An autopsy case of amyloid angiopathy-related cerebellar hemorrhage.

An 80-year-old man with dementia demonstrated cerebellar hemorrhage. Autopsy revealed pathology compatible with Alzheimer's disease and cerebral amyloid angiopathy (CAA). CAA was more prevalent in the occipital lobe than in the frontal, parietal, and temporal lobes; however, amyloid-ß (Aß)-containing senile plaques were less abundant in the occipital cortex than in the other cortices. In the cerebellum, abundant CAA-involved vessels were observed in the subarachnoid space and molecular layer and to a lesser extent in the Purkinje and granule layers. On consecutive sections, Aß1-42 immunohistochemistry revealed senile plaques and CAA-involved vessels with strong immunoreactivity whereas Aß1-40 immunohistochemistry identfied CAA-involved vessels with strong immunoreactivity and senile plaques with weak immunoreactivity in the cerebellar cortices.

A comparison of cerebral amyloid angiopathy in the cerebellum and CAA-positive occipital lobe of 60 brains from routine autopsies.

We semiquantitatively compared the frequency and severity of cerebral amyloid angiopathy (CAA) in the cerebellum and CAA-positive occipital lobe of 60 subjects from routine autopsies. In the 60 subjects with a CAA-positive occipital lobe, cerebellar CAA was observed in 29 subjects (48.3%), and the severity of cerebellar CAA was relatively mild compared with occipital lobe CAA. Capillary CAA was observed in the occipital lobe of 12 subjects and the cerebellum of three subjects. CAA-related vasculopathies were observed in the occipital lobe of 15 subjects and the cerebellum of two subjects. The severity of CAA-related vasculopathy was mild in both of these subjects. Amyloid-ß plaques were observed in the occipital lobe of 54 subjects (90%) and the cerebellum of 16 subjects (26.7%). The severity of amyloid-ß plaques in the cerebellum was mild compared with the occipital lobe. In summary, we confirmed that cerebellar CAA is frequently observed in the cerebellum but with a lower severity than CAA in the occipital lobe.

Amyloid-ß plaques may be reduced in advanced stages of cerebral amyloid angiopathy in the elderly.

We examined 29 cases in which cerebral amyloid angiopathy (CAA) was detected among routine aged autopsies. Most cases with severe CAA had many amyloid-ß (Aß) plaques in the occipital cortex. Nonetheless, two cases had few Aß plaques with many small vessels and capillaries with CAA. In the two cases, severe CAA was widely distributed, except in the frontal lobes. Aß deposits in capillaries often showed the characteristic pattern of dysphoric amyloid angiopathy. A few naked plaques were present. Although Aß plaques were sparse near small vessels with CAA, there were many Aß plaques distant from small vessels with CAA. Some of the remaining plaques had a moth-eaten appearance. Based on Aß-positive star-like appearance and results of double immunohistochemistry for glial fibrillary acidic protein and Aß1-42 , some astrocytes appeared to contain Aß. Ionized calcium-binding adapter molecule 1 (Iba1)-positive microglia were scattered within the neuropil, with some present around small vessels with CAA. Iba1-positive microglia also seemed to phagocytose Aß in several senile plaques by double immunostaining. Neurons and neurites identified with a monoclonal antibody against phosphorylated tau (clone AT8) were occasionally detected in sparse plaque areas, with AT8-identified dot-like structures present around capillaries with CAA. Accumulation of T lymphocytes was detected around vessels in the subarachnoid space in one case. The morphological changes detected in our two cases were similar to those of morphological markers of plaque clearance after Aß immunotherapy. Nonetheless, our cases did not receive Aß immunotherapy, but similar pathologies were observed. Overall, advanced CAA cases, including our two cases, may be examples of plaque clearance without Aß immunotherapy. Further studies are needed to resolve the mechanism of Aß plaque clearance using these cases.

Astrocytic tau pathologies in aged human brain.

