Brain structure in movement disorders: a neuroimaging perspective.

Purpose of review: An overview of recent advances in structural neuroimaging and their impact on movement disorders research is presented. Recent findings: Novel developments in computational neuroanatomy and improvements in magnetic resonance image quality have brought further insight into the pathophysiology of movement disorders. Sophisticated automated techniques allow for sensitive and reliable in-vivo differentiation of phenotype/genotype related traits and their interaction even at presymptomatic stages of disease. Summary: Voxel-based morphometry consistently demonstrates well defined patterns of brain structure changes in movement disorders. Advanced stages of idiopathic Parkinson's disease are characterized by grey matter volume decreases in basal ganglia. Depending on the presence of cognitive impairment, volume changes are reported in widespread cortical and limbic areas. Atypical Parkinsonian syndromes still pose a challenge for accurate morphometry-based classification, especially in early stages of disease progression. Essential tremor has been mainly associated with thalamic and cerebellar changes. Studies on preclinical Huntington's disease show progressive loss of tissue in the caudate and cortical thinning related to distinct motor and cognitive phenotypes. Basal ganglia volume in primary dystonia reveals an interaction between genotype and phenotype such that brain structure changes are modulated by the presence of symptoms under the influence of genetic factors. Tics in Tourette's syndrome correlate with brain structure changes in limbic, motor and associative fronto-striato-parietal circuits. Computational neuroanatomy provides useful tools for in-vivo assessment of brain structure in movement disorders, allowing for accurate classification in early clinical stages as well as for monitoring therapy effects and/or disease progression.

In vivo transformation of mouse conventional CD8alpha+ dendritic cells leads to progressive multisystem histiocytosis

Division and proliferation of dendritic cells (DCs) have been proposed to contribute to homeostasis and to prolonged antigen presentation. Whether abnormal proliferation of dendritic cells causes Langerhans cell histiocytosis (LCH) is a highly debated topic. Transgenic expression of simian virus 40 (SV40) T antigens in mature DCs allowed their transformation in vivo while maintaining their phenotype, function, and maturation capacity. The transformed cells were differentiated splenic CD8 alpha-positive conventional dendritic cells with increased Langerin expression. Their selective transformation was correlated with higher steady-state cycling compared with CD8 alpha-negative DCs in wild-type and transgenic mice. Mice developed a DC disease involving the spleen, liver, bone marrow, thymus, and mesenteric lymph node. Surprisingly, lesions displayed key immunohistologic features of Langerhans cell histiocytosis, including expression of Langerin and absence of the abnormal mitoses observed in Langerhans cell sarcomas. Our results demonstrate that a transgenic mouse model with striking similarities to aggressive forms of multisystem histiocytosis, such as the Letterer-Siwe syndrome, can be obtained by transformation of conventional DCs. These findings suggest that conventional DCs may cause some human multisystem LCH. They can reveal shared molecular pathways for human histiocytosis between humans and mice

Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain.

Most models for tauopathy use a mutated form of the Tau gene, MAPT, that is found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and that leads to rapid neurofibrillary degeneration (NFD). Use of a wild-type (WT) form of human Tau protein to model the aggregation and associated neurodegenerative processes of Tau in the mouse brain has thus far been unsuccessful. In the present study, we generated an original "sporadic tauopathy-like" model in the rat hippocampus, encoding six Tau isoforms as found in humans, using lentiviral vectors (LVs) for the delivery of a human WT Tau. The overexpression of human WT Tau in pyramidal neurons resulted in NFD, the morphological characteristics and kinetics of which reflected the slow and sporadic neurodegenerative processes observed in sporadic tauopathies, unlike the rapid neurodegenerative processes leading to cell death and ghost tangles triggered by the FTDP-17 mutant Tau P301L. This new model highlights differences in the molecular and cellular mechanisms underlying the pathological processes induced by WT and mutant Tau and suggests that preference should be given to animal models using WT Tau in the quest to understand sporadic tauopathies.

Prenatal brain atrophy due to a giant vein of Galen malformation.

We report a full-term newborn girl with a giant vein of Galen malformation and extreme cerebral atrophy of prenatal origin. She presented on the 3rd day of life with intractable congestive heart failure. The diagnosis of the vascular malformation was confirmed by ultrasound and magnetic resonance imaging.

Regenerative cell injection in denervated muscle reduces atrophy and enhances recovery following nerve repair.

INTRODUCTION: Functional muscle recovery after peripheral nerve injury is far from optimal, partly due to atrophy of the muscle arising from prolonged denervation. We hypothesized that injecting regenerative cells into denervated muscle would reduce this atrophy. METHODS: A rat sciatic nerve lesion was performed, and Schwann cells or adipose-derived stem cells, untreated or induced to a "Schwann-cell-like" phenotype (dASC), were injected into the gastrocnemius muscle. Nerves were either repaired immediately or capped to prevent muscle reinnervation. One month later, functionality was measured using a walking track test, and muscle atrophy was assessed by examining muscle weight and histology. RESULTS: Schwann cells and dASC groups showed significantly better scores on functional tests when compared with injections of growth medium alone. Muscle weight and histology were also significantly improved in these groups. CONCLUSION: Cell injections may reduce muscle atrophy and could benefit nerve injury patients.

