International validation of a behavioral scale in Parkinson's disease without dementia.

The "Ardouin Scale of Behavior in Parkinson's Disease" is a new instrument specifically designed for assessing mood and behavior with a view to quantifying changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This study was aimed at analyzing the psychometric attributes of this scale in patients with Parkinson's disease without dementia. In addition to this scale, the following measures were applied: the Unified Parkinson's Disease Rating Scale, the Montgomery and Asberg Depression Rating Scale, the Lille Apathy Rating Scale, the Bech and Rafaelsen Mania Scale, the Positive and Negative Syndrome Scale, the MacElroy Criteria, the Patrick Carnes criteria, the Hospital Anxiety and Depression Scale, and the Mini-International Neuropsychiatric Interview. Patients (n = 260) were recruited at 13 centers across four countries (France, Spain, United Kingdom, and United States). Cronbach's alpha coefficient for domains ranged from 0.69 to 0.78. Regarding test-retest reliability, the kappa coefficient for items was higher than 0.4. For inter-rater reliability, the kappa values were 0.29 to 0.81. Furthermore, most of the items from the Ardouin Scale of Behavior in Parkinson's Disease correlated with the corresponding items of the other scales, depressed mood with the Montgomery and Asberg Depression Rating Scale (ρ = 0.82); anxiety with the Hospital Anxiety and Depression Scale-anxiety (ρ = 0.56); apathy with the Lille Apathy Rating Scale (ρ = 0.60). The Ardouin Scale of Behavior in Parkinson's disease is an acceptable, reproducible, valid, and precise assessment for evaluating changes in behavior in patients with Parkinson's disease without dementia. © 2015 International Parkinson and Movement Disorder Society.

Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival.

Delaying clinical disease onset would greatly reduce neurodegenerative disease burden, but the mechanisms influencing early preclinical progression are poorly understood. Here, we show that in mouse models of familial motoneuron (MN) disease, SOD1 mutants specifically render vulnerable MNs dependent on endogenous neuroprotection signaling involving excitability and mammalian target of rapamycin (mTOR). The most vulnerable low-excitability FF MNs already exhibited evidence of pathology and endogenous neuroprotection recruitment early postnatally. Enhancing MN excitability promoted MN neuroprotection and reversed misfolded SOD1 (misfSOD1) accumulation and MN pathology, whereas reducing MN excitability augmented misfSOD1 accumulation and accelerated disease. Inhibiting metabotropic cholinergic signaling onto MNs reduced ER stress, but enhanced misfSOD1 accumulation and prevented mTOR activation in alpha-MNs. Modulating excitability and/or alpha-MN mTOR activity had comparable effects on the progression rates of motor dysfunction, denervation, and death. Therefore, excitability and mTOR are key endogenous neuroprotection mechanisms in motoneurons to counteract clinically important disease progression in ALS.

Marinesco-Sjögren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS.

Mechanisms underlying motor neuron subtype-selective endoplasmic reticulum (ER) stress and associated axonal pathology in amyotrophic lateral sclerosis (ALS) remain unclear. Here we show that the molecular environment of the ER between motor neuron subtypes is distinct, with characteristic signatures. We identify cochaperone SIL1, mutated in Marinesco-Sjögren syndrome (MSS), as being robustly expressed in disease-resistant slow motor neurons but not in ER stress-prone fast-fatigable motor neurons. In a mouse model of MSS, we demonstrate impaired ER homeostasis in motor neurons in response to loss of SIL1 function. Loss of a single functional Sil1 allele in an ALS mouse model (SOD1-G93A) enhanced ER stress and exacerbated ALS pathology. In SOD1-G93A mice, SIL1 levels were progressively and selectively reduced in vulnerable fast-fatigable motor neurons. Mechanistically, reduction in SIL1 levels was associated with lowered excitability of fast-fatigable motor neurons, further influencing expression of specific ER chaperones. Adeno-associated virus-mediated delivery of SIL1 to familial ALS motor neurons restored ER homeostasis, delayed muscle denervation and prolonged survival.

Is Parkinson's disease of early onset a separate disease entity?

