Accounting for functional loss in Alzheimer's disease and dementia with Lewy bodies: Beyond cognition

BackgroundThe relative contributions of cognitive, motor, and behavioral deficits to the impairment of physical or instrumental activities of daily living (ADLs) may differ in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).MethodsMultiple linear regression analyses were used to identify the amount of variability in physical self-maintenance and instrumental ADL ratings predicted by cognitive, motor, and behavioral indices separately for patients with autopsy-diagnosed DLB (n = 39) or AD (n = 39).ResultsMotor dysfunction accounted for significant variance in physical ADLs in DLB (R² change = 0.17), whereas behavioral (R² change = 0.23) and motor dysfunction (R² change = 0.13) accounted for significant variance in AD. Motor (R² change = 0.32) and cognitive (R² change = 0.10) dysfunction accounted for significant variance in instrumental ADLs in DLB, whereas cognitive (R² change = 0.36) and behavioral (R² change = 0.12) dysfunction accounted for significant variance in AD.ConclusionsCognitive, motor, and behavioral deficits contribute differently to ADL changes in DLB and AD. Thus, treatments designed to ameliorate a certain aspect of AD or DLB (e.g., cognitive dysfunction) may have a larger impact on everyday functioning in one disorder than the other.     

Concomitant pathologies among a spectrum of parkinsonian disorders

IntroductionMany clinicopathological studies do not specify the presence of other pathologies located within the brain, so disease heterogeneity may be under appreciated.ObjectiveThe purpose of this study was to determine the frequencies of concomitant pathologies among parkinsonian disorders.MethodsData from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), an ongoing longitudinal clinical-neuropathological study, was used to analyze concomitant pathologies, including Alzheimer's disease (AD), argyrophilic grains (Arg), cerebral amyloid angiopathy (CAA), cerebral white matter rarefaction (CWMR) and overlap of each parkinsonian disorder in clinico-pathologically defined Parkinson's disease (PD; N = 140), dementia with Lewy bodies (DLB; N = 90), progressive supranuclear palsy (PSP; N = 64), multiple system atrophy (MSA; N = 6), corticobasal degeneration (CBD; N = 7); and normal elderly (controls; N = 166).ResultsOf the neuropathologically-confirmed PD cases, 38% had a concomitant diagnosis of AD, 9% PSP, 25% Arg, 44% CWMR, and 24% CAA. For DLB, 89% had AD, 1% PSP, 21% Arg, 51% CWMR, and 50% CAA. For PSP cases, 36% had AD, 20% PD, 1% DLB, 44% Arg, 52% CWMR and 25% CAA. Similar heterogeneity was seen for MSA and CBD cases. Many cases had more than one of the above additional diagnoses.ConclusionsThese data demonstrate a great deal of concomitant pathologies among different types of parkinsonian disorders; this may help explain the heterogeneity of clinical findings.     

Multimodal EEG-MRI in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies

Differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) remains challenging; currently the best discriminator is striatal dopaminergic imaging. However this modality fails to identify 15–20% of DLB cases and thus other biomarkers may be useful. It is recognised electroencephalography (EEG) slowing and relative medial temporal lobe preservation are supportive features of DLB, although individually they lack diagnostic accuracy. Therefore, we investigated whether combined EEG and MRI indices could assist in the differential diagnosis of AD and DLB.Seventy two participants (21 Controls, 30 AD, 21 DLB) underwent resting EEG and 3 T MR imaging. Six EEG classifiers previously generated using support vector machine algorithms were applied to the present dataset. MRI index was derived from medial temporal atrophy (MTA) ratings. Logistic regression analysis identified EEG predictors of AD and DLB. A combined EEG-MRI model was then generated to examine whether there was an improvement in classification compared to individual modalities.For EEG, two classifiers predicted AD and DLB (model: χ² = 22.1, df = 2, p < 0.001, Nagelkerke R² = 0.47, classification = 77% (AD 87%, DLB 62%)). For MRI, MTA also predicted AD and DLB (model: χ² = 6.5, df = 1, p = 0.01, Nagelkerke R² = 0.16, classification = 67% (77% AD, 52% DLB). However, a combined EEG-MRI model showed greater prediction in AD and DLB (model: χ² = 31.1, df = 3, p < 0.001, Nagelkerke R² = 0.62, classification = 90% (93% AD, 86% DLB)).While suggestive and requiring validation, diagnostic performance could be improved by combining EEG and MRI, and may represent an alternative to dopaminergic imaging.     

