Sayaka Funabe

Neuropathologic analysis of Lewy‐related α‐synucleinopathy in olfactory mucosa

We analyzed the incidence and extent of Lewy‐related α‐synucleinopathy (LBAS) in the olfactory mucosa, as well as the central and peripheral nervous systems of consecutive autopsy cases from a general geriatric hospital. The brain and olfactory mucosa were immunohistochemically examined using antibodies raised against phosphorylated α‐synuclein. Thirty‐nine out of 105 patients (37.1%) showed LBAS in the central or peripheral nervous systems. Seven patients presented LBAS (Lewy neurites) in the olfactory lamina propria mucosa. One out of the seven cases also showed a Lewy neurite in a bundle of axons in the cribriform plate, but α‐synuclein deposits were not detected in the olfactory receptor neurons. In particular, high incidence of α‐synuclein immunopositive LBAS in the olfactory mucosa was present in the individuals with clinically as well as neuropathologically confirmed Parkinsons disease and dementia with Lewy bodies (6/8 cases, 75%). However, this pathologic alteration was rare in the cases with incidental or subclinical Lewy body diseases (LBD) (one out of 31 cases, 3.2%). In the olfactory bulb, the LBAS was usually present in the glomeruli and granular cells of most symptomatic and asymptomatic cases with LBD. Our studies further confirmed importance of the olfactory entry zone in propagation of LBAS in the human aging nervous system.

Lewy body pathology in a patient with a homozygous Parkin deletion

We report neuropathologic findings in a patient with homozygous deletions of exons 2 to 4 of parkin.

Neuropathological Asymmetry in Argyrophilic Grain Disease

The presence of argyrophilic grains in the neuropil is associated with a form of dementia. We investigated morphological asymmetry in 653 consecutive autopsy patients from a general geriatric hospital (age [mean ± SD] = 81.1 ± 8.9 years), focusing on those from patients with advanced argyrophilic grain disease. Paraffin sections of the bilateral posterior hippocampi were immunostained with anti-phosphorylated tau and anti-4-repeat tau antibodies and by the Gallyas-Braak method. In a side-to-side comparison, asymmetry was defined when either the extent or the density of argyrophilic grains was different. Of the 653 subjects, 65 (10%) had Stage 3 argyrophilic grain disease, and 59 (90.8%) showed histopathological asymmetry. Antemortem computed tomographic images (n = 24), magnetic resonance imaging scans (n = 8), and combined computed tomographic and magnetic resonance images (n = 15) were available; images from 20 of the 47 subjects showed asymmetry that correlated with the histopathological asymmetry. Cerebral cortical asymmetry consistent with the histopathology was also visible in N-isopropyl-123I-p-iodoamphetamine single photon emission computed tomographic images from 6 patients and 18F-labeled fluorodeoxyglucose positron emission tomographic images from 2 patients. Thus, asymmetric involvement of the medial temporal lobe in patients with advanced argyrophilic grain disease may represent a diagnostic feature and contribute to distinguishing dementia with grains from Alzheimer disease.

Increased number of astrocytes and macrophages/microglial cells in the corpus callosum in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by degeneration of both upper and lower motor neurons. Neuropathologically, degeneration of the corticospinal tracts is evident and may be associated with loss of motor neurons in the motor cortex. The data from a recently developed imaging technology, the diffusion tensor imaging method of MRI have suggested that white matter in the corpus callosum (CC) is lost in patients with ALS. However, the specific neuropathologic changes of the commissural fibers remain unclear. To investigate the pathologic changes of the CC in ALS, we analyzed midsagittal sections of the CC from eight individuals with ALS and eight controls by using conventional staining and immunohistochemistry with antibodies against CD68, GFAP and phosphorylated neurofilament (SMI‐31). The CC was divided into seven areas. The number of CD68‐immunoreactive macrophages/microglia and GFAP‐immunoreactive astrocytes was significantly higher in individuals with ALS than in controls in all areas of the CC except the rostrum. Among the patients with ALS, the number of macrophages/microglia and astrocytes was significantly higher in the posterior midbody and isthmus than in the rostrum. There was no significant difference in number of SMI‐31 immunoreactive axons between ALS and control group as well as among each area of the CC. These findings suggest that pathologic changes in the CC in ALS are present in the posterior midbody and isthmus, where callosal motor fibers may traverse between the two hemispheres. CD68 and GFAP immunohistochemistry are sensitive methods to detect those pathologic changes in routine paraffin‐embedded specimens.

Histopathologic Analysis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): A Report of a New Genetically Confirmed Case and Comparison to 2 Previous Cases.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a nonhypertensive hereditary cerebral small vessel disease that is caused by mutations in a single gene, HTRA1. The HTRA1 protein normally represses transforming growth factor-&bgr; (TGF-&bgr;) signaling and its mutations result in vascular changes. Ten homozygous, 1 compound heterozygous, and 1 homozygous frameshift mutation have been identified in the HTRA1 gene of patients with genetically confirmed CARASIL. However, few studies have compared neuropathologic findings in patients with the same or different mutations in HTRA1. We analyzed histopathologic alterations in 3 autopsied patients with genetically confirmed CARASIL: 2 of them had the HTRA1 p.R302X mutation and 1 had the HTRA1 p.A252T mutation. All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells. One CARASIL patient with the p.R302X mutation had atherosclerosis-like intimal thickening and arteriolosclerosis in the arteries of visceral organs, indicating that atherosclerotic changes are not confined to the intracranial vasculature but can occur throughout the body. CARASIL is a unique hereditary disease that shows similar neuropathology, systemic vascular pathology, and other TGF-&bgr;1-related pathology associated with HTRA1 mutation.

