Alteration of Brain Functional Networks in Early-Stage Parkinson’s Disease: A Resting-State fMRI Study

Although alterations of topological organization have previously been reported in the brain functional network of Parkinson’s disease (PD) patients, the topological properties of the brain network in early-stage PD patients who received antiparkinson treatment are largely unknown. This study sought to determine the topological characteristics of the large-scale functional network in early-stage PD patients. First, 26early-stage PD patients (Hoehn and Yahr stage:1-2) and 30 age-matched normal controls were scanned using resting-state functional MRI. Subsequently, graph theoretical analysis was employed to investigate the abnormal topological configuration of the brain network in early-stage PD patients. We found that both the PD patient and control groups showed small-world properties in their functional brain networks. However, compared with the controls, the early-stage PD patients exhibited abnormal global properties, characterized by lower global efficiency. Moreover, the modular structure and the hub distribution were markedly altered in early-stage PD patients. Furthermore, PD patients exhibited increased nodal centrality, primarily in the bilateral pallidum, the inferior parietal lobule, and the medial superior frontal gyrus, and decreased nodal centrality in the caudate nucleus, the supplementary motor areas, the precentral gyrus, and the middle frontal gyrus. There were significant negative correlations between the Unified Parkinson Disease Rating Scale motor scores and nodal centralities of superior parietal gyrus. These results suggest that the topological organization of the brain functional network was altered in early-stage PD patients who received antiparkinson treatment, and we speculated that the antiparkinson treatment may affect the efficiency of the brain network to effectively relieve clinical symptoms of PD.     

Co-Transplantation of GDNF-Overexpressing Neural Stem Cells and Fetal Dopaminergic Neurons Mitigates Motor Symptoms in a Rat Model of Parkinson’s Disease

Striatal transplantation of dopaminergic (DA) neurons or neural stem cells (NSCs) has been reported to improve the symptoms of Parkinson’s disease (PD), but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs) together with fetal DA neurons in the 6-OHDA rat model of PD. Striatal injection of mNSCs labeled by the contrast enhancer superparamagnetic iron oxide (SPIO) resulted in a hypointense signal in the striatum on T2-weighted magnetic resonance images that lasted for at least 8 weeks post-injection, confirming the long-term survival of injected stem cells in vivo. Co-transplantation of GDNF-mNSCs with fetal DA neurons significantly reduced apomorphine-induced rotation, a behavioral endophenotype of PD, compared to sham-treated controls, rats injected with mNSCs expressing empty vector (control mNSCs) plus fetal DA neurons, or rats injected separately with either control mNSCs, GDNF-mNSCs, or fetal DA neurons. In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP) and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo.     

Digitomotography in Parkinson’s Disease: A Cross-Sectional and Longitudinal Study

Motor symptoms in Parkinson’s disease (PD) are usually assessed with semi-quantitative tests such as the Unified PD Rating Scale (UPDRS) which are limited by subjectivity, categorical design, and low sensitivity. Particularly bradykinesia as assessed e.g. with speeded index finger tapping exhibits low validity measures. This exploratory study set out to (i) assess whether force transducer-based objective and quantitative analysis of motor coordination in index finger tapping is able to distinguish between PD patients and controls, and (ii) assess longitudinal changes. Sixteen early-stage and 17 mid-stage PD patients as well as 18 controls were included in the cross-sectional part of the study; thirteen, 16 and 16 individuals of the respective groups agreed in a reassessment 12 months later. Frequency, force, rhythmicity, regularity and laterality of speeded and metronome paced tapping were recorded by digitomotography using a quantitative motor system ("Q-Motor"). Analysis of cross-sectional data revealed most consistent differences between PD patients and controls in variability of tap performance across modalities assessed. Among PD patients, variability of taps and the ability to keep a given rhythm were associated with UPDRS motor and finger tapping scores. After 12 months, laterality parameters were reduced but no other parameters changed significantly. This data suggests that digitomotography provides quantitative and objective measures capable to differentiate PD from non-PD in a small cohort, however, the value of the assessment to track PD progression has to be further evaluated in larger cohorts of patients.     

Non-Motor Symptoms in Patients with Parkinson’s Disease – Correlations with Inflammatory Cytokines in Serum

Background

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety) are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD.

