Long-term follow-up study of nucleus ventralis intermedius and ventrolateralis thalamotomy using a microelectrode technique in parkinsonism

Long-term observation over 3-8 postoperative years of cases of Parkinson disease operated by stereotactic thalamotomy using a microelectrode recording technique is reported. The procedure is specifically useful in the following four groups: (1) tremor-dominant cases, (2) hemiparkinsonism, (3) cases with marked asymmetry in motor symptoms and (4) juvenile parkinsonism presenting levodopa-induced dyskinesia.     

Variations in rest-activity rhythm are associated with clinically measured disease severity in Parkinson’s disease

ABSTRACT

The continuous, longitudinal nature of accelerometry monitoring is well-suited to capturing the regular 24-hour oscillations in human activity across the day, the cumulative effect of our circadian rhythm and behavior. Disruption of the circadian rhythm in turn disrupts rest-activity rhythms. Although circadian disruption is a major feature of Parkinson’s disease (PD), rest-activity rhythms and their relationship with disease severity have not been well characterized in PD. 13 PD participants (Hoehn & Yahr Stage [H&Y] 1–3) wore a Philips Actiwatch Spectrum PRO continuously for two separate weeks. Rest-activity rhythms were quantified by fitting an oscillating 24-hour cosinor model to each participant-day of activity data. One-way ANOVAs adjusted for demographics revealed significant variation in the amount (MESOR, F = 12.76, p < .01), range (Amplitude, F = 9.62, p < .01), and timing (Acrophase, F = 2.7, p = .05) of activity across H&Y Stages. Those with higher H&Y Stages were significantly more likely to be active later in the day, where-as those who shifted between H&Y Stages during the study were significantly more active than those who did not change H&Y Stage. Being active later in the day was also significantly associated with higher scores on the Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Section III (motor symptom severity, p = .02), Section II (self-reported impact of motor symptoms on daily living, p = .01), and Total Score (p = .01) in an adjusted linear regression model; significant associations between MDS-UPDRS scores and activity levels were observed only in the unadjusted model. These findings demonstrate that continuous actigraphy is capable of detecting rest-activity disruption in PD, and provides preliminary evidence that rest-activity rhythms are associated with motor symptom severity and H&Y Stage.     

Longitudinal Study of the Development of Higher Mental Functions in Primary School Children

This article presents the results of a longitudinal population-based neuropsychological study of the development of higher mental functions (HMFs) in primary school children from grades 1 through 3 at a Moscow public school (n = 84). We monitored changes in HMFs in the total sample and in groups of children with different baseline HMFs (high, medium, low), as measured in the first grade, using seven indexes that reflect individual HMF components such as executive functions (voluntary regulation of activity), serial organization of movements and actions, processing of kinesthetic, auditory, visual, and visual-spatial information, and regulation of activation, at three time points (first, second, and third grades). The study found a generally positive trend in the structural and functional components of HMFs in the children who were tested. Groups of children with different baseline levels of HMFs steadily maintained their differences in the degree of development of the HMFs at each evaluation time point, although the greatest change in HMF components was found in children with initially low scores, and the least change was in children with initially high HMF scores. Among the components with the least change was voluntary regulation—that is, the programming, regulation, and control of one's activity. The fact that children with high baseline functioning did not change significantly in a given function from first to third grades may be related to a decline in learning motivation, insofar as their learning is then occurring in the zone of actual and not proximal development.     

Differences in rapid eye movement sleep behavior disorder manifestation between synucleinopathies and tauopathies

Rapid eye movement sleep behavior disorder (RBD) frequently occurs in synucleinopathies including multiple system atrophy, Parkinson’s disease, and dementia with Lewy bodies despite the clinical course of RBD being different between these disorders. Comparatively, the existence of RBD symptoms is relatively rare in patients with progressive supranuclear palsy, a tauopathy showing atypical parkinsonism compared with Parkinson’s disease. Moreover, in patients with Alzheimer’s disease, which is another tauopathy, RBD symptoms are less frequent than dementia with Lewy bodies, although both disorders share commonalities in terms of the existence of cortical dementia. Thus, RBD is thought to be relatively specific to synucleinopathies.

