Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T1/T2/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (Pcorrected < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1 with less white matter affection (early disease stages), contrary to patients with myotonic dystrophy type 2. Thus, depression in myotonic dystrophies might be a reactive adjustment disorder rather than a direct consequence of structural brain damage. Associations of white matter affection with age/disease duration as well as patterns of cerebral water diffusion parameters pointed towards an ongoing process of myelin destruction and/or axonal loss in our cross-sectional study design. Our data suggest that both myotonic dystrophy types 1 and 2 are serious white matter diseases with prominent callosal body and limbic system affection. White matter changes dominated the extent of grey matter changes, which might argue against Wallerian degeneration as the major cause of white matter affection in myotonic dystrophies.

The ongoing 1000 brains study (1000BRAINS) is an epidemiological and neuroscientific investigation of structural and functional variability in the human brain during aging. The two recruitment sources are the 10-year follow-up cohort of the German Heinz Nixdorf Recall (HNR) Study, and the HNR MultiGeneration Study cohort, which comprises spouses and offspring of HNR subjects. The HNR is a longitudinal epidemiological investigation of cardiovascular risk factors, with a comprehensive collection of clinical, laboratory, socioeconomic, and environmental data from population-based subjects aged 45-75 years on inclusion. HNR subjects underwent detailed assessments in 2000, 2006, and 2011, and completed annual postal questionnaires on health status. 1000BRAINS accesses these HNR data and applies a separate protocol comprising: neuropsychological tests of attention, memory, executive functions and language; examination of motor skills; ratings of personality, life quality, mood and daily activities; analysis of laboratory and genetic data; and state-of-the-art magnetic resonance imaging (MRI, 3 Tesla) of the brain. The latter includes (i) 3D-T1-and 3D-T2-weighted scans for structural analyses and myelin mapping; (ii) three diffusion imaging sequences optimized for diffusion tensor imaging, high-angular resolution diffusion imaging for detailed fiber tracking and for diffusion kurtosis imaging; (iii) resting-state and task-based functional MRI; and (iv) fluid-attenuated inversion recovery and MR angiography for the detection of vascular lesions and the mapping of white matter lesions. The unique design of 1000BRAINS allows: (i) comprehensive investigation of various influences including genetics, environment and health status on variability in brain structure and function during aging; and (ii) identification of the impact of selected influencing factors on specific cognitive subsystems and their anatomical correlates.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

A subtype-specific impairment of cognitive functions in spinocerebellar ataxia (SCA) patients is still debated. Thirty-two SCA patients (SCA1, 6; SC2, 3; SCA3, 15; SCA6, 8) and 14 matched healthy controls underwent neuropsychological evaluation testing attention, executive functions, episodic and semantic memory, and motor coordination. Severity of ataxia was assessed with the Scale for the Assessment and Rating of Ataxia (SARA), nonataxia symptoms with the Inventory of Non-Ataxia Symptoms. Depressive symptoms were evaluated with the Beck Depression Inventory. The SARA scores of our SCA patients (range 1–19.5) indicated an overall moderate ataxia, most pronounced in SCA6 and SCA1. Mean number of nonataxia symptoms (range 0–2.2) were most distinct in SCA1 and nearly absent in SCA6. SCA1 performed poorer than controls in 33% of all cognitive test parameters, followed by SCA2, SCA3, and SCA6 patients (17%). SCA 1–3 patients presented mainly attentional and executive dysfunctions while semantic and episodic memory functions were preserved. Attentional and executive functions were partly correlated with ataxia severity and fine motor coordination. All patients exhibited mildly depressed mood. Motor and dominant hand functions were more predictive for depressed mood than cognitive measures or overall ataxia. Besides motor impairments in all patients, SCA patients with extracerebellar pathology (SCA 1–3) were characterized by poor frontal attentional and executive dysfunction while mild cognitive impairments in predominantly cerebellar SCA6 patients appeared to reflect mainly cerebellar dysfunction. Regarding the everyday relevance of symptoms, (dominant) motor hand functioning emerged as a marker for the patient’s mood.

Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich's ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich's ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich's ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes.

Neuroimaging in myotonic dystrophies provided a major contribution to the insight into brain involvement which is highly prevalent in these multisystemic disorders. Particular in Myotonic Dystrophy Type 1, conventional MRI first revealed hyperintense white matter lesions, predominantly localized in the anterior temporal lobe. Brain atrophy and ventricle enlargement were additional early findings already described almost 30 years ago. Since then, more advanced and sophisticated imaging methods have been applied in Myotonic Dystrophy Types 1 and 2. Involvement of actually normal appearing white matter and widespread cortical affection in PET studies were key results toward the recognition of diffuse and not only focally localized brain pathology in vivo. Later, structural abnormalities of both, gray and white matter, have been found in both forms of the disorder, albeit more prominent in myotonic dystrophy type 1. In Type 1, a consistent widespread cortical and subcortical involvement of gray and white matter affecting all lobes, brainstem and cerebellum was observed. Spectroscopy studies gave additional evidence of neuronal and glial damage in both types. Central questions regarding the origin and spatiotemporal evolution of the CNS involvement and its relevance for clinical symptoms had already been raised 30 years ago, however are still not answered. Results of correlation analyses between neuroimaging and clinical parameters are diverse and with few exceptions not well reproducible across studies. It may be related to the fact that most of the reported studies included only small numbers of subjects, sometimes even not separating Myotonic Dystrophy Type 1 from Type 2. But this heterogeneity may also support the current point of view that the clinical impairments are not simply linked to specific and regionally circumscribed structural or functional brain alterations. It seems more convincing that disturbed networks build the functional and structural substrate of clinical symptoms in these disorders as it is proposed in other neuropsychiatric diseases. Consecutively, structural and functional network analyses may provide additional information regarding the link between brain pathology and clinical symptoms. Up to now, only cross-sectional neuroimaging studies have been published. To analyze the temporal evolution of brain affection, longitudinal studies are urgently needed, and systematic natural history data would be useful to identify potential biomarkers for therapeutic studies.

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Background:The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of autosomal dominant ataxias: some mutations, including SCA1, SCA2, and SCA3, are multisystemic disorders characterized by a variety of noncerebellar symptoms while others, like SCA6, give rise to a pure cerebellar syndrome.Objective: To identify impairments of the dopaminergic system and regional changes of glucose metabolism in SCA1, SCA2, SCA3, and SCA6. Methods:We used [ 11 C]d-threo-methylphenidate and [ 18 F]fluorodeoxyglucose positron emission tomography to identify cerebral dopamine terminal loss and specific regional metabolic patterns in SCA1, SCA2, SCA3, and SCA6. Results:The binding potential of [ 11 C]d-threo-methylphenidate was reduced in the striatum in SCA2 and SCA3; in contrast to patients with Parkinson disease, no increased susceptibility of the putamen was evident. Decreased regional cerebral glucose metabolism was found in the cerebellum of all patients with SCA, the brainstem of SCA1, SCA2, SCA3, the thalamus and putamen of SCA3, and the parietal cortex of patients with SCA2. A trend toward increased regional cerebral glucose metabolism was found in the temporal cortex of all patients with SCA, pronounced in SCA6.Conclusions: Specific biochemical patterns point to different mechanisms of neuronal dysfunction in SCA1, SCA2, SCA3, and SCA6; dopamine terminal loss is severe in SCA2 but distinct from Parkinson disease.