Orthostatic hypotension as a risk factor for longitudinal deterioration of cognitive function in the elderly.

BACKGROUND AND PURPOSE: Orthostatic hypotension is frequent with aging with a prevalence of 20%-30% in people aged 65 or older and is considered to increase the risk for coronary events, strokes and dementia. Our objective was to characterize the association of orthostatic hypotension and cognitive function longitudinally over 6 years in a large cohort of the elderly aged over 50 years. METHODS: In all, 495 participants were assessed longitudinally with the Schellong test and comprehensive cognitive testing using the extended CERAD neuropsychological test battery at baseline and after 6 years. In a subgroup of 92 participants, cerebral magnetic resonance imaging was evaluated for white matter changes using a modified version of the Fazekas score. RESULTS: The prevalence of orthostatic hypotension increases with aging reaching up to 30% in participants aged >70 years. Participants with orthostatic hypotension presented with a higher vascular burden index (1.03 vs. 0.69, P ≤ 0.001), tended to have a higher prevalence of cerebral white matter hyperintensities (91.7% vs. 68.8%, P = 0.091) and showed a faster deterioration in executive and memory function (Trail Making Test B 95 vs. 87 s, P ≤ 0.001; word list learning sum -0.53 vs. 0.38, P = 0.002) compared to participants without orthostatic hypotension. CONCLUSION: Orthostatic hypotension seems to be associated with cognitive decline longitudinally.

Patient's perception: shorter and more severe prodromal phase in GBA-associated PD.

BACKGROUND: Prevalence and time of occurrence of prodromal symptoms of Parkinson's disease (PD) in relation to the onset of classical motor manifestation varies between patients. Possible modifying factors might be different genetic architectures predisposing to varying burden of manifestations. OBJECTIVES: To characterize the prodromal phase in PD patients with heterozygous mutations in the GBA gene compared to PD patients without GBA mutation. METHODS: In a retrospective design, 151 participants [47 PD patients carrying a GBA mutation (PDGBA ), 52 idiopathic PD patients (PDidiopathic ), 52 healthy elderly (CON)] underwent a validated structured interview designed to assess prevalence and time of occurrence of prodromal symptoms. RESULTS: PDGBA showed a higher prevalence of prodromal symptoms and almost simultaneous occurrence of non-motor and early motor symptoms shortly before PD diagnosis whereas PDidiopathic reported a longer prodromal phase starting with non-motor symptoms. CONCLUSION: The short and severe prodromal phase in PDGBA might call for shorter assessment intervals in yet premanifest GBA mutation carriers.

Progression of prodromal motor and non-motor symptoms in the premotor phase study - 2-year follow-up data.

BACKGROUND AND PURPOSE: The neuropathological process starts years before the diagnosis of Parkinson's disease (PD). Assessment of prodromal features in healthy individuals may help to define those with high risk for future PD. Our aim was to evaluate the presence and progression of prodromal markers in individuals with low risk [healthy controls (HC), n = 14] and high risk for PD (HR-PD, n = 34) and early PD (n = 14) patients. METHODS: Several risk or prodromal markers were combined to define HR-PD. Other prodromal markers were followed in 6-month intervals for 2 years. As recommended by the Movement Disorder Society Task Force, likelihood ratios (LRs) of markers, motor scores and PD probability scores were calculated and compared. RESULTS: The baseline LR for non-motor prodromal markers was significantly higher in PD and HR-PD compared to HC. Within 2 years, changes in these LRs did not significantly differ between the groups. Motor worsening was significant only in the PD group (50% of the patients) against HR-PD (15%) and HC (7%). Change in the non-motor prodromal LR did not significantly correlate with motor worsening, but higher baseline non-motor LRs were associated with Unified Parkinson's Disease Rating Scale III values at 2 years of follow-up. CONCLUSIONS: Our study shows that the frequency of non-motor prodromal markers is higher in the HR-PD group but does not increase within 2 years. The progression of motor and non-motor markers seems to be independent, but higher baseline non-motor burden is associated with the motor status after 2 years. Moreover, our data argue for a high impact of motor markers in the risk estimation for future PD.

