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 degenerati...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- κ B 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.展开更多
Objective: To clarify the progression of autonomic symptoms and functional de terioration in pure autonomic failure (PAF), particularly in comparison with mul tiple system atrophy (MSA). Methods: The investigation inv...Objective: To clarify the progression of autonomic symptoms and functional de terioration in pure autonomic failure (PAF), particularly in comparison with mul tiple system atrophy (MSA). Methods: The investigation involved eight patients w ith PAF (M/F=7/1; mean age at onset, 57 years) and 22 with probable MSA matched for age at onset (M/F=14/8; onset 56 years). Subjects were followed up for neuro logical symptoms, activities of daily living, and autonomic function for more th an seven years. Autonomic functional tests were carried out. Results: In PAF, fa inting or sudomotor dysfunction occurred first, followed by constipation and syn cope. Urinary dysfunction developed late, and respiratory dysfunction was not ev ident. This clinical course contrasted sharply with that in MSA, where early uri nary dysfunction usually proceeded to sudomotor dysfunction or orthostatic hypot ension (p=0.004), followed by respiratory dysfunction (p=0.0004). Results of pha rmacological tests also distinguished PAF from MSA. Progression and prognosis in patients with PAF did not worsen, unlike the steady progressive autonomic dysfu nction in MSA (p < 0.0001, p < 0.0001, p=0.0009, and p=0.003, for progression to modified Rankin scale grade III, IV, V, and death, respectively). Conclusions: The time course and pattern of progression of autonomic failure differed signifi cantly between PAF and MSA. Patients with PAF had slower functional deterioratio n and a better prognosis.展开更多
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to strokes and vascular dementia. The average age of onset for stroke is 45 years wi...Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to strokes and vascular dementia. The average age of onset for stroke is 45 years with a range of about 30 to 70 years. We describe a Japanese CADASIL family showing S180C in the exon 4 of NOTCH3, presenting an anticipation of the onset age for stroke. MRI demonstrated a similar extent of white matter involvement in younger and older individuals, supporting the presence of anticipation. In addition, hallucinations in 71%of affected patients, and delusions in 57%were also described. Our findings in this family suggest that a specific NOTCH3 mutation was related to unique clinical features, although such correlations have seldom been encountered in CADASIL.展开更多
文摘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- κ B 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.
文摘Objective: To clarify the progression of autonomic symptoms and functional de terioration in pure autonomic failure (PAF), particularly in comparison with mul tiple system atrophy (MSA). Methods: The investigation involved eight patients w ith PAF (M/F=7/1; mean age at onset, 57 years) and 22 with probable MSA matched for age at onset (M/F=14/8; onset 56 years). Subjects were followed up for neuro logical symptoms, activities of daily living, and autonomic function for more th an seven years. Autonomic functional tests were carried out. Results: In PAF, fa inting or sudomotor dysfunction occurred first, followed by constipation and syn cope. Urinary dysfunction developed late, and respiratory dysfunction was not ev ident. This clinical course contrasted sharply with that in MSA, where early uri nary dysfunction usually proceeded to sudomotor dysfunction or orthostatic hypot ension (p=0.004), followed by respiratory dysfunction (p=0.0004). Results of pha rmacological tests also distinguished PAF from MSA. Progression and prognosis in patients with PAF did not worsen, unlike the steady progressive autonomic dysfu nction in MSA (p < 0.0001, p < 0.0001, p=0.0009, and p=0.003, for progression to modified Rankin scale grade III, IV, V, and death, respectively). Conclusions: The time course and pattern of progression of autonomic failure differed signifi cantly between PAF and MSA. Patients with PAF had slower functional deterioratio n and a better prognosis.
文摘Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to strokes and vascular dementia. The average age of onset for stroke is 45 years with a range of about 30 to 70 years. We describe a Japanese CADASIL family showing S180C in the exon 4 of NOTCH3, presenting an anticipation of the onset age for stroke. MRI demonstrated a similar extent of white matter involvement in younger and older individuals, supporting the presence of anticipation. In addition, hallucinations in 71%of affected patients, and delusions in 57%were also described. Our findings in this family suggest that a specific NOTCH3 mutation was related to unique clinical features, although such correlations have seldom been encountered in CADASIL.
