Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS.

BACKGROUND: Mutations in the microtubule associated protein tau (MAPT) and progranulin (PGRN) have been identified in several neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). Recently, C9orf72 repeat expansion was reported to cause FTLD and amyotrophic lateral sclerosis (ALS). To date, no comprehensive analyses of mutations in these three genes have been performed in Asian populations. The aim of this study was to investigate the genetic and clinical features of Japanese patients with MAPT, PGRN, or C9orf72 mutations. METHODS: MAPT and PGRN were analyzed by direct sequencing and gene dosage assays, and C9orf72 repeat expansion was analyzed by repeat-primed PCR in 75 (48 familial, 27 sporadic) Japanese patients with FTLD, PSP, or CBS. RESULTS: We found four MAPT mutations in six families, one novel PGRN deletion/insertion, and no repeat expansion in C9orf72. Intriguingly, we identified a de novo MAPT p.S285R mutation. All six patients with early-onset PSP and the abnormal eye movements that are not typical of sporadic PSP had MAPT mutations. The gene dosages of MAPT and PGRN were normal. DISCUSSION: MAPT p.S285R is the first reported de novo mutation in a sporadic adult-onset patient. MAPT mutation analysis is recommended in both familial and sporadic patients, especially in early-onset PSP patients with these abnormal eye movements. Although PGRN and C9orf72 mutations were rare in this study, the PGRN mutation was found in this Asian FTLD. These genes should be studied further to improve the clinicogenetic diagnoses of FTLD, PSP, and CBS.

Reevaluation of levodopa therapy for the treatment of advanced Parkinson's disease.

Levodopa is the most appropriate drug in theory for supplementing dopamine deficiency in the brain of Parkinson's disease (PD) patients. In consideration of the pharmacological properties of levodopa, measurement of 3,4-dihydroxyphenylalanine (DOPA) plasma concentration is significant and important in daily medical care. Akinesia of advanced PD patients comprises a combination of two distinct symptoms, hypokinesia and bradykinesia. It is probable that hypokinesia in PD does not originate from failure of neural pathways from the substantia nigra to motor striatum but is associated with dysfunction of the limbic striatum. Herein the pathophysiologic condition of the limbic striatum in PD patients is discussed and reasons suggested why drug efficacy of dopamine replenishment in this system is meager.

[Mesolimbic and mesocortical pathways in Parkinson disease].

In Parkinson disease patients who receive long-term antiparkinsonian medication, their original symptoms of rigidity, tremor and related motor disturbances markedly improve or disappear. However, the condition is still far from satisfactory in terms of maintaining independence in daily life activities even in these patients in whom the drug treatment is for improving motor disturbances. The reason is that they show abnormal behavior characterized by "spending the entire day in an idle state, which is perceived as laziness."This behavior is very annoying for the patient and the family. Despite the excellent effectiveness of drug treatment, this propensity toward idleness in mental and motor functions is not improved. Despite the denial of the depressive state and the absence of obvious cognitive disorder, such patients lack ambition and spend their time idly. However, although their motor function remains subliminal, such patients can carry out motor activities when the situation requires, but usually they do not have the drive to move. If we use the current nosological descriptions, the former is called "bradyphrenia" or psychic akinesia or slowness of thinking and the latter is called "akinesia". Akinesia is composed of two cardinal elements "bradykinesia" and "hypokinesia". Bradykinesia is the evaluation of quality of appeared motor behavior, and hypokinesia is the poverty of movement behavior. These two symptoms differ essentially. Hypokinesia is much more essential and is a cardinal element of akinesia. It indicates that the current drug treatment is ineffective for the improvement of hypokinesia and bradyphrenia. That is, these symptoms are a result of a dysfunction different from that causing residual motor symptoms or a result of other additional dysfunctions developing during the pathophysiological course of the disease. The dopamine (DA) system of the dorsal striatal pathway projecting from the substantia nigra pars compacta (A9) to the dorsal part of the striatum (motor striatum) functions in the control of speed and dexterity of movement. On the other hand, the DA system through the medial forebrain bundle projecting from the ventral tegmental area (VTA-A10) to the nucleus accumbens, ventral striatum (limbic striatum) and the cortex is associated with hypokinesia and bradyphrenia. This association can be confirmed by a long-term follow-up of Parkinson disease patients and experimental animal models lesioned in the ventral DA pathway (mesolimbic and mesocortical pathways).

[Electroconvulsive therapy for neurological disorders].

Electroconvulsive therapy (ECT) recovers the brain function through generalized convulsion induced by electrical stimulation of the brain. While the primary targets of ECT are psychiatric disorders such as depression, schizophrenia, and schizoaffective disorder, it has been well documented that ECT has therapeutic effects on muscular rigidity of Parkinson's disease and neuroleptics-induced malignant syndrome. Recently we demonstrated that ECT reduces intractable pain and allodynia associated with deafferentation pain disorders by recovering the function of the thalamic nucleus. ECT, if applied on appropriate clinical assessments, may contribute to the therapeutics of neuropsychiatric disorders.

