Cerebellar Pathology Research Articles

Cerebellum and apraxia.

As early as the beginning of the nineteenth century, a variety of nonmotor cognitive and affective impairments associated with cerebellar pathology were occasionally documented. A causal link between cerebellar disease and nonmotor cognitive and affective disorders has, however, been dismissed for almost two centuries. During the past decades, the prevailing view of the cerebellum as a mere coordinator of autonomic and somatic motor function has changed fundamentally. Substantial progress has been made in elucidating the neuroanatomical connections of the cerebellum with the supratentorial association cortices that subserve nonmotor cognition and affect. Furthermore, functional neuroimaging studies and neurophysiological and neuropsychological research have shown that the cerebellum is crucially involved in modulating cognitive and affective processes. This paper presents an overview of the clinical and neuroradiological evidence supporting the view that the cerebellum plays an intrinsic part in purposeful, skilled motor actions. Despite the increasing number of studies devoted to a further refinement of the typology and anatomoclinical configurations of apraxia related to cerebellar pathology, the exact underlying pathophysiological mechanisms of cerebellar involvement remain to be elucidated. As genuine planning, organization, and execution disorders of skilled motor actions not due to motor, sensory, or general intellectual failure, the apraxias following disruption of the cerebrocerebellar network may be hypothetically considered to form part of the executive cluster of the cerebellar cognitive affective syndrome (CCAS), a highly influential concept defined by Schmahmann and Sherman (Brain 121:561-579, 1998) on the basis of four symptom clusters grouping related neurocognitive and affective deficits (executive, visuospatial, affective, and linguistic impairments). However, since only a handful of studies have explored the possible role of the cerebellum in apraxic disorders, the pathophysiological mechanisms subserving cerebellar-induced apraxia remain to be elucidated.

Development of cerebellar pathology in the canine model of mucopolysaccharidosis type IIIA (MPS IIIA)

The temporal relationship between the onset of clinical signs in the mucopolysaccharidosis type IIIA (MPS IIIA) Huntaway dog model and cerebellar pathology has not been described. Here we sought to characterize the accumulation of primary (heparan sulfate) and secondary (GM3) substrates and onset of other changes in cerebellar tissues, and investigate the relationship to the onset of motor dysfunction in these animals. We observed that Purkinje cells were present in dogs aged up to and including 30.9months, however by 40.9months of age only ~12% remained, coincident with the onset of clinical signs. Primary and secondary substrate accumulation and inflammation were detected as early as 2.2months and axonal spheroids were observed from 4.3months in the deep cerebellar nuclei and later (11.6months) in cerebellar white matter tracts. Degenerating neurons and apoptotic cells were not observed at any time. Our findings suggest that cell autonomous mechanisms may contribute to Purkinje cell death in the MPS IIIA dog.

PS-117a Hyperoxia Reduces Astroglial Pdgf Expression And Impairs Oligodendroglial Development In The Cerebellum

<h3></h3> Although brain injury of preterm infants has widely been ascribed to the cerebrum, recent studies demonstrate that injury of the cerebellum often occurs, too. However, mechanisms of the cerebellar injury are hardly understood. In general, hypoxia-ischemia, infection/inflammation, and hyperoxia are supposed to be toxic stimuli in the immature brain. We used a hyperoxia model established in rats by using 80% O₂ exposure for 24 h from P6 to P7, and determined development and maturation of oligodendroglial cells in the cerebellum during recovery in room air until P30. Expression of platelet derived growth factor (PDGF)-A as a crucial factor for oligodendroglial development was determined in cerebellar tissue and in cultures of cerebellar astroglia. Volume of the cerebellum measured by MRI was significantly reduced in P30 rats after hyperoxia as compared to control litters (208 vs. 232 µL respectively, p &lt; 0.05). Myelination measured by MBP in immunostainings and Western blots was significantly reduced during recovery from P9 to P30. Numbers of NG2+TUNEL+ oligodendroglial precursor cells were increased by hyperoxia, and oligodendroglial maturation towards CC1+ stages was significantly diminished. Expression of PDGF-A was reduced after hyperoxia by 46% at P7 and by 27% at P30 (n = 4; p &lt; 0.01 each). In astrocyte cultures, exposure to 80% O₂ also caused a significant downregulation of PDGF-A expression by 42% (n = 6; p &lt; 0.01). Hyperoxia resembles critical features of the cerebellar pathology found in preterm infants. Astroglial changes caused by hyperoxia include reduced PDGF synthesis and are likely to contribute to oligodendroglial damage in the cerebellum.