[Genetic risk variants in Parkinson's disease and other movement disorders]. / Genetische Risikovarianten beim Parkinson-Syndrom und anderen Bewegungsstörungen.

Movement disorders are often genetically complex with genetic risk factors playing a major role. For example, monogenic causes of Parkinson's disease (PD) can be found in only 2-5% of patients who often have an early onset (<40 years). In the majority of patients, common genetic variants seem to contribute to the disease risk. To date, 24 genetic risk factors have been identified. For restless legs syndrome (RLS), six different risk variants have been reported but no monogenic cause is known yet. For the genetic risk factors of essential tremor and dystonia, which are less well studied, only five and two candidate variants, respectively, have been described but their roles still require independent confirmation. In this review, we provide an overview on the involved genes, their function, and discuss possible, disease mechanism-driven therapies.

[New therapy approaches for Parkinson's disease]. / Neue Therapieansätze bei der Parkinson-Erkrankung.

Over the last years major advances have been made in the identification of specific pathways underlying the pathophysiology of subgroups of patients with Parkinson' disease. These pathways include mitochondrial and lysosomal dysfunction as well as inflammatory patterns and represent the basis for new causative and disease-modifying treatment strategies, possibly not only for the respective subgroups of patients but hopefully also for the majority of patients with idiopathic Parkinson's disease. This article highlights the main treatment strategies focusing on causative and disease course-modifying strategies as well as quality of life.

Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease.

BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PDLRRK2 ) is highly variable, suggesting a strong influence of modifying factors. In this context, inflammation is a potential candidate inducing clinical subtypes. METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PDLRRK2 patients from the MJFF LRRK2 Consortium, stratified by three different subtypes as recently proposed for idiopathic Parkinson's disease: diffuse/malignant, intermediate and mainly pure motor. RESULTS: Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-ß (MIP-1-ß) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. CONCLUSIONS: Inflammation seems to be associated with the presence of a specific clinical subtype in PDLRRK2 that is characterized by a broad and more severely affected spectrum of motor and non-motor symptoms. The pro-inflammatory metabolites IL-8, MCP-1 and MIP-1-ß as well as BDNF are interesting candidates to be included in biomarker panels that aim to differentiate subtypes in PDLRRK2 and predict progression.

[Transition of Adolescents with Chronic Neurologic Disorders into Adult Health Care]. / Transition chronisch neurologisch kranker Jugendlicher in die Erwachsenenmedizin.

BACKGROUND: Transition of care from pediatric to adult services is a complex process. Factors influencing the success of health care transition of adolescents with chronic neurological disorders are poorly understood. METHODS: Young adults with chronic neurological disorders who had been cared for in an Interdisciplinary Pediatric Center participated in this study. Using the Patient Satisfaction Questionnaire Short-form (PSQ-18) we investigated whether satisfaction of these patients with their medical care in adult services was depending on the severity and complexity of their condition. They were assigned to a group of severely disabled patients (group 1; intellectual disability or learning disability plus motor handicap or degree of disability≥80, n=11) or a group 2 of patients with milder impairment (N=39). We used descriptive and t-statistics to compare both groups. RESULTS: Patients of group 1 reported slightly lower satisfaction with their present medical care in adult services (M=3.25; 95%-KI=[2.96-3.55]) compared to patients of group 2 (M=3.59; 95%.KI=[3.37-3.81]; p=0.084). Satisfaction with transition was significantly lower in group 1 (M=2.65; 95% KI=[2.29-3.01]) than in group 2 (M=3.11; 95% KI=[2.89-3.33], p=0.045). The difference of mean values of 0.46 reflects a moderate effect size (Hedges' g=0.68). CONCLUSION: Health care transition of adolescent patients with chronic neurological disorders is significantly more successful in patients with minor impairment compared to patients with severe complex neurological conditions.

Diagnostic and prognostic value of in vivo proton MR spectroscopy for Zellweger syndrome spectrum patients.

