[A case of caseous calcification of mitral annulus resulting in multiple cerebral infarctions].

The patient is a 73-year-old woman. She presented with dysarthria, and a head MRI revealed multiple acute cerebral infarctions in the bilateral cerebral hemisphere and cerebellar hemisphere. Transesophageal echocardiography after admission revealed a 16 mm large mobile calcification of the mitral annulus (caseous calcification of the mitral annulus; CCMA) on the posterior apex of the mitral valve annulus. Since the CCMA had a high risk of relapse, and a new infarction was detected on the 8th day, resection of the mass and mitral valve replacement surgery were performed. CCMA is a subtype of mitral annular calcification (MAC). When calcification progresses from the MAC state to form a mass, it is called a calcified amorphous tumor; CAT. Reports of embolic cerebral infarction caused by CAT are rare, but this is a rare report of an embolic cerebral infarction from CCMA presenting as CAT.

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

Neuron-specific analysis of histone modifications with post-mortem brains.

Histone modifications govern chromatin structures and regulate gene expression to orchestrate cellular functions in the central nervous system, where neuronal cells are postmitotic and developmentally inactive, the functional and age-dependent changes also accumulate in the epigenetic states. Because the brain is composed of several types of cells, such as the neurons, glial cells, and vascular cells, the analysis of histone modifications using bulk brain tissue might obscure alterations specific to neuronal cells. Furthermore, among the various epigenetic traits, analysis of the genome-wide distribution of DNA methylation in the bulk brain is predominantly a reflection of DNA methylation of the non-neuronal cells, which may be a potential caveat of previous studies on neurodegenerative diseases using bulk brains. In this study, we established a method of neuron-specific ChIP-seq assay, which allows for the analysis of genome-wide distribution of histone modifications specifically in the neuronal cells derived from post-mortem brains. We successfully enriched neuronal information with high reproducibility and high signal-to-noise ratio. Our method will further facilitate the understanding of neurodegeneration.

Chronic cerebral hypoperfusion shifts the equilibrium of amyloid ß oligomers to aggregation-prone species with higher molecular weight.

Epidemiological studies have shown that atherosclerotic risk factors accelerate the pathological process underlying Alzheimer's disease (AD) via chronic cerebral hypoperfusion. In this study, we aimed to clarify the mechanisms by which cerebral hypoperfusion may exacerbate AD pathology. We applied bilateral common carotid artery stenosis (BCAS) to a mice model of AD and evaluated how the equilibrium of amyloid ß oligomers respond to hypoperfusion. BCAS accelerated amyloid ß (Aß) convergence to the aggregation seed, facilitating the growth of Aß plaques, but without changing the total Aß amount in the brain. Furthermore, Aß oligomers with high molecular weight increased in the brain of BCAS-operated mice. Considering Aß is in an equilibrium among monomeric, oligomeric, and aggregation forms, our data suggest that cerebral hypoperfusion after BCAS shifted this equilibrium to a state where a greater number of Aß molecules participate in Aß assemblies to form aggregation-prone Aß oligomers with high molecular weight. The reduced blood flow in the cerebral arteries due to BCAS attenuated the dynamics of the interstitial fluid leading to congestion, which may have facilitated Aß aggregation. We suggest that cerebral hypoperfusion may accelerate AD by enhancing the tendency of Aß to become aggregation-prone.

Methylation changes and aberrant expression of FGFR3 in Lewy body disease neurons.

Lewy body disease (LBD) is characterized by accumulation of aggregated α-synuclein in the central nervous system as eosinophilic cytoplasmic inclusions called Lewy bodies. According to their distribution pattern, it is classified into brainstem LBD, limbic LBD and diffuse neocortical LBD. It has been reported that α-synuclein affects various points in the MAPK cascade but its relationship with FGF receptors, which are the most upstream of the pathway, has not been previously investigated. We discovered that among the four FGFRs, FGFR3 showed neuronal upregulation in LBD brains histopathologically. Further examination using neuron-specific methylome analysis revealed that the gene body of FGFR3 was hypermethylated in LBD, suggesting its increased transcription. Altered methylation was not observed in the non-neuronal genome. Altered methylation status was associated with the severity of α-synuclein pathology.

Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid ß (Aß) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aß. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aß burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

Tacrolimus-Induced Reversible Cerebral Vasoconstriction Syndrome with Delayed Multi-Segmental Vasoconstriction.

Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular syndrome characterized by multi-segmental constrictions of the cerebral arteries that resolves spontaneously within 3 months. Although RCVS is considered to be due to transient dysregulation of vascular tone, the exact pathomechanism remains unclear. We describe the case of a 15-year-old girl with RCVS induced by tacrolimus, who developed generalized seizure during the postoperative course of orthotropic heart transplantation. Magnetic resonance imaging at symptom onset showed a few vasoconstrictions accompanying brain edema and convexity subarachnoid hemorrhage. Although her neurological conditions rapidly improved after discontinuing tacrolimus, a repeat magnetic resonance angiogram demonstrated delayed progression of the multi-segmental vasoconstrictions followed by subsequent resolution. Our case demonstrates that cautious observation of the cerebral arteries using magnetic resonance angiography and careful management of vasoconstrictions with vasodilators are necessary for delayed vasoconstrictions even when the clinical symptoms improve.

Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum.

OBJECTIVE: To delineate molecular and clinical characteristics of 3 families with PRNP P105L mutation, a variant of Gerstmann-Sträussler-Scheinker syndrome whose main motor symptoms were parkinsonism and/or involuntary movements. METHODS: The causative mutation was first determined in the affected patients of family 1 using whole-exome sequencing, and then mutational analysis was extended to families 2 and 3. The clinical features of the patients of these 3 families were summarized. Haplotype analysis was performed using high-density single nucleotide polymorphism array. RESULTS: The whole-exome sequencing revealed that the heterozygous mutation c.314C>T (p.P105L) in PRNP was the only known pathogenic mutation shared by the 3 patients of the family with autosomal dominant parkinsonism. We further identified the same mutation in patients of the other 2 families with autosomal dominant parkinsonism and/or involuntary movements. The clinical features of our patients with PRNP P105L mutation included various motor symptoms such as parkinsonism and involuntary movements in addition to progressive dementia. The clinical features in part overlapped with those of other forms of inherited prion diseases, such as fatal familial insomnia and Huntington disease-like type 1. The patients with PRNP P105L mutation shared a haplotype spanning 7.1 Mb around PRNP, raising the possibility that the mutations in the patients originated from a common founder. CONCLUSION: Most of the patients presented with parkinsonism in addition to progressive dementia. Although spastic paraparesis has been emphasized as the main clinical feature, the clinical spectrum of patients with PRNP P105L is broader than expected.