Hypercapnia affects the functional coupling of resting state electroencephalographic rhythms and cerebral haemodynamics in healthy elderly subjects and in patients with amnestic mild cognitive impairment

ObjectiveCerebral vasomotor reactivity (VMR) and coherence of resting state electroencephalographic (EEG) rhythms are impaired in Alzheimer’s disease (AD) patients. Here we tested the hypothesis that these two variables could be related.MethodsWe investigated VMR and coherence of resting state EEG rhythms in nine normal elderly (Nold) and in 10 amnesic mild cognitive impairment (MCI) subjects. Resting state eyes-closed EEG data were recorded at baseline pre-CO₂ (ambient air, 2 min), during 7% CO₂/air mixture inhalation (hypercapnia, 90 s) and post-CO₂ (ambient air, 2 min) conditions. Simultaneous frontal bilateral near-infrared spectroscopy (NIRS) was performed to assess VMR by cortical oxy- and deoxy-haemoglobin concentration changes. EEG coherence across all electrodes was computed at delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–10.5 Hz), alpha 2 (10.5–13 Hz), beta 1 (13–20 Hz), beta 2 (20–30 Hz) and gamma (30–40 Hz) bands.ResultsIn Nold subjects, ‘total coherence’ of EEG across all frequency bands and electrode pairs decreased during hypercapnia, with full recovery during post-CO₂. Total coherence resulted lower in pre-CO₂ and post-CO₂ and presented poor reactivity during CO₂ inhalation in MCI patients compared with Nold subjects. Hypercapnia increased oxy-haemoglobin and decreased deoxy-haemoglobin concentrations in both groups. Furthermore, the extent of changes in these variables during CO₂ challenge was correlated with the EEG coherence, as a reflection of neurovascular coupling.ConclusionsHypercapnia induced normal frontal VMR that was detected by NIRS in both Nold and amnesic MCI groups, while it produced a reactivity of global functional coupling of resting state EEG rhythms only in the Nold group.SignificanceIn amnesic MCI patients, global EEG functional coupling is basically low in amplitude and does not react to hypercapnia.     

The diagnostic utility of cerebrospinal fluid alpha-synuclein analysis in dementia with Lewy bodies – A systematic review and meta-analysis

BackgroundDementia with Lewy Bodies (DLB) can be difficult to distinguish clinically from other dementias.ObjectiveTo investigate the diagnostic utility of CSF alpha-synuclein in differentiating between DLB and other dementias.MethodsElectronic databases were systematically searched for studies investigating reproducible alpha synuclein quantification methods. Random effects model was used to calculate weighted mean difference (WMD) and 95% confidence intervals between DLB and other groups.ResultsA total of 13 studies, comprising 2728 patients were included. Mean CSF alpha-synuclein concentration was significantly lower in DLB patients compared to those with Alzheimers disease (AD) [WMD ?0.24; 95% CI, ?0.45, ?0.03; p = 0.02]. No significant difference was found between patients with DLB compared to Parkinsons disease [WMD 0.05; 95% CI, ?0.17, 0.28; p = 0.65] or other neurodegenerative conditions.ConclusionCSF alpha synuclein may be of diagnostic use in differentiating between DLB and AD. We propose several recommendations to guide better design of future studies.     

ΔHR/ΔWR derived from CPET; A novel predictor of ‘off’ symptom in Parkinson's disease

IntroductionChronotropic incompetence (CI) is broadly defined as the inability of the heart to increase its rate commensurate with increased activity. In this study, we tried to clarify the link between CI and UPDRS part II (off-on), which was calculated by subtracting part II (on) from part II (off), in patients with Parkinson's disease (PD).MethodsThirty-six hospitalized patients were examined by using cardiopulmonary exercise testing (CPET) for exercise tolerance (ΔVO2/ΔWR and peak VO2/W) and the presence of CI (ΔHR/ΔWR), and using electrocardiogram for heart rate variability.ResultsWe originally divided the patients into three groups; Group I (ΔHR/ΔWR x100 <15) (N = 3), Group II (15≥, <60) (N = 28), Group III (>60) (N = 5). Since Group I and III were significantly smaller and older than Group II, we focused and divided into two groups; Group II CI (+), the PD patients with CI (15≤ ΔHR/ΔWR x100 <35), and Group II CI (−), those patients without that (35≤ ΔHR/ΔWR x100 <60). ΔVO2/ΔWR and peak VO2/W in CI (+) patients was lower than CI (−) (P = 0.022 and P = 0.096, respectively). HF power (parasympathetic activity) tends to be decreased, whereas LF/HF ratio (sympathetic activity) was increased in CI (+) patients as compared with CI (−). The UPDRS part II (off-on) of CI (+) patients was significantly higher than CI (−) (P = 0.023).ConclusionsIn PD patients, the difference between ‘on’ and ‘off’ in activities of daily living might be predicted by using ΔHR/ΔWR x100 obtained from CPET as an index.     

