Severe cerebrovascular pathology of the first supercentenarian to be autopsied in the world.

We report on a 116-year-old Japanese woman who was the first officially documented supercentenarian to be autopsied in the world. She lived a remarkably healthy life until suffering cerebral infarction at 109 years of age. She became Japan's oldest person at 113 years and died in 1995 from colon cancer at 116 years 175 days. Her medical records show the delayed onset of stroke, cancer, dementia, and heart disease and the importance of appropriate medical treatment and intensive dedicated care provided during the last stage of her life. She was the longest-lived person in Japan for 21 years from 1993 until 2014. The neuropathological findings of her autopsied brain were briefly reported in the Japanese literature in 1997. In this study, we reinvestigated her brain and spinal cord in more detail. Severe cerebrovascular lesions and cervical spondylotic myelopathy were found to be the main causes of her disability. Although the density of senile plaques was relatively high, the distribution of neurofibrillary tangles was limited. Ghost tangles and argyrophilic grains were mild. The mildness of tau pathological changes in her neurons, in other words the resistance of neurons to tau pathology, may be a factor responsible for her longevity.

Sloping Shoulders Sign: A Practical Radiological Sign for the Differentiation of Alzheimer's Disease and Argyrophilic Grain Disease.

BACKGROUND: Although hippocampal atrophy is a well-known imaging biomarker of Alzheimer's disease (AD), this finding is not useful to differentiate AD from argyrophilic grain disease (AGD) which is a common AD mimicker presenting with similar amnestic symptoms and medial temporal atrophy. Instead, we propose use of the "sloping shoulders sign", defined as a distinct configuration of the bilateral hippocampal heads showing lateral and downward slopes on axial magnetic resonance imaging (MRI). OBJECTIVE: We investigated the diagnostic utility of the "sloping shoulders sign" as a simple radiological discriminator of AD from AGD. METHODS: Using axial and coronal three-dimensional MRI, our newly proposed "sloping shoulders sign", other quantitative indices including the axial hippocampal head angle (AHHA), and well-known medial temporal atrophy (MTA) score were evaluated in pathologically-proven 24 AD and 11 AGD patients. RESULTS: Detection rate of the "sloping shoulders sign" was significantly higher in all AD groups (83%; 20/24) and AD with Braak neurofibrillary tangle V/VI stage subgroup (88%; 15/17) than in AGD patients (18% - 2/11; p < 0.001 and p < 0.001, respectively). In contrast to the MTA score, this sign as well as AHHA demonstrated higher diagnostic performance and reproducibility, especially to differentiate all AD patients from AGD ones (accuracies of 71.4% , 82.9% and 82.9%; Cohen's kappa of 0.70 and 0.81, and intraclass correlation coefficient of 0.96, respectively). CONCLUSION: The "sloping shoulders sign" is useful to differentiate advanced-stage AD from AGD. Its simplicity and reproducibility based on visual inspection using axial MRI make it suitable for routine clinical practice.

Selective extension of cerebral vascular calcification in an autopsy case of Fahr's syndrome associated with asymptomatic hypoparathyroidism.

We report an autopsy case of Fahr's syndrome in an 85-year-old woman associated with asymptomatic hypoparathyroidism. The patient was diagnosed as having brain calcification at 65 years of age. She developed mild dementia at 75, parkinsonism at 76, and severe dementia at 82. Computed tomography revealed extensive, symmetric intracranial calcification, involving both sides of the basal ganglia and cerebellar dentate nuclei, and severe cerebral atrophy that developed afterwards. A neuropathological examination revealed intracranial calcification, particularly in the wall of the arterioles and capillaries having numerous calcium deposits. Severe vascular calcification and severe neuronal loss without α-synuclein accumulation were found in the substantia nigra. There were high-level neuropathological changes indicative of Alzheimer's disease. Although the colocalization of calcium and amyloid-ß deposits in the same arterial wall was rare, both of them were located in a similar layer of the arterial wall. The vascular calcification in the basal ganglia spread continuously through the corona radiata into the selective cerebral areas along the medullary arteries, but did not involve the corpus callosum or insular region. Stone formation was observed at the corona radiata adjacent to the superolateral angles of the lateral ventricles. We hypothesized that there would be a stereotypical extension pattern of vascular calcification related to the arrangement of penetrating arteries in Fahr's syndrome.

Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism.

We herein report an autopsy case of a 69-year-old man with pseudopseudohypoparathyroidism. The patient suffered from mental retardation and spastic tetraparesis and had all the features of Albright's hereditary osteodystrophy with a normal response to parathyroid hormone in the Ellsworth-Howard test. Computed tomography demonstrated symmetrical massive brain calcification involving the bilateral basal ganglia, thalami, dentate nuclei and cerebral gray/white matter junctions, which was consistent with Fahr's syndrome. Magnetic resonance imaging revealed extensive white matter changes sparing the corpus callosum. Severe ossification of the posterior longitudinal ligament of the cervical spine was also demonstrated. A neuropathological examination revealed massive intracranial calcification within the walls of the blood vessels and capillaries with numerous calcium deposits. The calcium deposits aligned along the capillaries, and deposits in the vessel wall at the initial stage were confined to the border between the tunica media and adventitia. The vascular calcification in the basal ganglia continuously spread over the surrounding white matter into the cortex. The area of vascular calcification in the white matter was very well correlated with the area of the attenuated myelin staining. Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. We should recognize the continuous area of vascular calcification and its correlation with extensive white matter changes as possible causes of neuropsychiatric symptoms in pseudopseudohypoparathyroidism with Fahr's syndrome.

An autopsy case of hemiconvulsion-hemiplegia-epilepsy syndrome manifesting as cerebral hemiatrophy in an elderly man.