Methods and Materials

We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor (sIL-2R) and tumor necrosis factor-α (TNF-α) in blood samples from PD patients (n = 86) and healthy controls (n = 40). Symptoms of fatigue, depression, anxiety and sleeping difficulties were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT), the Hospital Anxiety and Depression Scale (HAD), and the Scales for Outcome in PD-Sleep Scale respectively.

Results

IL-6 was significantly higher in PD patients than in healthy controls. Compared to healthy controls, PD patients displayed significantly higher mean scores on HAD and lower scores on FACIT, thus indicating more severe symptoms as measured with these scales. Within the PD sample, high levels of both sIL-2R and TNF-α were significantly associated with more severe symptoms assessed by means of FACIT and HAD (depression and anxiety subscales). SIL-2-R levels were able to significantly predict FACIT and HAD scores after the effects of age, gender, anti-parkinsonian medications, and severity of motor symptoms were controlled for.

Discussion

We suggest that non-motor symptoms in PD patients, such as fatigue and depressive symptoms, might be generated via inflammatory mechanisms. This knowledge might contribute to the development of novel treatment options in PD, specifically targeting non-motor symptoms.     

Intact Acquisition and Short-Term Retention of Non-Motor Procedural Learning in Parkinson’s Disease

Procedural learning is a form of memory where people implicitly acquire a skill through repeated practice. People with Parkinson’s disease (PD) have been found to acquire motor adaptation, a form of motor procedural learning, similarly to healthy older adults but they have deficits in long-term retention. A similar pattern of normal learning on initial exposure with a deficit in retention seen on subsequent days has also been seen in mirror-reading, a form of non-motor procedural learning. It is a well-studied fact that disrupting sleep will impair the consolidation of procedural memories. Given the prevalence of sleep disturbances in PD, the lack of retention on following days seen in these studies could simply be a side effect of this well-known symptom of PD. Because of this, we wondered whether people with PD would present with deficits in the short-term retention of a non-motor procedural learning task, when the test of retention was done the same day as the initial exposure. The aim of the present study was then to investigate acquisition and retention in the immediate short term of cognitive procedural learning using the mirror-reading task in people with PD. This task involved two conditions: one where triads of mirror-inverted words were always new that allowed assessing the learning of mirror-reading skill and another one where some of the triads were presented repeatedly during the experiment that allowed assessing the word-specific learning. People with PD both ON and OFF their normal medication were compared to healthy older adults and young adults. Participants were re-tested 50 minutes break after initial exposure to probe for short-term retention. The results of this study show that all groups of participants acquired and retained the two skills (mirror-reading and word-specific) similarly. These results suggest that neither healthy ageing nor the degeneration within the basal ganglia that occurs in PD does affect the mechanisms that underpin the acquisition of these new non-motor procedural learning skills and their short-term memories.     

Levodopa Effects on Hand and Speech Movements in Patients with Parkinson’s Disease: A fMRI Study

Levodopa (L-dopa) effects on the cardinal and axial symptoms of Parkinson’s disease (PD) differ greatly, leading to therapeutic challenges for managing the disabilities in this patient’s population. In this context, we studied the cerebral networks associated with the production of a unilateral hand movement, speech production, and a task combining both tasks in 12 individuals with PD, both off and on levodopa (L-dopa). Unilateral hand movements in the off medication state elicited brain activations in motor regions (primary motor cortex, supplementary motor area, premotor cortex, cerebellum), as well as additional areas (anterior cingulate, putamen, associative parietal areas); following L-dopa administration, the brain activation profile was globally reduced, highlighting activations in the parietal and posterior cingulate cortices. For the speech production task, brain activation patterns were similar with and without medication, including the orofacial primary motor cortex (M1), the primary somatosensory cortex and the cerebellar hemispheres bilaterally, as well as the left- premotor, anterior cingulate and supramarginal cortices. For the combined task off L-dopa, the cerebral activation profile was restricted to the right cerebellum (hand movement), reflecting the difficulty in performing two movements simultaneously in PD. Under L-dopa, the brain activation profile of the combined task involved a larger pattern, including additional fronto-parietal activations, without reaching the sum of the areas activated during the simple hand and speech tasks separately. Our results question both the role of the basal ganglia system in speech production and the modulation of task-dependent cerebral networks by dopaminergic treatment.     

Parkinson’s Disease in Saudi Patients: A Genetic Study

Parkinson’s disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes.     