Two groups of patients suffering from Parkinson's disease were studied. The first group consisted of 23 patients with an onset age before 40 years; in the second group of 21 patients the onset was after age 50. The clinical findings and the course of the disease were very similar in each group. In spite of a longer disease duration in the patients with early onset of the disease there was no difference in motor impairment; the younger patients did better in mental testing and they were taking less dopaminergic medication. These differences are thought to be due to the age difference rather than to the existence of different disease entities. In the early onset group more familial cases (mostly affecting siblings) were found than in the older ones. The points in favour of there being a hereditary subgroup of early onset Parkinson's disease or of environmental factors causing the disease are reviewed.

Physiological time structure of the tibialis anterior motor activity during sleep in mice, rats and humans

The validation of rodent models for restless legs syndrome (Willis-Ekbom disease) and periodic limb movements during sleep requires knowledge of physiological limb motor activity during sleep in rodents. This study aimed to determine the physiological time structure of tibialis anterior activity during sleep in mice and rats, and compare it with that of healthy humans. Wild-type mice (n = 9) and rats (n = 8) were instrumented with electrodes for recording the electroencephalogram and electromyogram of neck muscles and both tibialis anterior muscles. Healthy human subjects (31 ± 1 years, n = 21) underwent overnight polysomnography. An algorithm for automatic scoring of tibialis anterior electromyogram events of mice and rats during non-rapid eye movement sleep was developed and validated. Visual scoring assisted by this algorithm had inter-rater sensitivity of 92-95% and false-positive rates of 13-19% in mice and rats. The distribution of the time intervals between consecutive tibialis anterior electromyogram events during non-rapid eye movement sleep had a single peak extending up to 10 s in mice, rats and human subjects. The tibialis anterior electromyogram events separated by intervals <10 s mainly occurred in series of two-three events, their occurrence rate in humans being lower than in mice and similar to that in rats. In conclusion, this study proposes reliable rules for scoring tibialis anterior electromyogram events during non-rapid eye movement sleep in mice and rats, demonstrating that their physiological time structure is similar to that of healthy young human subjects. These results strengthen the basis for translational rodent models of periodic limb movements during sleep and restless legs syndrome/Willis-Ekbom disease.

An unusual stroke-like clinical presentation of Creutzfeldt-Jakob disease: acute vestibular syndrome

INTRODUCTION Vertigo and dizziness are common neurological symptoms in general practice. Most patients have benign peripheral vestibular disorders, but some have dangerous central causes. Recent research has shown that bedside oculomotor examinations accurately discriminate central from peripheral lesions in those with new, acute, continuous vertigo/dizziness with nausea/vomiting, gait unsteadiness, and nystagmus, known as the acute vestibular syndrome. CASE REPORT A 56-year-old man presented to the emergency department with acute vestibular syndrome for 1 week. The patient had no focal neurological symptoms or signs. The presence of direction-fixed, horizontal nystagmus suppressed by visual fixation without vertical ocular misalignment (skew deviation) was consistent with an acute peripheral vestibulopathy, but bilaterally normal vestibuloocular reflexes, confirmed by quantitative horizontal head impulse testing, strongly indicated a central localization. Because of a long delay in care, the patient left the emergency department without treatment. He returned 1 week later with progressive gait disturbance, limb ataxia, myoclonus, and new cognitive deficits. His subsequent course included a rapid neurological decline culminating in home hospice placement and death within 1 month. Magnetic resonance imaging revealed restricted diffusion involving the basal ganglia and cerebral cortex. Spinal fluid 14-3-3 protein was elevated. The rapidly progressive clinical course with dementia, ataxia, and myoclonus plus corroborative neuroimaging and spinal fluid findings confirmed a clinicoradiographic diagnosis of Creutzfeldt-Jacob disease. CONCLUSIONS To our knowledge, this is the first report of an initial presentation of Creutzfeldt-Jacob disease closely mimicking vestibular neuritis, expanding the known clinical spectrum of prion disease presentations. Despite the initial absence of neurological signs, the central lesion location was differentiated from a benign peripheral vestibulopathy at the first visit using simple bedside vestibular tests. Familiarity with these tests could help providers prevent initial misdiagnosis of important central disorders in patients presenting vertigo or dizziness.

