Motor end-plate analysis to diagnose immune-mediated myasthenia gravis in seronegative patients.

This study aimed to evaluate the diagnostic usefulness of motor end-plate (MEP) analysis along with clustered acetylcholine receptor (AChR) antibody (Ab) assays in patients with myasthenia-like symptoms but negative routine AChR and muscle-specific kinase (MuSK) Ab tests. MEP analysis of muscle biopsies of the biceps brachii was performed in 20 patients to try to differentiate between those with or without immune-mediated myasthenia gravis (MG). Using a quantitative method, complement C3 deposition and AChR densities in MEPs were examined. Independently, cell-based assays were used to detect serum clustered-AChR Abs. Only five of 20 patients had complement deposition at MEPs; four of these patients had reduced AChR densities similar to those in patients with typical AChR Ab positive MG, and distinct from those in the remaining 15 patients. Two of the four serum samples from these patients had clustered-AChR Abs. All complement-positive patients were considered as having immune-mediated MG and improved with appropriate treatments; although one patient presented with MG 3 years later, the remaining patients had other diagnoses during over 10 years of follow-up. These results suggest the usefulness of MEP analysis of muscle biopsies in diagnosing immune-mediated MG in seronegative patients with myasthenia-like symptoms but, due to the invasiveness of the muscle biopsy procedure, clustered AChR Abs should, if possible, be tested first.

The Usefulness of Functional Near-Infrared Spectroscopy for the Assessment of Post-Stroke Depression.

Background: Post-stroke depression (PSD) is the most common mood disorder following stroke and is also the main factor that limits the recovery and rehabilitation of patients with stroke. The prevalence of PSD is ~30%. Since there is no gold standard for the diagnosis and evaluation of PSD, it is important to raise awareness of PSD and to establish methods for its evaluation, early diagnosis, and treatment. In the field of psychiatry, functional near-infrared spectroscopy (fNIRS) has been used as a diagnostic tool for the measurement of oxygenated hemoglobin (oxy-Hb). This study aimed to assess whether fNIRS could be applied in the diagnosis and evaluation of PSD. Methods: We recruited 45 patients with stroke, who were admitted to Nagasaki Kita Hospital between May 2015 and April 2019. The 17-item Hamilton Rating Scale for Depression (HAMD17), which is considered to be a useful screening and evaluation tool for PSD, was used for the assessment of patients after stroke; moreover, oxy-Hb was measured in the pre-frontal cortex. The subjects were divided into two groups: the depressed group (n = 13) and the non-depressed group (n = 32). We evaluated the correlation between the oxy-Hb integral values and HAMD17 scores. Results: We investigated the relationship between the oxy-Hb integral values and HAMD17 total scores, and found a negative correlation between them (ρ = -0.331, P < 0.005). There was a significant difference in the oxy-Hb integral values during the activation task period between the depressed and non-depressed groups (3.16 ± 2.7 and 1.71 ± 2.4, respectively; P = 0.040). The results indicated that the patients of the depressed group showed lower oxy-Hb integral values and lower activation in the frontal lobe in comparison with the patients of the non-depressed group. Conclusion: The present study highlights that the measurement of oxy-Hb by using fNIRS is a useful methodology for the diagnosis of PSD in patients after stroke.

Intentional Supernumerary Motor Phantom Limb after Right Cerebral Stroke: A Case Report.