Primary aortic sarcoma: a rare but critical cause of stroke.

A 64-year-old woman with an aortic mass experienced repeated recurrences of stroke (figure 1) and died 8 months later. The postmortem examination showed the tumor to almost completely obstruct the aortic lumen, while extending to the intracranial arteries without parenchymal invasion (figure 2). The pathologic diagnosis was undifferentiated aortic intimal sarcoma. Primary aortic sarcoma is a rare and aggressive tumor, with clinical symptoms including acute arterial embolism and disseminated metastasis.1 Although arch atheroma is sometimes identified as a cause of cerebral emboli,2 this case shows that primary aortic sarcoma should be included in the differential diagnosis of aortic arch diseases.

Parkinsonism in a patient with valosin-containing protein gene mutation showing: a case report

The valosin-containing protein (VCP) gene has been identified as being responsible for hereditary inclusion body myopathy (IBM) with Paget’s disease of the bones and frontotemporal dementia (IBMPFD) [1] as well as familial amyotrophic lateral sclerosis [2]. Pathologically, phosphorylated TDP-43 accumulates in various tissues, such as motor neurons in the anterior horn, cerebral cortex, bone, muscle, and substantia nigra [2–4]. Recently, a family with a VCP mutation showed diverse clinical manifestations, including parkinsonism; thus, the concept of multisystem proteinopathy was proposed [3]. Here we report a case of a patient with a VCP mutation who presented with limb-girdle muscle weakness/atrophy and Ldopa-unresponsive parkinsonism related to a progressive supranuclear palsy (PSP)-like symptoms. A 51-year-old woman visited our hospital because of postural abnormality and gait instability that had developed 7 years previously and had progressed gradually. Neurological examination revealed proximal weakness in her upper limbs, as indicated by aMedical ResearchCouncil scale grade of 4/5 for the deltoid and biceps brachii muscles, and in her trunk, as evidenced by a waddling gait. She had muscle atrophy of the upper-limb girdle, bilateral scapular winging (Fig. 1a), and lumbar hyperlordosis. However, facial, distal upper-limb, and lower-limb weakness were not observed. In addition, mild but significant parkinsonism (e.g., slight limitation of vertical eye movement compensated by doll’s eye phenomenon, loss of postural reflexes, cervical dystonic features, difficulty rising from a chair, mild bilateral rigidity, limited facial expression, and mild bradykinesia; Suppl Video) was observed. Generalized hyperreflexia without sensory loss, ataxia, and autonomic disturbances was not observed. No obvious dementia was noted, and her MiniMental State Examination scores were 29/30. A detailed past history suggested that she had gradually developed emotional blunting and showed a decline in personal grooming. She had a family history of muscle and neurological diseases: her father and uncle had similar symptoms of waddling gait and muscle weakness, and her uncle’s muscle biopsy revealed rimmed vacuolarmyopathy. In addition, her grandmother had been diagnosed with Parkinson’s disease. Brain magnetic resonance (MR) imaging revealed frontoparietal cortical atrophy (Fig. 2a), but the midbrain/ pons ratio (M/P ratio) [5] and MR parkinsonism index (MRPI) [6] were 0.257 and 10.55, respectively; this indicated that significant atrophies of the midbrain, pons, and superior/middle cerebellar peduncle were absent (Fig. 2b– d). Brain single-photon emission computed tomography (SPECT) showed significantly decreased blood flow in the frontotemporal cortex (Fig. 2e). Biopsy of the right biceps brachii muscle revealed IBM with rimmed vacuoles (Fig. 1b), and nuclear and cytoplasmic aggregates showed abnormal phosphorylated TDP-43 staining (data not shown). Genetic analysis revealed a p.R191Q mutation (c.572G[A) in VCP (Fig. 1c); thus, IBMPFD was diagnosed. She was started on levodopa/carbidopa therapy (300 mg/day), but her parkinsonism did not improve. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8467-2) contains supplementary material, which is available to authorized users.

The Brain Bank for Aging Research Project, Tokyo, Japan

the PI3-family kinases, ATM and ATR. After DNA damage, ATM autophosophorylates on serine1981, activating the kinase; ATR is also phosphorylated. Downstream targets of ATM include Chk2, a cell cycle checkpoint kinase. Methods: Immunohistochemistry was performed on brain sections of hippocampus and cerebellum obtained from AD and age-matched control subjects. TUNEL was used to directly document the presence of DNA damage. Results: Phosphorylated ATM, ATR and Chk2 (ATM*, ATR*, Chk2*) were detected in both large and small hippocampal and cerebellar neurons, and the extent of the labeling correlated well with the diagnosis of AD. When found in the nucleus, their presence correlated well with the TUNEL reaction. Surprisingly, ATM*, ATR* and Ch2* were also found in the cytoplasm in some cell populations, where their presence was poorly correlated with TUNEL-labeled nuclei. The nature of the cytoplasmic labeling varied significantly among the cell types. In cerebellar Purkinje cells, for example, ATM* was found distributed throughout the cell soma and thicker dendritic branches. By contrast, in hippocampal pyramidal cells, ATM*, ATR* and Ch2* were found in dense granules that labeled with granulovacuolar degeneration (GVD) markers. GVD localization was not observed for either 53BP1 or gH2AX, two DNA binding proteins associated with DNA damage. A significant proportion of the ATM*/ATR*/Ch2*-positive GVD granules were also positively stained by the phospho-tau marker AT8 and the autophagosome marker, LC3-II. Conclusions: As DNA damage is restricted to the cell nucleus, we suggest that the activation of the response proteins likely precedes and may help to initiate the formation of GVD granules.