     

alpha-Synuclein aggregates interfere with Parkin solubility and distribution: role in the pathogenesis of Parkinson disease

Parkinson disease (PD) belongs to a heterogeneous group of neurodegenerative disorders with movement alterations, cognitive impairment, and alpha-synuclein accumulation in cortical and subcortical regions. Jointly, these disorders are denominated Lewy body disease. Mutations in the parkin gene are the most common cause of familial parkinsonism, and a growing number of studies have shown that stress factors associated with sporadic PD promote parkin accumulation in the insoluble fraction. alpha-Synuclein and parkin accumulation and mutations in these genes have been associated with familial PD. To investigate whether alpha-synuclein accumulation might be involved in the pathogenesis of these disorders by interfering with parkin solubility, synuclein-transfected neuronal cells were transduced with lentiviral vectors expressing parkin. Challenging neurons with proteasome inhibitors or amyloid-beta resulted in accumulation of insoluble parkin and, to a lesser extent, alpha-tubulin. Similarly to neurons in the brains of patients with Lewy body disease, in co-transduced cells alpha-synuclein and parkin colocalized and co-immunoprecipitated. These effects resulted in decreased parkin and alpha-tubulin ubiquitination, accumulation of insoluble parkin, and cytoskeletal alterations with reduced neurite outgrowth. Taken together, accumulation of alpha-synuclein might contribute to the pathogenesis of PD and other Lewy body diseases by promoting alterations in parkin and tubulin solubility, which in turn might compromise neural function by damaging the neuronal cytoskeleton. These studies provide a new perspective on the potential nature of pathogenic alpha-synuclein and parkin interactions in Parkinson disease.     

Drosophila as a Model Organism for Investigating Molecular and Cellular Etiologies Underlying Complex Neurological Disorders in Humans

The fruit fly Drosophila has been utilized as a powerful biological system to address fundamental questions concerning neurological disorders in humans, since the related basic molecular components and signal transduction pathways in humans are mostly conserved in Drosophila. In addition, Drosophila offers great experimental advantages in genetics, behavioral analysis and cell and molecular biology. Pathogenesis and etiologies underlying several monogenic neurological disorders including familial Parkinson disease, Alzheimer's disease, or ataxia have been faithfully replicated in Drosophila system when causative mutations of those disorders were transgenically introduced or loss of function mutations of endogenous homologues were made. However, more than 90% of reported cases of neurological disorders are complex forms whose inheritance patterns do not follow a monogenic inheritance. Nevertheless, complex disorders are more often observed among the families or relatives of affected patients, strongly suggesting that they are most likely to be caused by interaction of multiple genetic mutations or combinations of genetic and environmental risk factors. Complex neurological disorders are include sporadic forms of Parkinson disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dystonia, epilepsy, and mental retardation, etc. Our understanding of the genetic defects and environmental risk factors involved in the onset and progression of complex neurological disorders are, however, still rudimentary. Thus identifying unknown factors involved in the onset and progression of complex neurological disorders in humans is one of the major challenges in medical sciences.     

Signature of Aberrantly Expressed microRNAs in the Striatum of Rotenone-Induced Parkinsonian Rats

Parkinson’s disease (PD) is a highly complex brain disorder regarding clinical presentation, pathogenesis, and therapeutics. The cardinal motor signs, i.e., rigidity, bradykinesia, and unilateral tremors, arise in consequence of a progressive neuron death during the prodromal phase. Although multiple transmission systems are involved in disease neurobiology, patients will cross the line between the prodromal and early stage of diagnosed PD when they had lost half of the dopaminergic nigrostriatal cells. As the neurons continue to die ascending the neuroaxis, patients will face a more disabling disease with motor and nonmotor signs. Shedding light on molecular mechanisms of neuron death is an urgent need for understanding PD pathogenesis and projecting therapeutics. This work examined the expression of microRNAs in the striatum of parkinsonian rats chronically exposed to rotenone (2.5 mg/Kg, i.p., daily for 10 days). Rotenone caused motor deficits, the loss of TH(+) cells in the nigrostriatal pathway, and a marked microgliosis. This parkinsonian rat striatum was examined at 26 days after the last rotenone injection, for quantification of microRNAs, miR-7, miR-34a, miR-26a, miR-132, miR-382, and Let7a, by qPCR. Parkinsonian rats presented a significant increase in miR-26a and miR-34a (1.5 and 2.2 fold, respectively, P?<?0.05), while miR-7 (0.5 fold, P?<?0.05) and Let7a were downregulated. This work reports for first time microRNAs aberrantly expressed in the striatum of rotenone-induced parkinsonian rats, suggesting that this dysregulation may contribute to PD pathogenesis. Beyond revealing new clues of neurodegeneration, our findings might prime further studies targeting miRNAs for neuroprotection or even for diagnosis proposal.     

