A conserved role for p48 homologs in protecting dopaminergic neurons from oxidative stress.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Both environmental and genetic factors are thought to contribute to the pathogenesis of PD. Although several genes linked to rare familial PD have been identified, endogenous risk factors for sporadic PD, which account for the majority of PD cases, remain largely unknown. Genome-wide association studies have identified many single nucleotide polymorphisms associated with sporadic PD in neurodevelopmental genes including the transcription factor p48/ptf1a. Here we investigate whether p48 plays a role in the survival of DA neurons in Drosophila melanogaster and Caenorhabditis elegans. We show that a Drosophila p48 homolog, 48-related-2 (Fer2), is expressed in and required for the development and survival of DA neurons in the protocerebral anterior medial (PAM) cluster. Loss of Fer2 expression in adulthood causes progressive PAM neuron degeneration in aging flies along with mitochondrial dysfunction and elevated reactive oxygen species (ROS) production, leading to the progressive locomotor deficits. The oxidative stress challenge upregulates Fer2 expression and exacerbates the PAM neuron degeneration in Fer2 loss-of-function mutants. hlh-13, the worm homolog of p48, is also expressed in DA neurons. Unlike the fly counterpart, hlh-13 loss-of-function does not impair development or survival of DA neurons under normal growth conditions. Yet, similar to Fer2, hlh-13 expression is upregulated upon an acute oxidative challenge and is required for the survival of DA neurons under oxidative stress in adult worms. Taken together, our results indicate that p48 homologs share a role in protecting DA neurons from oxidative stress and degeneration, and suggest that loss-of-function of p48 homologs in flies and worms provides novel tools to study gene-environmental interactions affecting DA neuron survival.

Venous pattern of polymicrogyria detected by susceptibility weighted imaging (SWI).

We report a case of a 9-year-old boy presenting with spastic-dystonic movement disorder of the right arm. MRI showed vast unilateral left-sided polymicrogyria (PMG) with perisylvian, temporal, frontal, and parietal location. Corresponding to the distinctly reduced gyration, the focal pattern of cortical veins in susceptibility weighted imaging (SWI) was absent due to missing sulcal depth. In contrast, adjacent regions with sufficient sulcal depth revealed a pattern with numerically increased and finer cortical veins. Therefore, with its atypical venous pattern SWI indicates an abnormal parenchymal anatomy and might be an additional helpful tool for diagnosing PMG.

Clinical and Breed Characteristics of Idiopathic Head Tremor Syndrome in 291 Dogs: A Retrospective Study.

Objective. To establish signalment and phenomenology of canine idiopathic head tremor syndrome (IHTS), an episodic head movement disorder of undetermined pathogenesis. Design. Retrospective case series. Animals. 291 dogs with IHTS diagnosed between 1999 and 2013. Procedures. Clinical information was obtained from an online community of veterinary information aggregation and exchange (Veterinary Information Network, 777 W Covell Boulevard, Davis, CA 95616) and conducted with their approval. Information on breed, sex, age of onset, tremor description, mentation during the event, effect of distractions and drugs, diagnostics, presence of other problems, and outcome was analyzed. Results. IHTS was found in 24 pure breeds. Bulldogs, Labrador Retrievers, Boxers, and Doberman Pinschers comprised 69%; mixed breeds comprised 17%. Average onset age was 29 months (range: 3 months to 12 years). First episode occurred before 48 months of age in 88%. Vertical (35%), horizontal (50%), and rotational (15%) movements were documented. Possible trigger events were found in 21%. Mentation was normal in 93%. Distractions abated the tremor in 87%. Most dogs did not respond to antiepileptic drugs. Conclusions and Clinical Relevance. This retrospective study documents IHTS in many breeds including Labrador Retrievers, Boxers, and mixed breeds.