A gait paradigm reveals different patterns of abnormal cerebellar motor learning in primary focal dystonias.

Accumulating evidence points to a role of the cerebellum in the pathophysiology of primary dystonia. The aim of this study was to investigate whether the abnormalities of cerebellar motor learning in primary dystonia are solely detectable in more pure forms of cerebellum-dependent associative motor learning paradigms, or whether these are also present in other motor learning paradigms that rely heavily on the cerebellum but in addition require a more widespread sensorimotor network. Twenty-six patients with various forms of focal dystonia and 10 age-matched healthy controls participated in a motor learning paradigm on a split-belt treadmill. By using reflective markers, three-dimensional kinematics were recorded using a 6-camera motion analysis system. Adaptation walking parameters were analyzed offline, comparing the different dystonia groups and healthy controls. Patients with blepharospasm and writer's cramp were significantly impaired on various adaptation walking parameters. Whereas results of cervical dystonia patients did not differ from healthy controls in terms of adaptation walking parameters, differences in parameters of normal gait were found. We have here demonstrated abnormal sensorimotor adaptation with the split-belt paradigm in patients with blepharospasm and writer's cramp. This reinforces the current concept of cerebellar dysfunction in primary dystonia, and that this extends beyond more pure forms of cerebellum-dependent associative motor learning paradigms. However, the finding of normal adaptation in cervical dystonia patients indicates that the pattern of cerebellar dysfunction may be slightly different for the various forms of primary focal dystonia, suggesting that actual cerebellar pathology may not be a primary driving force in dystonia.

The enigmatic linguistic cerebellum: clinical relevance and unanswered questions on nonmotor speech and language deficits in cerebellar disorders.

Clinical case descriptions and experimental evidence dating back to the early part of the 19th century from time to time documented a range of nonmotor cognitive and affective impairments following cerebellar pathology. However, a causal relationship between disruption of nonmotor cognitive and affective skills and cerebellar disease was dismissed for several decades and the classical view of the cerebellum as a mere coordinator of autonomic and somatic sensorimotor function prevailed for more than two centuries in behavioural neuroscience. The ignorance of early clinical evidence suggesting a much richer and complex role for the cerebellum than a pure sensorimotor one is remarkable given that in addition: 1) the cerebellum contains more neurons than the rest of the combined cerebral cortex and 2) no other structure has as many connections with other parts of the brain as the cerebellum. During the past decades, the long-standing view of the cerebellum as pure coordinator of sensorimotor function has been substantially modified. From the late 1970s onwards, major advances were made in elucidating the many functional neuroanatomical connections of the cerebellum with the supratentorial association cortices that subserve nonmotor language, cognition and affect. Combined with evidence derived from experimental functional neuroimaging studies in healthy subjects and neurophysiological and neuropsychological research in patients, the role of the cerebellum has been substantially extended to include that of a crucial modulator of cognitive and affective processes. In addition to its long-established role in coordinating motor aspects of speech production, clinical and experimental studies with patients suffering from etiologically different cerebellar disorders have identified involvement of the cerebellum in a variety of nonmotor language functions, including motor speech planning, language dynamics and verbal fluency, phonological and semantic word retrieval, expressive and receptive syntax processing, various aspects of reading and writing and aphasia-like phenomena. Despite considerable efforts currently devoted to further refine typology and anatomoclinical configurations of nonmotor linguistic dysfunctions linked to cerebellar pathology, the exact underlying pathophysiological mechanisms of cerebellar involvement remain to be elucidated.

Cerebellar dysregulation and heterogeneity of mood disorders.

This paper discusses diverse studies to consider the hypothesis that cerebellar pathology supports the heterogeneous metabolic pathologies of mood disorders. The evidence presented includes studies selected from the following areas of scientific research: magnetic resonance imaging, histology, clinical syndromes, comparative anatomy, neuronal connections, and mitochondrial dysfunction. The gamut of different scientific study methods confirms the validity of the involvement of the cerebellum in mood disorders.