A 47-year-old right-handed man was admitted to our hospital for rehabilitation after right basal ganglion hematoma. On day 57, he noticed a supernumerary motor phantom limb (SPL) involving his right arm, originating at the level of the elbow. The most notable finding of his SPL was the motor characteristic. When the subject had the intention to move the upper paralyzed limb simultaneously with the trainer's facilitating action, he said "there is another arm." The intention to move the paralyzed arm alone or passive movement of the paralyzed arm did not induce the SPL. He showed a severe left sensorimotor impairment and mild hemineglect, but no neglect syndromes of the body (e.g., asomatognosia, somatoparaphrenia, personification and misoplegia, or anosognosia) were observed. Brain MRI demonstrated a hematoma in the right temporal lobe subcortex, subfrontal cortex, putamen, internal capsule, and thalamus. Single-photon emission computed tomography images showed more widespread hypoperfusion in the right hemisphere in comparison to the lesions on MRI. However, the premotor cortex was preserved. Our case is different from Staub's case in that SPL was not induced by the intention to move the paralyzed limb alone; rather, it was induced when the patient intended to move the paralyzed limb with a trainer's simultaneous facilitating action. The SPL may reflect that an abnormal closed-loop function of the thalamocortical system underlies the phantom phenomenon. However, despite the severe motor and sensory impairment, the afferent pathway from the periphery to the premotor cortex may have been partially preserved, and this may have been related to the induction of SPL.

Pure Amorphagnosia without Tactile Object Agnosia.

A 54-year-old female showed amorphagnosia without ahylognosia and tactile agnosia 40 days after the onset of right cerebral infarction. Her basic somatosensory functions were normal. The appreciation of substance qualities (hylognosia) was preserved, but the patient's inability to recognize the size and shape (morphagnosia) was confined to 2- and 3-dimensional shapes (amorphagnosia) in the left hand. However, the patient's ability to recognize real daily objects was well preserved. Brain MRI after admission showed ischemic lesions confined to the right pre- and postcentral gyri and the medial frontal cortex on DWI and FLAIR images. An analysis of SPECT images revealed that the most decreased areas were localized to the pre- and postcentral gyri, superior and inferior parietal lobules, supramarginal gyrus, and angular gyrus. Considering the previous reported cases, the responsible lesion for the impaired perception of hylognosia and morphagnosia may not necessarily be confined to the right hemisphere. To date, 5 reports (6 cases) of tactile agnosia have been published; 4 cases presented with both ahylognosia and amorphagnosia, while 1 presented with only amorphagnosia, and another showed amorphagnosia and mild ahylognosia. Our case is the first to present with only amorphagnosia without tactile agnosia. The mechanism for the well-preserved recognition of real objects may depend on the preserved hylognosia. Of note, there have been no reports showing only ahylognosia without amorphagnosia. Further studies are necessary to clarify whether or not patients with preserved hylognosia or morphagnosia retain the ability to perceive real objects.

[A case of an anti-SRP myopathy with enlargement of the thymus].

A 54-year-old female was admitted to our hospital because of the Raynaud phenomenon and muscle weakness of the upper limbs. The neurological findings showed somatic and proximal limb weakness. Laboratory studies showed a high serum creatine kinase level. Computerized tomography (CT) revealed enlargement of the thymus. A muscle biopsy showed a small number of degenerating and regenerating fibers but no inflammatory infiltrations. At first, she was initially treated with a three-day course of intravenous methylprednisolone (1 g/day). However, the weakness progressed and the serum creatine kinase level remained high. She was subsequently treated with a combination of tacrolimus (3 mg/day) and prednisolone, but showed no any improvement of the muscle weakness. Following additional treatment with intravenous immunoglobulin, she showed improvement in her muscle weakness. Further, anti-signal recognition particle antibodies were identified after treatment. There have been no previous reports of myopathy with antibodies against the signal recognition particle and enlargement of the thymus, so we herein report the details of this unique case.

Bunina bodies in motor and non-motor neurons revisited: a pathological study of an ALS patient after long-term survival on a respirator.