Effects of treatment on orienting in Parkinson disease

Parkinson disease (PD) is a movement disorder affecting over one million Americans, and 1% of our population over 60 years of age. Currently, PD has an unknown cause, no predictive biomarker, and no cure, yet there are effective treatments (medicine and surgery) to chronically manage the motor symptoms. But, PD patients also develop cognitive symptoms (e.g., distractibility, executive dysfunction) that remain untreated or may decline as a result of treating the motor symptoms. To address this important issue, I measured covert orienting of attention and overt eye movements in PD patients to assess the patients' ability to automatically detect stimuli in their visual field, to predict and attend to where the stimuli would appear, and to volitionally look somewhere else. ^ PD patients completed the cognitive tasks under multiple treatment conditions, and their performance was compared to healthy adults. PD patients first completed the tasks after they had withdrawn from medication. Their unmedicated performance revealed exaggerated automatic orienting, poor predictability, and weak volitional orienting. PD patients then repeated the tasks while medication was giving its peak benefit. The medication returned automatic covert orienting toward normal but did not improve volitional covert orienting. Several PD patients completed the tasks a third time after receiving surgery (specifically, implantation of stimulating electrodes in a subcortical brain region to alleviate motor symptoms). The stimulation (without medication) returned automatic orienting toward normal, did not change predictability, and further impaired volitional orienting. Taken together, treatments prescribed to alleviate the motor symptoms (a patient's primary concern) only improve some cognitive functions. Future studies may establish criteria to predict which patients are more likely to have cognitive benefit from medication over surgery, or vice versa. ^ I have also hypothesized an anatomical model relating orienting circuitry to abnormal PD circuitry and the therapeutic targets. My results suggest medication is more effective restoring the orienting circuitry than stimulation. Further, automatic and volitional orienting abilities seem to be modulated independently, which differs from an earlier model proposing a dependent, inverse relationship. My results are further discussed in terms of response inhibition, response selection, and the location of the selection. ^

A systematic review of characteristics and validity of monitoring technologies to assess Parkinson’s disease symptoms and signs

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Síndrome de Leigh : descrição de um caso clínico e revisão teórica

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Spatial patterns of asynuclein positive glial cytoplasmic inclusions in multiple system atrophy

In cases of multiple system atrophy (MSA), glial cytoplasmic inclusions (GCI) were distributed randomly or present in large diffuse clusters (>1,600 μm in diameter) in most areas studied. These spatial patterns contrast with those reported for filamentous neuronal inclusions in the tauopathies and α-synucleinopathies. © 2003 Movement Disorder Society.

General features of Multiple System Atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of a group of neurodegenerative diseases referred to collectively as the ‘parkinsonian syndromes’. Characteristic of these syndromes is that the patient exhibits symptoms of ‘parkinsonism’, viz., a range of problems involving movement, most typically manifest in Parkinson’s disease (PD) itself1, but also seen in progressive supranuclear palsy (PSP), and to some extent in dementia with Lewy bodies (DLB). MSA is a relatively ‘new’ descriptive term and is derived from three previously described diseases, viz., olivopontocerebellar atrophy, striato-nigral degeneration, and Shy-Drager syndrome. The classical symptoms of MSA include parkinsonism, ataxia, and autonomic dysfunction.6 Ataxia describes a gross lack of coordination of muscle movements while autonomic dysfunction involves a variety of systems that regulate unconscious bodily functions such as heart rate, blood pressure, bladder function, and digestion. Although primarily a neurological disorder, patients with MSA may also develop visual signs and symptoms that could be useful in differential diagnosis. The most important visual signs may include oculomotor dysfunction and problems in pupil reactivity but are less likely to involve aspects of primary vision such as visual acuity, colour vision, and visual fields. In addition, the eye-care practitioner can contribute to the management of the visual problems of MSA and therefore, help to improve quality of life of the patient. Hence, this first article in a two-part series describes the general features of MSA including its prevalence, signs and symptoms, diagnosis, pathology, and possible causes.

Visual signs and symptoms of Multiple System Atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of a group of neurodegenerative diseases, which include Parkinson’s disease (PD) and progressive supranuclear palsy (PSP), and referred to as the ‘parkinsonian syndromes’. Although primarily a neurological disorder, patients with MSA may also develop visual signs and symptoms that could be useful in differential diagnosis. In addition, the eye-care practitioner may contribute to the management of visual problems of MSA patients and therefore, help to improve quality of life. This second article in the series considers the visual signs and symptoms of MSA with special reference to those features most useful in differential diagnosis of the parkinsonian syndromes.