Reactive Oxygen Species: Potential Regulatory Molecules in Response to Hypomagnetic Field Exposure

Organisms, including humans, could be exposed to hypomagnetic fields (HMFs, intensity <5 μT), e.g. in some artificially shielded magnetic environments and during deep-space flights. Previous studies have demonstrated that HMF exposure could have negative effects on the central nervous system and embryonic development in many animals. However, the underlying mechanisms remain unknown. Studies have revealed that HMFs affect cellular reactive oxygen species (ROS) levels and thereby alter physiological and biological processes in organisms. ROS, the major component of highly active free radicals, which are ubiquitous in biological systems, were hypothesized to be the candidate signaling molecules that regulate diverse physiological processes in response to changes in magnetic fields. Here, we summarize the recent advances in the study of HMF-induced negative effects on the central nervous system and early embryonic development in animals, focusing on cellular ROS and their role in response to HMFs. Furthermore, we discuss the potential mechanism through which HMFs regulate ROS levels in cells. © 2020 Bioelectromagnetics Society     

The prevalence of mental disorders among homeless people in high-income countries: An updated systematic review and meta-regression analysis

BackgroundHomelessness continues to be a pressing public health concern in many countries, and mental disorders in homeless persons contribute to their high rates of morbidity and mortality. Many primary studies have estimated prevalence rates for mental disorders in homeless individuals. We conducted a systematic review and meta-analysis of studies on the prevalence of any mental disorder and major psychiatric diagnoses in clearly defined homeless populations in any high-income country.Methods and findingsWe systematically searched for observational studies that estimated prevalence rates of mental disorders in samples of homeless individuals, using Medline, Embase, PsycInfo, and Google Scholar. We updated a previous systematic review and meta-analysis conducted in 2007, and searched until 1 April 2021. Studies were included if they sampled exclusively homeless persons, diagnosed mental disorders by standardized criteria using validated methods, provided point or up to 12-month prevalence rates, and were conducted in high-income countries. We identified 39 publications with a total of 8,049 participants. Study quality was assessed using the JBI critical appraisal tool for prevalence studies and a risk of bias tool. Random effects meta-analyses of prevalence rates were conducted, and heterogeneity was assessed by meta-regression analyses. The mean prevalence of any current mental disorder was estimated at 76.2% (95% CI 64.0% to 86.6%). The most common diagnostic categories were alcohol use disorders, at 36.7% (95% CI 27.7% to 46.2%), and drug use disorders, at 21.7% (95% CI 13.1% to 31.7%), followed by schizophrenia spectrum disorders (12.4% [95% CI 9.5% to 15.7%]) and major depression (12.6% [95% CI 8.0% to 18.2%]). We found substantial heterogeneity in prevalence rates between studies, which was partially explained by sampling method, study location, and the sex distribution of participants. Limitations included lack of information on certain subpopulations (e.g., women and immigrants) and unmet healthcare needs.ConclusionsPublic health and policy interventions to improve the health of homeless persons should consider the pattern and extent of psychiatric morbidity. Our findings suggest that the burden of psychiatric morbidity in homeless persons is substantial, and should lead to regular reviews of how healthcare services assess, treat, and follow up homeless people. The high burden of substance use disorders and schizophrenia spectrum disorders need particular attention in service development. This systematic review and meta-analysis has been registered with PROSPERO (CRD42018085216).Trial registrationPROSPERO CRD42018085216.

In an updated systematic review and meta analysis, Stefan Gutwinski, Stefanie Schreiter, and colleagues examine the prevalence of mental disorders among individuals who are homeless in high income countries.     

Cost-effectiveness evidence of mental health prevention and promotion interventions: A systematic review of economic evaluations