Bunina bodies (BBs) are small eosinophilic neuronal cytoplasmic inclusions (NCIs) found in the remaining lower motor neurons (LMNs) of patients with sporadic amyotrophic lateral sclerosis (SALS), being a specific feature of the cellular pathology. We examined a case of SALS, unassociated with TDP-43 or C9ORF72 mutation, of 12 years duration in a 75-year-old man, who had received artificial respiratory support for 9 years, and showed widespread multisystem degeneration with TDP-43 pathology. Interestingly, in this patient, many NCIs reminiscent of BBs were observed in the oculomotor nucleus, medullary reticular formation and cerebellar dentate nucleus. As BBs in the cerebellar dentate nucleus have not been previously described, we performed ultrastructural and immunohistochemical studies of these NCIs to gain further insight into the nature of BBs. In each region, the ultrastructural features of these NCIs were shown to be identical to those of BBs previously described in LMNs. These three regions and the relatively well preserved sacral anterior horns (S1 and S2) and facial motor nucleus were immunostained with antibodies against cystatin C (CC) and TDP-43. Importantly, it was revealed that BBs exhibiting immunoreactivity for CC were a feature of LMNs, but not of non-motor neurons, and that in the cerebellar dentate nucleus, the ratio of neurons with BBs and TDP-43 inclusions/neurons with BBs was significantly lower than in other regions. These findings suggest that the occurrence of BBs with CC immunoreactivity is intrinsically associated with the particular cellular properties of LMNs, and that the mechanism responsible for the formation of BBs is distinct from that for TDP-43 inclusions.

Pathology and sensitivity of current clinical criteria in corticobasal syndrome.

The aim of this study was to investigate corticobasal syndrome with respect to underlying pathologies, the ability of current clinical criteria to detect early stages of disease, and symptoms and signs predicting background pathologies. We retrospectively analyzed the clinicopathological findings from patients with corticobasal syndrome. We also analyzed whether those findings fulfilled the diagnostic criteria for corticobasal degeneration (CBD). Finally, we investigated characteristic clinical features that are specific to each background pathology. Of 10 consecutive autopsied patients who had corticobasal syndrome (mean age ± standard deviation, 67.9 ± 9.3 years; male:female ratio, 6:4), three had corticobasal degeneration pathology, three had progressive supranuclear palsy, three had Alzheimer's disease, and one had atypical four-repeat tauopathy. Nine patients fulfilled Mayo criteria, and all 10 patients fulfilled modified Cambridge criteria at the later stage, but only two patients fulfilled either clinical criteria within 2 years of disease onset. Five patients fulfilled the clinical criteria for possible CBD (p-CBD), and one patient fulfilled the clinical research criteria for probable sporadic CBD (cr-CBD) at the later stage. Only two patients fulfilled the criteria for either p-CBD or cr-CBD within 2 years of disease onset. Although we could not find any predictive characteristic clinical features that were specific to CBD pathology, only patients with progressive supranuclear palsy developed apraxia of eyelid opening and cerebellar ataxia. Myoclonus and memory impairment, especially if they appear at an early stage of the disease, may predict Alzheimer's disease pathology. Sensitivity of the available clinical criteria for corticobasal syndrome was poor within 2 years of disease onset.

Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis.

OBJECTIVE: We developed an assay that detects autoantibodies against the main immunogenic region (MIR) located at the extracellular end of the nicotinic acetylcholine receptor (AChR) α subunit, and investigated its clinical relevance in myasthenia gravis (MG). METHODS: In this retrospective cohort study, we measured MIR antibody (Ab) titres in sera obtained before treatment and analysed their associations with clinical parameters in 102 MG patients from two neurological centres. MIR Ab titres were determined using a modified competition immunoprecipitation assay in the presence or absence of monoclonal antibody 35. RESULTS: 11 of 23 (47.8%) ocular type and 66 of 72 (91.7%) generalised type MG patients were positive for the presence of MIR Abs, defined as a titre >16.8% (3 SDs above the mean for 70 healthy controls). A significantly higher MIR Ab titre (p<0.001) was shown in generalised type (47.9±19.2%) rather than in ocular type MG patients (16.4±8.4%). Bivariate regression analysis using both titre levels of MIR Ab and routine AChR binding Ab as variables revealed MIR Abs to be an exclusive indicator positively associated with disease severity (Myasthenia Gravis Foundation of America classification, p<0.0001; Quantitative MG score, p=0.008), the presence of bulbar symptoms (p<0.0001) and thymoma (p=0.016), and negatively associated with ocular MG (p<0.0001). CONCLUSIONS: MIR Ab titre levels show much better correlations with factors related to disease severity compared with AChR binding Ab titres. The MIR Ab assay may be useful for predicting MG symptom severity, especially for discriminating between ocular and generalised types of MG.

