A resting-state fMRI pattern of spinocerebellar ataxia type 3 and comparison with 18F-FDG PET.

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published 18F-FDG PET pattern found in the same sample (rho = 0.78, P = 0.0003). Also, a high correlation was found with the Scale for Assessment and Rating of Ataxia scores (r = 0.63, P = 0.007). No correlations were found with neuropsychological test scores, nor with levels of grey matter atrophy. Compared with the 18F-FDG PET pattern, the fSCA3-RP included a more extensive contribution of the mediofrontal cortex, putatively representing changes in default network activity. This rs-fMRI identification of additional regions is proposed to reflect a consequence of the nature of the BOLD technique, enabling measurement of dynamic network activity, compared to the more static 18F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use.

Emotion Recognition and Traffic-Related Risk-Taking Behavior in Patients with Neurodegenerative Diseases.

OBJECTIVES: Neurodegenerative diseases (NDDs), such as Alzheimer's disease, frontotemporal dementia, dementia with Lewy bodies, and Huntington's disease, inevitably lead to impairments in higher-order cognitive functions, including the perception of emotional cues and decision-making behavior. Such impairments are likely to cause risky daily life behavior, for instance, in traffic. Impaired recognition of emotional expressions, such as fear, is considered a marker of impaired experience of emotions. Lower fear experience can, in turn, be related to risk-taking behavior. The aim of our study was to investigate whether impaired emotion recognition in patients with NDD is indeed related to unsafe decision-making in risky everyday life situations, which has not been investigated yet. METHODS: Fifty-one patients with an NDD were included. Emotion recognition was measured with the Facial Expressions of Emotions: Stimuli and Test (FEEST). Risk-taking behavior was measured with driving simulator scenarios and the Action Selection Test (AST). Data from matched healthy controls were used: FEEST (n = 182), AST (n = 36), and driving simulator (n = 18). RESULTS: Compared to healthy controls, patients showed significantly worse emotion recognition, particularly of anger, disgust, fear, and sadness. Furthermore, patients took significantly more risks in the driving simulator rides and the AST. Only poor recognition of fear was related to a higher amount of risky decisions in situations involving a direct danger. CONCLUSIONS: To determine whether patients with an NDD are still fit to drive, it is crucial to assess their ability to make safe decisions. Measuring emotion recognition may be a valuable contribution to this judgment.

Structural Network Analysis Using Diffusion MRI Tractography in Parkinson's Disease and Correlations With Motor Impairment.

Functional impairment of spatially distributed brain regions in Parkinson's disease (PD) suggests changes in integrative and segregative network characteristics, for which novel analysis methods are available. To assess underlying structural network differences between PD patients and controls, we employed MRI T1 gray matter segmentation and diffusion MRI tractography to construct connectivity matrices to compare patients and controls with data originating from two different centers. In the Dutch dataset (Data-NL), 14 PD patients, and 15 healthy controls were analyzed, while 19 patients and 18 controls were included in the Canadian dataset (Data-CA). All subjects underwent T1 and diffusion-weighted MRI. Patients were assessed with Part 3 of the Unified Parkinson's Disease Rating Scale (UPDRS). T1 images were segmented using FreeSurfer, while tractography was performed using ExploreDTI. The regions of interest from the FreeSurfer segmentation were combined with the white matter streamline sets resulting from the tractography, to construct connectivity matrices. From these matrices, both global and local efficiencies were calculated, which were compared between the PD and control groups and related to the UPDRS motor scores. The connectivity matrices showed consistent patterns among the four groups, without significant differences between PD patients and control subjects, either in Data-NL or in Data-CA. In Data-NL, however, global and local efficiencies correlated negatively with UPDRS scores at both the whole-brain and the nodal levels [false discovery rate (FDR) 0.05]. At the nodal level, particularly, the posterior parietal cortex showed a negative correlation between UPDRS and local efficiency, while global efficiency correlated negatively with the UPDRS in the sensorimotor cortex. The spatial patterns of negative correlations between UPDRS and parameters for network efficiency seen in Data-NL suggest subtle structural differences in PD that were below sensitivity thresholds in Data-CA. These correlations are in line with previously described functional differences. The methodological approaches to detect such differences are discussed.

