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In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which progranulin exerts protective effects on ischaemic brain injury remains unknown. Furthermore, the therapeutic potential of progranulin against acute focal cerebral ischaemia, including combination treatment with tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of progranulin after ischaemia as well as the therapeutic effects of progranulin on ischaemic brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in progranulin expression in ischaemic Sprague- Dawley rats, including increased levels of progranulin expression in microglia within the ischaemic core, and increased levels of progranulin expression in viable neurons as well as induction of progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory isoform of progranulin (~88 kDa) decreased, whereas the glycosylated immature isoform of progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature isoform was secreted only from the microglia. Second, we demonstrated that progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. We found that progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischaemia via anti-inflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43 as demonstrated in progranulin knockout mice (C57BL/6 background). Finally, we demonstrated the therapeutic potential of progranulin against acute focal cerebral ischaemia using a rat autologous thrombo-embolic model with delayed tissue plasminogen activator treatment. Intravenously administered recombinant progranulin reduced cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes (P = 0.007, 0.038, 0.007 and 0.004, respectively). In conclusion, progranulin may be a novel therapeutic target that provides vascular protection, antineuroinflammation, and neuroprotection related in part to vascular endothelial growth factor, interleukin 10, and TAR DNAbinding protein-43, respectively. [ABSTRACT FROM AUTHOR]

Background: The mechanism underlying nocturnal sudden death in patients with MSA remains unclear. It may be explained by upper airway obstruction, such as vocal cord abductor paralysis; an impairment of the respiratory center, such as Cheyne-Stokes respiration; or an impaired hypoxemic ventilatory response. Objective: To investigate the mechanism of sleep disordered breathing in multiple system atrophy (MSA) Design: We recruited 21 patients with probable MSA who were admitted sequentially to our hospital, and performed daytime blood gas analysis, pulmonary function tests, polysomnography, and fiberoptic laryngoscopy during wakefulness and with the patient under anesthesia. Results: A decrease in arterial oxygen pressure and an increase in alveolar-arterial oxygen gradient significantly correlated with disease duration (P=.045 and .046, respectively). Polysomnography demonstrated Cheyne-Stokes respiration in 3 (15%) of 20 patients. Fiberoptic laryngoscopy during wakefulness showed that 3 (14%) of the 21 patients exhibited vocal cord abductor paralysis, and laryngoscopy under anesthesia showed that 9 (45%) of 20 patients exhibited vocal cord abductor paralysis. Laryngoscopy under anesthesia also revealed that 11 (55%) of 20 patients showed upper airway obstruction, in places other than the vocal cords, including obstruction at the base of the tongue or soft palate. In addition, it demonstrated novel laryngopharyngeal findings, such as floppy epiglottis and airway obstruction at the arytenoid. Conclusions: We observed daytime hypoxemia with an increased alveolar-arterial oxygen gradient, Cheyne-Stokes respiration, and novel abnormal laryngopharyngeal movements in patients with MSA. We also found that laryngoscopy under anesthesia might be useful for evaluating upper airway obstruction. The significance of these findings to the mechanism of sudden death in those with MSA needs to be examined at the arytenoid. [ABSTRACT FROM AUTHOR]

Autosomal dominant choreas are genetically heterogeneous disorders including Huntington disease (HD), Huntington disease like 1 (HDL1), Huntington disease like 2 (HDL2), dentatorubro-pallidoluysian atrophy (DRPLA), spinocerebellar ataxia type 17 (SCA17) and benign hereditary chorea (BHC). We identified two Japanese families with adult-onset benign chorea without dementia inherited in an autosomal dominant pattern. All affected individuals presented slowly progressive choreic movements in their upper and lower extremities, trunk and head with an age of onset ranging from 40 to 66 (average 54.3), which were markedly improved by haloperidol. The affected individuals also developed reduced muscle tones in their extremities. The findings obtained in the brain CT or MRI studies of nine affected individuals were normal. These clinical features resemble those of the so-called ‘senile chorea’. HD, HDL1, HDL2, DRPLA, SCA17 and BHC caused by mutations in the TITF-1 gene were excluded by mutational and linkage analyses. A genome-wide linkage analysis revealed linkage to chromosome 8q21.3–q23.3 with a maximum cumulative two-point log of the odds (LOD) score of 4.74 at D8S1784 (θ = 0.00). Haplotype analysis of both the families defined the candidate region as 21.5 Mb interval flanked by M9267 and D8S1139. We named this adult-onset dominant inherited chorea ‘benign hereditary chorea type 2 (BHC2)’. [ABSTRACT FROM AUTHOR]

Objective: Fifty percent of patients with amyotrophic lateral sclerosis (ALS) have cervical spondylotic myelopathy (CSM) as a complication. Because patients with ALS do not develop bulbar signs and symptoms at onset, differentiating them from patients with CSM is sometimes difficult. We aimed to determine whether the apparent diffusion coefficients (ADCs) of intracranial corticospinal tracts can be used to distinguish between patients with ALS and those with CSM. Methods: We evaluated 19 consecutive patients with ALS who did not have CSM by cervical MRI, 16 patients with CSM, and 11 healthy controls. We examined the mean ADCs in the precentral gyrus, the corona radiata, the posterior limbs of the internal capsule (PLIC), and the cerebral peduncle by 3 T magnetic resonance imaging (MRI). The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM. Results: The mean ADCs in the intracranial corticospinal tracts in patients with ALS were compared with those in patients with CSM (p < 0.05). Additionally, the mean ADCs in the precentral gyrus, the PLIC, and the cerebral peduncle in the patients with ALS, including the patients who were initially diagnosed as having clinically possible ALS on the basis of the revised El Escorial criteria and did not develop bulbar symptoms at onset, were also higher than those in patients with CSM (p < 0.05). Conclusions: Elevated ADCs in the intracranial corticospinal tracts might be useful for distinguishing ALS from CSM in the early stage of the disease. [ABSTRACT FROM AUTHOR]