Síndrome afectivo-cognitivo cerebeloso secundario a tumor cerebeloso

Cerebellar cognitive affective syndrome is characterized by disturbances of executive function, impaired spatial cognition, linguistic difficulties, and personality change.The case of an 11year old boy is presented, with behavior problems, learning difficulties and social interaction problems. In the physical examination he had poor visual contact, immature behavior, reduced expressive language and global motor disability with gait dyspraxia, with no defined cerebellar motor signs. In the neuropsychological evaluation he has a full scale overall intellectual quotient of 84, with signs of cerebellar cognitive affective syndrome. A tumour affecting inferior cerebellar vermis was observed in the magnetic resonance imaging, which had not significantly grown during 5years of follow up.The cerebellum participates in controlling cognitive and affective functions. Cerebellar pathology must be considered in the differential diagnosis of children with cognitive or learning disorder with associated behavioral and emotional components.

From mice to men: lessons from mutant ataxic mice.

Ataxic mutant mice can be used to represent models of cerebellar degenerative disorders. They serve for investigation of cerebellar function, pathogenesis of degenerative processes as well as of therapeutic approaches. Lurcher, Hot-foot, Purkinje cell degeneration, Nervous, Staggerer, Weaver, Reeler, and Scrambler mouse models and mouse models of SCA1, SCA2, SCA3, SCA6, SCA7, SCA23, DRPLA, Niemann-Pick disease and Friedreich ataxia are reviewed with special regard to cerebellar pathology, pathogenesis, functional changes and possible therapeutic influences, if any. Finally, benefits and limitations of mouse models are discussed.

Cognitive Phenotype in Ataxia-Telangiectasia

BackgroundPediatric cerebrocerebellar neurodegenerative disorders such as ataxia-telangiectasia (AT) have not been examined in detail for neuropsychologic changes. Such studies may contribute to the further understanding of ataxia-telangiectasia and to the role of the cerebrocerebellar system in the development of cognitive function in childhood. MethodsTwenty-two patients with the classic phenotype of ataxia-telangiectasia were grouped into early stage cerebellar disease (group AT-I) versus late stage cerebrocerebellar disease (group AT-II) and examined for neurocognitive features. Results were compared with those of healthy control subjects and with standard norms. ResultsPatients in AT-I group scored low average compared with standard norms on all tests and were impaired compared with healthy control subjects for verbal intelligence quotient (P < 0.001), vocabulary and comprehension (P = 0.007), processing speed (P = 0.005), visuospatial processing (P = 0.020), and working memory (P = 0.046). Patients in AT-II group scored below average compared with standard norms on all tests and were impaired compared with control subjects for attention (P < 0.001), working memory (P < 0.001), and abstract reasoning (P < 0.001). Comprehension scores were lower for patients in AT-II than in AT-I group (P = 0.002), whereas vocabulary scores showed no difference between groups (P = 0.480). ConclusionCognitive impairments in ataxia-telangiectasia present early, coinciding with cerebellar pathology and are characteristic of the cerebellar cognitive affective syndrome. Widespread and deeper cognitive deficits manifest in later stages of ataxia-telangiectasia when additional noncerebellar pathology develops. These results are the first indications of distinct cerebellar and extracerebellar and/or subcortical contributions to the range of cognitive domains affected in ataxia-telangiectasia and need to be confirmed in future studies.

The clinical impact of cerebellar grey matter pathology in multiple sclerosis.

BackgroundThe cerebellum is an important site for cortical demyelination in multiple sclerosis, but the functional significance of this finding is not fully understood.ObjectiveTo evaluate the clinical and cognitive impact of cerebellar grey-matter pathology in multiple sclerosis patients.MethodsForty-two relapsing-remitting multiple sclerosis patients and 30 controls underwent clinical assessment including the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale (EDSS) and cerebellar functional system (FS) score, and cognitive evaluation, including the Paced Auditory Serial Addition Test (PASAT) and the Symbol-Digit Modalities Test (SDMT). Magnetic resonance imaging was performed with a 3T scanner and variables of interest were: brain white-matter and cortical lesion load, cerebellar intracortical and leukocortical lesion volumes, and brain cortical and cerebellar white-matter and grey-matter volumes.ResultsAfter multivariate analysis high burden of cerebellar intracortical lesions was the only predictor for the EDSS (p<0.001), cerebellar FS (p = 0.002), arm function (p = 0.049), and for leg function (p<0.001). Patients with high burden of cerebellar leukocortical lesions had lower PASAT scores (p = 0.013), while patients with greater volumes of cerebellar intracortical lesions had worse SDMT scores (p = 0.015).ConclusionsCerebellar grey-matter pathology is widely present and contributes to clinical dysfunction in relapsing-remitting multiple sclerosis patients, independently of brain grey-matter damage.

Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group.

Consensus diagnostic criteria for multiple system atrophy consider dementia as a nonsupporting feature, despite emerging evidence demonstrating that cognitive impairments are an integral part of the disease. Cognitive disturbances in multiple system atrophy occur across a wide spectrum from mild single domain deficits to impairments in multiple domains and even to frank dementia in some cases. Frontal-executive dysfunction is the most common presentation, while memory and visuospatial functions also may be impaired. Imaging and neuropathological findings support the concept that cognitive impairments in MSA originate from striatofrontal deafferentation, with additional contributions from intrinsic cortical degeneration and cerebellar pathology. Based on a comprehensive evidence-based review, the authors propose future avenues of research that ultimately may lead to diagnostic criteria for cognitive impairment and dementia associated with multiple system atrophy.

Dorsal root ganglionopathy is responsible for the sensory impairment in CANVAS

To elucidate the neuropathology in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), a novel cerebellar ataxia comprised of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a peripheral sensory deficit. Brain and spinal neuropathology in 2 patients with CANVAS, together with brain and otopathology in another patient with CANVAS, were examined postmortem. Spinal cord pathology demonstrated a marked dorsal root ganglionopathy with secondary tract degeneration. Cerebellar pathology showed loss of Purkinje cells, predominantly in the vermis. The likely underlying sensory pathology in CANVAS is loss of neurons from the dorsal root and V, VII, and VIII cranial nerve ganglia-in other words, it is a "neuronopathy" rather than a "neuropathy." Clinically, CANVAS is a differential diagnosis for both spinocerebellar ataxia type 3 (or Machado-Joseph disease) and Friedreich ataxia. In addition, there are 6 sets of sibling pairs, implying that CANVAS is likely to be a late-onset recessive or autosomal dominant with reduced penetrance disorder, and identification of the culprit gene is currently a target of investigation.

The role of the cerebellum in the pathogenesis of cortical myoclonus

The putative involvement of the cerebellum in the pathogenesis of cortical myoclonic syndromes has been long hypothesized, as neuropathological changes in patients with cortical myoclonus have most commonly been found in the cerebellum rather than in the suspected culprit, the primary somatosensory cortex. A model of increased cortical excitability due to loss of cerebellar inhibitory control via cerebello-thalamo-cortical connections has been proposed, but evidence remains equivocal. Here, we explore this hypothesis by examining syndromes that present with cortical myoclonus and ataxia. We first describe common clinical characteristics and underlying neuropathology. We critically view information on cerebellar physiology with regard to motorcortical output and compare findings between hypothesized and reported neurophysiological changes in conditions with cortical myoclonus and ataxia. We synthesize knowledge and focus on neurochemical changes in these conditions. Finally, we propose that the combination of alterations in inhibitory neurotransmission and the presence of cerebellar pathology are important elements in the pathogenesis of cortical myoclonus.

Language impairment in cerebellar ataxia

Several studies have suggested that language impairment can be observed in patients with cerebellar pathology. The aim of this study was to investigate language performance in patients with spinocerebellar ataxia type 6 (SCA6). We assessed speech and language in 29 SCA6 patients with standardized linquistic tests and correlated this with the severity of ataxia, as quantified by the Scale of Assessment and Rating of Ataxia. Individual patients show mild-to-moderate linguistic impairment. Linguistic abnormalities were most distinct on the writing and comprehension subtests. A strong correlation between severity of ataxia and linguistic performance was consistently found. This study confirms the occurrence of linguistic impairments in patients with cerebellar degenerative diseases, such as SCA6. The relation between linguistic abnormalities and severity of ataxia provides further evidence for a role of the cerebellum in linguistic processing.

Is there cerebellar pathology in essential tremor?