Functional cortical source connectivity of resting state electroencephalographic alpha rhythms shows similar abnormalities in patients with mild cognitive impairment due to Alzheimer’s and Parkinson’s diseases

Objective

This study tested the hypothesis that markers of functional cortical source connectivity of resting state eyes-closed electroencephalographic (rsEEG) rhythms may be abnormal in subjects with mild cognitive impairment due to Alzheimer’s (ADMCI) and Parkinson’s (PDMCI) diseases compared to healthy elderly subjects (Nold).

Diffusion imaging in dementia with Lewy bodies: Associations with amyloid burden,atrophy, vascular factors and clinical features

IntroductionWhite matter disruption in dementia has been linked to a variety of factors including vascular disease and cortical pathology. We aimed to examine the relationship between white matter changes on diffusion tensor imaging (DTI) in DLB and factors including vascular disease, structural atrophy and amyloid burden.MethodsParticipants with DLB (n = 29), Alzheimer's disease (AD, n = 17) and healthy controls (n = 20) had clinical and neuropsychological assessments followed by structural and diffusion tensor 3T MRI and ¹⁸F-Florbetapir PET-CT imaging. Voxelwise statistical analysis of white matter fractional anisotropy (FA) and mean diffusivity (MD) was carried out using Tract-Based Spatial Statistics with family-wise error correction (p < 0.05).ResultsDLB and AD groups demonstrated widespread increased MD and decreased FA when compared with controls. There were no differences between the DLB and AD groups. In DLB, increased MD and decreased FA correlated with decreased grey matter and hippocampal volumes as well as vascular disease. There was no correlation with cortical florbetapir SUVR. The relationship between DTI changes and grey matter/hippocampal volumes remained after including Cumulative Illness Rating Scale-Geriatric vascular score as a covariate.ConclusionsWidespread disruption of white matter tracts is present in DLB and is associated with vascular disease, reduced hippocampal volume and reduced grey matter volume, but not with cortical amyloid deposition. The mechanism behind the correlation observed between hippocampal volume and white matter tract disruption should be investigated in future cohorts using tau imaging, as hippocampal atrophy has been shown to correlate with tau deposition in DLB.     

Sleep deprivation and Modafinil affect cortical sources of resting state electroencephalographic rhythms in healthy young adults

ObjectiveIt has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project (www.pharmacog.org): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers.MethodsrsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware.ResultsIn the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2–4 Hz) and alpha (8–13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities.ConclusionsThe present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness.SignificanceFuture research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia.     

DNA methylation changes at TREM2 intron 1 and TREM2 mRNA expression in patients with Alzheimer's disease

ObjectivesRecent genome-wide association studies revealed that Triggering receptor expressed on myeloid cells 2 (TREM2) was associated with Alzheimer's disease (AD) and other neurodegenerative diseases. We previously reported that TREM2 mRNA is highly expressed in leukocytes of AD patients compared to those in healthy controls. However, the mechanism of TREM2 expression change is still not known. In this study, we examined the involvement of the DNA methylation status of TREM2 in its high gene expression.Materials and methodsFifty AD subjects and age- and sex-matched control subjects were recruited (25 males, 25 females; 79.9 ± 5.27 and 79.4 ± 3.92 years old, respectively). TREM2 mRNA expression and the percentage of DNA methylation at four CpG sites in intron 1 of TREM2 were studied using their peripheral leukocytes.ResultsWe confirmed that TREM2 mRNA expression in leukocytes was significantly higher in AD patients than in controls (p = 0.007). The percentage methylation at three CpG sites in TREM2 intron 1 was significantly lower in AD subjects than in control: CpG1, 9.4 ± 3.2 vs 11.9 ± 4.0 (p = 0.001); CpG2, 15.4 ± 4.9 vs 19.1 ± 4.8 (p = 0.001); CpG3, 20.8 ± 5.5 vs 25.5 ± 5.4 (p < 0.001); and the average percentage methylation of all CpG sites: 13.5 ± 3.7 vs 16.1 ± 3.8 (p = 0.002), respectively. In addition, there were significant negative correlations between TREM2 mRNA expression and the percentage DNA methylation of each of CpG sites (CpG1, r = −0.416, p < 0.001; CpG2, r = −0.510, p < 0.001; CpG3, r = −0.504, p < 0.001; CpG4, r = −0.356, p < 0.001).ConclusionsLower DNA methylation at TREM2 intron 1 caused higher TREM2 mRNA expression in the leukocytes of AD subjects versus controls and may be a biomarker for AD.     