Defects in the biogenesis of peroxisomes cause a clinically and genetically heterogeneous group of neurometabolic disorders, the Zellweger syndrome spectrum (ZSS). Diagnosis predominantly is based on characteristic clinical symptoms, a typical biochemical profile, as well as on identification of the molecular defect in any of the 12 known human PEX genes. The diagnostic workup can be hindered if the typical clinical symptoms are missing and predicting the clinical course of a given patient is almost unfeasible. As a safe and noninvasive method to analyze specific chemical compounds in localized brain regions, in vivo proton magnetic resonance spectroscopy (MRS) can provide an indication in this diagnostic process and may help predict the clinical course. However, to date, there are very few reports on this topic. In this study, we performed localized in vivo proton MRS without confounding contributions from T1- and T2-relaxation effects at 2 Tesla in a comparably large group of seven ZSS patients. Patients' absolute metabolite concentrations in cortical gray matter, white matter, and basal ganglia were assessed and compared with age-matched control values. Our results confirm and extend knowledge about in vivo MRS findings in ZSS patients. Besides affirmation of nonspecific reduction of N-acetylaspartate + N-acetylaspartylglutamate (tNAA) in combination with lipid accumulation as a diagnostic hint for this disease group, the amount of tNAA loss seems to reflect disease burden and may prove to be of prognostic value regarding the clinical course of an already diagnosed patient.

GBA-associated parkinsonism and dementia: beyond α-synucleinopathies?

BACKGROUND AND PURPOSE: To date the role of GBA mutations beyond α-synucleinopathies in the parkinsonism-dementia spectrum is still unclear. The aim of the study was to screen for GBA mutations in progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), primary progressive aphasia (PPA) and the behavioural variant of frontotemporal dementia (bvFTD). METHODS: In all, 303 patients with a clinical diagnosis of PSP (n = 157), CBS (n = 39), PPA (n = 35) and bvFTD (n = 72) and 587 neurologically healthy controls were screened for the most common GBA mutations. RESULTS: GBA mutations were detected in one healthy control and four patients with a clinical diagnosis of PSP (n = 1), probable CBS (n = 2) and PPA (n = 1, with concomitant C9orf72 expansion). Overall the prevalence of GBA mutations was low in non-α-synucleinopathies but significantly higher in the CBS subgroup compared to controls. CONCLUSION: Although numbers are small, our findings indicate that the clinical phenotype of GBA-associated neurodegenerative disease is more heterogeneous than previously assumed, including phenotypes not usually associated with underlying α-synucleinopathies. This may be of relevance, once causal therapeutic strategies for GBA-associated neurodegenerative disease are developed.

Obtaining a genetic diagnosis in a child with disability: impact on parental quality of life.

Recent progress in genetic testing has facilitated obtaining an etiologic diagnosis in children with developmental delay/intellectual disability (DD/ID) or multiple congenital anomalies (MCA) or both. Little is known about the benefits of diagnostic elucidation for affected families. We studied the impact of a genetic diagnosis on parental quality of life (QoL) using a validated semiquantitative questionnaire in families with a disabled child investigated by array-based comparative genomic hybridization (aCGH). We received completed questionnaires from 95 mothers and 76 fathers of 99 families. We used multivariate analysis for adjustment of potential confounders. Taken all 99 families together, maternal QoL score (percentile rank scale 51.05) was significantly lower than fathers' QoL (61.83, p = 0.01). Maternal QoL score was 20.17 [95% CI (5.49; 34.82)] percentile rank scales higher in mothers of children with diagnostic (n = 34) aCGH as opposed to mothers of children with inconclusive (n = 65) aCGH (Hedges' g = 0.71). Comparison of these QoL scores with retrospectively recalled QoL before aCGH revealed an increase of maternal QoL after diagnostic clarification. Our results indicate a benefit for maternal QoL if a genetic test, here aCGH, succeeds to clarify the etiologic diagnosis in a disabled child.

Prodromal features for Parkinson's disease--baseline data from the TREND study.