Relatively spared mesocorticolimbic dopaminergic system in juvenile parkinsonism.

This study aims to examine the function of the mesocorticolimbic dopaminergic system, including the amygdala, in recognizing emotions in juvenile parkinsonism (JP). Eleven patients with JP and 16 age-matched controls selected one basic emotion (happiness, sadness, anger, fear, surprise, or disgust) that best described the emotional state represented by visual and auditory stimuli. There was no significant difference between the patients and normal controls in their recognition of emotions. The spared emotion recognition in JP could be attributed to the absence of any pathological changes or the normal dopamine concentrations in the mesocorticolimbic system in this condition.

[Intravenous thrombolytic therapy and its unresolved problems in Japan].

Since October 2005, following government approval for tPA use in acute ischemic stroke, over 5,000 patients have been given intravenous thrombolytic therapy in Japan. According to the newest but incomplete report on post-marketing investigations, whereas the rate of hemorrhagic complications remains the same, the proportion of good outcomes is slightly lower than that in Europe. This may reflect the higher inclusion rate of cardioembolic stroke and severe stroke patients in Japan. Many important, unresolved problems still exist concerning tPA therapy even in Japan. In particular, improvement of the emergency medical systems which transport acute stroke patients for thrombolysis to the primary stroke center appropriately and rapidly, and the establishment of in-hospital systems for tPA therapy including extensive co-medical staff and neuroradiological equipment, have priority. Moreover, high expectations are held for new stroke MR techniques including "diffusion-perfusion mismatch", combined additional antithrombotic drugs or intra-arterial cathetherization maneuvers, and ultrasound examinations with contrast media, to achieve a more favorable outcome with this therapy.

Cerebral arteriopathy with extracranial artery involvement in a patient with ulcerative colitis.

Arteriopathy of the central nervous system (CNS) complicated with ulcerative colitis is a rare condition, moreover the involvement of extracranial arteries has not been documented. An 18-year-old female complained of a severe pulsatile headache and nausea. She had been diagnosed and treated for ulcerative colitis for four years. Magnetic resonance imaging of the brain showed normal results; however, magnetic resonance angiography (MRA) revealed severe irregularity of the intracerebral arteries. After treatment with prednisolone, the patient fully recovered and the irregularity of the intracerebral arteries was dramatically improved. Vasculitis was strongly suggested as the cause of arteriopathy of the CNS in the present case. Involvement of extracranial arteries such as the carotid artery was also incidentally discovered by duplex ultrasonography and the HLA typing suggested genetic susceptibility to Takayasu's arteritis. Findings from our patient suggest that extracranial arterial involvement should be considered in the case of arteriopathy of the CNS associated with ulcerative colitis.

Factors influencing outcome in Guillain-Barré Syndrome: comparison of plasma adsorption against other treatments.

OBJECTIVE: This study was performed to evaluate which factors influence the outcome of Guillain-Barré Syndrome (GBS), focusing on the choice of treatments. METHODS: Sixty-three GBS patients were retrospectively studied and the following factors were evaluated: sex, age, days from onset of disease to the start of treatment, severity of symptoms, prior infection, autonomic dysfunction, bulbar palsy, anti-ganglioside antibody, and disease form, as well as the choice of treatment. Plasma adsorption (PA, n=39), plasma exchange (PE, n=14), or immunoglobulin treatment (IVIg, n=10) were performed in this study. Outcomes were evaluated using the functional grading scale (FGS) of Hughes. RESULTS: The number of days needed for one functional grade improvement was significantly longer in the elderly, the severe symptom group, and patients with acute motor axonal form, and days needed for two functional grade improvement was significantly longer in the elderly, patients with autonomic dysfunction, and acute motor axonal form. The choice of treatments (PA, PE, or IVIg) did not significantly influence the outcome as determined by both univariate and multivariate analysis. CONCLUSION: Although patient age, symptoms, and disease form influenced the outcome, treatment methods did not significantly influence the outcome. Since PA does not result in a risk of unknown infection, choosing a PA treatment may be justified, especially for patients (or doctors) who may be anxious about a possibility of unknown infection.

Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2.

We performed [123I] MIBG myocardial scintigraphy in two of three patients with PARK2 from unrelated families and examined the heart tissues from the three patients immunohistochemically using an antibody against tyrosine hydroxylase (TH) to see whether cardiac sympathetic nerve is involved. Cardiac uptake of MIBG was normal except for a slight decrease in the late phase in one of the patients. Postmortem examination revealed that TH-immunoreactive nerve fibers in the epicardium were well preserved in all three patients. The present study confirmed that cardiac sympathetic nerve is well preserved in PARK2 with a homozygous exon deletion, which accounts for normal cardiac uptake of MIBG. Moreover, normal cardiac uptake of MIBG might be of potential diagnostic value to indicate the absence of Lewy body pathology, even in patients with levodopa-responsive Parkinsonism, as in PARK2.