We investigated the disease progression and survival in 230 Japanese patients with multiple system atrophy (MSA; 131 men, 99 women; 208 probable MSA, 22 definite; mean age at onset, 55.4 years). Cerebellar dysfunction (multiple system atrophy-cerebellar; MSA-C) predominated in 155 patients, and parkinsonism (multiple system atrophy-parkinsonian; MSA-P) in 75. The median time from initial symptom to combined motor and autonomic dysfunction was 2 years (range 1-10). Median intervals from onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were 3, 5, 8 and 9 years, respectively. Patients manifesting combined motor and autonomic involvement within 3 years of onset had a significantly increased risk of not only developing advanced disease stage but also shorter survival (P < 0.01). MSA-P patients had more rapid functional deterioration than MSA-C patients (aid-requiring walking, P = 0.03; confinement to a wheelchair, P < 0.01; bedridden state, P < 0.01), but showed similar survival. Onset in older individuals showed increased risk of confinement to a wheelchair (P < 0.05), bedridden state (P = 0.03) and death (P < 0.01). Patients initially complaining of motor symptoms had accelerated risk of aid-requiring walking (P < 0.01) and confinement to a wheelchair (P < 0.01) compared with those initially complaining of autonomic symptoms, while the time until confinement to a bedridden state and survival were no worse. Gender was not associated with differences in worsening of function or survival. On MRI, a hyperintense rim at the lateral edge of the dorsolateral putamen was seen in 34.5% of cases, and a 'hot cross bun' sign in the pontine basis (PB) in 63.3%. These putaminal and pontine abnormalities became more prominent as MSA-P and MSA-C features advanced. The atrophy of the cerebellar vermis and PB showed a significant correlation particularly with the interval following the appearance of cerebellar symptoms in MSA-C (r = 0.71, P < 0.01, r = 0.76 and P < 0.01, respectively), but the relationship between atrophy and functional status was highly variable among the individuals, suggesting that other factors influenced the functional deterioration. Atrophy of the corpus callosum was seen in a subpopulation of MSA, suggesting hemispheric involvement in a subgroup of MSA patients. The present study suggested that many factors are involved in the progression of MSA but, most importantly, the interval from initial symptom to combined motor and autonomic dysfunction can predict functional deterioration and survival in MSA.

The steady-state mRNA levels of the four neurotrophic factors of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) and their receptors (p75NGFR, trkA, trkB and trkC) in the adult human peripheral nervous system (PNS) as well as nonneural tissues were examined using quantitative reverse transcription-polymerase chain reaction (RT-PCR). NGF and BDNF mRNA levels were high in the heart and spleen as well as in the dorsal root ganglia (DRG) and spinal cord, showing similar spatial expression patterns, while NT-3 mRNA levels were more pronounced in the liver and spleen. In contrast to these neurotrophins, GDNF mRNA expression occurred at the highest levels in the muscle, and it was also comparatively high in the spinal cord. p75NGFR mRNA was expressed extensively throughout the PNS tissues and in the spleen. The spatial expression patterns differed among trkA, and trkB and trkC mRNAs. trkA mRNA was greatly expressed in the DRG, sympathetic ganglia and spleen, while the trkB and trkC mRNA levels were high in the DRG, spinal cord and brain. The levels of trkB and trkC mRNAs with tyrosine kinase domain, compared to those with extracellular domain, were relatively high in the DRG, whereas they were low in the spinal cord and brain. The spatial patterns of the distributions of neurotrophic factors and their receptors mRNA levels in the adult human PNS and nonneural tissues are largely similar to those reported in other mammals, but these findings provide further, more specific, understanding relevant to the therapeutic approach to human diseases.

The causative pathomechanism of sporadic amyotrophic lateral sclerosis (ALS) is not clearly understood. Using microarray technology combined with laser-captured microdissection, gene expression profiles of degenerating spinal motor neurons isolated from autopsied patients with sporadic ALS were examined. Gene expression was quantitatively assessed by real-time reverse transcription polymerase chain reaction and in situ hybridization. Spinal motor neurons showed a distinct gene expression profile from the whole spinal ventral horn. Three percent of genes examined were downregulated, and 1% were upregulated in motor neurons. Downregulated genes included those associated with cytoskeleton/axonal transport, transcription, and cell surface antigens/receptors, such as dynactin, microtubule-associated proteins, and early growth response 3 (EGR3). In contrast, cell death-associated genes were mostly upregulated. Promoters for cell death pathway, death receptor 5, cyclins A1 and C, and caspases-1, -3, and -9, were upregulated, whereas cell death inhibitors, acetyl-CoA transporter, and NF-kappaB were also upregulated. Moreover, neuroprotective neurotrophic factors such as ciliary neurotrophic factor (CNTF), Hepatocyte growth factor (HGF), and glial cell line-derived neurotrophic factor were upregulated. Inflammation-related genes, such as those belonging to the cytokine family, were not, however, significantly upregulated in either motor neurons or ventral horns. The motor neuron-specific gene expression profile in sporadic ALS can provide direct information on the genes leading to neurodegeneration and neuronal death and are helpful for developing new therapeutic strategies.

A cytoarchitectonic study of spinal ventral horn cells was performed to identify age-related changes. The diameter distribution of ventral horn neurons of the fourth lumbar segment of the spinal cord and their size and topographical distributions were investigated in 14 autopsy cases. These cases represented patients of 18-100 years of age who had died of non-neurological diseases. The results indicate that small neurons widely distributed in the intermediate zone of the ventral horn significantly diminished with aging (P < 0.0005, r = -0.898), whereas medium-sized and large neurons located in the medial and lateral nuclei showed only a slight decrease with advancing age. The total number of neurons in the whole ventral horn was also noted to decrease significantly with aging (P < 0.0005, r = -0.899). While small neurons in the intermediate zone of the ventral horn are thought to be mostly interneurons, their physiological function still remains obscure in many respects. The findings of this study provide insight into age-related cell loss in terms of size and location.

The ventral horn cells of the fourth lumbar segment were morphometrically analysed in six cases of amyotrophic lateral sclerosis (ALS; there common forms and three pseudopolyneuritic forms), six of multiple system atrophy (MSA) with autonomic failure, four of X-linked recessive bulbospinal neuronopathy (X-BSNP), and seven age-matched autopsy cases of non-neurological disorders. In the common form of ALS, large and medium-sized neurons of the medial and lateral nuclei were markedly lost; small neurons in the intermediate zone were slightly diminished but fairly well preserved. In the pseudopolyneuritic form of ALS, marked loss was present in the large and medium-sized neurons, and in the small neurons located in the intermediate zone as well. In the MSA, in contrast to ALS, there was a marked reduction in small neurons in the intermediate zone, and large and medium-sized neurons of the medial and lateral nuclei tended to be preserved. In X-BSNP, large and medium-sized neurons were almost completely lost and small neurons were also markedly depopulated. These findings indicated that the pattern of neuron loss in the ventral horn is distinct among these diseases depending on size, location and function of the ventral horn cell population. These disease-specific patterns of neuron loss suggest a difference in the process of neuronal degeneration of ventral horn cells among the disease examined.