Argyrophilic and tau-positive abnormal structures in astrocytes are frequent in aged brains, with a new nomenclature of aging-related tau astrogliopathy (ARTAG) proposed. The two major cytomorphologies of ARTAG are thorn-shaped astrocytes (TSA) and granular or fuzzy tau immunoreactivity in processes of astrocytes (GFA). We selected 28 cases in which many AT8-identified astrocytic tauopathies were observed in the central nervous system from 330 routine aged autopsied cases, including Alzheimer's disease. AT8-identified and Gallyas silver staining-positive TSA were observed in subpial, subependymal, perivascular areas as well as white matter. These TSA were 4-repeat (4R) tau-positive. In contrast, 3-repeat (3R)-tau was negative in TSA, but positive in short thick cell processes, likely neuropil threads, in subpial and subependymal areas. The frequency of 3R-tau-positive processes was variable. Small dot-like AT8-identified astrocytic processes surrounding vessels in the neuropil were also positive for 4R-tau, but negative for 3R-tau. GFA in cerebral gray matter were AT8-identified and Gallyas-positive, and positive for 4R-tau but negative for 3R-tau. In this study, we did not identify 3R-tau+/4R-tau+ or 3R-tau+/4R-tau- astrocytes. Further studies are needed to clarify the nature and progression of glial tau-positive structures in ARTAG.

Comparison of AT8 immunoreactivity in the locus ceruleus and hippocampus of 154 brains from routine autopsies.

We compared semiquantitatively AT8 immunoreactivity in the locus ceruleus (LC) and hippocampus of 154 brains from routine autopsies to investigate the initial sites of phosphorylated tau (phospho-tau) development. The numbers of AT8-positive neurons and the severity of AT8-positive neuropil threads (NTs) in the LC were strongly associated: there were no cases with AT8-positive neurons that lacked NTs and 20 cases (13%) had only NTs in the LC. Phospho-tau pathologies in the LC were almost equally on both sides, although some cases (7.8%) showed unilateral predominance. The numbers of AT8-positive neurons in the LC and the numbers of AT8-positive neurons and NTs in the hippocampus were also strongly associated. There were only two cases with AT8-positive neurons in the LC that lacked phospho-tau pathology in the hippocampus, and 21 cases (13.6%) with phospho-tau pathology in the hippocampus that lacked AT8-positive neurons in the LC. The numbers of AT8-positive NTs in the LC and AT8-positive neurons and NTs in the hippocampus were also strongly associated. There were seven cases (4.5%) with AT8-positive NTs in the LC that lacked phospho-tau pathology in the hippocampus, and five cases (3.2 %) with phospho-tau pathologies in the hippocampus that lacked AT8-positive NTs in the LC. In this study, we could not confirm that phospho-tau pathologies begin in the LC. We suspect their simultaneous occurrences in both hippocampal regions and in LC.

Cytoplasmic TDP-43 accumulation in cells of the adrenal medulla in individuals with or without amyotrophic lateral sclerosis.

The transactive response DNA-binding protein of 43 kDa (TDP-43) is normally located predominantly in the nucleus, whereas pathological TDP-43 is mostly found in the cytoplasm. Cytoplasmic TDP-43 accumulation has not yet been reported in normal general organs. In our preliminary study, paraffin sections of the general organs of individuals with or without amyotrophic lateral sclerosis (ALS) were immunostained with antibodies against TDP-43 and phosphorylated TDP-43 (pTDP-43). Diffuse and granular immunostaining pattern of TDP-43 and pTDP-43 were observed frequently in the cytoplasm of renal tubular cells, and less frequently in the cells of several organs; however, the majority of these immunoreactivities were nonspecific biotin reactions. Conversely, many TDP-43-positive and pTDP-43-negative cytoplasmic accumulations were observed in the adrenal medulla in every individual (with or without ALS). Skein-like or round inclusions were not observed. The cells in the adrenal medulla were well preserved, and the cytoplasmic TDP-43 accumulations were frequent in the cells of all routine autopsy cases without loss of nuclear TDP-43 immunostaining; therefore, we considered that this was a physiological phenomenon. This is the first study that demonstrated the cytoplasmic accumulation of TDP-43 in routinely autopsied cases.

High levels of plasma neurofilament light chain correlated with brainstem and peripheral nerve damage.