Density and spatial pattern of β-amyloid (Aβ) deposits in corticobasal degeneration

Corticobasal degeneration (CBD) is a rare, progressive movement disorder characterized neuropathologically by widespread neuronal and glial pathology including tau-immunoreactive neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), and astrocytic plaques (AP). However, ß -amyloid (A ß) deposits have been observed in the cerebral cortex and/or hippocampus in some cases of CBD. To clarify the role of Aß deposition in CBD, the densities and spatial patterns of the Aß deposits were studied in three cases. In two cases, expressing apolipoprotein E (APOE) genotypes 2/3 or 3/3, the densities of the Aß deposits were similar to those in normal elderly brain. In the remaining case, expressing APOE genotype 3/4, Aß deposition was observed throughout the cerebral cortex, sectors CA1 and CA2 of the hippocampus, and the molecular layer of the dentate gyrus. The densities of the Aß deposits in this case were typical of those observed in Alzheimer's disease (AD). In the three cases, clustering of Aß deposits, with clusters ranging in size from 200 to >6400 µm in diameter, was evident in 25/27 (93%) of analyses. In addition, the clusters of Aß deposits were regularly distributed parallel to the tissue boundary in 52% of analyses, a spatial pattern similar to that observed in AD. These results suggest: (1) in some CBD cases, Aß pathology is age-related, (2) more extensive Aß deposition is observed in some cases, the density and spatial patterns of the Aß deposits being similar to AD, and (3) extensive deposition of Aß in CBD may be associated with APOE allele e4.

Visual signs and symptoms of multiple system atrophy

Multiple system atrophy (MSA) is a rare movement disorder and a member of the 'parkinsonian syndromes', which also include Parkinson's disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB) and corticobasal degeneration (CBD). Multiple system atrophy is a complex syndrome, in which patients exhibit a variety of signs and symptoms, including parkinsonism, ataxia and autonomic dysfunction. It can be difficult to separate MSA from the other parkinsonian syndromes but if ocular signs and symptoms are present, they may aid differential diagnosis. Typical ocular features of MSA include blepharospasm, excessive square-wave jerks, mild to moderate hypometria of saccades, impaired vestibular-ocular reflex (VOR), nystagmus and impaired event-related evoked potentials. Less typical features include slowing of saccadic eye movements, the presence of vertical gaze palsy, visual hallucinations and an impaired electroretinogram (ERG). Aspects of primary vision such as visual acuity, colour vision or visual fields are usually unaffected. Management of the disease to deal with problems of walking, movement, daily tasks and speech problems is important in MSA. Optometrists can work in collaboration with the patient and health-care providers to identify and manage the patient's visual deficits. A more specific role for the optometrist is to correct vision to prevent falls and to monitor the anterior eye to prevent dry eye and control blepharospasm.

Machine learning for large-scale wearable sensor data in Parkinson disease:concepts, promises, pitfalls, and futures

For the treatment and monitoring of Parkinson's disease (PD) to be scientific, a key requirement is that measurement of disease stages and severity is quantitative, reliable, and repeatable. The last 50 years in PD research have been dominated by qualitative, subjective ratings obtained by human interpretation of the presentation of disease signs and symptoms at clinical visits. More recently, “wearable,” sensor-based, quantitative, objective, and easy-to-use systems for quantifying PD signs for large numbers of participants over extended durations have been developed. This technology has the potential to significantly improve both clinical diagnosis and management in PD and the conduct of clinical studies. However, the large-scale, high-dimensional character of the data captured by these wearable sensors requires sophisticated signal processing and machine-learning algorithms to transform it into scientifically and clinically meaningful information. Such algorithms that “learn” from data have shown remarkable success in making accurate predictions for complex problems in which human skill has been required to date, but they are challenging to evaluate and apply without a basic understanding of the underlying logic on which they are based. This article contains a nontechnical tutorial review of relevant machine-learning algorithms, also describing their limitations and how these can be overcome. It discusses implications of this technology and a practical road map for realizing the full potential of this technology in PD research and practice. © 2016 International Parkinson and Movement Disorder Society.