Unraveling the Relationship between Motor Symptoms,Affective States and Contextual Factors in Parkinson’s Disease: A Feasibility Study of the Experience Sampling Method

Background

In Parkinson''s disease (PD), the complex relationship between motor symptoms, affective states, and contextual factors remains to be elucidated. The Experience Sampling Method provides (ESM) a novel approach to this issue. Using a mobile device with a special purpose application (app), motor symptoms, affective states and contextual factors are assessed repeatedly at random moments in the flow of daily life, yielding an intensive time series of symptoms and experience. The aim of this study was to study the feasibility of this method.

Method

We studied the feasibility of a five-day period of ESM in PD and its ability to objectify diurnal fluctuations in motor symptom severity and their relation with affect and contextual factors in five PD patients with motor fluctuations.

Results

Participants achieved a high compliance, with 84% of assessment moments completed without disturbance of daily activities. The utility of the device was rated 8 on a 10-point scale. We were able to capture extensive diurnal fluctuations that were not revealed by routine clinical assessment. In addition, we were able to detect clinically relevant associations between motor symptoms, emotional fluctuations and contextual factors at an intra-individual level.

Conclusions

ESM represents a viable and novel approach to elucidate relationships between motor symptoms, affective states and contextual factors at the level of individual subjects. ESM holds promise for clinical practice and scientific research.     

Early-Life Factors and Risk of Parkinson’s Disease: A Register-Based Cohort Study

Parkinson’s disease (PD) may take decades to develop and early life exposures such as infection may be important. However, few epidemiological studies have evaluated early life risk factors in relation to PD risk. We therefore examined such associations in a prospective analysis of 3 545 612 individuals born in Sweden between 1932 and 1970 without PD on January 1, 2002. Incident PD cases were identified using the Swedish Patient Register during 2002–2010. Information on sibship size, number of older and younger siblings, multiple births, parental age, birth month and season was obtained from the Swedish Multi-Generation Register. Monthly data on national burden of influenza-like illness during 1932–1970 were obtained from the Swedish Public Health Agency. Hazard ratios with 95% confidence intervals (CI) were estimated using Cox proportional hazards regression. During the follow-up, 8779 incident PD cases were identified. As expected, older age, male sex, parental occupation as farmers, and family history of PD were associated with higher PD risk. Overall, early life factors, including flu burden in the year of birth, were not associated with PD risk, although we did find a lower PD risk among participants with older siblings than those without (HR = 0.93, 95%CI: 0.89, 0.98). Our study therefore provided little support for important etiological contributions of early life factors to the PD risk late in life. The finding of a lower PD risk among individuals with older siblings will need confirmation and further investigation.     

Icariin: A Potential Neuroprotective Agent in Alzheimer’s Disease and Parkinson’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases worldwide. They are characterized by the loss of neurons and synapses in special parts of the central nervous system (CNS). There is no definitive treatment for AD and PD, but extensive studies are underway to identify the effective drugs which can slow the progression of these diseases by affecting the factors involved in their pathophysiology (i.e., aggregated proteins, neuroinflammation, and oxidative stress). Icariin, a natural compound isolated from Epimedii herba, is known because of its anti-inflammatory and anti-oxidant properties. In this regard, there are numerous studies indicating its potential as a natural compound against the progression of CNS disorders, such as neurodegenerative diseases. Therefore, this review aims to re-examine findings on the pharmacologic effects of icariin on factors involved in the pathophysiology of AD and PD.

     

The Effect of Motivation on Movement: A Study of Bradykinesia in Parkinson’s Disease

Background

Bradykinesia is a cardinal feature of Parkinson’s disease (PD). Despite its disabling impact, the precise cause of this symptom remains elusive. Recent thinking suggests that bradykinesia may be more than simply a manifestation of motor slowness, and may in part reflect a specific deficit in the operation of motivational vigour in the striatum. In this paper we test the hypothesis that movement time in PD can be modulated by the specific nature of the motivational salience of possible action-outcomes.

Methodology/Principal Findings

We developed a novel movement time paradigm involving winnable rewards and avoidable painful electrical stimuli. The faster the subjects performed an action the more likely they were to win money (in appetitive blocks) or to avoid a painful shock (in aversive blocks). We compared PD patients when OFF dopaminergic medication with controls. Our key finding is that PD patients OFF dopaminergic medication move faster to avoid aversive outcomes (painful electric shocks) than to reap rewarding outcomes (winning money) and, unlike controls, do not speed up in the current trial having failed to win money in the previous one. We also demonstrate that sensitivity to distracting stimuli is valence specific.

