The early neuropathological features of amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) are protein aggregates in motor neurons and microglial activation. Similar pathology characterizes Guamanian ALS/Parkinsonism dementia complex, which may be triggered by the cyanotoxin β-N-methylamino-l-alanine (BMAA). We report here the occurrence of ALS/MND-type pathological changes in vervets (Chlorocebus sabaeus; n = 8) fed oral doses of a dry powder of BMAA HCl salt (210 mg/kg/day) for 140 days. Spinal cords and brains from toxin-exposed vervets were compared to controls fed rice flour (210 mg/kg/day) and to vervets coadministered equal amounts of BMAA and l-serine (210 mg/kg/day). Immunohistochemistry and quantitative image analysis were used to examine markers of ALS/MND and glial activation. UHPLC-MS/MS was used to confirm BMAA exposures in dosed vervets. Motor neuron degeneration was demonstrated in BMAA-dosed vervets by TDP-43+ proteinopathy in anterior horn cells, by reactive astrogliosis, by activated microglia, and by damage to myelinated axons in the lateral corticospinal tracts. Vervets dosed with BMAA + l-serine displayed reduced neuropathological changes. This study demonstrates that chronic dietary exposure to BMAA causes ALS/MND-type pathological changes in the vervet and coadministration of l-serine reduces the amount of reactive gliosis and the number of protein inclusions in motor neurons.
Background: Large decompressive craniectomies may be life-saving; however, they may also result in syndrome of the trephined. This postrecovery sequela is characterized by dizziness, fatigue, depression, weakness, speech slowing, gait disturbance, and impaired mentation. Because this entity is poorly understood, the authors attempted to quantify the functional improvement in patients with syndrome of the trephined after cranial vault reconstruction. Methods: Patients with cranial vault defects (>50 cm2) from trauma, meningioma, and hemorrhage were studied preoperatively and postoperatively (6 months) after cranial vault reconstruction using (1) the Cognistat Active Form and (2) the Functional Independence Measure instrument (n = 40). Cranial vault reconstructive techniques varied from split cranial bone to alloplastic implants (polyetheretherketone or titanium mesh). Results: Of the 143 patients treated with decompressive craniectomies, 28 percent (n = 40) developed symptoms of syndrome of the trephined. A larger craniectomy defect size correlated with development of syndrome of the trephined. Time from craniectomy to presentation of symptoms was 4.5 months. Time from craniectomy to cranial vault reconstruction was 6.1 months. Time from cranial vault reconstruction to symptom improvement was 4.3 days. Complete functional recovery of syndrome of the trephined was seen in 70 percent. Type of cranial vault reconstruction included polyetheretherketone implant (57.5 percent), split calvarial graft (22.5 percent), and titanium mesh (20 percent), and was not a determinant of functional improvement. Cognistat assessment score noted improvement (from 38 to 69); likewise, the Functional Independence Measure measurement tool showed improvement (from 38 to 98). Conclusions: Syndrome of the trephined occurs more frequently than previously described in posttraumatic patients with large cranial vault defects. Cranial vault reconstruction leads to significant, quantifiable functional improvement in a large number of patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
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