Health-Related Problems and Changes After 1 Year as Assessed With the Geriatric ICF Core Set (GeriatrICS) in Community-Living Older Adults Who Are Frail Receiving Person-Centered and Integrated Care From Embrace.

OBJECTIVE: To assess the prevalence, severity, and change in health-related problems in a sample of older adults who received individual care and support from Embrace, for the whole sample, per subgroup based on complexity of care needs and frailty, and for those who had at baseline a health-related problem. DESIGN: A pretest-posttest study with assessments at baseline and after 12 months. SETTING: Community. PARTICIPANTS: Older adults aged 75 years and older (N=136) who are frail (n=56) or who have complex care needs (n=80). INTERVENTION: Participants received care and support by Embrace, a person-centered and integrated care service for community-living older adults supporting them to age in place. A multidisciplinary team provided care and support, with intensity depending on the older adults' risk profile. MAIN OUTCOME MEASURE: Health-related problems as perceived by older adults and measured with the Geriatric International Classification of Functioning, Disability and Health Core Set. RESULTS: Health-related problems were related to 6 coherent clusters: (1) Mental Functions; (2) Physical Health; (3) Mobility; (4) Personal Care; (5) Nutrition; and (6) Support. The most prevalent and most severe problems at baseline were related to Mental Functions and Mobility. Changes in the prevalence of problems after 12 months varied. Severity scores decreased or remained stable, except for Mobility items which showed a varying changing pattern in participants with complex care needs. Prevalence and severity of problems for those with a problem at baseline decreased after 12 months. Frail participants with a problem had higher baseline severity scores than those with complex care needs experiencing a problem, but differences in changes between individuals who are frail and those with complex care needs were small. CONCLUSIONS: The results are encouraging and may indicate that individual, person-centered and integrated care and support from Embrace offers a route to counteracting the decline in physical, cognitive and social functioning associated with aging.

The cerebral metabolic topography of spinocerebellar ataxia type 3.

Introduction: We aimed to uncover the pattern of network-level changes in neuronal function in Spinocerebellar ataxia type 3 (SCA3). Methods: 17 genetically-confirmed SCA3 patients and 16 controls underwent structural MRI and static resting-state [18F]­Fluoro­deoxyglucose Positron Emission Tomography (FDG-PET) imaging. A SCA3-related pattern (SCA3-RP) was identified using a multivariate method (scaled subprofile model and principal component analysis (SSM PCA)). Participants were evaluated with the Scale for Assessment and Rating of Ataxia (SARA) and with neuropsychological examination including tests for language, executive dysfunction, memory, and information processing speed. The relationships between SCA3-RP expression and clinical scores were explored. Voxel based morphology (VBM) was applied on MRI-T1 images to assess possible correlations between FDG reduction and grey matter atrophy. Results: The SCA3-RP disclosed relative hypometabolism of the cerebellum, caudate nucleus and posterior parietal cortex, and relatively increased metabolism in somatosensory areas and the limbic system. This topography, which was not explained by regional atrophy, correlated significantly with ataxia (SARA) scores (ρ = 0.72; P = 0.001). SCA3 patients showed significant deficits in executive function and information processing speed, but only letter fluency correlated with SCA3-RP expression (ρ = 0.51; P = 0.04, uncorrected for multiple comparisons). Conclusion: The SCA3 metabolic profile reflects network-level alterations which are primarily associated with the motor features of the disease. Striatum decreases additional to cerebellar hypometabolism underscores an intrinsic extrapyramidal involvement in SCA3. Cerebellar-posterior parietal hypometabolism together with anterior parietal (sensory) cortex hypermetabolism may reflect a shift from impaired feedforward to compensatory feedback processing in higher-order motor control. The demonstrated SCA3-RP provides basic insight in cerebral network changes in this disease.

Integrated and Person-Centered Care for Community-Living Older Adults: A Cost-Effectiveness Study.

