Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation.

BACKGROUND AND PURPOSE: To establish and validate diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) due to colony-stimulating factor 1 receptor (CSF1R) mutation. METHODS: We developed diagnostic criteria for ALSP based on a recent analysis of the clinical characteristics of ALSP. These criteria provide 'probable' and 'possible' designations for patients who do not have a genetic diagnosis. To verify its sensitivity and specificity, we retrospectively applied our criteria to 83 ALSP cases who had CSF1R mutations (24 of these were analyzed at our institutions and the others were identified from the literature), 53 cases who had CSF1R mutation-negative leukoencephalopathies and 32 cases who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with NOTCH3 mutations. RESULTS: Among the CSF1R mutation-positive cases, 50 cases (60%) were diagnosed as 'probable' and 32 (39%) were diagnosed as 'possible,' leading to a sensitivity of 99% if calculated as a ratio of the combined number of cases who fulfilled 'probable' or 'possible' to the total number of cases. With regard to specificity, 22 cases (42%) with mutation-negative leukoencephalopathies and 28 (88%) with CADASIL were correctly excluded using these criteria. CONCLUSIONS: These diagnostic criteria are very sensitive for diagnosing ALSP with sufficient specificity for differentiation from CADASIL and moderate specificity for other leukoencephalopathies. Our results suggest that these criteria are useful for the clinical diagnosis of ALSP.

Glial fibrillary acidic protein mutations in adult-onset Alexander disease: clinical features observed in 12 Japanese patients.

OBJECTIVE: To clarify the clinical manifestations of adult-onset Alexander disease (AOAD) in Japanese patients with glial fibrillary acidic protein (GFAP) gene mutations. METHODS AND MATERIALS: Twelve patients of AOAD with GFAP mutations detected in our centre were examined for neurological and magnetic resonance imaging (MRI) findings. RESULTS: Major symptoms were pyramidal and bulbar signs. In addition, three patients presented abnormal behaviour and/or memory disturbance. Two of the three patients also had Parkinsonism and had been diagnosed with fronto-temporal dementia or progressive supranuclear palsy until GFAP mutations were detected. Abnormalities of the medulla oblongata and cervical spinal cord were observed on MRI in all patients. CONCLUSIONS: Patients presenting with pyramidal and/or bulbar signs with abnormalities of the medulla oblongata and cervical spinal cord on MRI should be considered for GFAP analysis as this is the typical presentation of AOAD. Abnormal behaviour and cognitive disorders including deterioration of memory were rare symptoms but could be an obstacle to diagnosing Alexander disease.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

Tumor necrosis factor gene polymorphisms in patients with sporadic Parkinson's disease.

We studied promoter region polymorphisms in the tumor necrosis factor (TNF) gene at position -1031, -863, and -857, in 172 Japanese patients with sporadic Parkinson's disease (PD). The frequency of the -1031C allele, a high producer of TNF, increased significantly in early onset PD patients compared with controls. In addition, PD patients with the -1031C allele showed a significantly earlier onset than those without -1031C allele, after stratification of the data by an interleukin-1beta gene polymorphism. Our findings suggest that TNF might have a toxic effect in PD.

Riluzole stimulates nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis in cultured mouse astrocytes.

Riluzole is an antiexcitotoxic agent used for the treatment of amyotrophic lateral sclerosis, and reported to have neuroprotective effects in animal models of Parkinson's disease, Huntington's disease and brain ischemia. We investigated the effects of riluzole on synthesis of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in cultured mouse astrocytes. The protein and mRNA levels were measured by enzyme-linked immunosorbent assay and semiquantitative reverse transcription-polymerase chain reaction, respectively. Treatment with riluzole at 100 microg/ml (426 microM) for 24 h increased the contents of NGF, BDNF, and GDNF in the culture medium 109-fold, 2.0-fold and 3.1-fold over the control, respectively. The drug-induced relative mRNA levels of NGF, BDNF, and GDNF were 7.3-fold at 2 h, 2.1-fold at 4 h, and 1.9-fold at 2 h, respectively. These results indicate that riluzole stimulates synthesis of NGF, BDNF and GDNF in cultured astrocytes. Riluzole might exert neuroprotective effects, at least in part, via stimulation of neurotrophic factors.

