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[Introduction] Both recessive and dominant genetic forms of Parkinson’s disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson’s disease in a cohort from central Spain., [Methods/patients] We analyzed a cohort of 117 unrelated patients with early onset Parkinson’s disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson’s disease and other Parkinsonisms and CNV screening., [Results] Twenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes., [Conclusions] Our results contribute to the understanding of the genetic architecture associated with early onset Parkinson’s disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson’s disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson’s disease., This study was supported by grants from the Spanish Ministry of Economy and Competitiveness [PI14/01823, PI16/01575, PI18/01898] co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña. Pilar Gómez-Garre was supported by the "Miguel Servet" (from ISCIII-FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programs. Silvia Jesús Maestre was supported by the "Juan Rodés" program (from ISCIII-FEDER). Cristina Tejera was supported by VPPI-US from the Universidad de Sevilla.

• Feeding dystonia, trunk spasms, head-drops and orolingual mutilations are distinctive features of ChAc.

Objective: Although the cerebello-thalamo-cortical network has often been suggested to be of importance in the pathogenesis of essential tremor (ET), the origins of tremorgenic activity in this disease are not fully understood. We used a combination of cortical thickness imaging and neurophysiological studies to analyze whether the severity of tremor was associated with anatomical changes in the brain in ET patients. Methods: Magnetic resonance imaging (MRI) and a neurophysiological assessment were performed in 13 nondemented ET patients. High field structural brain MRI images acquired in a 3T scanner and analyses of cortical thickness and surface were carried out. Cortical reconstruction and volumetric segmentation was performed with the FreeSurfer image analysis software. We used high-density surface electromyography (hdEMG) and inertial measurement units (IMUs) to quantify the tremor severity in upper extrimities of patients. In particular, advanced computer tool was used to reliably identify discharge patterns of individual motor units from surface hdEMG and quantify motor unit synchronization. Results: We found significant association between increased motor unit synchronization (i.e., more severe tremor) and cortical changes (i.e., atrophy) in widespread cerebral cortical areas, including the left medial orbitofrontal cortex, left isthmus of the cingulate gyrus, right paracentral lobule, right lingual gyrus, as well as reduced left supramarginal gyrus (inferior parietal cortex), right isthmus of the cingulate gyrus, left thalamus, and left amygdala volumes. Interpretation: Given that most of these brain areas are involved in controlling movement sequencing, ET tremor could be the result of an involuntary activation of a program of motor behavior used in the genesis of voluntary repetitive movements., This work was funded by FEDER grant ; National Institutes of Health grant ; NINDS grants R01 NS39422;, R01 NS094607;, R01 NS085136;, R01 NS073872;, and R01 NS088257; European Commission grant ICT‐2011‐287739; Ministry of Economy and Competitiveness grant RTC‐2015‐3967‐1; Spanish Health Research Agency grants FIS PI12/01602; and FIS PI16/00451; Spanish Ministry of Economy and Competitiveness grants DPI‐2015‐68664‐C4‐1‐R; and DPI2015‐72638‐EXP; Claire O'Neil Essential Tremor Research grant ; Slovenian Research Agency grant J2‐7357.

There remains much to learn about the changes in cortical anatomy that are associated with tremor severity in Parkinson's disease (PD). For this reason, we used a combination of structural neuroimaging to measure cortical thickness and neurophysiological studies to analyze whether PD tremor was associated with cortex integrity. Magnetic resonance imaging and neurophysiological assessment were performed in 13 nondemented PD patients (9 women, 69.2%) with a clearly tremor-dominant phenotype. Cortical reconstruction and volumetric segmentation were performed with the Freesurfer image analysis software. Assessment of tremor was performed by means of high-density surface electromyography (hdEMG) and inertial measurement units (IMUs). Individual motor unit discharge patterns were identified from surface hdEMG and tremor metrics quantifying motor unit synchronization from IMUs. Increased motor unit synchronization (i.e., more severe tremor) was associated with cortical changes (i.e., atrophy) in wide-spread cortical areas, including caudal middle frontal regions bilaterally (dorsal premotor cortices), left inferior parietal lobe (posterior parietal cortex), left lateral orbitofrontal cortex, cingulate cortex bilaterally, left posterior and transverse temporal cortex, and left occipital lobe, as well as reduced left middle temporal volume. Given that the majority of these areas are involved in controlling movement sequencing, our results support Albert's classic hypothesis that PD tremor may be the result of an involuntary activation of a program of motor behavior used in the genesis of rapid voluntary alternating movements.