OBJECTIVES: To assess the cost-effectiveness of Embrace, an integrated primary care service for older adults. DATA SOURCES: Care and support claims from health care insurers, long-term care administration, and municipalities for enrolled older adults between 2011 and 2013. STUDY DESIGN: A total of 1,456 older adults, listed with 15 general practitioners practices in the Netherlands, were stratified into risk profiles ("Robust," "Frail," and "Complex care needs") and randomized to Embrace or care-as-usual groups. Incremental costs were calculated per quality-adjusted life year, per day able to age in place, and per percentage point risk profile improvement. PRINCIPAL FINDINGS: Total average costs were higher for Embrace compared to care-as-usual. Differences in health-associated outcomes were small and not statistically significant. Probabilities that Embrace is cost-effective were below 80 percent, except for "risk profile improvements" within risk profile "Complex care needs." Complete case analysis resulted in smaller differences in total average costs across conditions and differences in health-associated outcomes remained small. CONCLUSIONS: According to current standards, Embrace is not considered cost effective after 12 months. However, it could be considered worthwhile in terms of "risk profile improvements" for older adults with "Complex care needs," if society is willing to invest substantially.

Effects of a population-based, person-centred and integrated care service on health, wellbeing and self-management of community-living older adults: A randomised controlled trial on Embrace.

OBJECTIVE: To evaluate the effects of the population-based, person-centred and integrated care service 'Embrace' at twelve months on three domains comprising health, wellbeing and self-management among community-living older people. METHODS: Embrace supports older adults to age in place. A multidisciplinary team provides care and support, with intensity depending on the older adults' risk profile. A randomised controlled trial was conducted in fifteen general practices in the Netherlands. Older adults (≥75 years) were included and stratified into three risk profiles: Robust, Frail and Complex care needs, and randomised to Embrace or care as usual (CAU). Outcomes were recorded in three domains. The EuroQol-5D-3L and visual analogue scale, INTERMED for the Elderly Self-Assessment, Groningen Frailty Indicator and Katz-15 were used for the domain 'Health.' The Groningen Well-being Indicator and two quality of life questions measured 'Wellbeing.' The Self-Management Ability Scale and Partners in Health scale for older adults (PIH-OA) were used for 'Self-management.' Primary and secondary outcome measurements differed per risk profile. Data were analysed with multilevel mixed-model techniques using intention-to-treat and complete case analyses, for the whole sample and per risk profile. RESULTS: 1456 eligible older adults participated (49%) and were randomized to Embrace (n(T0) = 747, n(T1) = 570, mean age 80.6 years (SD 4.5), 54.2% female) and CAU (n(T0) = 709, n(T1) = 561, mean age 80.8 years (SD 4.7), 55.6% female). Embrace participants showed a greater-but clinically irrelevant-improvement in self-management (PIH-OA Knowledge subscale effect size [ES] = 0.14), and a greater-but clinically relevant-deterioration in health (ADL ES = 0.10; physical ADL ES = 0.13) compared to CAU. No differences in change in wellbeing were observed. This picture was also found in the risk profiles. Complete case analyses showed comparable results. CONCLUSIONS: This study found no clear benefits to receiving person-centred and integrated care for twelve months for the domains of health, wellbeing and self-management in community-living older adults.

Stability and relative validity of the Neuromuscular Disease Impact Profile (NMDIP).

BACKGROUND: The aim of this study was to examine the stability and relative validity (RV) of the Neuromuscular Disease Impact Profile (NMDIP) using criterion-related groups. In a previous study the NMDIP-scales showed good internal consistency, convergent and discriminant validity. Known-groups analysis showed that the NMDIP discriminates between categories of extent of limitations. METHODS: A cross-sectional postal survey study was performed on patients diagnosed with a NMD and registered at the Department of Neurology, University Medical Center Groningen, the Netherlands. Participants were asked to complete the preliminary NMDIP, the Medical Outcome study Short Form Questionnaire (SF-36), the World Health Organization Quality Of Life-abbreviation version (WHOQOL-bref), and two generic domain specific measures: the Groningen Activity Restriction Scale (GARS) and the Impact on Participation and Autonomy Questionnaire (IPAQ). The variables 'Extent of Limitations' and 'Quality of Life' were used to create criterion-related groups. Stability over time was tested using the Wilcoxon Signed Rank Test for paired samples and the intraclass correlation coefficients for repeated measures. RV was examined by comparing the ability of NMDIP with generic multidimensional health impact measures, and domain specific measures in discriminating between criterion-related subgroups using the Kruskal-Wallis H-test. RESULTS: Response rate was 70% (n = 702). The NMDIP-scales showed sufficient stability over time, and satisfactory or strong RV. In general, the NMDIP scales performed as well as or better than the concurrent measurement instruments. CONCLUSIONS: The NMDIP proved to be a valid and reliable disease-targeted measure with a broad scope on physical, psychological and social functioning.