Technology in Parkinson's disease:challenges and opportunities

The miniaturization, sophistication, proliferation, and accessibility of technologies are enabling the capture of more and previously inaccessible phenomena in Parkinson's disease (PD). However, more information has not translated into a greater understanding of disease complexity to satisfy diagnostic and therapeutic needs. Challenges include noncompatible technology platforms, the need for wide-scale and long-term deployment of sensor technology (among vulnerable elderly patients in particular), and the gap between the "big data" acquired with sensitive measurement technologies and their limited clinical application. Major opportunities could be realized if new technologies are developed as part of open-source and/or open-hardware platforms that enable multichannel data capture sensitive to the broad range of motor and nonmotor problems that characterize PD and are adaptable into self-adjusting, individualized treatment delivery systems. The International Parkinson and Movement Disorders Society Task Force on Technology is entrusted to convene engineers, clinicians, researchers, and patients to promote the development of integrated measurement and closed-loop therapeutic systems with high patient adherence that also serve to (1) encourage the adoption of clinico-pathophysiologic phenotyping and early detection of critical disease milestones, (2) enhance the tailoring of symptomatic therapy, (3) improve subgroup targeting of patients for future testing of disease-modifying treatments, and (4) identify objective biomarkers to improve the longitudinal tracking of impairments in clinical care and research. This article summarizes the work carried out by the task force toward identifying challenges and opportunities in the development of technologies with potential for improving the clinical management and the quality of life of individuals with PD. © 2016 International Parkinson and Movement Disorder Society.

Tourette's syndrome and associated disorders: a systematic review

To compile data on Tourette's syndrome (TS), tics and associated disorders. METHODS: A systematic review of the literature was conducted using the 5S levels of organization of healthcare research evidence (systems, summaries, synopses, syntheses, studies), based on the model described by Haynes. The search keywords were Tourette, tics and comorbidity, which were cross-referenced. Studies provided by publishers and articles being processed on July 31, 2013, were also included. RESULTS: Of all studies retrieved during the search, 64 were selected because they analyzed the epidemiology, clinical features and etiopathogenesis of TS and its comorbidities. TS is classified as a hyperkinetic movement disorder, and at least 90% of the patients have neuropsychiatric comorbidities, of which attention deficit hyperactivity and obsessive-compulsive disorders are the most common. The syndrome is clinically heterogeneous and has been associated with a dysfunction of cortico-striatal-thalamic-cortical circuits involving various neurotransmitters. Although its genetic etiology has been widely studied, other factors may be important to understand this syndrome and its associated disorders. CONCLUSIONS: TS is a neurodevelopmental disorder that results from the impact of stress factors on a vulnerable biological substrate during the critical periods of neurodevelopment. The study of TS and its comorbidities may contribute, at different levels, to the understanding of several neuropsychiatric disorders of clinical and therapeutic relevance.

Functional Magnetic Resonance Imaging Neurofeedback and Motor training for Parkinson’s Disease: Randomised Trial

Objective: Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient’s own brain activity to self-regulate brain networks which in turn could lead to a change in behaviour and clinical symptoms. The objective was to determine the effect of neurofeedback and motor training and motor training (MOT) alone on motor and non-motor functions in Parkinson’s disease (PD) in a 10-week small Phase I randomised controlled trial. Methods: 30 patients with PD (Hoehn & Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with motor training. Group 2 (MOT: 15 patients) received motor training alone. The primary outcome measure was the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention ‘off-medication’. The secondary outcome measures were the ‘on-medication’ MDS-UPDRS, the Parkinson’s disease Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. Results: Patients in the NF group were able to upregulate activity in the supplementary motor area by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the ‘off-medication’ state (95% confidence interval: -2.5 to -6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to -6.8). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. Interpretation: This Phase I study suggests that NF combined with motor training is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions. Clinical Trial website : Unique Identifier: NCT01867827 URL: https://clinicaltrials.gov/ct2/show/NCT01867827?term=NCT01867827&rank=1