Conflict of intentions due to callosal disconnection.

OBJECTIVES: Three patients with callosal syndrome manifested a peculiar symptom in that they were unable to perform intended whole body actions because another intention emerged in competition with the original one. Attempts were made to clarify the symptomatology of this manifestation and its possible mechanism is discussed. METHODS: The three patients are described and previous reports on patients with callosal damage were reviewed. Four additional patients with similar symptoms were found and the clinical features common to all seven patients were examined. RESULTS: This symptom could not be attributed to unilateral movement disorders such as unilateral apraxia, intermanual conflict, or compulsive manipulation of tools. The manifestations included marked hesitation in initiating actions, interruption of actions, repetitive actions, and performance of unintended actions with difficulty in correcting them. All patients, except one, had a lesion in the posterior half of the body of the corpus callosum, and there was no significant involvement of the cerebral cortex. The symptom became manifest later than 4 weeks after callosal damage. It occurred during spontaneous actions, but not during well automated actions nor when following instructions. CONCLUSION: This symptom, tentatively named "conflict of intentions", can be regarded as a fragment of diagonistic dyspraxia originally described by Akelaitis, although it can occur independently of intermanual conflict. Normally, the right and left cerebral hemispheres may be complementarily modifying automated whole body actions in order to adapt behaviour to changes of the environment as well as to the intention. Partial callosal disconnection without significant cortical involvement would exaggerate the disparity between the role of each hemisphere through the reorganisation of neural systems after callosal damage. Such double, often contrary, behavioural tendencies may sometimes simultaneously enter the patient's awareness.

A case report of comorbid eating disorder and factitious disorder.

A review of the literature on comorbid eating disorder and factitious disorder reveals that they are very rare. In this report the authors present the case of a 26-year-old Japanese female, who, in the midst of treatment for eating disorder, was found to be fabricating her physical symptoms, by injecting unclean water into her intravenous bottle. As a result she was diagnosed with factitious disorder.

Infarct tolerance accompanied enhanced BDNF-like immunoreactivity in neuronal nuclei.

A prolonged period (48 h) of cortical spreading depression (CSD) induced resistance against severe focal cerebral ischemia (infarct tolerance), however, the mechanism behind this is unknown. The infarct tolerance was a transient phenomenon; the resistance increased linearly for the initial 12 days, peaking from 12 to 15 days after a preconditioning of CSD, and was decreased thereafter. This study examined the time course of brain-derived neurotrophic factor (BDNF), heat shock protein (hsp)27 and 70, and glial fibrillary acidic protein (GFAP) expressions after CSD in the brain. Immunohistochemical expression of BDNF, hsp27, hsp70, or GFAP following a prolonged period of CSD induced by KCl-infusion, or following NaCl-infusion was analyzed by regional densitometry for 24 days in the rat neocortex. In addition, BDNF protein was measured quantitatively by two-site ELISA assay in the neocortex (n=6 at each time point). The GFAP expression was elevated in astrocytes (compared to the normal level of immunodensity) during the period peaking on day 3-6 following the CSD. The hsp27 immunoreactivity was also elevated in astrocytes from day 1 to 12 peaking on day 1 and 6, but there was no expression of hsp70 during the period following CSD. The immunoreactivity for BDNF was elevated in neurons from day 0 to 18 peaking on day 1 and 6. The protein levels of BDNF in the neocortex were significantly elevated from day 0 to 12 peaking on days 0 and 6 (compared to the normal level) (P<0.05). Using a laser-scanning confocal imaging system, the BDNF-like immunoreactivity in neuronal nuclei was found to increase linearly peaking on day 12, which correlated well with the development of infarct tolerance. The intranuclear increase in BDNF-like protein might contribute to the induction of infarct tolerance in the brain.