Integrated Care for Older Adults Improves Perceived Quality of Care: Results of a Randomized Controlled Trial of Embrace.

BACKGROUND: All community-living older adults might benefit from integrated care, but evidence is lacking on the effectiveness of such services for perceived quality of care. OBJECTIVE: To examine the impact of Embrace, a community-based integrated primary care service, on perceived quality of care. DESIGN: Stratified randomized controlled trial. PARTICIPANTS: Integrated care and support according to the "Embrace" model was provided by 15 general practitioners in the Netherlands. Based on self-reported levels of case complexity and frailty, a total of 1456 community-living older adults were stratified into non-disease-specific risk profiles ("Robust," "Frail," and "Complex care needs"), and randomized to Embrace or control groups. INTERVENTION: Embrace provides integrated, person-centered primary care and support to all older adults living in the community, with intensity of care dependent on risk profile. MEASUREMENTS: Primary outcome was quality of care as reported by older adults on the Patient Assessment of Integrated Elderly Care (PAIEC). Effects were assessed using mixed model techniques for the total sample and per risk profile. Professionals' perceived level of implementation of integrated care was evaluated within the Embrace condition using the Assessment of Integrated Elderly Care. KEY RESULTS: Older adults in the Embrace group reported a higher level of perceived quality of care than those in the control group (B = 0.33, 95 % CI = 0.15-0.51, ES d = 0.19). The advantages of Embrace were most evident in the "Frail" and "Complex care needs" risk profiles. We found no significant advantages for the "Robust" risk profile. Participating professionals reported a significant increase in the perceived level of implementation of integrated care (ES r = 0.71). CONCLUSIONS: This study shows that providing a population-based integrated care service to community-living older adults improved the quality of care as perceived by older adults and participating professionals.

Construct Validity and Reliability of the SARA Gait and Posture Sub-scale in Early Onset Ataxia.

Aim: In children, gait and posture assessment provides a crucial marker for the early characterization, surveillance and treatment evaluation of early onset ataxia (EOA). For reliable data entry of studies targeting at gait and posture improvement, uniform quantitative biomarkers are necessary. Until now, the pediatric test construct of gait and posture scores of the Scale for Assessment and Rating of Ataxia sub-scale (SARA) is still unclear. In the present study, we aimed to validate the construct validity and reliability of the pediatric (SARAGAIT/POSTURE) sub-scale. Methods: We included 28 EOA patients [15.5 (6-34) years; median (range)]. For inter-observer reliability, we determined the ICC on EOA SARAGAIT/POSTURE sub-scores by three independent pediatric neurologists. For convergent validity, we associated SARAGAIT/POSTURE sub-scores with: (1) Ataxic gait Severity Measurement by Klockgether (ASMK; dynamic balance), (2) Pediatric Balance Scale (PBS; static balance), (3) Gross Motor Function Classification Scale -extended and revised version (GMFCS-E&R), (4) SARA-kinetic scores (SARAKINETIC; kinetic function of the upper and lower limbs), (5) Archimedes Spiral (AS; kinetic function of the upper limbs), and (6) total SARA scores (SARATOTAL; i.e., summed SARAGAIT/POSTURE, SARAKINETIC, and SARASPEECH sub-scores). For discriminant validity, we investigated whether EOA co-morbidity factors (myopathy and myoclonus) could influence SARAGAIT/POSTURE sub-scores. Results: The inter-observer agreement (ICC) on EOA SARAGAIT/POSTURE sub-scores was high (0.97). SARAGAIT/POSTURE was strongly correlated with the other ataxia and functional scales [ASMK (rs = -0.819; p < 0.001); PBS (rs = -0.943; p < 0.001); GMFCS-E&R (rs = -0.862; p < 0.001); SARAKINETIC (rs = 0.726; p < 0.001); AS (rs = 0.609; p = 0.002); and SARATOTAL (rs = 0.935; p < 0.001)]. Comorbid myopathy influenced SARAGAIT/POSTURE scores by concurrent muscle weakness, whereas comorbid myoclonus predominantly influenced SARAKINETIC scores. Conclusion: In young EOA patients, separate SARAGAIT/POSTURE parameters reveal a good inter-observer agreement and convergent validity, implicating the reliability of the scale. In perspective of incomplete discriminant validity, it is advisable to interpret SARAGAIT/POSTURE scores for comorbid muscle weakness.