BACKGROUND AND OBJECTIVES: Blood neurofilament light chain (NfL) is a minimally invasive, but highly sensitive biomarker of neurological diseases. However, diseases and neurological damage associated with increased NfL remain unclear. Therefore, the present study investigated factors associated with increased plasma NfL levels in various neurological diseases, focal lesions and pathological processes. METHODS: This was a retrospective cohort study on 410 participants with various neurological diseases and 17 healthy and cognitively unimpaired controls (HCU). Plasma samples were analyzed to measure NfL using ECL immunoassay. The focal lesions were classified as the cerebrum, cerebellum, brainstem, meninges, spinal cord, peripheral nerves, neuromuscular junction, and muscles based on medical records. A multiple regression analysis and receiver operating characteristic curve (ROC) analysis were performed to investigate whether plasma NfL levels predict specific diseases and focal lesions. RESULTS: Plasma NfL levels discriminated between the HCU and all disease groups (area under the curve (AUC), 0.97), with a cut-off value of 63.4 pg/mL. A multiple regression analysis of focal lesions adjusted by pathogenic processes showed that brainstem and peripheral nerve involvement was associated with higher plasma NfL levels. A cut-off value of 53.8 pg/mL of NfL discriminated between the HCU and neurological disease group except for brainstem or peripheral disorders (AUC 0.962), while a cut-off value of 208.0 pg/mL distinguished this group from brainstem or peripheral nervous system disorders (AUC 0.716). DISCUSSION: These results demonstrate that plasma NfL has a potential to be a highly sensitive biomarker for neurological diseases and focal lesions.

A case of chronic progressive autoimmune GFAP astrocytopathy with extensive meningoencephalomyelitis and contrast enhancement on MRI.

•We herein present a case of chronic progressive autoimmune GFAP astrocytopathy.•Symmetrical high-intensity signals on FLAIR were observed in the white matter of the temporal and occipital lobes, lateral cerebral ventricle walls, hippocampus, amygdala, and occipital cortex, with extensive Gd enhancement in radial perivascular lesions and the ependyma in the choroid plexus.•Improvements were achieved by 4 courses of IVMP and one of IVIg.

Clinical Evaluation of Cerebrospinal Fluid p217tau and Neurofilament Light Chain Levels in Patients with Alzheimer's Disease or Other Neurological Diseases.

BACKGROUND: The cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 217 (p217tau) or 181 (p181tau), and neurofilament light chain (NfL) are definite biomarkers of tauopathy and neurodegeneration in Alzheimer's disease (AD). OBJECTIVE: To validate their utility in excluding other neurological diseases and age-related changes in clinical settings. METHODS: We developed monoclonal antibodies against p217tau and NfL, established novel ELISAs, and analyzed 170 CSF samples from patients with AD or other neurological diseases. RESULTS: In AD, p217tau is a more specific and abundant CSF component than p181tau. However, CSF NfL levels increase age-dependently and to a greater extent in central and peripheral nervous diseases than in AD. CONCLUSIONS: CSF p217tau correlates better with AD neurodegeneration than other tau-related biomarkers and the major phosphorylated tau species. The clinical usage of NfL as a neurodegeneration biomarker in AD requires exclusion of various central and peripheral neurological diseases.

Yamaguchi fox-pigeon imitation test (YFPIT) for dementia in clinical practice.