Functional anatomical study of psychogenic amnesia.

Psychogenic amnesia is characterized by an inability to recall information already stored in the patient's memory. It is usually related to a stressful or traumatic event that cannot be explained by manifest brain damage. To examine the underlying functional disturbance of brain areas in this condition, we performed a positron emission tomography (PET) activation study on a psychogenic amnesic patient and on 12 normal control subjects. A task requiring explicit retrograde memory of faces was compared with a control task. To assess functional modifications associated with the processes of recovery, a second PET study was performed on the patient 12 months after onset. During the task, activation of the right anterior medial temporal region including the amygdala was increased in the psychogenic amnesic patient. Activation of the bilateral hippocampal regions increased only in the control subjects. During recovery, the right anterior medial temporal region became less active while the right hippocampal region became more active. Activation levels also differed in the anterior cingulate cortex, prefrontal cortex and some other cortical regions between control subjects and the patient. These findings suggest that the changes in these limbic and limbic-cortical functions are related to symptoms of the psychogenic amnesia.

Apomorphine up-regulates NGF and GDNF synthesis in cultured mouse astrocytes.

Apomorphine, a D1/D2 dopamine agonist, is an anti-parkinsonian drug. We examined the effects of apomorphine on synthesis of neurotrophic factors in cultured mouse astrocytes. After 24 h incubation with apomorphine, NGF and GDNF contents in the culture medium increased to 122-fold and 1.8-fold of the control, respectively; whereas the BDNF content did not change significantly. In Northern blot analysis, expression of NGF mRNA in astrocytes reached the maximum level at 6 h after addition of the drug. By semiquantitative RT-PCR analysis, the GDNF transcript level was found to reach 2.9-fold of the control level at 15 h. These results suggest that apomorphine may exert neuroprotective effects by stimulation of NGF and GDNF synthesis in astrocytes.

Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic Parkinson's disease.

We studied genetic polymorphisms in the promoter region (position -511) and exon 5 (position +3953) of the interleukin (IL)-1beta gene in 122 Japanese patients with Parkinson's disease (PD) and 112 controls. We also examined polymorphisms in the IL-1alpha and the IL-1 receptor antagonist genes. No significant difference was found in these genetic markers between PD patients and controls. However, PD patients with homozygotes for allele 1 at position -511 of the IL-1beta gene (IL-1B-511*1), a low producer of IL-1beta, were significantly earlier in the disease onset than those with the IL-1B-511*2 homozygotes, a high producer of IL-1beta. This suggests that IL-1beta might play a role, possibly a protective effect for dopaminergic neurons, in PD. Further population and functional studies are necessary to clarify the role of IL-1beta in PD patients.

Selegiline and desmethylselegiline stimulate NGF, BDNF, and GDNF synthesis in cultured mouse astrocytes.

We investigated the effects of selegiline and desmethylselegiline on synthesis of neurotrophic factors in cultured mouse astrocytes. Treatment with 2 mM selegiline for 24 h increased the contents of NGF, BDNF, and GDNF in the culture medium 26-, 1.7-, and 4.2-fold over the control, respectively. With this drug the maximum relative mRNA levels of NGF, BDNF, and GDNF were 6.2-fold at 2 h, 3.4-fold at 6 h, and 2.7-fold at 2 h, respectively. Selegiline at 0.2 mM completely inhibited the MAO activity, but had no effect on the content of neurotrophic factors, suggesting that stimulation of neurotrophic factors by selegiline is independent of MAO-B inhibition. Desmethylselegiline at 1.68 mM for 24 h elevated the NGF, BDNF, and GDNF contents 4.1-, 1.7-, and 2.4-fold over the control, respectively; and the relative transcript levels of NGF, BDNF, and GDNF reached 2.6-fold at 2 h, 1.7-fold at 6 h, and 1.8-fold at 2 h, respectively. These findings suggest that selegiline and desmethylselegiline may protect neurons by up-regulating endogenous NGF, BDNF, and GDNF synthesis.