Conclusions/Significance

We suggest this pattern of results can be explained in terms of low dopamine levels in the Parkinsonian state leading to an insensitivity to appetitive outcomes, and thus an inability to modulate movement speed in the face of rewards. By comparison, sensitivity to aversive stimuli is relatively spared. Our findings point to a rarely described property of bradykinesia in PD, namely its selective regulation by everyday outcomes.     

Neuropsychiatric Symptoms in Parkinson’s Disease Dementia Are More Similar to Alzheimer’s Disease than Dementia with Lewy Bodies: A Case-Control Study

MethodsWe conducted a retrospective case-control study on 125 newly diagnosed consecutive PDD patients and age- and dementia stage-matched controls with either DLB (N = 250) or AD (N = 500) who visited the same hospital over the same period. For each case and control, neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI).ResultsOverall, 513 (58.6%) patients were female and 362 (41.4%) were male. Comparisons of clinical data revealed that the PDD group, similar to the AD group, had a lower NPI total score, NPI caregiver burden score, and rate of antipsychotic use (all p < 0.001) than the DLB group. One or more psychiatric symptoms were reported in 95.2% of the PDD, 99.2% of the DLB, and 96.8% of the AD patients. The PDD group had lower subscores in the items of delusions, hallucinations, agitation, anxiety, irritation, aberrant motor behavior compared to the DLB group. Severe neuropsychiatric symptoms among all dementia patients were associated with younger age, more advanced stage, and a diagnosis of DLB.ConclusionNeuropsychiatric symptoms in PDD were more like those in AD than in DLB. Severe neuropsychiatric symptoms in degenerative dementia were associated with younger age, more advanced stage of dementia, and a diagnosis of DLB.     

Serum Uric Acid and Nigral Iron Deposition in Parkinson’s Disease: A Pilot Study

Background

Uric acid (UA) is an endogenous antioxidant which is known to reduce oxidative stress and also chelate iron ion. Recent studies have provided evidence that UA may play a neuroprotective role in Parkinson’s disease (PD). However, it is unknown whether UA relates to nigral iron deposition, which is a characteristic pathophysiological alteration in PD. The aim of this study was to determine the potential relationship of these two markers in patients with PD.

Methods

A total of 30 patients of PD and 25 age- and gender- matched healthy controls underwent 3-Tesla MRI and laboratory tests including serum UA levels. We assessed iron levels by measuring phase shift values using susceptibility-weighted image. Mean phase shift values of the substantia nigra (SN), red nucleus, head of the caudate nucleus, globus pallidus, putamen, thalamus, and frontal white matter were calculated and correlated with serum UA levels.

Results

Serum UA levels were significantly decreased in the PD patients than in the controls. Phase shift values in bilateral SN were significantly increased in the PD patients than in the controls. There was no significant correlation between serum UA levels and nigral phase shift values.

Conclusions

As previous studies, low serum UA level and increased nigral iron content in the PD was reconfirmed in this study. However, we failed to find the relationship between these two markers. Our data suggest that serum UA may not be important determinant of nigral iron deposition in PD.     

Neuroanatomical Correlates of Theory of Mind Deficit in Parkinson’s Disease: A Multimodal Imaging Study

BackgroundParkinson’s disease (PD) patients show theory of mind (ToM) deficit since the early stages of the disease, and this deficit has been associated with working memory, executive functions and quality of life impairment. To date, neuroanatomical correlates of ToM have not been assessed with magnetic resonance imaging in PD. The main objective of this study was to assess cerebral correlates of ToM deficit in PD. The second objective was to explore the relationships between ToM, working memory and executive functions, and to analyse the neural correlates of ToM, controlling for both working memory and executive functions.MethodsThirty-seven PD patients (Hoehn and Yahr median = 2.0) and 15 healthy controls underwent a neuropsychological assessment and magnetic resonance images in a 3T-scanner were acquired. T1-weighted images were analysed with voxel-based morphometry, and white matter integrity and diffusivity measures were obtained from diffusion weighted images and analysed using tract-based spatial statistics.ResultsPD patients showed impairments in ToM, working memory and executive functions; grey matter loss and white matter reduction compared to healthy controls. Grey matter volume decrease in the precentral and postcentral gyrus, middle and inferior frontal gyrus correlated with ToM deficit in PD. White matter in the superior longitudinal fasciculus (adjacent to the parietal lobe) and white matter adjacent to the frontal lobe correlated with ToM impairment in PD. After controlling for executive functions, the relationship between ToM deficit and white matter remained significant for white matter areas adjacent to the precuneus and the parietal lobe.ConclusionsFindings reinforce the existence of ToM impairment from the early Hoehn and Yahr stages in PD, and the findings suggest associations with white matter and grey matter volume decrease. This study contributes to better understand ToM deficit and its neural correlates in PD, which is a basic skill for development of healthy social relationships.     