Pathological tremor is a common but highly complex movement disorder, affecting ∼5% of population older than 65 years. Different methodologies have been proposed for its quantification. Nevertheless, the discrimination between Parkinson’s disease tremor and essential tremor remains a daunting clinical challenge, greatly impacting patient treatment and basic research. Here, we propose and compare several movement-based and electromyography-based tremor quantification metrics. For the latter, we identified individual motor unit discharge patterns fromhigh-density surface electromyograms and characterized the neural drive to a single muscle and how it relates to other affected muscles in 27 Parkinson’s disease and 27 essential tremor patients. We also computed several metrics from the literature. The most discriminative metrics were the symmetry of the neural drive to muscles, motor unit synchronization, and the mean log power of the tremor harmonics in movement recordings. Noteworthily, the first two most discriminative metrics were proposed in this study. We then used decision tree modelling to find the most discriminative combinations of individualmetrics, which increased the accuracy of tremor type discrimination to 94%. In summary, the proposed neural drive-basedmetrics were themost accurate at discriminating and characterizing the two most common pathological tremor types. pre-print 3394 KB

Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2-to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptomsconstipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.

Background A variety of symptoms may precede the classical motor features of Parkinson disease (PD). However, it is not known whether cognitive dysfunction precedes the motor phase of PD. We examined whether patients with incident PD had had global cognitive function disturbances three years prior to diagnosis when compared with matched controls in a cohort of community-dwelling subjects. Methods All participants were age 65 years or older (median 76 years) and were enrolled in the Neurological Disorders in Central Spain (NEDICES) study in central Spain. We identified all participants with incident PD (N = 23), diagnosed in the follow-up examination (1997–1998), who had performed an expanded 37-item version of the Mini-Mental State Examination (37-MMSE) at the baseline evaluation (1994–1995). These 23 were 1:4 matched to 92 controls. Results Baseline 37-MMSE scores were 27.9 ± 4.9 (28) in PD patients and 28.7 ± 6.5 (31) in controls (p = 0.212). There were no patient–control differences in orientation, immediate recall, attention and calculation, memory recall, language, or visuospatial copying. In analyses that adjusted for several possible confounding factors, there were no case–control differences. Conclusions In this population-based sample, patients with incident PD did not have evidence of significant global cognitive function disturbances three years prior to their diagnosis when compared with matched controls. Our data suggest that global cognitive dysfunction does not precede the diagnosis of PD.

To evaluate the mortality, thirteen years after the baseline wave (1994), of participants suffering dementia in the Neurological Disorders in Central Spain (NEDICES) Cohort Study, we conducted a population-based cohort study in the elderly (65 years and more) with 5,278 screened participants at baseline. Mortality has been evaluated by means of the National Death Registry of Spain at 1-5-2007, 13 years after enrolment. Cox's proportional hazards regression models were used to evaluate the hazard of death according to dementia severity and type, adjusting for potential covariates (gender, age, level of education, and co-morbidity). Survival was estimated using Kaplan-Meier method. Of the 5,278 participants screened at baseline, 306 had dementia. Mortality at 13 years was: 275 deaths (89.9%) in dementia subjects; and 2,426 (49.0%) in subjects without dementia. Mortality was higher and statistically significant in dementia subjects. The degree of dementia (DSM-III-R) correlated with the risk of mortality, from mild (HR = 2.23; CI: 1.77-2.82) to moderate (HR =3.10; CI: 2.47-3.89) and severe dementia (HR = 4.98; CI: 3.85-6.44). Survival was similar in Alzheimer's disease and vascular dementia. Factors associated with higher mortality in Cox proportional hazard models were older age, male gender, and comorbidity. Using Population Attributable risk (PAR%), dementia was related to 11.3% of all deaths. Dementia intensity increases the mortality risk at ten years in the NEDICES Study as in other cohort studies. Age, gender, and co-morbidity are associated with higher mortality in dementia patients. Almost one third of deaths in persons over 85 years-old could be attributable to dementia.