Central and peripheral defects in motor units of the diaphragm of spinal muscular atrophy mice.

Spinal muscular atrophy (SMA) is characterized by motoneuron loss and muscle weakness. However, the structural and functional deficits that lead to the impairment of the neuromuscular system remain poorly defined. By electron microscopy, we previously found that neuromuscular junctions (NMJs) and muscle fibres of the diaphragm are among the earliest affected structures in the severe mouse SMA model. Because of certain anatomical features, i.e. its thinness and its innervation from the cervical segments of the spinal cord, the diaphragm is particularly suitable to characterize both central and peripheral events. Here we show by immunohistochemistry that, at postnatal day 3, the cervical motoneurons of SMA mice receive less stimulatory synaptic inputs. Moreover, their mitochondria become less elongated which might represent an early stage of degeneration. The NMJs of the diaphragm of SMA mice show a loss of synaptic vesicles and active zones. Moreover, the partly innervated endplates lack S100 positive perisynaptic Schwann cells (PSCs). We also demonstrate the feasibility of comparing the proteomic composition between diaphragm regions enriched and poor in NMJs. By this approach we have identified two proteins that are significantly upregulated only in the NMJ-specific regions of SMA mice. These are apoptosis inducing factor 1 (AIFM1), a mitochondrial flavoprotein that initiates apoptosis in a caspase-independent pathway, and four and a half Lim domain protein 1 (FHL1), a regulator of skeletal muscle mass that has been implicated in several myopathies.

Aberrant association of misfolded SOD1 with Na+/K+ATPase-α3 impairs its activity and contributes to motor neuron vulnerability in ALS.

Amyotrophic lateral sclerosis (ALS) is an adult onset progressive motor neuron disease with no cure. Transgenic mice overexpressing familial ALS associated human mutant SOD1 are a commonly used model for examining disease mechanisms. Presently, it is well accepted that alterations in motor neuron excitability and spinal circuits are pathological hallmarks of ALS, but the underlying molecular mechanisms remain unresolved. Here, we sought to understand whether the expression of mutant SOD1 protein could contribute to altering processes governing motor neuron excitability. We used the conformation specific antibody B8H10 which recognizes a misfolded state of SOD1 (misfSOD1) to longitudinally identify its interactome during early disease stage in SOD1G93A mice. This strategy identified a direct isozyme-specific association of misfSOD1 with Na+/K+ATPase-α3 leading to the premature impairment of its ATPase activity. Pharmacological inhibition of Na+/K+ATPase-α3 altered glutamate receptor 2 expression, modified cholinergic inputs and accelerated disease pathology. After mapping the site of direct association of misfSOD1 with Na+/K+ATPase-α3 onto a 10 amino acid stretch that is unique to Na+/K+ATPase-α3 but not found in the closely related Na+/K+ATPase-α1 isozyme, we generated a misfSOD1 binding deficient, but fully functional Na+/K+ATPase-α3 pump. Adeno associated virus (AAV)-mediated expression of this chimeric Na+/K+ATPase-α3 restored Na+/K+ATPase-α3 activity in the spinal cord, delayed pathological alterations and prolonged survival of SOD1G93A mice. Additionally, altered Na+/K+ATPase-α3 expression was observed in the spinal cord of individuals with sporadic and familial ALS. A fraction of sporadic ALS cases also presented B8H10 positive misfSOD1 immunoreactivity, suggesting that similar mechanism might contribute to the pathology.

Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease.

BACKGROUND Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMT(HH)), intermediate (Val/Met, COMT(HL)) and low metabolizers (Met/Met, COMT(LL)). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype. METHODS Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan(®) SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions. RESULTS Genotype distribution was: 11 (27.5%) COMT(HH), 26 (65%) COMT(HL) and 3 (7.5%) COMT(LL). There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMT(HL+LL) BP = 1.32 ± 0.04) than high metabolizers (COMT(HH), BP = 1.6 ± 0.08; F(1.34) = 9.0, p = 0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r = 0.44, p = 0.04) (p < 0.001) were highly correlated. There was a gender effect, but no gender-genotype interaction. CONCLUSIONS Striatal denervation differs according to COMT-Val158Met polymorphism. COMT activity may play a role as a compensatory mechanism in PD motor symptoms.