BackgroundThe prevention of mental disorders and promotion of mental health and well-being are growing fields. Whether mental health promotion and prevention interventions provide value for money in children, adolescents, adults, and older adults is unclear. The aim of the current study is to update 2 existing reviews of cost-effectiveness studies in this field in order to determine whether such interventions are cost-effective.Methods and findingsElectronic databases (including MEDLINE, PsycINFO, CINAHL, and EconLit through EBSCO and Embase) were searched for published cost-effectiveness studies of prevention of mental disorders and promotion of mental health and well-being from 2008 to 2020. The quality of studies was assessed using the Quality of Health Economic Studies Instrument (QHES). The protocol was registered with PROSPERO (# CRD42019127778). The primary outcomes were incremental cost-effectiveness ratio (ICER) or return on investment (ROI) ratio across all studies.A total of 65 studies met the inclusion criteria of a full economic evaluation, of which, 23 targeted children and adolescents, 35 targeted adults, while the remaining targeted older adults. A large number of studies focused on prevention of depression and/or anxiety disorders, followed by promotion of mental health and well-being and other mental disorders. Although there was high heterogeneity in terms of the design among included economic evaluations, most studies consistently found that interventions for mental health prevention and promotion were cost-effective or cost saving. The review found that targeted prevention was likely to be cost-effective compared to universal prevention. Screening plus psychological interventions (e.g., cognitive behavioural therapy [CBT]) at school were the most cost-effective interventions for prevention of mental disorders in children and adolescents, while parenting interventions and workplace interventions had good evidence in mental health promotion. There is inconclusive evidence for preventive interventions for mental disorders or mental health promotion in older adults. While studies were of general high quality, there was limited evidence available from low- and middle-income countries.The review was limited to studies where mental health was the primary outcome and may have missed general health promoting strategies that could also prevent mental disorder or promote mental health. Some ROI studies might not be included given that these studies are commonly published in grey literature rather than in the academic literature.ConclusionsOur review found a significant growth of economic evaluations in prevention of mental disorders or promotion of mental health and well-being over the last 10 years. Although several interventions for mental health prevention and promotion provide good value for money, the varied quality as well as methodologies used in economic evaluations limit the generalisability of conclusions about cost-effectiveness. However, the finding that the majority of studies especially in children, adolescents, and adults demonstrated good value for money is promising. Research on cost-effectiveness in low-middle income settings is required.Trial registrationPROSPERO registration number: CRD42019127778.

In a systematic review, Long Khanh-Dao Le and colleagues investigate the cost effectiveness of mental health interventions among children, adolescents, and adults.     

Olfactory Dysfunction and Neurotransmitter Disturbance in Olfactory Bulb of Transgenic Mice Expressing Human A53T Mutant α-Synuclein

Parkinson disease is a multi-system neurodegenerative disease characterized by both motor and non-motor symptoms. Hyposmia is one of the early non-motor symptoms occurring in more than 90% of Parkinson disease cases, which can precede motor symptoms even several years. Up to now, the relationship between hyposmia and Parkinson disease remains elusive. Lack of proper animal models of hyposmia restricts the investigation. In this study we assessed olfactory function in Prp-A53T-α-synuclein transgenic (αSyn^A53T) mice which had been reported to show age-dependent motor impairments and intracytoplasmic inclusions. We also examined cholinergic and dopaminergic systems in olfactory bulb of αSyn^A53T mice by immunofluorescent staining, enzyme linked immunosorbent assay and western blot. We found that compared to wild type littermates, αSyn^A53T mice at 6 months or older displayed a deficit of odor discrimination and odor detection. No significant changes were found in olfactory memory and odor habituation. Furthermore compared to wildtype littermates, in olfactory bulb of αSyn^A53T mice at 10 months old we detected a marked decrease of cholinergic neurons in mitral cell layer and a decrease of acetylcholinesterase activity, while dopaminergic neurons were found increased in glomerular layer, accompanied with an increase of tyrosine hydroxylase protein. Our studies indicate that αSyn^A53T mice have olfactory dysfunction before motor deficits occur, and the cholinergic and dopaminergic disturbance might be responsible for the Parkinson disease-related olfactory dysfunction.     

Prion-like activity of Cu/Zn superoxide dismutase

Neurodegenerative diseases belong to a larger group of protein misfolding disorders, known as proteinopathies. There is increasing experimental evidence implicating prion-like mechanisms in many common neurodegenerative disorders, including Alzheimer disease, Parkinson disease, the tauopathies, and amyotrophic lateral sclerosis (ALS), all of which feature the aberrant misfolding and aggregation of specific proteins. The prion paradigm provides a mechanism by which a mutant or wild-type protein can dominate pathogenesis through the initiation of self-propagating protein misfolding. ALS, a lethal disease characterized by progressive degeneration of motor neurons is understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within and around motor neurons that can contribute to neurotoxicity. It is well established that misfolded/oxidized SOD1 protein is highly toxic to motor neurons and plays a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of SOD1 and comment on its proposed mechanisms of intercellular transmission.     

