Attenuated CSF-1R signalling drives cerebrovascular pathology.

Cerebrovascular pathologies occur in up to 80% of cases of Alzheimer's disease; however, the underlying mechanisms that lead to perivascular pathology and accompanying blood-brain barrier (BBB) disruption are still not fully understood. We have identified previously unreported mutations in colony stimulating factor-1 receptor (CSF-1R) in an ultra-rare autosomal dominant condition termed adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p-Tau were some of the primary neuropathological features of this condition. We have identified two families with different dominant acting alleles with variants located in the kinase region of the CSF-1R gene, which confer a lack of kinase activity and signalling. The protein product of this gene acts as the receptor for 2 cognate ligands, namely colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). Here, we show that depletion in CSF-1R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF-1R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of Csf-1r heterozygosity in macrophages. Finally, we show that endothelial/microglial crosstalk and concomitant attenuation of CSF-1R signalling causes re-modelling of BBB-associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer's-like dementias.

Mirror therapy and treadmill training for a patient with chronic stroke: A case report.

INTRODUCTION: A large proportion of patients with chronic stroke have permanent lower limb functional disability leading to reduced levels of independent mobility. Individually, both mirror therapy and treadmill training have been shown to improve aspects of lower limb functioning in patients with stroke. This case report examined whether a new combination of both interventions would lead to improvements in lower limb functional disability for a patient with chronic stroke. CASE DESCRIPTION: The participant was a 50-year-old female who had a left middle cerebral artery infarction (47 months' post stroke). Due to hemiparesis, she had lower limb motor impairment and gait deficits. INTERVENTION: The participant engaged in a combination of mirror therapy and treadmill training for 30 minutes per day, 3 days per week, for 4 weeks. OUTCOMES: Modified Ashworth Scale, Fugl-Meyer Assessment-Lower Extremity and the 10 m Walk Test demonstrated clinically meaningful change. The 6 Minute Walk Test did not demonstrate meaningful change. DISCUSSION: The positive outcomes from this new combination therapy for this participant are encouraging given the relatively small dose of training and indicate the potential benefit of mirror therapy as an adjunct to treadmill training for enhancing lower limb muscle tone, motor function and walking velocity in patients with chronic stroke.

Unilateral Strength Training and Mirror Therapy in Patients With Chronic Stroke: A Pilot Randomized Trial.

OBJECTIVE: The aim of the study was to investigate the feasibility and potential effectiveness of mirror-aided cross-education compared with cross-education alone in poststroke upper limb recovery. DESIGN: A pilot randomized controlled parallel group study was carried out. Thirty-two patients with chronic stroke followed a 4-wk isometric strength training program performed with the less-affected upper limb three times per week. Participants in the mirror and strength training group observed the reflection of the exercising arm in the mirror. Participants in the strength training only group exercised without a mirror entirely. Participant compliance, adverse effects, and suitability of outcome measures assessed feasibility. Effectiveness outcomes included maximal isometric strength measured with the Biodex Dynamometer, the Modified Ashworth Scale, and the Chedoke Arm and Hand Activity Inventory. RESULTS: Compliance was high with no adverse effects. The use of the Biodex Dynamometer must be reviewed. Mirror therapy did not augment the cross-education effect (P > 0.05) in patients with chronic stroke when training isometrically. CONCLUSIONS: This pilot trial established the feasibility of a randomized controlled trial comparing mirror-aided cross-education with cross-education alone for poststroke upper limb recovery. Mirror therapy did not augment cross-education when training isometrically. However, results indicate that the combination of interventions should be investigated further applying an altered training protocol.