We report an autopsy case of hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome in a 79-year-old man. HHE syndrome usually occurs in children younger than 4 years of age. Although most HHE syndrome patients live into adult life, only a few cases of the syndrome have been reported in the elderly. In our case, cerebral hemiatrophy, left mesial temporal sclerosis and crossed cerebellar atrophy were observed. Because this is the oldest case ever reported, we further investigated age-related neuropathological changes and found an interhemispheric difference in amyloid-ß-related neuropathologic changes. There were almost no senile plaques or amyloid-laden vessels in the left hemisphere. As far as we know, this is the first report of age-related neuropathology in a brain manifesting HHE syndrome.

ß-III Tubulin fragments inhibit α-synuclein accumulation in models of multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease caused by α-synuclein aggregation in oligodendrocytes and neurons. Using a transgenic mouse model overexpressing human α-synuclein in oligodendrocytes, we previously demonstrated that oligodendrocytic α-synuclein inclusions induce neuronal α-synuclein accumulation and progressive neuronal degeneration. α-Synuclein binds to ß-III tubulin, leading to the neuronal accumulation of insoluble α-synuclein in an MSA mouse model. The present study demonstrates that α-synuclein co-localizes with ß-III tubulin in the brain tissue from patients with MSA and MSA model transgenic mice as well as neurons cultured from these mice. Accumulation of insoluble α-synuclein in MSA mouse neurons was blocked by the peptide fragment ß-III tubulin (residues 235-282). We have determined the α-synuclein-binding domain of ß-III tubulin and demonstrated that a short fragment containing this domain can suppress α-synuclein accumulation in the primary cultured cells. Administration of a short α-synuclein-binding fragment of ß-III tubulin may be a novel therapeutic strategy for MSA.

Characteristics of alpha-synucleinopathy in centenarians.

To investigate the characteristics of alpha-synucleinopathy in the brains of centenarians, the autopsied brains and spinal cords from 23 cases were studied. Coronal slices were prepared from a section of the cerebral hemisphere, following the guidelines of the Consortium to Establish a Registry for Alzheimer's Disease (AD) (CERAD) and the consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB). Spinal cord specimens were prepared at each segment from the third cervical to the third sacral segment. In all cases, we performed standard stainings of hematoxylin-eosin, Klüver-Barrera, and Gallyas-Braak combined with Luxol fast blue/cresyl violet, and alpha-synuclein (AS), phosphorylated tau (AT8) and beta-amyloid protein immunostainings. One-way ANOVA analysis, Chi-square or Fisher exact test were used for statistical analysis. Overall, AS-positive structures were found in 8 (34.8%) of our 23 centenarians, 6 (35.3%) of 17 demented patients, and four (40%) out of ten AD patients. The frequencies of AS lesions in the brains with senile plaque (SP) stage 0-A, B, and C were 27.7, 33, and 50%, respectively. No statistical differences were found among the frequencies of AS lesions in the subgroups of NFT stages I-II, III-IV, and V-VI (P=0.478). Most cases showed a widespread distribution of AS-positive structures except for one patient, in whose brain only the medulla was involved. The distribution pattern of AS-positive lesions was similar to that in Parkinson's disease or DLB, but the pigmented neurons in substantia nigra were relatively well preserved. Our findings indicate that there is a high frequency of alpha-synucleinopathy in centenarians, SP-positive and AS-positive lesions may involve a synergistic interaction.

Argyrophilic grain disease: frequency and neuropathology in centenarians.

Argyrophilic grain disease (AGD) is a progressive degenerative disease of the human brain, the prevalence of which increases with advancing age. The features of AGD in autopsied brains from 32 centenarians were studied using phosphorylated tau (AT8) immunostaining combined with Gallyas-Braak staining and 4R tau-specific antibody (RD4) immunostaining. Ten of 32 centenarians were diagnosed as AGD, yielding an overall frequency of 31.3%. In the demented group, nine (39.1%) of 23 cases were found with argyrophilic grains (AGs), while in the non-demented group, AGs were found in only one (11.1%) of nine cases, the difference between them being significant (P<0.05). Among the cases with Alzheimer's disease (AD), five (41.7%) of 12 were found with AGs. One (25%) of four cases with senile dementia with tangles (SDT) also suffered from AGD. Dementia caused by "pure" AGD accounted for 13% (3/23) among demented subjects. Our findings indicated that there is a high frequency of AGD in centenarians. In agreement with previous studies, we favor the view that age may be one of the risk factors for AGD.

Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice.

Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.

PDGF upregulates delayed rectifier via Src family kinases and sphingosine kinase in oligodendroglial progenitors.

An increase in the expression of the delayed rectifier current (I(K)) has been shown to correlate with mitogenesis in many cell types. However, pathways involved in the upregulation of I(K) by growth factors in oligodendroglial progenitors (OPs) have not been well-elucidated. In this study, we found that treatment with platelet-derived growth factor (PDGF) and basic fibroblast growth factor but not ciliary neurotrophic factor resulted in increased I(K) density and upregulation of Kv1.5 and Kv1.6 mRNA transcripts. The effect of PDGF on I(K) was blocked by mimosine, a cell cycle inhibitor, and by genistein, a tyrosine kinase inhibitor. Using inhibitors of PDGF-activated pathways, we found that PDGF-induced upregulation of Kv1.5 and I(K) density involves Src family tyrosine kinases, sphingosine kinase, and intracellular Ca(2+) but not ERK1/2 or phosphatidylinositol 3-kinase pathways. Furthermore, agents that were effective inhibitors of PDGF-induced I(K) upregulation also attenuated OP proliferation, supporting the concept that I(K) is an important link between PDGF-activated signaling cascades and cell cycle progression.