sleep overnight PSG.

Materials and Methods:

This prospective study included 30 with newly diagnosed levodopa-naïve patients with PD, fulfilling the UK-PD society brain bank clinical diagnostic criteria (M:F = 25:5; age: 57.2 ± 10.7 years). The disease severity scales and sleep related questionnaires were administered, and then patients were subjected to overnight PSG.

Results:

The mean duration of illness was 9.7 ± 9.5 months. The mean Hoehn and Yahr stage was 1.8 ± 0.4. The mean Unified Parkinson''s Disease Rating Scale (UPDRS) motor score improved from 27.7 ± 9.2 to 17.5 ± 8.9 with sustained usage of levodopa. Nocturnal sleep as assessed by Pittsburgh Sleep Quality Index (PSQI) was impaired in 10 (33.3%) patients (mean PSQI score: 5.1 ± 3.1). Excessive day time somnolence was recorded in three patients with Epworth Sleepiness Scale (ESS) score ≥ 10 (mean ESS score: 4.0 ± 3.4). PSG analysis revealed that poor sleep efficiency of <85% was present in 86.7% of patients (mean: 68.3 ± 21.3%). The latencies to sleep onset (mean: 49.8 ± 67.0 minutes) and stage 2 sleep (36.5 ± 13.1%) were prolonged while slow wave sleep was shortened. Respiration during sleep was significantly impaired in which 43.3% had impaired apnoea hyperpnoea index (AHI) ≥5, mean AHI: 8.3 ± 12.1). Apnoeic episodes were predominantly obstructive (obstructive sleep apnea, OSA index = 2.2 ± 5.1). These patients had periodic leg movement (PLM) disorder (56.7% had PLM index of 5 or more, mean PLMI: 27.53 ± 4 9.05) that resulted in excessive daytime somnolence.

Conclusions:

To conclude, sleep macro-architecture is altered in frequently and variably in levodopa-naïve patients of PD and the alterations are possibly due to disease process per se.     

Platelet serotonin uptake in drug-naïve depressive patients before and after treatment with citalopram

We investigated the kinetic parameters of serotonin (5-HT) uptake into platelets in a group of 26 drug-na?ve patients suffering from major depression before and after 3-7 weeks of treatment with citalopram. The degree of depression was rated using the Hamilton Depression Rating Scale (HDRS). The 5-HT uptake characteristics in untreated depressive patients were not significantly different from those of normal subjects. The apparent Michaelis constant (K(M)) was significantly increased, the apparent maximal velocity (V(max)) was not different from baseline, and the uptake efficiency (V(max)/K(M)) was significantly decreased after citalopram treatment. A significantly positive correlation between K(M) and V(max) was found in all groups. There was a significantly lower V(max) and V(max)/K(M) in the female compared with the male depressed patients before citalopram treatment; a hypothesis was supported that lowered 5-HT uptake may reflect a gender-linked vulnerability to a serotonin-related depression. A significant negative correlation between 5-HT uptake efficiency and the initial HDRS score suggests that platelet 5-HT uptake can be used as a marker of effective depressive disorder pharmacotherapy. The initial severity of depression was significantly negatively correlated with V(max), which supported a hypothesis that the initial severity of depressive disorder could be related to the lower V(max).     

Characteristics of apathy in treatment-naïve patients with Parkinson’s disease

Introduction: Although apathy is a common psychiatric symptom of Parkinson’s disease (PD), there are many unknown aspects of its pathology. This study aimed to investigate the characteristics of apathy in treatment-naïve patients with early-stage PD. Methods: Fifty treatment-naïve patients with early-stage PD were divided into 1 of 2 groups—apathetic or non-apathetic—based on Starkstein Apathy Scale (AS) scores. Cognitive function, depressive symptoms, olfactory function, and motor severity were compared between the two groups using validated assessment scales. Multiple linear regression was performed to assess the association between AS scores and clinical parameters. Results: Apathy (AS score ≥16) was observed in 13 (26%) patients. Assessment scale scores (Beck Depression Inventory-Second Edition [p?<?.004]; modified Hoehn & Yahr stage [p?=?.039]; Unified Parkinson’s Disease Rating Scale part III [p?<?.001]) were significantly higher in apathetic patients than in non-apathetic patients. Significant association between these scale scores and AS score was also evident (all p ≤ .001). There were no significant differences in the test scores derived from several other validated scales. Conclusion: Apathy was observed in 26% of treatment-naïve patients with early-stage PD. Significant association between apathy and motor severity was found, suggesting that dysfunction of the dopaminergic pathway is involved in the pathology of apathy.     

Motor cortex plasticity can indicate vulnerability to motor fluctuation and high L-DOPA need in drug-naïve Parkinson's disease

IntroductionMotor cortex plasticity is reported to be decreased in Parkinson's disease in studies which pooled patients in various stages of the disease. Whether the early decrease in plasticity is related to the motor signs or is linked to the future development of motor complications of treatment is unclear. The aim of the study was to test if motor cortex plasticity and its cerebellar modulation are impaired in treatment-naïve Parkinson's disease, are related to the motor signs of the disease and predict occurrence of motor complications of treatment.MethodsTwenty-nine denovo patients with Parkinson's disease were longitudinally assessed for motor complications for four years. Using transcranial magnetic stimulation, the plasticity of the motor cortex and its cerebellar modulation were measured (response to paired-associative stimulation alone or preceded by 2 active cerebellar stimulation protocols), both in the untreated state and after a single dose of L-DOPA. Twenty-six matched, healthy volunteers were tested, only without L-DOPA.ResultsPatients and healthy controls had similar proportions of responders and non-responders to plasticity induction. In the untreated state, the more efficient was the cerebellar modulation of motor cortex plasticity, the lower were the bradykinesia and rigidity scores. The extent of the individual plastic response to paired associative stimulation could indicate a vulnerability to develop early motor fluctuation but not dyskinesia.ConclusionsMeasuring motor cortex plasticity in denovo Parkinson's disease could be a neurophysiological parameter that may help identify patients with greater propensity for early motor fluctuations.