[Histochemical findings of and fine structural changes in motor endplates in diseases with neuromuscular transmission abnormalities].

We herein review the histochemical findings and fine structural changes of motor endplates associated with diseases causing neuromuscular transmission abnormalities. In anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG), type 2 fiber atrophy is observed, and the motor endplates show a reduction in the nerve terminal area, simplification of the postsynaptic membrane, decreased number of acetylcholine receptors, and deposition of immune complexes. In anti-MuSK antibody-positive MG, the fine structure shows a decrease in the postsynaptic membrane length, but the secondary synaptic cleft is preserved. There is no decrease in the number of AChRs, and there are no deposits of immune complexes at the motor endplates. Patients with Lambert-Eaton myasthenic syndrome show type 2 fiber atrophy, their motor endplates show a decrease in both the mean postsynaptic area and postsynaptic membrane length in the brachial biceps muscle. Congenital myasthenic syndrome with episodic apnea is characterized only by small-sized synaptic vesicles; the postsynaptic area is preserved. In subjects with congenital myasthenic syndrome with acetylcholinesterase deficiency, quantitative electron microscopy reveals a significant decrease in the nerve terminal size and presynaptic membrane length; further, the Schwann cell processes extend into the primary synaptic cleft, and partially or completely occlude the presynaptic membrane. The postsynaptic folds are degenerated, and associated with pinocytotic vesicles and labyrinthine membranous networks. Patients with slow-channel congenital myasthenia syndrome show type 1 fiber predominance, and their junctional folds are typically degenerated with widened synaptic space and loss of AChRs. Patients with AChR deficiency syndrome caused by recessive mutations in AChR subunits also show type 1 fiber predominance, and while most junctional folds are normal, some are simplified and have smaller than normal endplates. Rapsin and MuSK mutations cause type 1 fiber predominance, and the small postsynaptic area is associated with AChR decrease.

[A patient with prosopagnosia which developed after an infarction in the left occipital lobe in addition to an old infarction in the right occipital lobe].

A 66-year-old, right-handed male, was admitted to our hospital with difficulty in recognizing faces and colors. He had suffered a stroke in the right occipital region three years earlier that had induced left homonymous hemianopsia, but not prosopagnosia. A neurological examination revealed prosopagnosia, color agnosia, constructional apraxia, and topographical disorientation, but not either hemineglect or dressing apraxia. The patient was unable to distinguish faces of familiar persons such as his family and friends, as well as those of unfamiliar persons such as doctors and nurses. Brain MRI demonstrated an old infarction in the right medial occipital lobe and a new hemorrhagic infarction in the left medial occipital lobe, including the fusiform and lingual gyrus. It is unclear whether a purely right medial occipital lesion can be responsible for prosopagnosia, or whether bilateral medial occipital lesions are necessary for this occurrence. The current case indicated that bilateral medial occipital lesions play an important role in inducing porsopagnosia.

Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity.

Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.

Age-related white matter hyperintensities attenuated by compression from a chronic subdural hematoma: possible contribution of brain interstitial fluid to the formation of leukoaraiosis.

The origin of patchy white matter hyperintensities commonly seen in the elderly on magnetic resonance (MR) images with long repetition time (TR) is still controversial. We describe MR findings in older patients in whom white matter hyperintensities were attenuated by compression of the cerebral hemisphere from a chronic subdural hematoma. These sequential MR findings substantiate the hypothesis that leukoaraiosis may arise when drainage of the bulk flow of brain interstitial fluid is disturbed.

Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology.

Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (<5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.

[Overview: MuSK/Dok-7].