Movement DisordersVolume 29, Issue 4 p. 435-436 Editorial Is there cerebellar pathology in essential tremor? Kurt A. Jellinger MD, Corresponding Author Kurt A. Jellinger MD Institute of Clinical Neurobiology, Vienna, AustriaCorrespondence to: Kurt A. Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria; kurt.jellinger@univie.ac.atSearch for more papers by this author Kurt A. Jellinger MD, Corresponding Author Kurt A. Jellinger MD Institute of Clinical Neurobiology, Vienna, AustriaCorrespondence to: Kurt A. Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria; kurt.jellinger@univie.ac.atSearch for more papers by this author First published: 01 March 2014 https://doi.org/10.1002/mds.25852Citations: 11 Funding agencies: The study was partly supported by the Society for the Support of Research in Experimental Neurology (Vienna, Austria). Relevant conflicts of interest/financial disclosures: Nothing to report. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume29, Issue4April 2014Pages 435-436 RelatedInformation

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development

BackgroundThe homeobox transcription factor Engrailed2 (En2) has been studied extensively in neurodevelopment, particularly in the midbrain/hindbrain region and cerebellum, where it exhibits dynamic patterns of expression and regulates cell patterning and morphogenesis. Because of its roles in regulating cerebellar development and evidence of cerebellar pathology in autism spectrum disorder (ASD), we previously examined an ENGRAILED2 association and found evidence to support EN2 as a susceptibility gene, a finding replicated by several other investigators. However, its functions at the cell biological level remain undefined. In the mouse, En2 gene is expressed in granule neuron precursors (GNPs) just as they exit the cell cycle and begin to differentiate, raising the possibility that En2 may modulate these developmental processes.MethodsTo define En2 functions, we examined proliferation, differentiation and signaling pathway activation in En2 knockout (KO) and wild-type (WT) GNPs in response to a variety of extracellular growth factors and following En2 cDNA overexpression in cell culture. In vivo analyses of cerebellar GNP proliferation as well as responses to insulin-like growth factor-1 (IGF1) treatment were also conducted.ResultsProliferation markers were increased in KO GNPs in vivo and in 24-h cultures, suggesting En2 normally serves to promote cell cycle exit. Significantly, IGF1 stimulated greater DNA synthesis in KO than WT cells in culture, a finding associated with markedly increased phospho-S6 kinase activation. Similarly, there was three-fold greater DNA synthesis in the KO cerebellum in response to IGF1 in vivo. On the other hand, KO GNPs exhibited reduced neurite outgrowth and differentiation. Conversely, En2 overexpression increased cell cycle exit and promoted neuronal differentiation.ConclusionsIn aggregate, our observations suggest that the ASD-associated gene En2 promotes GNP cell cycle exit and differentiation, and modulates IGF1 activity during postnatal cerebellar development. Thus, genetic/epigenetic alterations of EN2 expression may impact proliferation, differentiation and IGF1 signaling as possible mechanisms that may contribute to ASD pathogenesis.

Crossed Cerebellar Diaschisis in Acute Isolated Thalamic Infarction Detected by Dynamic Susceptibility Contrast Perfusion MRI

PurposeCrossed cerebellar diaschisis (CCD) is a state of neural depression caused by loss of connections to injured neural structures remote from the cerebellum usually evaluated by positron emission tomography. Recently it has been shown that dynamic susceptibility contrast perfusion weighted MRI (PWI) may also be feasible to detect the phenomenon. In this study we aimed to assess the frequency of CCD on PWI in patients with acute thalamic infarction.MethodsFrom a MRI report database we identified patients with acute isolated thalamic infarction. Contralateral cerebellar hypoperfusion was identified by inspection of time to peak (TTP) maps and evaluated quantitatively on TTP, mean transit time (MTT), cerebral blood flow and volume (CBF, CBV) maps. A competing cerebellar pathology or an underlying vascular pathology were excluded.ResultsA total of 39 patients was included. Common symptoms were hemiparesis (53.8%), hemihypaesthesia (38.5%), dysarthria (30.8%), aphasia (17.9%), and ataxia (15.4%). In 9 patients (23.1%) PWI showed hypoperfusion in the contralateral cerebellar hemisphere. All of these had lesions in the territory of the tuberothalamic, paramedian, or inferolateral arteries. Dysarthria was observed more frequently in patients with CCD (6/9 vs. 6/30; OR 8.00; 95%CI 1.54–41.64, p = 0.01). In patients with CCD, the median ischemic lesion volume on DWI (0.91 cm3, IQR 0.49–1.54 cm3) was larger compared to patients with unremarkable PWI (0.51 cm3, IQR 0.32–0.74, p = 0.05). The most pronounced changes were found in CBF (0.94±0.11) and MTT (1.06±0.13) signal ratios, followed by TTP (1.05±0.02).ConclusionsMultimodal MRI demonstrates CCD in about 20% of acute isolated thalamic infarction patients. Lesion size seems to be a relevant factor in its pathophysiology.

