Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies

Plasma neurofilament light chain levels predict improvement in late phase after stroke

BACKGROUND: Although functional recovery is most pronounced in the first 6 months after stroke, improvement is possible also in the late phase. We explored the value of plasma neurofilament light chain (NfL), a biomarker of axonal injury and secondary neurodegeneration, for the prediction of functional improvement in late phase after stroke. METHODS: We measured baseline plasma NfL levels in 115 participants of a trial on the efficacy of multimodal rehabilitation in late phase after stroke. We determined the association between NfL levels, impairment in balance, gait and cognitive domains, and improvement 3 and 9 months later. RESULTS: Plasma NfL levels were associated with the degree of impairment in all three domains. Individuals with meaningful improvement in balance and gait capacity had higher plasma NfL levels compared with non-improvers (P=0.001 and P=0.018, respectively). Higher NfL levels were associated with improvement in balance (OR 2.34, CI: 1.35-4.27, P=0.004) and gait (OR 2.27, CI: 1.25-4.32, P=0.009). Elevated plasma NfL levels showed a positive predictive value for cognitive improvement, and this effect was specific for the intervention targeting the cognitive domain. The association of NfL levels with cognitive improvement withstood correction for baseline impairment, age and total years of schooling (OR 7.54, CI: 1.52-45.66, P=0.018). CONCLUSIONS: In addition to its established role as a biomarker in the acute phase, elevated circulating NfL levels may predict functional improvement in late phase after stroke. Our results should prompt further studies into the use of plasma NfL as a biomarker in late phase after stroke

Protein-Energy Malnutrition Exacerbates Stroke-Induced Forelimb Abnormalities and Dampens Neuroinflammation

Protein-energy malnutrition (PEM) pre-existing at stroke onset is believed to worsen functional outcome, yet the underlying mechanisms are not fully understood. Since brain inflammation is an important modulator of neurological recovery after stroke, we explored the impact of PEM on neuroinflammation in the acute period in relation to stroke-initiated sensori-motor abnormalities. Adult rats were fed a low-protein (LP) or normal protein (NP) diet for 28 days before inducing photothrombotic stroke (St) in the forelimb region of the motor cortex or sham surgery; the diets continued for 3 days after the stroke. Protein-energy status was assessed by a combination of body weight, food intake, serum acute phase proteins and corticosterone, and liver lipid content. Deficits in motor function were evaluated in the horizontal ladder walking and cylinder tasks at 3 days after stroke. The glial response and brain elemental signature were investigated by immunohistochemistry and micro-X-ray fluorescence imaging, respectively. The LP-fed rats reduced food intake, resulting in PEM. Pre-existing PEM augmented stroke-induced abnormalities in forelimb placement accuracy on the ladder; LP-St rats made more errors (29 ± 8%) than the NP-St rats (15 ± 3%; P < 0.05). This was accompanied by attenuated astrogliosis in the peri-infarct area by 18% and reduced microglia activation by up to 41 and 21% in the peri-infarct area and the infarct rim, respectively (P < 0.05). The LP diet altered the cortical Zn, Ca, and Cl signatures (P < 0.05). Our data suggest that proactive treatment of pre-existing PEM could be essential for optimal post-stroke recovery

Complement: a novel factor in basal and ischemia-induced neurogenesis

Through its involvement in inflammation, opsonization, and cytolysis, the complement protects against infectious agents. Although most of the complement proteins are synthesized in the central nervous system (CNS), the role of the complement system in the normal or ischemic CNS remains unclear. Here we demonstrate for the first time that neural progenitor cells and immature neurons express receptors for complement fragments C3a and C5a (C3a receptor (C3aR) and C5a receptor). Mice that are deficient in complement factor C3 (C3(−/−)) lack C3a and are unable to generate C5a through proteolytic cleavage of C5 by C5-convertase. Intriguingly, basal neurogenesis is decreased both in C3(−/−) mice and in mice lacking C3aR or mice treated with a C3aR antagonist. The C3(−/−) mice had impaired ischemia-induced neurogenesis both in the subventricular zone, the main source of neural progenitor cells in adult brain, and in the ischemic region, despite normal proliferative response and larger infarct volumes. Thus, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis

The effects of a rhythm and music-based therapy program and therapeutic riding in late recovery phase following stroke: a study protocol for a three-armed randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Stroke represents one of the most costly and long-term disabling conditions in adulthood worldwide and there is a need to determine the effectiveness of rehabilitation programs in the late phase after stroke. Limited scientific support exists for training incorporating rhythm and music as well as therapeutic riding and well-designed trials to determine the effectiveness of these treatment modalities are warranted.</p> <p>Methods/Design</p> <p>A single blinded three-armed randomized controlled trial is described with the aim to evaluate whether it is possible to improve the overall health status and functioning of individuals in the late phase of stroke (1-5 years after stroke) through a rhythm and music-based therapy program or therapeutic riding. About 120 individuals will be consecutively and randomly allocated to one of three groups: (T1) rhythm and music-based therapy program; (T2) therapeutic riding; or (T3) control group receiving the T1 training program a year later. Evaluation is conducted prior to and after the 12-week long intervention as well as three and six months later. The evaluation comprises a comprehensive functional and cognitive assessment (both qualitative and quantitative), and questionnaires. Based on the International classification of functioning, disability, and health (ICF), the outcome measures are classified into six comprehensive domains, with participation as the primary outcome measure assessed by the Stroke Impact Scale (SIS, version 2.0.). The secondary outcome measures are grouped within the following domains: body function, activity, environmental factors and personal factors. Life satisfaction and health related quality of life constitute an additional domain.</p> <p>Current status</p> <p>A total of 84 participants were randomised and have completed the intervention. Recruitment proceeds and follow-up is on-going, trial results are expected in early 2014.</p> <p>Discussion</p> <p>This study will ascertain whether any of the two intervention programs can improve overall health status and functioning in the late phase of stroke. A positive outcome would increase the scientific basis for the use of such interventions in the late phase after stroke.</p> <p>Trial registration</p> <p>Clinical Trials.gov Identifier: NCT01372059</p