Development and psychometric evaluation of a measure to evaluate the quality of integrated care: the Patient Assessment of Integrated Elderly Care.

BACKGROUND: Novel population-based integrated care services are being developed to adequately serve the growing number of elderly people. Suitable, reliable and valid measurement instruments are needed to evaluate the quality of care delivered. OBJECTIVE: To develop a measure to evaluate the quality of integrated care from the perspective of elderly people, the Patient Assessment of Integrated Elderly Care (PAIEC), and then to assess its psychometric properties. METHODS/DESIGN: After the Patient Assessment of Chronic Illness Care was adapted to the PAIEC, a cross-sectional postal-survey study was performed among 223 elderly people who received integrated elderly care and support. We assessed the factor structure, internal consistency, known groups and divergent validity using robust nonparametric tests. RESULTS: Mean age of participants was 83 years (standard deviation 4.7), and 69% was female. The original five-factor model was rejected; a good fit was found for a three-factor model, when excluding the item on patients' satisfaction with care. The PAIEC and its subscales showed good internal consistency (ordinal alphas > 0.90). Known-groups validity was supported regarding number of medications, prevalence of chronic conditions and home care received. No differences were found between groups based on sociodemographic aspects. Divergent validity was supported by low correlations (Spearman's rank correlation coefficients < 0.30) between PAIEC scales and measures of quality of life, complexity of care needs and frailty. CONCLUSION: The PAIEC seems to have considerable potential as a reliable and valid measurement instrument that evaluates quality of integrated care and support from the perspective of elderly people.

A novel diagnostic approach to patients with myoclonus.

Myoclonus is a hyperkinetic movement disorder characterized by brief, involuntary muscular jerks. Recognition of myoclonus and determination of the underlying aetiology remains challenging given that both acquired and genetically determined disorders have varied manifestations. The diagnostic work-up in myoclonus is often time-consuming and costly, and a definitive diagnosis is reached in only a minority of patients. On the basis of a systematic literature review up to June 2015, we propose a novel diagnostic eight-step algorithm to help clinicians accurately, efficiently and cost-effectively diagnose myoclonus. The large number of genes implicated in myoclonus and the wide clinical variation of these genetic disorders emphasize the need for novel diagnostic techniques. Therefore, and for the first time, we incorporate next-generation sequencing (NGS) in a diagnostic algorithm for myoclonus. The initial step of the algorithm is to confirm whether the movement disorder phenotype is consistent with, myoclonus, and to define its anatomical subtype. The next steps are aimed at identification of both treatable acquired causes and those genetic causes of myoclonus that require a diagnostic approach other than NGS. Finally, other genetic diseases that could cause myoclonus can be investigated simultaneously by NGS techniques. To facilitate NGS diagnostics, we provide a comprehensive list of genes associated with myoclonus.

Experiences of Community-Living Older Adults Receiving Integrated Care Based on the Chronic Care Model: A Qualitative Study.

BACKGROUND: Integrated care models aim to solve the problem of fragmented and poorly coordinated care in current healthcare systems. These models aim to be patient-centered by providing continuous and coordinated care and by considering the needs and preferences of patients. The objective of this study was to evaluate the opinions and experiences of community-living older adults with regard to integrated care and support, along with the extent to which it meets their health and social needs. METHODS: Semi-structured interviews were conducted with 23 older adults receiving integrated care and support through "Embrace," an integrated care model for community-living older adults that is based on the Chronic Care Model and a population health management model. Embrace is currently fully operational in the northern region of the Netherlands. Data analysis was based on the grounded theory approach. RESULTS: Responses of participants concerned two focus areas: 1) Experiences with aging, with the themes "Struggling with health," "Increasing dependency," "Decreasing social interaction," "Loss of control," and "Fears;" and 2) Experiences with Embrace, with the themes "Relationship with the case manager," "Interactions," and "Feeling in control, safe, and secure". The prospect of becoming dependent and losing control was a key concept in the lives of the older adults interviewed. Embrace reinforced the participants' ability to stay in control, even if they were dependent on others. Furthermore, participants felt safe and secure, in contrast to the fears of increasing dependency within the standard care system. CONCLUSION: The results indicate that integrated care and support provided through Embrace met the health and social needs of older adults, who were coping with the consequences of aging.