Mitochondrial DNA (mtDNA) A 3243G mutation associated with an annular perimacular retinal atrophy

BACKGROUND: A point mutation at the locus 3243 of the mitonchondrial DNA (mtDNA) is associated with either the MIDD syndrome (maternally inherited diabetes, deafness), the MELAS syndrome (myopathy, encephalitis, lactic acidosis, stroke) or cardiac, digestive, endocrine or exocrine dysfunctions. We report a peculiar maculopathy in two patients with an mtDNA 3243 mutation. HISTORY AND SIGNS: Case 1: A visually asymptomatic 40-year-old woman was examined for screening of diabetic retinopathy. Visual acuity was 10 / 10 in both eyes. Case 2: A 54-year-old woman with deafness and diabetes complained of visual loss. Visual acuity was 6 / 10 for the right eye and 0.5 / 10 for the left eye. Both patients exhibited a chorioretinal areolar atrophy. Case 1 was followed over 15 years and exhibited a slow progression of the maculopathy with moderate loss of visual acuity to 6 / 10 in both eyes, but marked handicap from the annular scotoma. THERAPY AND OUTCOME: None. CONCLUSION: Both patients presented a perimacular annular retinal atrophy. Patients harbouring mtDNA 3243 mutation should be examined for the presence of a maculopathy, even if they are asymptomatic. Conversely, the finding of such a geographic maculopathy should suggest the possibility of a point mutation at the locus 3243 of the mitochondrial DNA, especially in the presences of diabetes mellitus and/or deafness

New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations.

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Positive effects of an angiotensin II type 1 receptor antagonist in Camurati-Engelmann disease: a single case observation.

Camurati-Engelmann disease is characterized by hyperostosis of the long bones and the skull, muscle atrophy, severe limb pain, and progressive joint contractures in some patients. It is caused by heterozygous mutations in the transforming growth factor β1 (TGFβ1) believed to result in improper folding of the latency-associated peptide domain of TGFβ1 and thus in increased or deregulated bioactivity. Losartan, an angiotensin II type 1 receptor antagonist, has been found to downregulate the expression of TGFβ type 1 and 2 receptors. Clinical trials with losartan have shown a benefit in Marfan syndrome, while trials are underway for Duchenne muscular dystrophy and other myopathies associated with TGFβ1 signaling. We hypothesized that due to its anti-TGFβ1 activity, losartan might be beneficial in Camurati-Engelmann disease. This report concerns a boy who presented at age 13 years with severe limb pain and difficulty in walking. Clinical and radiographic evaluation results were compatible with Camurati-Engelmann disease and the diagnosis was confirmed by mutation analysis (c.652C > T [p.Arg218Cys]). The boy underwent an experimental treatment with losartan at a dosage of 50 mg/day, orally. During the treatment period of 18 months, the intensity and frequency of limb pain decreased significantly (as shown by a pain diary), and muscle strength improved, allowing the boy to resume walking and climbing stairs. No obvious side effects were observed. We cautiously conclude that TGFβ1 inhibition with losartan deserves further evaluation in the clinical management of Camurati-Engelmann disease.

PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.

Disentangling in vivo the effects of iron content and atrophy on the ageing human brain.

Evidence from magnetic resonance imaging (MRI) studies shows that healthy aging is associated with profound changes in cortical and subcortical brain structures. The reliable delineation of cortex and basal ganglia using automated computational anatomy methods based on T1-weighted images remains challenging, which results in controversies in the literature. In this study we use quantitative MRI (qMRI) to gain an insight into the microstructural mechanisms underlying tissue ageing and look for potential interactions between ageing and brain tissue properties to assess their impact on automated tissue classification. To this end we acquired maps of longitudinal relaxation rate R1, effective transverse relaxation rate R2* and magnetization transfer - MT, from healthy subjects (n=96, aged 21-88 years) using a well-established multi-parameter mapping qMRI protocol. Within the framework of voxel-based quantification we find higher grey matter volume in basal ganglia, cerebellar dentate and prefrontal cortex when tissue classification is based on MT maps compared with T1 maps. These discrepancies between grey matter volume estimates can be attributed to R2* - a surrogate marker of iron concentration, and further modulation by an interaction between R2* and age, both in cortical and subcortical areas. We interpret our findings as direct evidence for the impact of ageing-related brain tissue property changes on automated tissue classification of brain structures using SPM12. Computational anatomy studies of ageing and neurodegeneration should acknowledge these effects, particularly when inferring about underlying pathophysiology from regional cortex and basal ganglia volume changes.

Hereditary diffuse leukoencephalopathy with axonal spheroids: More than just a rare disease.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a progressive white matter disease with a wide range of clinical symptoms including dementia, behavioral changes, seizures, pyramidal signs, ataxia, and parkinsonism.(1-3) Affected individuals develop symptoms in their early 40s with an average survival time of 10 years. HDLS is inherited as an autosomal dominant trait. Recently, mutations in the colony-stimulating factor 1 receptor gene (CSF-1R) were identified as the genetic cause of HDLS.(4) White matter lesions, easily demonstrated on MRI studies, involve predominantly the frontal lobes and corpus callosum with subsequent cortical atrophy. MRI abnormalities are present prior to symptom onset.(5,6) Histopathology shows widespread myelin and axon destruction with axonal dilations termed spheroids, as well as pigmented macrophages.

Identification of muscle-specific calpain and beta-sarcoglycan genes in progressive autosomal recessive muscular dystrophies.

The autosomal recessive forms of limb-girdle muscular dystrophies are encoded by at least five distinct genes. The work performed towards the identification of two of these is summarized in this report. This success illustrates the growing importance of genetics in modern nosology.