Yumiko Motoi

Neuronal localization of a novel mosaic apolipoprotein E receptor, LR11, in rat and human brain

A new type of mosaic protein was recently discovered as a new member of the low density lipoprotein receptor (LDLR) family, designated as LR11. The predominant expression of LR11 transcripts in brain tissue and the presence of elements found in neural adhesion molecules suggested a function(s) in the central nervous system (CNS). In order to gain insight about this complex receptor in the CNS, we raised a rabbit polyclonal antibody and examined immunohistochemically rat and human brain tissue. A strong LR11 immunoreactivity was found to be localized mainly in neurons throughout the brain in both species. A detailed mapping in the rat brain showed a distribution of LR11 immunoreactivity in a widespread population of neurons, though the intensity varied between different locations. The most prominent immunoreactivity was observed in neurons of the hippocampus, some nuclei of brain stem and Purkinje cells, whereas neurons of the thalamus and the hypothalamus showed weak staining. Uniquely, the single LR11 immunoreactive cytoplasmic puncta were observed in the proximity of apical dendrites, most conspicuously in the pyramidal neurons of hippocampus. In the human brain, one to four immunoreactive puncta were seen within individual neurons. The neuronal localization of LR11 and its unique association of cytoplasmic structure, presumably botrysome, may suggest the roles of LR11 in both the lipoprotein metabolism and intracellular trafficking in certain neuronal population of the CNS.

A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology

We report a novel mutation of tau (L266V missense mutation in exon 9) which may cause a type of familial frontotemporal dementia. The brain of a patient showed Pick body–like inclusions and unique tau‐positive, argyrophilic astrocytes with stout filaments and naked, round, or irregular argyrophilic inclusions with deposits of both three‐repeat and four‐repeat tau. Recombinant tau with a L266V mutation showed a reduced ability to promote microtubule assembly, which may be the primary effect of the mutation. Ann Neurol 2003;53:000–000

White Matter Alteration of the Cingulum in Parkinson Disease with and without Dementia: Evaluation by Diffusion Tensor Tract–Specific Analysis

BACKGROUND AND PURPOSE: In PD, the neurodegenerative process begins in the brain stem and extends to the limbic system and finally into the cerebral cortex. We used diffusion tensor tractography to investigate the FA of the cingulate fiber tracts in patients with PD with and without dementia. MATERIALS AND METHODS: Fifteen patients with PD, 15 patients with PDD, and 15 age-matched healthy controls underwent diffusion tensor imaging with a 3T MR imager. Diffusion tensor tractography images of the anterior and posterior cingulate fiber tracts were generated. Mean diffusivity and FA were measured along the tractography of the anterior and posterior cingulate fiber tracts. One-way ANOVA with the Scheffé post hoc test was used to compare results among the groups. RESULTS: FA was significantly lower in patients with PDD than in healthy controls in both the anterior and the posterior cingulate fiber tracts (P = .003, P = .015) and significantly lower in patients with PD than in healthy controls (P = .003) in the anterior cingulate fiber tract. There were no significant mean diffusivity differences among the groups. MMSE and FA values of the anterior cingulate fiber tracts in patients with PDD were significantly correlated (r = 0.633, P < .05). CONCLUSIONS: The reduced FA in patients with PD and PDD might reflect neuropathologic changes such as Lewy body pathology in the cingulate fibers. This abnormality might contribute to the dementing process in PD.

Diffusional kurtosis imaging of cingulate fibers in Parkinson disease: Comparison with conventional diffusion tensor imaging

OBJECTIVE The pathological changes in Parkinson disease begin in the brainstem; reach the limbic system and ultimately spread to the cerebral cortex. In Parkinson disease (PD) patients, we evaluated the alteration of cingulate fibers, which comprise part of the limbic system, by using diffusional kurtosis imaging (DKI). METHODS Seventeen patients with PD and 15 age-matched healthy controls underwent DKI with a 3-T MR imager. Diffusion tensor tractography images of the anterior and posterior cingulum were generated. The mean kurtosis (MK) and conventional diffusion tensor parameters measured along the images in the anterior and posterior cingulum were compared between the groups. Receiver operating characteristic (ROC) analysis was also performed to compare the diagnostic abilities of the MK and conventional diffusion tensor parameters. RESULTS The MK and fractional anisotropy (FA) in the anterior cingulum were significantly lower in PD patients than in healthy controls. The area under the ROC curve was 0.912 for MK and 0.747 for FA in the anterior cingulum. MK in the anterior cingulum had the best diagnostic performance (mean cutoff, 0.967; sensitivity, 0.87; specificity, 0.94). CONCLUSIONS DKI can detect alterations of the anterior cingulum in PD patients more sensitively than can conventional diffusion tensor imaging. Use of DKI can be expected to improve the ability to diagnose PD.