Stacked autoencoders as new models for an accurate Alzheimer’s disease classification support using resting-state EEG and MRI measurements

ObjectiveThis retrospective and exploratory study tested the accuracy of artificial neural networks (ANNs) at detecting Alzheimer’s disease patients with dementia (ADD) based on input variables extracted from resting-state electroencephalogram (rsEEG), structural magnetic resonance imaging (sMRI) or both.MethodsFor the classification exercise, the ANNs had two architectures that included stacked (autoencoding) hidden layers recreating input data in the output. The classification was based on LORETA source estimates from rsEEG activity recorded with 10–20 montage system (19 electrodes) and standard sMRI variables in 89 ADD and 45 healthy control participants taken from a national database.ResultsThe ANN with stacked autoencoders and a deep leaning model representing both ADD and control participants showed classification accuracies in discriminating them of 80%, 85%, and 89% using rsEEG, sMRI, and rsEEG + sMRI features, respectively. The two ANNs with stacked autoencoders and a deep leaning model specialized for either ADD or control participants showed classification accuracies of 77%, 83%, and 86% using the same input features.ConclusionsThe two architectures of ANNs using stacked (autoencoding) hidden layers consistently reached moderate to high accuracy in the discrimination between ADD and healthy control participants as a function of the rsEEG and sMRI features employed.SignificanceThe present results encourage future multi-centric, prospective and longitudinal cross-validation studies using high resolution EEG techniques and harmonized clinical procedures towards clinical applications of the present ANNs.     

White-matter vascular lesions correlate with alpha EEG sources in mild cognitive impairment

It is an open issue if vascular and Alzheimer's disease (AD) lesions represent additive factors in the development of mild cognitive impairment (MCI), as a preclinical stage of Alzheimer's disease (AD) at group level. In the present study, we tested the hypothesis that electroencephalographic (EEG) alpha rhythms, which are affected (i.e. decreased in amplitude) by AD processes, are relatively preserved in MCI subjects in whom the cognitive decline is mainly explained by white-matter vascular load. Resting EEG was recorded in 40 healthy elderly (Nold), 80 MCI, and 40 AD subjects. In the MCI subjects, white-matter vascular load was quantified based on MRI (0-30 Wahlund visual rating scale). EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), and beta 2 (20-30Hz). Low resolution electromagnetic source tomography (LORETA) was used for EEG source analysis. As expected, we observed that alpha 1 sources in parietal, occipital, and temporal areas were lower in amplitude in the AD and MCI subjects than in the Nold subjects, whereas the amplitude of wide delta sources was higher in the AD than in the Nold and MCI subjects. As novel results, the amplitude of parietal, occipital, and temporal alpha 1 sources was higher in the MCI V+ (high vascular load; N=42; MMSE=26) than MCI V- group (low vascular load; N=37; MMSE=26.7). Furthermore, a weak but significant (p<0.05) positive statistical correlation was found between the parietal alpha 1 sources and the score of Wahlund scale across all MCI subjects (i.e. the more severe white-matter lesions, the higher parietal alpha source power). The present results are in line with the additive model of cognitive impairment postulating that this arises as the sum of neurodegenerative and cerebrovascular lesions.     