BACKGROUND AND PURPOSE: A number of non-motor features are known to precede motor manifestations of Parkinson's disease (PD). They are supposed to already represent the prodromal neurodegenerative state in those who later develop PD and are thus called prodromal markers. In this study, three prodromal markers, depression, rapid eye movement behaviour disorder (RBD) and hyposmia, were selected and were related to other prodromal features in elderly individuals without PD. METHODS: From the Tübinger Evaluation of Risk Factors for Early Detection of Neurodegeneration (TREND) study, 698 healthy individuals aged 50-80 years reporting one or more of the selected prodromal markers (SPMs), but without neurodegenerative disorders, were evaluated and classified according to the status of prodromal markers. Other prodromal PD-related features were assessed with a 23-item questionnaire and compared between participants with and without the three SPMs. RESULTS: Individuals with the SPMs for PD endorsed more of the additional possible prodromal features of PD than those without; of 23 possible prodromal features, the median number identified amongst participants with no SPMs was two, compared with four with one marker, five with two and seven with three (P < 0.001). Regarding individual SPMs, participants with depression and RBD endorsed five of 23 markers, compared with three for those with hyposmia (P = 0.001). There was no significant increase in the number of prodromal features amongst those with two SPMs compared with those with only one marker. CONCLUSIONS: Individuals with the SPMs for PD report a higher prevalence of other prodromal PD symptoms. This may indicate that these markers can identify individuals at risk for PD.

A Novel SLC6A8 Mutation in a Large Family with X-Linked Intellectual Disability: Clinical and Proton Magnetic Resonance Spectroscopy Data of Both Hemizygous Males and Heterozygous Females.

X-linked creatine transport (CRTR) deficiency, caused by mutations in the SLC6A8 gene, leads to intellectual disability, speech delay, epilepsy, and autistic behavior in hemizygous males. Additional diagnostic features are depleted brain creatine levels and increased creatine/creatinine ratio (cr/crn) in urine. In heterozygous females the phenotype is highly variable and diagnostic hallmarks might be inconclusive. This survey aims to explore the intrafamilial variability of clinical and brain proton Magnetic Resonance Spectroscopy (MRS) findings in males and females with CRTR deficiency. X-chromosome exome sequencing identified a novel missense mutation in the SLC6A8 gene (p.G351R) in a large family with X-linked intellectual disability. Detailed clinical investigations including neuropsychological assessment, measurement of in vivo brain creatine concentrations using quantitative MRS, and analyses of creatine metabolites in urine were performed in five clinically affected family members including three heterozygous females and one hemizygous male confirming the diagnosis of CRTR deficiency. The severe phenotype of the hemizygous male was accompanied by most distinct aberrations of brain creatine concentrations (-83% in gray and -79% in white matter of age-matched normal controls) and urinary creatine/creatinine ratio. In contrast, the heterozygous females showed varying albeit generally milder phenotypes with less severe brain creatine (-50% to -33% in gray and -45% to none in white matter) and biochemical urine abnormalities. An intrafamilial correlation between female phenotype, brain creatine depletion, and urinary creatine abnormalities was observed. The combination of powerful new technologies like exome-next-generation sequencing with thorough systematic evaluation of patients will further expand the clinical spectrum of neurometabolic diseases.

[Genetics of movement disorders]. / Genetik von Bewegungsstörungen.

A number of genetic causes of movement disorders including Parkinson disease, dystonia, restless legs syndrome or essential tremor have been elucidated in recent years. This process was accelerated by novel technologies including genome-wide association studies (GWAS) and next generation sequencing (NGS). Although monogenic forms are overall rare, they provide a unique opportunity to investigate mutation carriers who are still in the presymptomatic phase. As these subjects present individuals at risk to develop the disease, they have been included in longitudinal studies to unravel disease mechanisms and elucidate novel therapeutic targets. In addition, cell culture and animal studies have been performed to functionally characterize proteins mutated in different movement disorders to provide further insight into disturbed cellular pathways. In this article, we summarize known monogenic forms and the associated phenotype as well as genetic risk factors and review the function of relevant genes and proteins.

Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. The phenotypic features of patients with clinically significant CNV were compared with those without pathogenic CNVs. Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.

Early-onset LBSL: how severe does it get?