A preliminary diffusional kurtosis imaging study of Parkinson disease: comparison with conventional diffusion tensor imaging

IntroductionDiffusional kurtosis imaging (DKI) is a more sensitive technique than conventional diffusion tensor imaging (DTI) for assessing tissue microstructure. In particular, it quantifies the microstructural integrity of white matter, even in the presence of crossing fibers. The aim of this preliminary study was to compare how DKI and DTI show white matter alterations in Parkinson disease (PD).MethodsDKI scans were obtained with a 3-T magnetic resonance imager from 12 patients with PD and 10 healthy controls matched by age and sex. Tract-based spatial statistics were used to compare the mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) maps of the PD patient group and the control group. In addition, a region-of-interest analysis was performed for the area of the posterior corona radiata and superior longitudinal fasciculus (SLF) fiber crossing.ResultsFA values in the frontal white matter were significantly lower in PD patients than in healthy controls. Reductions in MK occurred more extensively throughout the brain: in addition to frontal white matter, MK was lower in the parietal, occipital, and right temporal white matter. The MK value of the area of the posterior corona radiata and SLF fiber crossing was also lower in the PD group.ConclusionDKI detects changes in the cerebral white matter of PD patients more sensitively than conventional DTI. In addition, DKI is useful for evaluating crossing fibers. By providing a sensitive index of brain pathology in PD, DKI may enable improved monitoring of disease progression.

Long-term oral lithium treatment attenuates motor disturbance in tauopathy model mice: implications of autophagy promotion.

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms including inhibition of glycogen synthase kinase-3 (GSK-3), a major tau kinase. Recently, it has been shown that, in various neurodegenerative proteinopathies, lithium could induce autophagy. To analyze how lithium is therapeutically beneficial in tauopathies, transgenic mice overexpressing human mutant tau (P301L) were treated with oral lithium chloride (LiCl) for 4 months starting at the age of 5 months. At first, we examined the effects of treatment on behavior (using a battery of behavioral tests), tau phosphorylation (by biochemical assays), and number of neurofibrillary tangles (NFTs) (by immunohistopathology). In comparison with control mice, LiCl-treated mice showed a significantly better score in the sensory motor tasks, as well as decreases in tau phosphorylation, soluble tau level, and number of NFTs. Next, we examined lithium effects on autophagy using an antibody against microtubule-associated protein 1 light chain 3 (LC3) as an autophagosome marker. The number of LC3-positive autophagosome-like puncta was increased in neurons of LiCl-treated mice. Neurons containing NFTs were completely LC3-negative, whereas LC3-positive autophagosome-like puncta contained phosphorylated-tau (p-tau). The protein level of p62 was decreased in LiCl-treated mice. These data suggested that oral long-term lithium treatment could attenuate p-tau-induced motor disturbance not only by inhibiting GSK-3 but also by enhancing autophagy in tauopathy model mice.

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.

Lithium and Autophagy

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms, including autophagy regulation, in various neuropsychiatric conditions. In neurodegenerative diseases, lithium enhances degradation of aggregate-prone proteins, including mutated huntingtin, phosphorylated tau, and α-synuclein, and causes damaged mitochondria to degrade, while in a mouse model of cerebral ischemia and Alzheimers disease autophagy downregulation by lithium is observed. The signaling pathway of lithium as an autophagy enhancer might be associated with the mammalian target of rapamycin (mTOR)-independent pathway, which is involved in myo-inositol-1,4,5-trisphosphate (IP3) in Huntingtons disease and Parkinsons disease. However, the mTOR-dependent pathway might be involved in inhibiting glycogen synthase kinase-3β (GSK3β) in other diseases. Lithiums autophagy-enhancing property may contribute to the therapeutic benefit of patients with neuropsychiatric disorders.

Glial expression of fibroblast growth factor‐9 in rat central nervous system

We examined the expression of fibroblast growth factor (FGF)‐9 in the rat central nervous system (CNS) by immunohistochemistry and in situ hybridization studies. FGF‐9 immunoreactivity was conspicuous in motor neurons of the spinal cord, Purkinje cells, and neurons in the hippocampus and cerebral cortex. In addition to the neuronal localization of FGF‐9 immunoreactivity that we reported previously, the present double‐label immunohistochemistry clearly demonstrated that the immunoreactivity was present in glial fibrillary acidic protein (GFAP)‐positive astrocytes preferentially present in the white matter of spinal cord and brainstem of adult rats and in CNPase‐positive oligodendrocytes that were arranged between the fasciculi of nerve fibers in cerebellar white matter and corpus callosum of both adult and young rats. There was a tendency for FGF‐9 immunoreactivity in oligodendrocytes to be more pronounced in young rats than in adult rats. The variation of oligodendrocyte FGF‐9 immunoreactivity in adult rats was also more pronounced than that in young rats. With in situ hybridization, FGF‐9 mRNA was observed in astrocytes in the white matter of rat spinal cord and oligodendrocytes in the white matter of cerebellum and corpus callosum of adult and young rats. The expression of FGF‐9 mRNA in glial cells was lower than in neurons, and not all glial cells expressed FGF‐9. In the present study, we demonstrated that FGF‐9 was expressed not only in neurons but also in glial cells in the CNS. FGF‐9 was considered to have important functions in adult and developing CNS. GLIA 28:53–65, 1999.

Soluble amyloid precursor protein α in the cerebrospinal fluid as a diagnostic and prognostic biomarker for idiopathic normal pressure hydrocephalus

Cognitive impairment is difficult to improve after shunt operation in patients with idiopathic normal pressure hydrocephalus (iNPH). This study aims to identify cerebrospinal fluid (CSF) biomarkers predictive of improvement in cognitive function.