BACKGROUND: In out-patient clinics, having simple procedures to check for signs of dementia is invaluable. In the present study, we evaluated the imitation of hand gestures to detect visuomotor deficits in dementia in clinical practice. METHODS: In all, 1219 subjects were enrolled in the present study, including 497 with Alzheimer's disease (AD), 98 with dementia with Lewy bodies (DLB), 71 with other types of dementia diseases, 175 with a Clinical Dementia Rating (CDR) of 0.5, and 378 normal controls. All subjects were aged 65 years or older. Subjects were recruited from 10 clinics and two communities. Visuomotor function was evaluated by the Yamaguchi fox-pigeon imitation test (YFPIT), which consists of a simple one-handed sign for 'fox' and a complex two-handed sign for 'pigeon', a rapid, game-like test with low psychological burden. RESULTS: The success rate (successful/total) for imitating the 'pigeon' hand gesture was reduced as the severity of the dementia increased: 85.7% in normal controls, 60.6% in CDR 0.5 (mild cognitive impairment), 39.2% in CDR 1 (mild dementia), 21.2% in CDR 2 (moderate dementia), and 5.7% in CDR 3 (severe dementia). The success rate for imitating the 'pigeon' hand gesture was higher in patients with DLB than AD within the CDR 1 group (51.2% vs 35.4%, respectively), but lower for patients with DLB than AD within the CDR 2 group (12.5% vs 24.4%, respectively). The success of imitating the hand gesture for 'fox' was similar for patients with AD and DLB. Of those subjects who failed to imitate the hand gesture for 'pigeon', 49.5% of those with AD showed the palm-palm pattern (both palms facing outward), suggesting deficits of perspective conversion from the first-person to the third-person. Conversely, 52.8% of patients with DLB showed a dorsum-dorsum pattern (both dorsa facing outwards), suggesting deterioration of visual attention and recognition. CONCLUSION: In conclusion, the YFPIT is a useful test to detect visuomotor deficits in dementia that can differentiate between AD and DLB.

IgG4-related hypothalamo-hypophysitis.

•A patient exhibited IgG4-related hypothalamo-hypophysitis.•Prominent high-signal areas of swelling were observed in the hypothalamus, tuber cinereum, infundibulum, and bilateral optic nerve systems.•MRI T1WI with contrast media demonstrated enhanced neurohypophysis and cystic swelling, and compressed anterior pituitary.•MRI findings improved rapidly after 4 days of steroid therapy.

Improved Neuroimaging Findings and Cognitive Function in a Case of High-altitude Cerebral Edema.

High-altitude cerebral edema (HACE) is a rare condition of acute mountain sickness that manifests as consciousness disturbance and truncal ataxia. Neuroimaging shows vasogenic edema with microbleeds in the white matter and the corpus callosum. We herein report a case of HACE in which the patient showed widespread hyperintense signals with extensive microbleeds in the white matter and corpus callosum on MRI, as well as cognitive dysfunction. Rehabilitation to improve the higher brain function facilitated the recovery of the patient's cognitive impairment and was accompanied by improved MRI findings.

Age-Related Cognitive Decline and Prevalence of Mild Cognitive Impairment in the Iwaki Health Promotion Project.

BACKGROUND: The Iwaki Health Promotion Project (IHPP) is a community-based study for the prevention of lifestyle-related diseases and improvement of quality of life. OBJECTIVE: Between 2014 and 2017, a total of 4,442 Iwaki town residents from 19 to 93 years of age participated in annual surveys to clarify the natural course of age-related cognitive decline and mild cognitive impairment (MCI). METHODS: Modified OLD and SED-11Q questionnaires, MMSE, Logical Memory II, educational history, and APOE genotypes were examined at the first screening. MCI and dementia were diagnosed at the second examination by detailed neurological examination, CDR, and MRI, and followed for 3 years. Spline regression analyses based on a linear mixed model was adopted for statistical analysis. RESULTS: MMSE scores declined with age from 55 to 64 years. There was also interaction between levels of education and ages. At the second examination, 56 MCI and 5 dementia patients were identified. None of the MCI cases progressed to dementia during the 3 years. During follow-up examinations, 13 cases showed improved MMSE scores (0.95 point/year), 5 remained stable, and 7 deteriorated (-0.83 point/year). Five cases showed improved CDR-SOB scores (-0.28 point/year), 9 remained stable, and 6 deteriorated (0.3 point/year). CONCLUSION: IHPP revealed that age- and education-related cognitive decline began and advanced from 55 years of age. The prevalence of MCI and dementia was estimated to be 5.9%in the Iwaki town cohort over 60 yeas of age. About 30%of MCI cases showed progression of cognitive decline.