Vagus nerve stimulation-induced cognitive enhancement: Hippocampal neuroplasticity in healthy male rats

BackgroundVagus nerve stimulation (VNS) improves cognition in humans and rodents, but the effects of a single session of VNS on performance and plasticity are not well understood.ObjectiveBehavioral performance and hippocampal (HC) electrophysiology/neurotrophin expression were measured in healthy adult rats after VNS paired training to investigate changes in cognition and synaptic plasticity.MethodsPlatinum/iridium electrodes were surgically implanted around the left cervical branch of the VN of anesthetized male Sprague-Dawley rats (N = 47). VNS (100 μs biphasic pulses, 30 Hz, 0.8 mA) paired Novel Object Recognition (NOR)/Passive Avoidance Task (PAT) were assessed 24 h after training and post-mortem tissue was collected 48 h after VNS (N = 28). Electrophysiology recordings were collected using a microelectrode array system to assess functional effects on HC slices 90 min after VNS (N = 19). Sham received the same treatment without VNS and experimenters were blinded.ResultsStimulated rats exhibited improved performance in NOR (p < 0.05, n = 12) and PAT (p < 0.05, n = 14). VNS enhanced long-term potentiation (p < 0.05, n = 7–12), and spontaneous spike amplitude (p < 0.05, n = 7–12) and frequency (p < 0.05, n = 7–12) in the CA1. Immunohistochemical analysis found increased brain-derived neurotrophic factor expression in the CA1 (p < 0.05, n = 8–9) and CA2 (p < 0.01, n = 7–8).ConclusionThese findings suggest that our VNS parameters promote synaptic plasticity and target the CA1, which may mediate the positive cognitive effects of VNS. This study significantly contributes to a better understanding of VNS mediated HC synaptic plasticity, which may improve clinical utilization of VNS for cognitive enhancement.     

Cortical sources of resting state electroencephalographic rhythms in Parkinson’s disease related dementia and Alzheimer’s disease

Objective

Here we test the hypothesis that cortical source mapping of resting state electroencephalographic (EEG) rhythms could characterize neurodegenerative disorders inducing cognitive impairment such as Parkinson’s disease related dementia (PDD) and Alzheimer’s disease (AD).

Methods

To address this issue, eyes-closed resting state EEG rhythms were recorded in 13 PDD, 20 AD, and 20 normal elderly (Nold) subjects. Age, gender, and education were carefully matched across the three groups. Mini Mental State Evaluation (MMSE) score probed subjects’ global cognitive status, and was matched between the PDD and AD groups. EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10.5 Hz), alpha2 (10.5–13 Hz), beta1 (13–20 Hz), and beta2 (20–30 Hz). EEG cortical sources were estimated by low resolution brain electromagnetic source tomography (LORETA).

Results

With respect to the Nold and AD groups, the PPD group was characterized by peculiar abnormalities of central delta sources and posterior cortical sources of theta and beta1 rhythms. With respect to the Nold group, the PDD and AD groups mainly pointed to lower posterior cortical sources of alpha1 rhythms, which were positively correlated to MMSE score across all PDD and AD subjects as a whole (the lower the alpha sources, the lower the MMSE score). This alpha decrease was greater in the AD than PPD patients.

Conclusions

The results suggest that topography and frequency of eyes-closed resting state cortical EEG rhythms distinguished PDD and AD groups.

Significance

We report the existence of different effects of neurodegeneration on the cortical neural synchronization mechanisms generating resting state EEG rhythms in PDD and AD patients.     

Does attentional dysfunction and thalamic atrophy predict decline in dementia with Lewy bodies?

IntroductionTo evaluate the clinical characteristics of DLB subjects who died within 1 year of assessment compared to those who survived and investigate their patterns of in vivo regional thalamic atrophy using structural MRI.MethodsSeventy subjects (35 DLB, 35 aged controls) underwent 3 T T1-weighted MR scanning as well as clinical and cognitive assessments, including a computerised assessment of attention. All subjects were contacted after 12 months for reassessment.For both hemispheres, using FSL FIRST, the thalamus was automatically segmented followed by inter-subject vertex-wise analyses involving group comparisons and behavioural correlates.ResultsThere was significant bilateral atrophy in the ventral-dorsal and pulvinar regions in DLB relative to controls (p_corrected < 0.05). The DLB group was then re-categorised based on 12-month mortality data: DLB-a (n = 26) and DLB-d (n = 9) (a = alive, d = death within 12 months of study assessment). Compared to controls, significant attentional dysfunction and bilateral atrophy of the pulvinar, ventral and dorsal nuclei were observed in DLB-d (p_corrected < 0.05), whereas in DLB-a, atrophy was far less extensive.ConclusionsDistinct patterns of thalamic atrophy occur in DLB that may relate to the attentional dysfunction and cognitive fluctuations that characterise this disorder. Relative to controls, the extent of attentional impairment and pattern of thalamic degeneration differ in those patients who died within 12 months of assessment, despite having an otherwise similar level of dementia severity. These findings may provide insight into the neurobiological changes underpinning important clinical characteristics and disease heterogeneity.     