[Psychopathological study on schizophrenic autism through the paintings of a case of simple schizophrenia].

Autism is the symptom which has the most specific features of schizophrenia. However, the content of pathological experience of the patients has not yet been clarified as it was never told by themselves. In the present study, a case of simple schizophrenia with a major symptom of autism is reported. Schizophrenic autism was studied psychopathologically by drawing tests. The analysis of drawings was summarized by the following characteristics. 1. The objects were drawn so as to be small at the center. The composition was further characterized by the overwhelmingly predominant empty space of its circumference, which we termed "reversed zoom lens effect". This seemed to show that the objects were isolated and removed from the patient. 2. The entire image of the theme was not drawn. 3. Lack of vitality was observed in all the drawings. On the basis of the above characteristics of these drawings and the clinical findings, the following were suggested as the pathology of the patient's experience: 1. The "reversed zoom lens composition" seen in the drawings suggested that the psychological distance between objects and the patient might be expanded. 2. The patient was alienated from the objective world to which he had once been accustomed as the object lacked vitality and familiarity. 3. The pathology of schizophrenic autism observed in the patient could be expressed as "alienation from objective experience." 4. It was considered that although akin to depersonalization, "alienation from objective experience" was the pathology characteristic of schizophrenia.

Developmental expression of NMDA receptor subunits and the emergence of glutamate neurotoxicity in primary cultures of murine cerebral cortical neurons.

Using primary cultures of murine cerebral cortices, we investigated the developmental expression of N-methyl-D-aspartate (NMDA) receptor subunits in relation to the appearance of NMDA receptor-mediated glutamate neurotoxicity. The cultures were not affected by glutamate exposure on culture days 7-9, but became sensitive to glutamate neurotoxicity on day 11. The expression of NMDA receptor subunit messenger RNAs (mRNAs) was investigated by means of reverse transcription polymerase chain reaction (RT-PCR). The epsilon 3-NR2C and epsilon 4-NR2D transcripts could not be detected in the culture. The epsilon 2-NR2B and zeta 1-NR1 subunit mRNAs, on the other hand, could be detected clearly and continuously from the culture initiation, and the epsilon 1-NR2A subunit mRNA became clearly detectable on culture day 4. The expression of these three subunits' proteins in the glutamate-insensitive stage (culture day 8) and the sensitive stage (day 11) were studied by means of Western blotting. The epsilon 2-NR2B and zeta 1-NR1 subunit proteins were clearly expressed on culture days 8 and 11, but the epsilon 1-NR2A subunit protein could hardly be detected on either day 8 or day 11. These results suggest that the glutamate neurotoxicity in the primary culture was mediated mainly by epsilon 2/zeta 1 NMDA receptors. The time lag between the protein expression of the epsilon 2-NR2B and zeta 1-NR1 subunits and the emergence of glutamate neurotoxicity may be necessary for the maturation of functional NMDA receptor systems, including heteromeric receptor formation, increase in receptor density and maturation of the postreceptor signal transduction system.

Differential expression of neuroD in primary cultures of cerebral cortical neurons.

We have investigated the expression patterns of a basic helix-loop-helix regulatory gene, neuroD, in primary cultures of murine cerebral cortical neurons. The differentiation states of neurons in primary cultures were determined by the sensitivity of neurons to glutamate toxicity and the expression of specific proteins such as the phosphorylated form of a 200-kDa neurofilament, HPC-1/syntaxin 1A, and cell adhesion molecule L1. The expression of neuroD was determined by RT-PCR analysis and in situ hybridization. The experimental results thus obtained revealed that neuronal maturation is initiated between Day 7 and Day 11 in the culture as already known, and that the expression of neuroD decreases with increasing days in culture. Based on these findings, it was concluded that neuroD is expressed in immature neurons but not in mature ones.