Most studies of mortality in Parkin- son's disease have been clinical studies, yielding results that are not representative of the general population. We assessed the risk of mortality from Parkinson's dis- ease in the Neurological Disorders in Central Spain (NEDICES) study, a prospective population-based study in which Parkinson's disease patients who were not ascertained through medical practitioners were also included. The cohort consisted of 5262 elderly subjects (mean baseline age, 73.0 years), including 81 with Par- kinson's disease at baseline (1994-1995). Thirteen-year mortality was assessed. Two thousand seven hundred and one of 5262 subjects (51.3%) died over a median follow-up of 12.0 years (range, 0.04-14.8 years), includ- ing 66 of 81 subjects (81.5%) with Parkinson's disease at baseline and 2635 of 5181 subjects (50.8%) without Parkinson's disease at baseline. In an unadjusted Cox model, the hazard ratio of mortality was increased in subjects with Parkinson's disease (hazard ratio, 2.29; 95% confidence interval, 1.80-2.93; P < .001) versus subjects without Parkinson's disease (reference group). In a Cox model that adjusted for a variety of demo- graphic factors and comorbidities, the risk of mortality remained elevated in subjects with Parkinson's disease (hazard ratio, 1.75; 95% CI, 1.32-2.31, P < .001). In additional Cox models, Parkinson's disease patients with dementia had particularly high risks of mortality (adjusted hazard ratio, 2.62; 95% CI, 1.40-4.90; P < .001). In this prospective population-based study, Parkinson's disease was an independent predictor of mortality in the elderly. Parkinson's disease patients with dementia had particularly high risks of mortality. V C 2011 Movement Disorder Society

Essential tremor (ET) has been associated with a spectrum of clinical features, with both motor and nonmotor elements, including cognitive deficits. We employed resting-state functional magnetic resonance imaging (fMRI) to assess whether brain networks that might be involved in the pathogenesis of nonmotor manifestations associated with ET are altered, and the relationship between abnormal connectivity and ET severity and neuropsychological function. Resting-state fMRI data in 23 ET patients (12 women and 11 men) and 22 healthy controls (HC) (12 women and 10 men) were analyzed using independent component analysis, in combination with a ‘‘dualregression’’ technique, to identify the group differences of resting-state networks (RSNs) (default mode network [DMN] and executive, frontoparietal, sensorimotor, cerebellar, auditory/language, and visual networks). All participants underwent a neuropsychological and neuroimaging session, where resting-state data were collected. Relative to HC, ET patients showed increased connectivity in RSNs involved in cognitive processes (DMN and frontoparietal networks) and decreased connectivity in the cerebellum and visual networks. Changes in network integrity were associated not only with ET severity (DMN) and ET duration (DMN and left frontoparietal network), but also with cognitive ability.Moreover, in at least 3 networks (DMN and frontoparietal networks), increased connectivity was associated with worse performance on different cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language) and depressive symptoms. Further, in the visual network, decreased connectivity was associated with worse performance on visuospatial ability. ET was associated with abnormal brain connectivity in major RSNs that might be involved in both motor and nonmotor symptoms. Our findings underscore the importance of examining RSNs in this population as a biomarker of disease. post-print 626 KB

Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.

Many neuromuscular disorders involve the heart, occasionally with overt clinical disease. Muscular dystrophies (dystrophinopathies, limb girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy, Steinert's myotonic dystrophy), congenital myopathies, inflammatory myopathies and metabolic diseases (glycogenosis, periodic paralysis, mitochondrial diseases) may produce dilated or hypertrophic cardiomyopathy and heart rhythm or conduction disturbances. Furthermore the heart is commonly involved in some hereditary and degenerative diseases (Friedreich's ataxia and Kugelberg-Welander syndrome) and acquired (Guillain-Barre syndrome) or inherited (Refsum's disease and Charcot-Marie-Tooth syndrome) polyneuropathies. A cardiologist's high clinical suspicion and a simple but systematic skeletal muscle and peripheral nerve investigation, including muscle enzymes quantification, neurophysiological study and muscle biopsy, are necessary for an accurate diagnosis. In selected patients, more sophisticated biochemical and genetic analysis will be necessary. In most cases, endomyocardial biopsy is not essential for the diagnosis.

Most studies of mortality in Parkinson's disease have been clinical studies, yielding results that are not representative of the general population. We assessed the risk of mortality from Parkinson's disease in the Neurological Disorders in Central Spain (NEDICES) study, a prospective population-based study in which Parkinson's disease patients who were not ascertained through medical practitioners were also included. The cohort consisted of 5262 elderly subjects (mean baseline age, 73.0 years), including 81 with Parkinson's disease at baseline (1994-1995). Thirteen-year mortality was assessed. Two thousand seven hundred and one of 5262 subjects (51.3%) died over a median follow-up of 12.0 years (range, 0.04-14.8 years), including 66 of 81 subjects (81.5%) with Parkinson's disease at baseline and 2635 of 5181 subjects (50.8%) without Parkinson's disease at baseline. In an unadjusted Cox model, the hazard ratio of mortality was increased in subjects with Parkinson's disease (hazard ratio, 2.29; 95% confidence interval, 1.80-2.93; P.001) versus subjects without Parkinson's disease (reference group). In a Cox model that adjusted for a variety of demographic factors and comorbidities, the risk of mortality remained elevated in subjects with Parkinson's disease (hazard ratio, 1.75; 95% CI, 1.32-2.31, P.001). In additional Cox models, Parkinson's disease patients with dementia had particularly high risks of mortality (adjusted hazard ratio, 2.62; 95% CI, 1.40-4.90; P.001). In this prospective population-based study, Parkinson's disease was an independent predictor of mortality in the elderly. Parkinson's disease patients with dementia had particularly high risks of mortality.

