CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

The clinicopathologic features of two Japanese sisters with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) are described. Neither patient had a history of hypertension, and both experienced cerebrovascular events before reaching their forties. Severe degenerative changes in the lumbar spine and knee joints were seen on radiographs. MRI showed extensive cerebral white matter lesions, which revealed remarkable arteriosclerotic changes on autopsy.

To evaluate functional change in the spinal reflex pathway with ageing, we studied heteronymous Ia facilitation from the quadriceps to soleus muscle in 30 normal volunteers (aged 24-68 years). The size of the test H-reflex of the soleus muscle was adjusted to 25% that of the maximal M-response. The conditioning stimulus was adjusted to 1.5-fold the motor threshold to stimulate all the Ia fibres in the femoral nerve. Facilitation was quantified as the slope of the very early part of facilitation, within 0.8 ms of onset. This procedure enabled us to evaluate the extent of monosynaptic Ia facilitation without contamination by other effects. The extent of facilitation decreased linearly with age. This decrease in facilitation could reflect a decrease in the number of Ia fibres and in their conduction velocities, and an increase in presynaptic inhibition on Ia terminals. The increase in presynaptic inhibition may be an adaptive phenomenon in the ageing of the neuromuscular system or, alternatively, a deteriorating process with decreasing flexible supraspinal modulation.

Objectives In European countries and the United States the incidence of elderly-onset myasthenia gravis (MG) has recently been increasing. To investigate whether the incidence of the elderly-onset MG has increased in Nagano Prefecture of Japan, we divided the patients into young and elderly groups, and retrospectively examined their incidence.Patients and Methods On the basis of two-step questionnaires sent to hospitals and the patient list of the intractable disease registration system in Nagano Prefecture we studied 213 MG patients diagnosed between 1982 and 2001. This 20-year period was divided into 4 fiveyear terms, and the incidence of MG in young-(younger than 65) and elderly-onset (65 or older) groups was investigated separately for each term.Results The ratio of the elderly-onset group showed a significantly positive correlation with terms irrespective of associated thymoma (r=0.98, p<0.05). There was a significant difference in the mean onset age among the 4 terms (p<0.005). The standardized incidence of MG gradually increased in both young-and elderly-onset groups as well as in the whole age range. The elderly group showed a particularly high incidence in females (12.01/million/year) and in patients without thymoma (8.78/million/year) in the final five years.Conclusions We confirmed that the incidence of elderly-onset MG has recently been increasing in the Nagano Prefecture. Since the change of the age distribution in this district is almost identical to that of the whole country, the incidence of MG might have been increasing in Japan as a whole, particularly in the elderly population.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a distinctive clinicopathologic entity characterized by young adult-onset non-hypertensive vasculopathic encephalopathy accompanied by alopecia and disco-vertebral degeneration. CARASIL arteriopathy is histopathologically characterized by intense arteriosclerosis without the deposition of granular osmiophilic materials. Until now, the obliterative arteriosclerosis is the presumptive cause of subcortical ischemia in CARASIL; however, a detailed vascular pathology leading to diffuse leukoencephalopathy remains unclear. In this study, we examined two autopsied CARASIL brains in comparison with an autopsy case of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Intensity of arterial sclerotic changes of CARASIL was evaluated by sclerotic index analysis. Immunohistochemical investigations were performed using a battery of primary antibodies, which recognized vascular cellular and extracellular components. As a result, sclerotic changes were disclosed to be mild and infrequent in CARASIL, in contrast to CADASIL that showed severe obliterative arterial changes. In CARASIL, conversely, most of the arteries were centrifugally enlarged and some were collapsed. We further revealed that arterial medial smooth muscle cells (SMCs) in patients with CARASIL were extensively lost, even in arteries without sclerotic changes. Arterial adventitia in CARASIL was conspicuously thin and immunoreactivities for type I, III, and VI collagens and fibronectin were appreciably weak in this region, indicating a reduction in the mural extracellular matrix (ECM). Because of the medial and adventitial degeneration, CARASIL brains likely receive marked fluctuations in blood flow because of deviations in the structural and functional basis of autoregulation mechanisms. We thus consider that diffuse leukoencephalopathy in CARASIL may be caused by arterial medial SMC loss with mural ECM reduction. We speculate that the abnormalities in the ECM are causatively related to the SMC degeneration, since the ECM is a crucial signal determining the biophysiological properties of arterial SMCs.