Long-stay psychiatric patients: a prospective study revealing persistent antipsychotic-induced movement disorder

Objective

The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness.

Method

Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia.

Results

The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder.

Conclusions

Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.     

Motor neurons rely on motor proteins

The importance of active axonal transport to the neuron has been highlighted by the recent discoveries that mutations in microtubule motor proteins result in neurodegenerative diseases. Mutations affecting microtubule motor function have been shown to cause hereditary forms of Charcot-Marie-Tooth disease (type 2A), hereditary spastic paraplegia and motor neuron disease. Although motor neurons appear to be uniquely susceptible to defects in axonal transport, recent work has identified links between perturbations in axonal transport and the pathogenesis of other neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. More broadly, cytoskeletal abnormalities might also be at the root of related disorders such as spinal muscular atrophy, supporting a key role for axonal transport in the pathogenesis of many neurodegenerative diseases.     

Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer’s and Parkinson’s diseases

Disbalance of zinc (Zn²⁺) and copper (Cu²⁺) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer’s disease, and Parkinson’s disease. Among these, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn²⁺ and Cu²⁺ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn²⁺ and Cu²⁺ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn²⁺ and Cu²⁺.     

Mechanically tuned 3 dimensional hydrogels support human mammary fibroblast growth and viability

Background

Carcinoma associated fibroblasts (CAFs or myofibroblasts) are activated fibroblasts which participate in breast tumor growth, angiogenesis, invasion, metastasis and therapy resistance. As such, recent efforts have been directed toward understanding the factors responsible for activation of the phenotype. In this study, we have investigated how changes in the mechanical stiffness of a 3D hydrogel alter the behavior and myofibroblast-like properties of human mammary fibroblasts (HMFs).

Results

Here, we utilized microbial transglutaminase (mTG) to mechanically tune the stiffness of gelatin hydrogels and used rheology to show that increasing concentrations mTG resulted in hydrogels with greater elastic moduli (G’). Upon encapsulation of HMFs in 200 (compliant), 300 (moderate) and 1100 Pa (stiff) mTG hydrogels, it was found that the HMFs remained viable and proliferated over the 7 day culture period. Specifically, rates of proliferation were greatest for HMFs in moderate hydrogels. Regarding morphology, HMFs in compliant and moderate hydrogels exhibited a spindle-like morphology while HMFs in stiff hydrogels exhibited a rounded morphology with several large cellular protrusions. Quantification of cell morphology revealed that HMFs cultured in all mTG hydrogels overall assumed a more elongated phenotype over time in culture; however, few significant differences in morphology were observed between HMFs in each of the hydrogel conditions. To determine whether matrix stiffness upregulated expression of ECM and myofibroblast markers, western blot was performed on HMFs in compliant, moderate and stiff hydrogels. It was found that ECM and myofibroblast proteins varied in expression during both the culture period and according to matrix stiffness with no clear correlation between matrix stiffness and a myofibroblast phenotype. Finally, TGF-β levels were quantified in the conditioned media from HMFs in compliant, moderate and stiff hydrogels. TGF-β was significantly greater for HMFs encapsulated in stiff hydrogels.

Conclusions

Overall, these results show that while HMFs are viable and proliferate in mTG hydrogels, increasing matrix stiffness of mTG gelatin hydrogels doesn’t support a robust myofibroblast phenotype from HMFs. These results have important implications for further understanding how modulating 3D matrix stiffness affects fibroblast morphology and activation into a myofibroblast phenotype.

     

The multiple mechanisms of amyloid deposition: The role of parkin

Amyloid deposition is one of the central neuropathological abnormalities in Alzheimer disease (AD) but it also takes places in many neurodegenerative diseases such as prionic disorders, Huntington''s disease (HD) and others. Up to very recently amyloid formation was considered a very slow process of deposition of an abnormal protein due to genetic abnormalities or post-translational modification of the deposited protein. Recent data suggest that the process of amyloidogenesis may be much more rapid in many cases and due to multiple mechanisms.We have found a mouse model of progressive neurodegeneration that resemble motor, behavioral and pathological hallmarks of parkinsonism and tauopathies, but surprisingly, also present amyloid deposits in brain and peripheral organs. Here we review some of these recent works which may provide new insight into the process of formation of amyloid and, perhaps, new ideas for its treatment.Key words: □-amyloid, Alzheimer disease, chaperones, fronto-temporal dementia, parkin, Parkinson disease, PSP, proteosome, tau protein, tauopathies, autophagy, transgenic mice