Low levels of vitamin D are associated with multimorbidity: results from the LifeLines Cohort Study.

BACKGROUND: The prevalence of multimorbidity (≥ 1 disease within an individual) is rapidly increasing. So far, studies on the relationship between vitamin D and morbidity are mainly focusing on effects on single disease domains only, while vitamin D biology is associated with several diseases throughout the human body. METHODS: We studied 8,726 participants from the LifeLines Cohort Study (a cross-sectional, population-based cohort study) and used the self-developed composite morbidity score to study the association between vitamin D levels and multimorbidity. RESULTS: Study participants (mean age 45 ± 13 years, 73% females) had a mean plasma vitamin D level of 59 ± 22 nmol/L. In participants aged between 50 and 60 years, 58% had ≥ 2 affected disease domains, while morbidity score increased with age (70-80 years: 82% morbidity score > 1; > 80 years: 89% morbidity score > 1). Each incremental reduction by 1 standard deviation (SD) of vitamin D level was associated with an 8% higher morbidity score (full model OR 0.92, 95% CI 0.88-0.97, P = 0.001). Participants with vitamin D levels < 25 nmol/L were at highest risk for increasing morbidity prevalence (versus > 80 nmol/L, OR 1.34, 95% CI 1.07-1.67, P = 0.01). CONCLUSIONS: Low levels of vitamin D are associated with higher prevalence of multimorbidity, especially in participants with vitamin D levels < 25 nmol/L. Collectively, our results favor a general, rather than an organ-specific, approach when assessing the impact of vitamin D deficiency.

The Geriatric ICF Core Set reflecting health-related problems in community-living older adults aged 75 years and older without dementia: development and validation.

PURPOSE: The aim of the present study was to develop a valid Geriatric ICF Core Set reflecting relevant health-related problems of community-living older adults without dementia. METHODS: A Delphi study was performed in order to reach consensus (≥70% agreement) on second-level categories from the International Classification of Functioning, Disability and Health (ICF). The Delphi panel comprised 41 older adults, medical and non-medical experts. Content validity of the set was tested in a cross-sectional study including 267 older adults identified as frail or having complex care needs. RESULTS: Consensus was reached for 30 ICF categories in the Delphi study (fourteen Body functions, ten Activities and Participation and six Environmental Factors categories). Content validity of the set was high: the prevalence of all the problems was >10%, except for d530 Toileting. The most frequently reported problems were b710 Mobility of joint functions (70%), b152 Emotional functions (65%) and b455 Exercise tolerance functions (62%). No categories had missing values. CONCLUSION: The final Geriatric ICF Core Set is a comprehensive and valid set of 29 ICF categories, reflecting the most relevant health-related problems among community-living older adults without dementia. This Core Set may contribute to optimal care provision and support of the older population. Implications for Rehabilitation The Geriatric ICF Core Set may provide a practical tool for gaining an understanding of the relevant health-related problems of community-living older adults without dementia. The Geriatric ICF Core Set may be used in primary care practice as an assessment tool in order to tailor care and support to the needs of older adults. The Geriatric ICF Core Set may be suitable for use in multidisciplinary teams in integrated care settings, since it is based on a broad range of problems in functioning. Professionals should pay special attention to health problems related to mobility and emotional functioning since these are the most prevalent problems in community-living older adults.

Autosomal recessive cerebellar ataxia type 3 due to ANO10 mutations: delineation and genotype-phenotype correlation study.

IMPORTANCE: ANO10 mutations have been reported to cause a novel form of autosomal recessive cerebellar ataxia (ARCA). Our objective was to report 9 ataxic patients carrying 8 novel ANO10 mutations to improve the delineation of this form of ARCA and provide genotype-phenotype correlation. OBSERVATIONS: The ANO10 gene has been sequenced in 186 consecutive patients with ARCA. The detailed phenotype of patients with ANO10 mutations was investigated and compared with the 12 previously reported cases. The mean age at onset was 33 years (range, 17-43 years), and the disease progression was slow. Corticospinal tract signs were frequent, including extensor plantar reflexes and/or diffuse tendon reflexes and/or spasticity. No patient in our series had peripheral neuropathy. Magnetic resonance imaging of the brains of our patients revealed marked cerebellar atrophy. The most frequent mutation, a mononucleotide expansion from a polyA repeat tract (c.132dupA) that causes protein truncation, was never observed in homozygosity. Only 2 truncating mutations were reported in homozygosity, one of which (c.1150-1151del) was associated with juvenile or adolescent onset and mental retardation, whereas we show that the presence of at least 1 missense or in-frame mutation is associated with adult onset and slow progression. CONCLUSIONS AND RELEVANCE: An ANO10 mutation is responsible for ARCA that is mainly characterized by cerebellar atrophy and lack of peripheral neuropathy. We therefore suggest naming this entity autosomal recessive cerebellar ataxia type 3 (ARCA3).