Plasma cytokine profile in synucleinophaties with dementia

Immune response may play a pivotal role in the pathogenesis of the common synucleinopathy as Parkinson’s disease (PD) and could be mediated with the accumulation of neurotoxic alpha-synuclein. There is limited evidence for immune response in another synucleinopathy as dementia with Lewy bodies (DLB). Recent data suggest that immune response may contribute to cognitive impairment. We aimed to estimate plasma cytokine profile in patients with synucleinopathies with dementia (PD dementia (PDD), DLB). Plasma cytokine levels (interferon-gamma (IFN-gamma), interleukin (IL)-4 (IL-4), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1)). were estimated in 16 patients with DLB, 19 patients with PDD, 28 patients with PD without dementia (PD) and 19 individuals without neurological disorders (controls) using Luminex array system. Cognitive status was assessed with the Mini–Mental State Examination (MMSE). TNF-alpha and IL-6 plasma levels were elevated in patients with synucleinopathies with dementia (DLB, PDD) compared to controls and IL-10 plasma level was increased in PDD compared to controls (p < 0.05). IFN-gamma levels were decreased in PD and PDD patients compared to controls (p < 0.001, p = 0.026, respectively) and in PD patients than in DLB patients (p = 0.032). Patients with PD, PDD, and DLB were characterized by increased plasma levels of MCP-1 compared to controls (p < 0.001). At the same time, no differences in TNF-alpha, IL-10, IL-6 plasma levels in PD patients compared to controls were found. Our study demonstrated more pronounced immune response in synucleinopathies associated with dementia compared to PD without demetia.     

Prevalence and profile of Restless Legs Syndrome in Parkinson's disease and other neurodegenerative disorders: A case-control study

BackgroundRestless Legs Syndrome (RLS) is associated with impaired central dopaminergic neurotransmission. Though a link between RLS and parkinsonism has been proposed, the prevalence of RLS in parkinsonian disorders is poorly documented.ObjectiveTo determine the prevalence of RLS in patients with Parkinson's Disease (PD), Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB).MethodsWe evaluated 187 consecutive patients with parkinsonian disorders (PD = 134, PSP = 27, MSA = 21, DLB = 5) and 172 healthy controls. RLS was diagnosed using the International RLS Study Group (IRLSSG) criteria and the severity of RLS was assessed in patients with definite RLS. Quality of sleep was evaluated with established scales.ResultsThe prevalence of RLS was higher in patients compared to controls (9.6% vs. 2.9%; p = 0.009) and was highest in PD (11.9%). RLS was present in only one patient each with MSA and PSP and none with DLB. The mean IRLSSG severity score of patients was 16.2 ± 6.5. The global Pittsburgh Sleep Quality Index score and Epworth Sleepiness Scale score were significantly higher in patients compared to controls (p < 0.001). PD patients with RLS had lower Parkinson's Disease Sleep Scale (PDSS) score compared to patients without RLS (p = 0.023). There was no significant difference in gender, age, duration and severity of PD between the two groups.ConclusionsOur study found a higher prevalence of RLS in PD compared to healthy controls or other parkinsonian disorders. Apart from PDSS score, there was no significant difference in the clinical characteristics of PD patients with and without RLS.     

Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation

Mitochondrial complex I dysfunction, oxidative stress and immune-activation are consistently reported in bipolar disorder (BD). Mitochondrial production of reactive oxygen species was recently linked to activation of an inflammatory redox sensor, the nod-like receptor family pyrin domain-containing 3 (NLRP3). Upon its activation, NLRP3 recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to form the NLRP3-inflamamsome, activating IL-1β. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflamamsome in BD. Post-mortem frontal cortex from patients with BD (N = 9), schizophrenia (N = 10), and non-psychiatric controls (N = 9) were donated from the Harvard Brain Tissue Resource Center. Levels of NLRP3, ASC and caspase-1 were measured by western blotting, ELISA and Luminex. While we found no effects of age, sex or post-mortem delay, lower levels of complex I (F_2,25 = 3.46, p < 0.05) and NDUFS7, a subunit of complex I (F_2,25 = 4.13, p < 0.05), were found in patients with BD. Mitochondrial NLRP3 (F_2,25 = 3.86, p < 0.05) and ASC (F_2,25 = 4.61, p < 0.05) levels were higher in patients with BD. However, levels of caspase 1 (F_2,25 = 4.13, p < 0.05 for both), IL-1β (F_2,25 = 7.05, p < 0.01), IL-6 (F_2,25 = 5.48, p < 0.05), TNFα (F_2,25 = 7.14, p < 0.01) and IL-10 (F_2,25 = 5.02, p < 0.05) were increased in both BD and schizophrenia. These findings suggest that immune-activation in the frontal cortex may occur both in patients with BD and schizophrenia, while complex I dysfunction and NLRP3-inflammasome activation may be more specific to BD.     

Longitudinal study of striatal aromatic l-amino acid decarboxylase activity in patients with idiopathic rapid eye movement sleep behavior disorder

Study objectivesTo determine if nigrostriatal dopaminergic system function, evaluated by aromatic l-amino acid decarboxylase (AADC) activity using 6-[¹⁸F]fluoro-meta-tyrosine brain positron emission tomography (FMT-PET) can accurately and efficiently identify idiopathic rapid-eye-movement behavior disorder (IRBD) individuals at risk for conversion to a clinical diagnosis of Parkinson's disease (PD) or dementia with Lewy bodies (DLB).MethodsWe assessed prospectively striatal aromatic l-amino acid decarboxylase activity using FMT brain PET imaging in IRBD patients who were followed systematically every 1–3 months for 1–10 years. IRBD patients (n = 27) were enrolled in this prospective cohort study starting in 2009. Those who underwent follow-up scans between January 2011 and September 2014 (n = 24) were analyzed in the present study.ResultsOf the 24 IRBD patients with baseline and follow-up FMT-PET scans, 11 (45.8%) developed PD (n = 6) or DLB (n = 5). Compared to IRBD patients who were still disease-free, those who developed PD (n = 5) or DLB with parkinsonism (n = 1) had significantly reduced bilateral putaminal FMT uptake during the follow-up. Furthermore, the rate of FMT decline between baseline and follow-up scans was higher in all converted patients, even for those with DLB without parkinsonism, than in IRBD patients who remained disease-free.ConclusionsFMT-PET, which represents a dynamic change in AADC activity over time, may also be a useful predictor for the risk of conversion to PD or DLB over short-term clinical follow-up periods, or when testing neuroprotective and restorative strategies in the prodromal phases of PD or DLB.     

Fatigue correlates with LRRK2 G2385R variant in Chinese Parkinson's disease patients

IntroductionFatigue is common in patients with Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) G2385R variant predisposes individuals to develop PD in China. The aim of this study was to evaluate whether the LRRK2 G2385R variant is associated with fatigue in patients with PD.MethodsFatigue was evaluated by the Parkinson Fatigue Scale (PFS) in 329 PD patients and 180 controls, a cut-off score of ≥3.3 was used to define the presence of fatigue. All the enrolled PD patients were assessed by a comprehensive battery of motor and non-motor questionnaires. PD patients were genotyped for the G2385R variant. Associations of fatigue with the clinical assessments and with the G2385R variant in PD patients were analyzed by logistic regression.ResultsFatigue frequency was 55.62%. A logistic regression model found that the female sex (OR = 10.477; 95%CI: 2.806–39.120; p < 0.001), motor function (OR = 1.060; 95%CI: 1.012–1.110; p = 0.013), sleep disturbance (OR = 0.943; 95%CI: 0.910–0.976; p = 0.001) and depression severity (OR = 0.843; 95%CI: 0.736–0.965; p = 0.013) collectively predict the presence of fatigue in PD patients. After adjustment for demographics and associated clinical factors, the G2385R variant was associated with an increased risk for the presence of fatigue (OR = 10.699; 95% CI = 2.387–47.958; p = 0.002) in the PD population in this study.ConclusionWe confirm that fatigue in PD patients is common, and we have strengthened the associations between fatigue and female sex, motor severity and non-motor symptoms, particularly depression and sleep disturbances. Overall, we found that carriers of the G2385R variant were more prone to fatigue than non-carriers in PD patients.