Recurrent Lobar Hemorrhages and Multiple Cortical Superficial Siderosis in a Patient of Alzheimer's Disease With Homozygous APOE ε2 Allele Presenting Hypobetalipoproteinemia and Pathological Findings of 18F-THK5351 Positron Emission Tomography: A Case Report.

In Alzheimer's disease, the apolipoprotein E gene (APOE) ε2 allele is a protective genetic factor, whereas the APOE ε4 allele is a genetic risk factor. However, both the APOE ε2 and the APOE ε4 alleles are genetic risk factors for lobar intracerebral hemorrhage. The reasons for the high prevalence of lobar intracerebral hemorrhage and the low prevalence of Alzheimer's disease with the APOE ε2 allele remains unknown. Here, we describe the case of a 79-year-old Japanese female with Alzheimer's disease, homozygous for the APOE ε2 allele. This patient presented with recurrent lobar hemorrhages and multiple cortical superficial siderosis. The findings on the 11C-labeled Pittsburgh Compound B-positron emission tomography (PET) were characteristic of Alzheimer's disease. 18F-THK5351 PET revealed that the accumulation of 18F-THK 5351 in the right pyramidal tract at the pontine level, the cerebral peduncle of the midbrain, and the internal capsule, reflecting the lesions of the previous lobar intracerebral hemorrhage in the right frontal lobe. Moreover, 18F-THK5351 accumulated in the bilateral globus pallidum, amygdala, caudate nuclei, and the substantia nigra of the midbrain, which were probably off-target reaction, by binding to monoamine oxidase B (MAO-B). 18F-THK5351 were also detected in the periphery of prior lobar hemorrhages and a cortical subarachnoid hemorrhage, as well as in some, but not all, areas affected by cortical siderosis. Besides, 18F-THK5351 retentions were observed in the bilateral medial temporal cortices and several cortical areas without cerebral amyloid angiopathy or prior hemorrhages, possibly where tau might accumulate. This is the first report of a patient with Alzheimer's disease, carrying homozygous APOE ε2 allele and presenting with recurrent lobar hemorrhages, multiple cortical superficial siderosis, and immunohistochemically vascular amyloid ß. The 18F-THK5351 PET findings suggested MAO-B concentrated regions, astroglial activation, Waller degeneration of the pyramidal tract, neuroinflammation due to CAA related hemorrhages, and possible tau accumulation.

Cerebral Microbleeds, Cerebrospinal Fluid, and Neuroimaging Markers in Clinical Subtypes of Alzheimer's Disease.

Lobar cerebral microbleeds (CMBs) in Alzheimer's disease (AD) are associated with cerebral amyloid angiopathy (CAA) due to vascular amyloid beta (Aß) deposits. However, the relationship between lobar CMBs and clinical subtypes of AD remains unknown. Here, we enrolled patients with early- and late-onset amnestic dominant AD, logopenic variant of primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA) who were compatible with the AD criteria. We then examined the levels of cerebrospinal fluid (CSF) biomarkers [Aß1-42, Aß1-40, Aß1-38, phosphorylated tau 181 (P-Tau), total tau (T-Tau), neurofilament light chain (NFL), and chitinase 3-like 1 protein (YKL-40)], analyzed the number and localization of CMBs, and measured the cerebral blood flow (CBF) volume by 99mTc-ethyl cysteinate dimer single photon emission computerized tomography (99mTc ECD-SPECT), as well as the mean cortical standard uptake value ratio by 11C-labeled Pittsburgh Compound B-positron emission tomography (11C PiB-PET). Lobar CMBs in lvPPA were distributed in the temporal, frontal, and parietal lobes with the left side predominance, while the CBF volume in lvPPA significantly decreased in the left temporal area, where the number of lobar CMBs and the CBF volumes showed a significant inversely correlation. The CSF levels of NFL in lvPPA were significantly higher compared to the other AD subtypes and non-demented subjects. The numbers of lobar CMBs significantly increased the CSF levels of NFL in the total AD patients, additionally, among AD subtypes, the CSF levels of NFL in lvPPA predominantly were higher by increasing number of lobar CMBs. On the other hand, the CSF levels of Aß1-38, Aß1-40, Aß1-42, P-Tau, and T-Tau were lower by increasing number of lobar CMBs in the total AD patients. These findings may suggest that aberrant brain hypoperfusion in lvPPA was derived from the brain atrophy due to neurodegeneration, and possibly may involve the aberrant microcirculation causing by lobar CMBs and cerebrovascular injuries, with the left side dominance, consequently leading to a clinical phenotype of logopenic variant.