MuSK/Dok-7 mediate the clustering of acetylcholine receptor (AChR) during synapse formation and are expressed at the mature neuromuscular junction. These proteins are deeply associated with myasthenia gravis (MG) and congenital myasthenic syndrome (CMS). Compared with MG patients with AChR antibodies, those with muscle-specific tyrosine kinase (MuSK) antibodies are more likely to present oculobulbar than limb weakness, myasthenic crisis and muscle wasting. None have thymoma, so the indication for thymectomy should be investigated. MuSK antibodies do not appear to cause complement-mediated morphological motor endplate damage, but how they cause myasthenic symptoms is unclear. As the results, the three types of MG presently characterized by known antibody targets are classified into 1) AChR antibody-positive, 2) MuSK antibody -positive, and 3) double seronegative type which the above-mentioned antibodies are negative. In 2006, MuSK-interacting cytoplasmic protein termed Dok-7 has been found. Subsequently, mutations in Dok-7 as a cause of CMS were identified, providing evidence for a crucial role of Dok-7 in maintaining synaptic structure. Their effect on MuSK/Dok -7 function needs to be explored.

Total tau protein in cerebrospinal fluid and diffusion-weighted MRI as an early diagnostic marker for Creutzfeldt-Jakob disease.

BACKGROUND: We have recently begun to doubt the effectiveness of periodic sharp wave complexes observed on electroencephalographs and the detection of 14-3-3 protein in cerebrospinal fluid (CSF) as diagnostic criteria for Creutzfeldt-Jakob disease (CJD). Diffusion-weighted magnetic resonance imaging (DWI) and the detection of total tau (t-tau) protein in CSF may be more sensitive diagnostic criteria. METHODS: Among 44 CJD patients, we selected 21 subjects that suffered from early-stage CJD, which was defined as cases in the 6 weeks following the onset of the disease. The sensitivities of DWI and electroencephalographs, as well as those of t-tau protein, 14-3-3 protein, neuron-specific enolase (NSE), and S-100b protein in CSF were compared as diagnostic markers for early-stage CJD. RESULTS: NSE, S-100b protein, t-tau protein, and 14-3-3 protein were detected in the samples from 57.1, 4.8, 95.2, and 76.2% of the 21 early-stage CJD patients, respectively. Additionally, DWI was used to positively identify 90.5% of these cases. CONCLUSION: We concluded that t-tau protein was the most sensitive of the diagnostic markers for CJD. Moreover, the data in this study showed that detection of t-tau protein combined with DWI identified 98% of the early-stage cases, and these tests should be included as diagnostic criteria for CJD.

Chronological changes in MRI and CSF biochemical markers in Creutzfeldt-Jakob disease patients.

BACKGROUND: There are currently no markers for evaluating chronological changes in Creutzfeldt-Jakob disease (CJD). We examined if chronological changes in biochemical markers in cerebrospinal fluid (CSF) and diffusion-weighted magnetic resonance imaging (DWI) were utilizable for this purpose. METHODS: Ten independent patients were divided into two groups of 5 patients each. We analyzed CSF biochemical markers, DWI and the clinical course in one group. In the remaining group, only the CSF biochemical markers were analyzed before and after the onset of akinetic mutism. RESULTS: The level of total tau (t-tau) protein in CSF in the early phase after disease onset was 2,655 +/- 423.9 pg/ml, reaching a mean peak of 14,675 +/- 1,240 pg/ml in the middle phase and gradually declining after that. Just before patients deteriorated into akinetic mutism, t-tau protein titers reached a maximum (8,786 +/- 2,975 pg/ml). There were dramatic changes in t-tau protein levels throughout the clinical course, unlike the other markers. DWI was not always utilizable, because of discordance with clinical symptoms seen in this study. Four cases exhibited peaks in t-tau protein levels while the patients fell into akinetic mutism except 1 case. CONCLUSION: Our results suggest that t-tau protein is the most sensitive marker of disease progression in CJD patients.

[Hyperintense optic nerve lesion on T2-weighted MRI imaging in the acute stage of Leber's hereditary optic neuropathy: a case report].

