Tremor severity in Parkinson's disease and cortical changes of areas controlling movement sequencing: A preliminary study.

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.

The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study).

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.

Mortality from Parkinson's disease: a population-based prospective study (NEDICES).

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.

[Mitochondrial DNA depletion and POLG mutations in a patient with sensory ataxia, dysarthria and ophthalmoplegia]. / Depleción del ácido desoxirribonucleico mitocondrial y mutaciones de POLG en un paciente con neuropatía sensorial atáxica, disartria y oftalmoplejía.

BACKGROUND AND OBJECTIVE: 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. PATIENT AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

A genetic analysis of a Spanish population with early onset Parkinson's disease.

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.

Inter-Rater Agreement in the Clinical Diagnosis of Essential Tremor: Data from the NEDICES-2 Pilot Study.

BACKGROUND: Our aim was to assess the diagnostic agreement among the neurologists in the Neurological Disorders in Central Spain 2 (NEDICES-2) study; these neurologists were assigning diagnoses of essential tremor (ET) vs. no ET. METHODS: Clinical histories and standardized video-taped neurological examinations of 26 individuals (11 ET, seven Parkinson's disease, three diagnostically unclear, four normal, one with a tremor disorder other than ET) were provided to seven consultant neurologists, six neurology residents, and five neurology research fellows (18 neurologists total). For each of the 26 individuals, neurologists were asked to assign a diagnosis of "ET" or "no ET" using diagnostic criteria proposed by the Movement Disorders Society (MDS). Inter-rater agreement was assessed both with percent concordance and non-weighted κ statistics. RESULTS: Overall κ was 0.61 (substantial agreement), with no differences between consultant neurologists (κ = 0.60), neurology residents (κ = 0.61), and neurology research fellows (κ = 0.66) in subgroup analyses. Subanalyses of agreement only among those 15 subjects with a previous diagnosis of ET (11 patients) and those with a previous diagnosis of being normal (four individuals) showed an overall κ of 0.51 (moderate agreement). DISCUSSION: In a population-based epidemiological study, substantial agreement was demonstrated for the diagnosis of ET among neurologists of different levels of expertise. However, agreement was lower than that previously reported using the Washington Heights-Inwood Genetic Study of Essential Tremor criteria, and a head-to-head comparison is needed to assess which is the tool of choice in epidemiological research in ET.

Premotor cognitive status in a cohort of incident Parkinson disease patients (NEDICES).

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.

Dementia-associated mortality at thirteen years in the NEDICES Cohort Study.

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.

Population-based case-control study of cognitive function in early Parkinson's disease (NEDICES).

BACKGROUND: 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 controls 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 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. RESULTS: 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 (p<0.001) and fruit fluency (p=0.04) as well as in a delayed free recall memory test (p=0.04) than controls. CONCLUSIONS: 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.