AIM: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is known as a relatively mild leukoencephalopathy. We investigated the occurrence of severe variants of LBSL with extensive brain magnetic resonance imaging (MRI) abnormalities. METHOD: MRIs of approximately 3,000 patients with an unknown leukoencephalopathy were retrospectively reviewed for extensive signal abnormalities of the cerebral and cerebellar white matter, posterior limb of the internal capsule, cerebellar peduncles, pyramids, and medial lemniscus. Clinical data were retrospectively collected. RESULTS: Eleven patients fulfilled the MRI criteria (six males); six had DARS2 mutations. Clinical and laboratory findings did not distinguish between patients with and without DARS2 mutations, but MRI did. Patients with DARS2 mutations more often had involvement of structures typically affected in LBSL, including decussatio of the medial lemniscus, anterior spinocerebellar tracts, and superior and inferior cerebellar peduncles. Also, involvement of the globus pallidus was associated with DARS2 mutations. Earliest disease onset was neonatal; earliest death at 20 months. INTERPRETATION: This study confirms the occurrence of early infantile, severe LBSL, extending the known phenotypic range of LBSL. Abnormality of specific brainstem tracts and cerebellar peduncles are MRI findings that point to the correct diagnosis.

GBA-associated PD presents with nonmotor characteristics.

OBJECTIVE: To evaluate whether there exists distinct characteristics in glucocerebrosidase (GBA)-associated Parkinson disease (PD) with regard to motor and nonmotor symptoms as well as imaging characteristics assessed by transcranial sonography (TCS). METHODS: Twenty patients with PD with heterozygous GBA mutations (N370S, L444P) (GBA-PD) in comparison to 20 patients with sporadic PD negative for GBA mutations (sPD) were included. We assessed motor impairment with the Unified Parkinson's Disease Rating Scale-III. Nonmotor symptoms were evaluated using the Montreal Cognitive Assessment, Neuropsychiatric Inventory, revised form of the Beck Depression Inventory, Parkinson Disease Sleep Scale, Sniffin' Sticks, and Unified Multiple System Atrophy Rating Scale items 9-12. TCS imaging was used to detect morphologic characteristics. RESULTS: Patients with GBA-PD more often had a variety of nonmotor symptoms, namely dementia, neuropsychiatric disturbances, and autonomic dysfunction, and had more severe cases, than patients with sPD. They also demonstrated a higher prevalence of a reduced echogenicity of the brainstem raphe assessed by TCS. CONCLUSIONS: Especially nonmotor symptoms seem to be very common in GBA-PD. Further studies are needed to validate these observations in order to better understand the pathogenesis of GBA-PD and develop specific therapeutic concepts.

Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus-Merzbacher disease.

BACKGROUND: Among the hypomyelinating leukoencephalopathies with onset in childhood, Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) constitute a large subgroup with almost indistinguishable clinical and neuroradiologic features. Whereas PMD is due to X-linked PLP1 mutations, PMLD is genetically heterogeneous, with about 8% of patients carrying autosomal recessive GJA12/GJC2 mutations. The aim of this study was to evaluate whether neurophysiologic testing may separate PMD from GJA12/GJC2-associated PMLD. METHODS: Retrospective data collection study with reevaluation of evoked potentials (EP) and nerve conduction studies (NCS) in 10 patients from 7 families with PMLD due to various GJA12/GJC2 mutations and 8 boys from 7 families with classic PMD caused by a PLP1 duplication or missense mutation. RESULTS: In brainstem auditory EP, waves III-V were absent in all patients with PMD, but clearly recordable in 11 of 13 investigations in 8 patients with PMLD. Visual evoked potentials and somatosensory evoked potentials revealed conduction delay in both PMD and PMLD, without significant difference. NCS were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD. CONCLUSION: In a patient with clinical and neuroradiologic features of Pelizaeus-Merzbacher disease/Pelizaeus-Merzbacher-like disease and a pedigree consistent with both conditions, brainstem auditory evoked potentials provide good selectivity between these disorders and point in the right direction for identifying the primary genetic defect.