Genetic Variations of GAK in Two Chinese Parkinson’s Disease Populations: A Case-Control Study

Cyclin G-associated kinase (GAK) modifies α–synuclein expression levels and affects the susceptibility of Parkinson’s disease (PD). The single-nucleotide polymorphism (SNP) rs1564282 of GAK gene has a significant association to the risk of PD among Caucasian populations. To date there is only one data with regards to ethnic Chinese from Mainland China. Here, we conducted a case-control study in two independent cohorts of Han Chinese populations from Taiwan and Singapore to validate this association. A total of 1,755 subjects (871 PD patients and 884 controls) were recruited. The results showed that neither the CT, TT genotypes nor the minor allele T of SNP rs1564282 were associated with PD among the subjects from Taiwan and Singapore as well as in the pooled analysis. Differences in our study population with regards to published literature may be due to epigenetic factors and gene-gene or gene-environmental interactions. Further studies in other Chinese populations will be of interest to validate these findings.     

Upregulation of GPR109A in Parkinson’s Disease

Background

Anecdotal animal and human studies have implicated the symptomatic and neuroprotective roles of niacin in Parkinson’s disease (PD). Niacin has a high affinity for GPR109A, an anti-inflammatory receptor. Niacin is also thought to be involved in the regulation of circadian rhythm. Here we evaluated the relationships among the receptor, niacin levels and EEG night-sleep in individuals with PD.

Methods and Findings

GPR109A expression (blood and brain), niacin index (NAD-NADP ratio) and cytokine markers (blood) were analyzed. Measures of night-sleep function (EEG) and perceived sleep quality (questionnaire) were assessed. We observed significant up-regulation of GPR109A expression in the blood as well as in the substantia nigra (SN) in the PD group compared to age-matched controls. Confocal microscopy demonstrated co-localization of GPR109A staining with microglia in PD SN. Pro and anti-inflammatory cytokines did not show significant differences between the groups; however IL1-β, IL-4 and IL-7 showed an upward trend in PD. Time to sleep (sleep latency), EEG REM and sleep efficiency were different between PD and age-matched controls. Niacin levels were lower in PD and were associated with increased frequency of experiencing body pain and decreased duration of deep sleep.

Conclusions

The findings of associations among the GPR109A receptor, niacin levels and night-sleep function in individuals with PD are novel. Further studies are needed to understand the pathophysiological mechanisms of action of niacin, GPR109A expression and their associations with night-sleep function. It would be also crucial to study GPR109A expression in neurons, astrocytes, and microglia in PD. A clinical trial to determine the symptomatic and/or neuroprotective effect of niacin supplementation is warranted.     

Relationship between Motor Symptoms,Cognition, and Demographic Characteristics in Treated Mild/Moderate Parkinson’s Disease

Background

Although Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized primarily by motor symptoms, PD patients, at all stages of the disease, can experience cognitive dysfunction. However, the relationships between cognitive and motor symptoms and specific demographic characteristics are not well defined, particularly for patients who have progressed to requiring dopaminergic medication.

Objective

To examine relationships between motor and cognitive symptoms and various demographic factors in mild to moderate, PD patients requiring anti-PD medication.

Methods

Cognitive function was assessed in 94 subjects with a variety of neuropsychological tests during baseline evaluations as part of an experimental treatment study. Data were analyzed in relation to Unified Parkinson’s Disease Rating Scale motor scores and demographic variables.

Results

Of the UPDRS subscores analyzed, posture/balance/gait was associated with the highest number of adverse cognitive outcomes followed by speech/facial expression, bradykinesia, and rigidity. No associations were detected between any of the cognitive performance measures and tremor. Motor functioning assessed in the “off” condition correlated primarily with disease duration; neuropsychological performance in general was primarily related to age.

Conclusion

In PD patients who have advanced to requiring anti-PD therapies, there are salient associations between axial signs and cognitive performance and in particular, with different aspects of visuospatial function suggesting involvement of similar circuits in these functions. Associations between executive functions and bradykinesia also suggest involvement similar circuits in these functions.     