Long-term consequences of the posterior reversible encephalopathy syndrome in eclampsia and preeclampsia: a review of the obstetric and nonobstetric literature.

This review summarizes the long-term consequences of the posterior reversible encephalopathy syndrome (PRES) that have been described in the obstetric literature (eclampsia and preeclampsia) and compares these with data from the nonobstetric literature. Preeclampsia is characterized by new-onset hypertension and proteinuria after the 20th week of pregnancy. Neurological symptoms include headache; visual deficits; confusion; seizures; and, in the most severe cases, intracranial hemorrhage. Eclampsia is an acute cerebral complication of preeclampsia, defined as the occurrence of tonic-clonic seizures in pregnant or recently postpartum women. With severe preeclampsia, in conjunction with neurological symptoms, or eclampsia, neuroimaging changes consistent with PRES can be seen. Posterior reversible encephalopathy syndrome is a specific clinicoradiological syndrome presenting with headaches, visual impairment, seizures, and altered mental status. Characteristic neuroimaging features are consistent with cerebral edema predominantly in the parietal and occipital lobes. In addition to preeclampsia/eclampsia, PRES has been associated with various conditions in the nonobstetric population, that is, severe hypertension, transplantation, or autoimmune disease, in combination with immunosuppressive therapy or high-dose chemotherapy for various malignant conditions. Long-term sequelae of both preeclampsia/eclampsia and other PRES-related conditions are poorly described. After eclampsia or preeclampsia, nonspecific white matter lesions may be found on magnetic resonance imaging, which may or may not be related to the PRES episode. Previously (pre)eclamptic women report cognitive failures; however, no neurocognitive impairment has been shown so far. Various nonobstetric PRES-related conditions have been described with long-term neuroimaging abnormalities as well as cognitive problems, epilepsy, or visual impairment. Although no firm conclusions can be drawn because of the heterogeneity of reported cases, some general comments can be made. Because most persistent long-term problems are present in the nonobstetric population, the main determinant for these long-term problems may be the underlying condition that gave rise to the PRES episode. In addition, most reports suggest that late diagnosis or inadequate therapy may contribute, emphasizing the need for early recognition, adequate treatment, follow-up, and support.

Striatal metabolism and psychomotor speed as predictors of motor onset in Huntington's disease.

The clinical diagnosis of Huntington's disease (HD) is based on the motor symptoms, although these can be preceded by cognitive and behavioral changes. Biomarker studies have shown that structural imaging modalities are useful biomarkers of HD onset, while functional imaging measures have been studied less often for this purpose. Our aim was to investigate the combined value of 18-fluorodesoxyglucose (FDG)-PET and cognitive measures as biomarkers of HD onset. Twenty-two premanifest mutation carriers of HD (PMCs) and 11 healthy controls were assessed twice with FDG-PET scan, neurological and neuropsychological assessments over a 2-year interval. Seventeen PMCs had an additional third neurological evaluation, 10 years after baseline. Disease load was defined as the probability of motor onset within 5 years. Metabolism in putamen, caudate and pallidum of PMCs was significantly lower than that of controls, at both assessments. Almost half of the PMCs had converted to manifest HD 10 years later and all converters had low average or abnormal putaminal metabolism at 2 year follow-up. In contrast, all PMCs with normal putaminal metabolism at 2 year follow-up remained premanifest during the following 8 years. Furthermore, glucose metabolism of putamen explained a substantial part of the variance in disease load. A composite score of psychomotor tests contributed significantly to the prediction model as well, while cognitive performance was comparable for PMCs and controls. We conclude that in future clinical trials a combination of psychomotor tests and putaminal glucose metabolism may be used to identify PMCs close to motor onset of HD.