AAV9-mediated Expression of a Non-self Protein in Nonhuman Primate Central Nervous System Triggers Widespread Neuroinflammation Driven by Antigen-presenting Cell Transduction

Many studies have demonstrated that adeno-associated virus serotype 9 (AAV9) transduces astrocytes and neurons when infused into rat or nonhuman primate (NHP) brain. We previously showed in rats that transduction of antigen-presenting cells (APC) by AAV9 encoding a foreign protein triggered a full neurotoxic immune response. Accordingly, we asked whether this phenomenon occurred in NHP. We performed parenchymal or intrathecal infusion of AAV9 encoding green fluorescent protein (GFP), a non-self protein derived from jellyfish, or human aromatic L-amino acid decarboxylase (hAADC), a self-protein, in separate NHP. Animals receiving AAV9-GFP into cisterna magna (CM) became ataxic, indicating cerebellar pathology, whereas AAV9-hAADC animals remained healthy. In transduced regions, AAV9-GFP elicited inflammation associated with early activation of astrocytic and microglial cells, along with upregulation of major histocompatibility complex class II (MHC-II) in glia. In addition, we found Purkinje neurons lacking calbindin after AAV9-GFP but not after AAV9-hAADC delivery. Our results demonstrate that AAV9-mediated expression of a foreign-protein, but not self-recognized protein, triggers complete immune responses in NHP regardless of the route of administration. Our results warrant caution when contemplating use of serotypes that can transduce APC if the transgene is not syngeneic with the host. This finding has the potential to complicate preclinical toxicology studies in which such vectors encoding human cDNA's are tested in animals.

Schizophrenia-Like Psychosis and Dandy-Walker Variant Comorbidity: Case Report

Dandy-Walker variant is a developmental malformation consisting of cerebellar hypoplasia and cystic dilatation of the fourth ventricle. Previous research has proposed a possible role for the cerebellum in cognition and in schizophrenia. In this paper we report a schizophrenia-like psychotic disorder in a 30 year-old woman with Dandy-Walker variant. The patient was treated with risperidone 6 mg/day, biperiden 4 mg/day and risperidone depot 50 mg injections fortnightly, and most of the symptoms were ameliorated within 2 months. The similar cognitive profile to populations with cerebellar pathology and rarity of the condition strongly suggests that there may be direct relationship between cerebellar pathology and appearence of psychotic symptoms.

Cerebellar pathology in Friedreich's ataxia: atrophied dentate nuclei with normal iron content.

BackgroundIn Friedreich's ataxia (FA) the genetically decreased expression of the mitochondrial protein frataxin leads to disturbance of the mitochondrial iron metabolism. Within the cerebellum the dentate nuclei (DN) are primarily affected. Histopathological studies show atrophy and accumulation of mitochondrial iron in DN. Dentate iron content has been suggested as a biomarker to measure the effects of siderophores/antioxidant treatment of FA. We assessed the iron content and the volume of DN in FA patients and controls based on ultra-high-field MRI (7 Tesla) images.MethodsFourteen FA patients (mean age 38.1 yrs) and 14 age- and gender-matched controls participated. Multi-echo gradient echo and susceptibility weighted imaging (SWI) sequences were acquired on a 7 T whole-body scanner. For comparison SWI images were acquired on a 1.5 T MR scanner. Volumes of the DN and cerebellum were assessed at 7 and 1.5 T, respectively. Parametric maps of T2 and T2* sequences were created and proton transverse relaxation rates were estimated as a measure of iron content.ResultsIn FA, the DN and the cerebellum were significantly smaller compared to controls. However, proton transverse relaxation rates of the DN were not significantly different between both groups.ConclusionsApplying in vivo MRI methods we could demonstrate significant atrophy of the DN in the presence of normal iron content. The findings suggest that relaxation rates are not reliable biomarkers in clinical trials evaluating the potential effect of FA therapy.