Successful basilar artery dilatation in pure bilateral cerebral peduncular infarctions using balloon angioplasty.

•An extremely rare case of bilateral cerebral peduncular infarctions (BCPI) is reported.•The detection of the pure Mickey Mouse ears sign on MRI is an indicator of a need for reperfusion therapy.•Severe stenosis of the basilar artery (BA) and a poor collateral supply from both posterior cerebral arteries were seen.•Balloon angioplasty for the BA stenosis ameliorated the stenosis and produced a favorable outcome.

Plasma antibodies to Abeta40 and Abeta42 in patients with Alzheimer's disease and normal controls.

Antibodies to amyloid beta protein (Abeta) are present naturally or after Abeta vaccine therapy in human plasma. To clarify their clinical role, we examined plasma samples from 113 patients with Alzheimer's disease (AD) and 205 normal controls using the tissue amyloid plaque immunoreactivity (TAPIR) assay. A high positive rate of TAPIR was revealed in AD (45.1%) and age-matched controls (41.2%), however, no significance was observed. No significant difference was observed in the MMS score or disease duration between TAPIR-positive and negative samples. TAPIR-positive plasma reacted with the Abeta40 monomer and dimer, and the Abeta42 monomer weakly, but not with the Abeta42 dimer. TAPIR was even detected in samples from young normal subjects and young Tg2576 transgenic mice. Although the Abeta40 level and Abeta40/42 ratio increased, and Abeta42 was significantly decreased in plasma from AD groups when compared to controls, no significant correlations were revealed between plasma Abeta levels and TAPIR grading. Thus an immune response to Abeta40 and immune tolerance to Abeta42 occurred naturally in humans without a close relationship to the Abeta burden in the brain. Clarification of the mechanism of the immune response to Abeta42 is necessary for realization of an immunotherapy for AD.

Genetic analysis of the cystatin C gene in familial and sporadic ALS patients.

Bunina bodies, small eosinophilic intraneuronal inclusions, stain positive for cystatin C and are the only specific pathological hallmark of amyotrophic lateral sclerosis (ALS). We screened the cystatin C gene (CST3) for mutations in 57 sporadic ALS patients and 12 familial ALS cases that did not possess a SOD1 mutation. We detected the known polymorphism in exon 1, a G/A transition at +73, in both familial and sporadic ALS patients. However, the allelic and genotypic frequencies of the +73 G/A polymorphism did not differ between ALS patients and control samples. No other mutation was detected in the ALS patients. The results reported here indicate that there may not be a direct genetic link between cystatin C and ALS, and it may be that deficits occur in proteins that interact with cystatin C.

Immunoreactivities of p62, an ubiqutin-binding protein, in the spinal anterior horn cells of patients with amyotrophic lateral sclerosis.

An ubiquitin-binding protein, p62, is one of the components of the ubiquitin-containing inclusions in several human neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of skein-like inclusions, Lewy body-like inclusions, and basophilic inclusions in the remaining anterior horn cells, in which these inclusions contain ubiquitin, while the other characteristic inclusions of Bunina type are ubiquitin-negative. We examined the spinal cord from 28 ALS cases including two ALS with dementia and two ALS with basophilic inclusions, using antibody to p62. The results demonstrated that p62 localized in skein-like inclusions, Lewy body-like inclusions and basophilic inclusions. The number of p62-positive inclusions observed in the remaining anterior horn cells of each section was variable among the ALS cases. In contrast, Bunina bodies, that do not contain ubiquitin, were negative for p62. As far as we examined, the 11 non-ALS cases did not show any p62 immunoreactivities in the anterior horn cells. Our results suggested that p62 plays important roles in forming the inclusions and may be associated with the protection of the neurons from degenerative processes involving ubiquitin.