A 46-year-old man was admitted to our hospital for acute onset, bilateral visual disturbance. Neither papilledema nor optic atrophy was found. Brain MRI revealed a hyperintense lesion in the optic chiasm on T2-weighted imaging. No enhancement was detected in gadolinium-enhanced MRIs. Based on these results, a diagnosis of retrobulbar neuritis was made, and steroid pulse therapy was performed. However, the visual acuity did not improve at all. We therefore suspected Leber's hereditary optic neuropathy (LHON) and thus performed a PCR analysis of the mitochondrial DNA. It revealed a G to A transition at nucleotide position 11778 of the mitochondrial DNA, which has been frequently observed in LHON patients in Japan. Based on the above findings, when middle-aged patients present an acute onset of visual loss, LHON should be included in the differential diagnosis.

14-3-3 protein, total tau and phosphorylated tau in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease and neurodegenerative disease in Japan.

1. Sporadic Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and fatal disease. Patients with CJD usually become akinetic mutism within approximately 6 months. In addition, clinical signs and symptoms at early stage of sporadic CJD may not be easy to distinguish from other neurodegenerative diseases by neurological findings. However, diagnostic biochemical parameters including 14-3-3 protein, S100, neuron-specific enorase in cerebrospinal fluid (CSF) have been used as diagnostic markers, elevated titers of these markers can also be observed in CSF in other neurodegenerative diseases. Therefore, we examined other biochemical markers to discriminate CJD from other neurodegenerative diseases in CSF. 2. We analyzed CSF samples derived from 100 patients with various neurodegenerative disorders by Western blot of 14-3-3 protein, quantification of total tau (t-tau) protein, and phosphorylated tau (p-tau) protein. All patients with CJD in this study showed positive 14-3-3 protein and elevated t-tau protein (>1000 pg/mL) in CSF. We also detected positive 14-3-3 protein bands in two patients in non-CJD group (patients with dementia of Alzheimer's type; DAT) and also detected elevated t-tau protein in three patients in non-CJD group. Elevated t-tau protein levels were observed in two patients with DAT and in one patient with cerevrovascular disease in acute phase. 3. To distinguish patients with CJD from non-CJD patients with elevated t-tau protein in CSF, we compared the ratio of p-tau and t-tau proteins. The p-/t-tau ratio was dramatically and significantly higher in DAT patients rather than in CJD patients. 4.Therefore, we concluded that the assay of t-tau protein may be useful as 1st screening and the ratio of p-tau protein/t-tau protein would be useful as 2nd screening to discriminate CJD from other neurodegenerative diseases.

Sporadic four-repeat tauopathy with frontotemporal degeneration, parkinsonism and motor neuron disease.

We report a sporadic tauopathy of 6-year duration in a 76-year-old woman. Her initial symptoms were asymmetrical parkinsonism and muscle weakness, with apraxia appearing 2 years later. The brain showed frontal and temporal cerebral atrophy; severe neuronal loss and gliosis were observed in the precentral cortex (loss of Betz cells was also evident) and premotor area, and in the medial temporal lobe, including the temporal tip, amygdala, and hippocampal CA1-subiculum border zone. The substantia nigra showed moderate neuronal loss and gliosis. In the spinal cord, loss of the anterior horn cells and degeneration of the corticospinal tracts were a characteristic feature. In addition, in the affected regions, the remaining neurons were often found to contain intracytoplasmic inclusions resembling neurofibrillary tangles. Tau immunostaining revealed widespread glial-predominant lesions in the cerebral gray and white matter. In contrast, predominance of neuronal lesions (pretangles/tangles) was a feature in the subcortical gray matter, including the spinal cord. The remaining upper and lower motor neurons were also affected by tau pathology. Accumulated tau in these glial cells and neurons was clearly recognized by a specific antibody against four-repeat (4R) tau. The ultrastructural presence of tau-positive tubular structures was confirmed in the glial cells and neurons (tangles). Immunoblotting of a frozen frontal lobe sample revealed accumulation of 4R-predominant tau isoforms. No mutations were found in the tau gene. These findings indicate that a sporadic 4R tauopathy can cause frontotemporal degeneration, parkinsonism, and motor neuron disease. The present case could represent a new clinicopathological phenotype of non-familial tauopathy.