Diagnosing the Prodromal State of Alzheimer's Disease

Mild Cognitive Impairment- Amnestic Subtype (MCIa) is a putative prodromal stage of Alzheimer’s Disease (AD) characterized by focal deficits in episodic verbal memory. Less is known about relative deficits in visuospatial learning, although there is ample evidence indicating involvement of the hippocampus in visuospatial learning, as well as hippocampal degeneration in early AD. The aim of this study was to better characterize the components of working memory dysfunction in people with MCIa to increase the ability to reliably diagnose this disease. Fifty-six elderly adults diagnosed with MCIa and 94 healthy elderly completed a hidden maze learning task. Results indicated similar functioning between groups on measures of reasoning, problem solving, and accuracy. However, MCIa subjects were less efficient at learning the hidden path, making more errors per second on average (Cohen’s d= -.78) and requiring a longer time to complete the maze (Cohen’s d=.77). The learning curve between the first two trials was four times as steep for healthy elderly compared to MCIa (slopes = 4.9 vs. 1.24, respectively), indicating that MCIa subjects exhibited relative difficulty in holding and making effective use of an internal spatial map in order to improve performance. Our results suggest that MCIa patients have focal deficits in visuospatial working memory, with relative preservation of functioning on other more global measures of cognitive functioning. This particular pattern of results may be specific to the amnestic variant of MCI.

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. ^

Trends in utilization of computer tomography (CT) scans for victims of motor vehicle collision (MVCs) in a level I trauma center from 1996 to 2006

Purpose. To evaluate trends in the utilization of head, abdominal, thoracic and other body regions CTs in the management of victims of MVC at a level I trauma center from 1996 to 2006.^ Method. From the trauma registry, I identified patients involved in MVC's in a level I trauma center and categorized them into three age groups of 13-18, 19-55 and ≥56. I used International Classification of Disease (ICD-9-CM) codes to find the type and number of CTs examinations performed for each patient. I plotted the mean number of CTs per patient against year of admission to find the crude estimate of change in utilization pattern for each type of CT. I used logistic regression to assess whether repetitive CTs (≥ 2) for head, abdomen, thorax and other body regions were associated with age group and year of admission for MVC patients. I adjusted the estimates for gender, ethnicity, insurance status, mechanism and severity of injury, intensive care unit admission status, patient disposition (dead or alive) and year of admission.^ Results. Utilization of head, abdominal, thoracic and other body regions CTs significantly increased over 11-year period. Utilization of head CT was greatest in the 13-18 age group, and increased from 0.58 CT/patient in 1996 to 1.37 CT/patient in 2006. Abdominal CTs were more common in the ≥56+ age group, and increased from 0.33 CT/patient in 1996 to 0.72 CT/patient in 2006. Utilization of thoracic CTs was higher in the 56+ age group, and increased from 0.01 CT/patient in 1996 to 0.42 CT/patient in 2006. Utilization of other CTs did not change materially during the study period for adolescents, adults or older adults. In the multivariable analysis, after adjustment for potential confounders, repetitive head CTs significantly increased in the 13-18 age group (95% CI: 1.29-1.87, p=<0.001) relative to the 19-55 age group. Repetitive thoracic CT use was lower in adolescents (95% CI: 0.22-0.70, p=<0.001) relative to the 19-55 age group.^ Conclusion. There has been a substantial increase in the utilization of head, abdominal, thoracic and other CTs in the management of MVC patients. Future studies need to identify if increased utilization of CTs have resulted in better health outcome for these patients. ^