Population-based assessments of cognitive function in patients with early Parkinson's disease (PD) are rare. We examined whether patients with early PD have cognitive deficits when compared with matched controlsAll participants were age 65 years or older (median=76 years) and were enrolled in the Neurological Disorders in Central Spain (NEDICES) study in central Spain. We identified all participants with early PD (5 years duration) (N=46). These were matched to 138 controls. Neuropsychological test scores were compared in PD patients vs. controls. In logistic regression models, we adjusted for the effects of confounding variables. In these models, the dependent variable was the neuropsychological test score (lowest quartile vs. all other quartiles) and the independent variable was PD vs. control.Sixteen of 46 patients (34.8%) with early PD were previously undiagnosed. Subjective memory complaint was present in 27 (58.7%) PD patients vs. 51 (37.0%) controls (p=0.010). In logistic regression models that adjusted for gender, education, and depressive symptoms or antidepressant use, PD patients performed less well on the 37-item version of the Mini-Mental State Examination (p=0.04), animal (p0.001) and fruit fluency (p=0.04) as well as in a delayed free recall memory test (p=0.04) than controls.In this population-based sample of older patients with early PD, the rate of subjective and object cognitive impairment was appreciable. Patients with PD of less than five years duration performed relatively poorly on tests of global cognition, verbal fluency and memory. Clinicians should be vigilant to these cognitive difficulties even in the early stages of PD.

[Fundamento y objetivo]: Un amplio espectro de enfermedades mitocondriales está producido por mutaciones de POLG y se caracterizan por una alteración en la integridad del genoma mitocondrial. La oftalmoplejía progresiva externa suele ser el marcador clínico en los casos de deleciones múltiples, pero no lo es en aquellas enfermedades que cursan con depleción del ácido desoxirribonucleico mitocondrial (ADNmt). En este trabajo presentamos un paciente con la tríada clínica que define el síndrome de neuropatía sensorial atáxica, disartria y oftalmoplejía, las mutaciones del gen POLG y la presencia inusual de una marcada disminución en el contenido del ADNmt en el músculo esquelético. [Paciente y método]: El paciente presentó un cuadro clínico caracterizado por neuropatía sensorial atáxica, disartria y oftalmoplejía. El diagnóstico se realizó mediante estudios histológicos y análisis molecular del ADNmt y del gen POLG. [Resultados]: La biopsia del nervio sural detectó una pérdida intensa de las fibras nerviosas mielinizadas gruesas. El estudio molecular reveló mutaciones en el gen POLG, así como deleciones múltiples y una marcada depleción del genoma mitocondrial. [Conclusiones]: Los pacientes con síndromes atáxicos de origen mitocondrial presentan fenotipos mitocondriales moleculares diferentes, por lo que se aconseja la búsqueda de mutaciones del gen POLG en todos ellos, independientemente de la anomalía que presenten en el genoma mitocondrial.

A broad spectrum of clinical disorders is produced by mutations in the DNA polymerase gamma mitochondrial (POLG) gene which are associated with altered mitochondrial DNA (mtDNA) integrity. The majority of disorders characterized by multiple mtDNA deletions present with progressive external ophthalmoplegia, though this feature is not usually found in syndromes caused by mtDNA depletion. We report on a patient having the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoplegia (SANDO), POLG mutations and reduced muscle mtDNA content.The patient presented with sensory ataxic neuropathy, dysarthria and ophthalmoplegia. Diagnosis was established by using histological and genetic procedures (nerve biopsy, mtDNA molecular analysis in skeletal muscle and mutation screening in the POLG gene).Sural nerve biopsy showed marked loss of large myelinated fibers. Skeletal muscle analysis revealed multiple mtDNA deletions, a marked decrease in mtDNA copy number and pathogenic mutations in the POLG gene.POLG mutations must be considered in all patients with the cardinal findings of the SANDO phenotype, without taking into account the type of abnormalities encountered in the mitochondrial genome.