Interhemispheric Functional and Structural Disconnection in Alzheimer’s Disease: A Combined Resting-State fMRI and DTI Study

Neuroimaging studies have demonstrated that patients with Alzheimer’s disease presented disconnection syndrome. However, little is known about the alterations of interhemispheric functional interactions and underlying structural connectivity in the AD patients. In this study, we combined resting-state functional MRI and diffusion tensor imaging (DTI) to investigate interhemispheric functional and structural connectivity in 16 AD, 16 mild cognitive impairment (MCI), as well as 16 cognitive normal healthy subjects (CN). The pattern of the resting state interhemispheric functional connectivity was measured with a voxel-mirrored homotopic connectivity (VMHC) method. Decreased VMHC was observed in AD and MCI subjects in anterior brain regions including the prefrontal cortices and subcortical regions with a pattern of AD<MCI<CN. Increased VMHC was observed in MCI subjects in posterior brain regions with patterns of AD/CN < MCI (sensorimotor cortex) and AD < CN/MCI (occipital gyrus). DTI analysis showed the most significant difference among the three cohorts was the fractional anisotropy in the genu of corpus callosum, which was positively associated with the VMHC of prefrontal and subcortical regions. Across all the three cohorts, the diffusion parameters in the genu of corpus callosum and VMHC in the above brain regions had significant correlation with the cognitive performance. These results demonstrate that there are specific patterns of interhemispheric functional connectivity changes in the AD and MCI, which can be significantly correlated with the integrity changes in the midline white matter structures. These results suggest that VMHC can be used as a biomarker for the degeneration of the interhemispheric connectivity in AD.     

Daytime Sleepiness in Parkinson’s Disease: A Reappraisal

Background

Excessive daytime sleepiness is a frequent complaint in Parkinson’s disease (PD); however the frequency and risk factors for objective sleepiness remain mostly unknown. We investigated both the frequency and determinants of self-reported and objective daytime sleepiness in patients with Parkinson’s disease (PD) using a wide range of potential predictors.

Methods

One hundred and thirty four consecutive patients with PD, without selection bias for sleep complaint, underwent a semi-structured clinical interview and a one night polysomnography followed by a multiple sleep latency test (MSLT). Demographic characteristics, medical history, PD course and severity, daytime sleepiness, depressive and insomnia symptoms, treatment intake, pain, restless legs syndrome, REM sleep behaviour disorder, and nighttime sleep measures were collected. Self-reported daytime sleepiness was defined by an Epworth Sleepiness Scale (ESS) score above 10. A mean sleep latency on MSLT below 8 minutes defined objective daytime sleepiness.

Results

Of 134 patients with PD, 46.3% had subjective and only 13.4% had objective sleepiness with a weak negative correlation between ESS and MSLT latency. A high body mass index (BMI) was associated with both ESS and MSLT, a pain complaint with ESS, and a higher apnea/hypopnea index with MSLT. However, no associations were found between both objective and subjective sleepiness, and measures of motor disability, disease onset, medication (type and dose), depression, insomnia, restless legs syndrome, REM sleep behaviour disorder and nighttime sleep evaluation.

Conclusion

We found a high frequency of self-reported EDS in PD, a finding which is however not confirmed by the gold standard neurophysiological evaluation. Current treatment options for EDS in PD are very limited; it thus remains to be determined whether decreasing pain and BMI in association with the treatment of sleep apnea syndrome would decrease significantly daytime sleepiness in PD.     

Mechanisms of Neural and Behavioral Dysfunction in Alzheimer’s Disease

This review critically examines progress in understanding the link between Alzheimer’s disease (AD) molecular pathogenesis and behavior, with an emphasis on the impact of amyloid-β. We present the argument that the AD research field requires more multifaceted analyses into the impacts of Alzheimer’s pathogenesis which combine simultaneous molecular-, circuit-, and behavior-level approaches. Supporting this argument is a review of particular research utilizing similar, “systems-level” methods in mouse models of AD. Related to this, a critique of common physiological and behavioral models is made—highlighting the likely usefulness of more refined and specific tools in understanding the relationship between candidate molecular pathologies and behavioral dysfunction. Finally, we propose challenges for future research which, if met, may greatly extend our current understanding of how AD molecular pathology impacts neural network function and behavior and possibly may lead to refinements in disease therapeutics.