Desarollo de un sistema interactivo para estimulación cognitiva en HTML5

En España hay más de 115.500 personas que padecen Parkinson. Esto la convierte en la segunda enfermedad neurodegenerativa más común, por detrás del Alzheimer. La mayoría de los enfermos se encuentran en edades comprendidas entre los 50 y los 80 años, lo que unido al incremento de la esperanza de vida hace que se prevea un incremento del número de enfermos de Parkinson en pocos años. El Parkinson es un desorden crónico y degenerativo que afecta a la parte del cerebro encargada del sistema motor, es decir, la encargada de coordinar la actividad, el tono muscular y los movimientos, así como a las capacidades cognitivas. Esta patología crónica, de momento, no tiene cura. A los pacientes se les aplican tratamientos farmacológicos para frenar la progresión de la enfermedad. Además, se aplican terapias adicionales como la fisioterapia, la logopedia, la musicoterapia, la estimulación cognitiva o la terapia ocupacional. El uso de las Tecnologías de la Información y Comunicaciones en el campo de la estimulación cognitiva permite que personas con deterioro cognitivo puedan realizar sesiones de estimulación desde su domicilio de forma remota, complementando las terapias individuales y/o grupales que haya indicado el terapeuta. Además, evita desplazamientos hasta el centro de atención, que en ocasiones pueden ser difíciles de efectuar por encontrarse en lugares alejados o por problemas de movilidad del afectado. Asimismo, el uso de este tipo tecnología permite que los resultados de los ejercicios realizados por los pacientes se puedan almacenar para que el terapeuta los pueda analizar en cualquier momento y de esta manera ir adecuando la terapia. Finalmente, la plataforma que se propone cuenta con el valor añadido de permitir la interactividad con los terapeutas y la posibilidad de adaptar los ejercicios a cada paciente, según las necesidades que presente cada uno. SUMMARY. In Spain, there are more than 115.500 people with Parkinson disease. Due to this, it is the second most common neurodegenerative disease, only behind Alzheimer's disease. Most patients have ages between 50 and 80 years of age, which together with the increase in life expectancy to provide an increase in the number of patients with Parkinson's in a few years. Most patients have aged between 50 and 80 years old, which together with the increase of life expectancy provide a growth in the number of people with Parkinson’s in a few years. Parkinson's is a chronic and degenerative disorder that affects the part of the brain responsible for the motor system, i.e., responsible for coordinating activity, muscle tone and movements, as well as cognitive abilities. Nowadays, this chronic pathology has no cure. Pharmacological treatments are applied to patients for slowing down the advance of this disease. In addition, there are additional therapies such as physiotherapy, speech therapy, music therapy, cognitive stimulation or occupational therapy. The use of the Information Technologies and Communications in the field of cognitive stimulation allows people with cognitive impairment may carry out stimulation sessions in their home remotely, complementing individual therapies or group therapies provided by the therapist. This minimizes trips to the attention center, which sometimes can be difficult due to they live in remote places or they are mobility-reduced people. In addition, the use of such technology allows that the results of the exercises personalized by patients can store so that the therapist can analyze them at any time and therefore he or she adapts the therapy. Finally, the proposed platform brings the added value of allowing interaction with the therapists and the possibility of adapting the exercises to each patient according to his or her needs.

A telehealth system for Parkinson's disease remote monitoring. The PERFORM approach.

This paper summarizes the experience and the lessons learned from the European project PERFORM (A sophisticated multi-parametric system FOR the continuous effective assessment and monitoring of motor status in Parkinson's disease and other neurodegenerative diseases). PERFORM is aimed to provide a telehealth system for the remote monitoring of Parkinson's disease patients (PD) at their homes. This paper explains the global experience with PERFORM. It summarizes the technical performance of the system and the feedback received from the patients in terms of usability and wearability.

A telehealth system for Parkinson's disease remote monitoring. The PERFORM approach

This paper summarizes the experience and the lessons learned from the European project PERFORM (A sophisticated multi-parametric system FOR the continuous effective assessment and monitoring of motor status in Parkinson s disease and other neurodegenerative diseases). PERFORM is aimed to provide a telehealth system for the remote monitoring of Parkinson s disease patients (PD) at their homes. This paper explains the global experience with PERFORM. It summarizes the technical performance of the system and the feedback received from the patients in terms of usability and wearability.