Clinicopathological study of dementia with grains presenting with parkinsonism compared with a typical case.

Argyrophilic grain disease (AGD) is one of the major pathological backgrounds of senile dementia. Dementia with grains refers to cases of dementia for which AGD is the sole background pathology responsible for dementia. Recent studies have suggested an association between dementia with grains and parkinsonism. In this study, we aimed to present two autopsy cases of dementia with grains. Case 1 was an 85-year-old man who exhibited amnestic dementia and parkinsonism, including postural instability, upward gaze palsy, and neck and trunk rigidity. The patient was clinically diagnosed with progressive supranuclear palsy and Alzheimer's disease. Case 2 was a 90-year-old man with pure amnestic dementia, clinically diagnosed as Alzheimer's disease. Recently, we used cryo-electron microscopy to confirm that the tau accumulated in both cases had the same three-dimensional structure. In this study, we compared the detailed clinical picture and neuropathological findings using classical staining and immunostaining methods. Both cases exhibited argyrophilic grains and tau-immunoreactive structures in the brainstem and basal ganglia, especially in the nigrostriatal and limbic systems. However, Case 1 had more tau immunoreactive structures. Considering the absence of other disease-specific structures such as tufted astrocytes, astrocytic plaques and globular glial inclusions, lack of conspicuous cerebrovascular disease, and no history of medications that could cause parkinsonism, our findings suggest an association between AGD in the nigrostriatal system and parkinsonism.

CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease.

BACKGROUND AND OBJECTIVES: CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer disease (AD) and has recently been regarded to reflect ß-amyloid and/or p-tau deposition in the AD brain. Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by intranuclear inclusions in neurons, glial cells, and other somatic cells. Symptoms include dementia, neuropathy, and others. CSF biomarkers were not reported. The objective of this study was to investigate whether CSF biomarkers including p-tau181 are altered in patients with NIID. METHODS: This was a retrospective observational study. CSF concentrations of p-tau181, total tau, amyloid-beta 1-42 (Aß42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with Alzheimer clinical syndrome biologically confirmed based on CSF biomarker profiles, and patients clinically diagnosed with other neurocognitive disorders (dementia with Lewy bodies [DLB], 24; frontotemporal dementia [FTD], 13; progressive supranuclear palsy [PSP], 21; and corticobasal syndrome [CBS], 13). Amyloid PET using Pittsburgh compound B (PiB) was performed in 6 patients with NIID. RESULTS: The mean age of patients with NIID, AD, DLB, FTD, PSP, and CBS was 71.3, 74.6, 76.8, 70.2, 75.5, and 71.9 years, respectively. CSF p-tau181 was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared with DLB, PSP, and CBS and was comparable between NIID and AD. CSF p-tau181 was above the cutoff value (50.0 pg/mL) in 11 of 12 patients with NIID (91.7%). Within these patients, only 2 patients showed decreased CSF Aß42, and these patients showed negative or mild local accumulation in PiB PET, respectively. PiB PET scans were negative in the remaining 4 patients tested. The proportion of patients with increased CSF p-tau181 and normal Aß42 (A-T+) was significantly higher in NIID (75%) compared with DLB, PSP, and CBS (4.2%, 4.8%, and 7.7%, respectively). CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared with disease controls. DISCUSSION: CSF p-tau181 was increased in patients with NIID without amyloid accumulation. Although the deposition of p-tau has not been reported in NIID brains, the molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.

Autopsy Validation of the Diagnostic Accuracy of 123I-Metaiodobenzylguanidine Myocardial Scintigraphy for Lewy Body Disease.

BACKGROUND AND OBJECTIVES: 123I-meta-iodobenzyl-guanidine (123I-MIBG) myocardial scintigraphy is used as a diagnostic imaging test to differentiate Lewy body diseases (LBDs), including Parkinson disease and dementia with Lewy bodies, from other similar diseases. However, this imaging test lacks validation of its diagnostic accuracy against the gold standard. Our aim was to validate the diagnostic accuracy of 123I-MIBG myocardial scintigraphy for LBD against autopsy, the gold standard. METHODS: This retrospective, cross-sectional study included consecutive autopsy patients from the Brain Bank for Aging Research who had undergone 123I-MIBG myocardial scintigraphy. We compared the 123I-MIBG myocardial scintigraphy findings with autopsy findings. Furthermore, the proportion of residual tyrosine hydroxylase (TH)-immunoreactive sympathetic fibers in the anterior wall of the left ventricle was investigated to assess the condition of the cardiac sympathetic nerves assumed to cause reduced 123I-MIBG uptake in LBDs. RESULTS: We analyzed the data of 56 patients (30 with pathologically confirmed LBDs and 26 without LBD pathology). Compared with the neuropathologic diagnosis, the early heart-to-mediastinum (H/M) ratio had a sensitivity and specificity of 70.0% (95% CI 50.6%-85.3%) and 96.2% (95% CI 80.4%-99.9%), respectively. The delayed H/M ratio had a sensitivity and specificity of 80.0% (95% CI 61.4%-92.3%) and 92.3% (95% CI 74.9%-99.1%), respectively. The washout rate had a sensitivity and specificity of 80.0% (95% CI 61.4%-92.3%) and 84.6% (95% CI 65.1%-95.6%), respectively. The proportion of residual TH-immunoreactive cardiac sympathetic fibers strongly correlated with the amount of cardiac 123I-MIBG uptake when assessed with early and delayed H/M ratio values (correlation coefficient 0.75 and 0.81, respectively; p < 0.001). DISCUSSION: This clinicopathologic validation study revealed that 123I-MIBG myocardial scintigraphy could robustly differentiate LBDs from similar diseases. Abnormal 123I-MIBG myocardial scintigraphy findings strongly support the presence of LBD and cardiac sympathetic denervation. However, LBD pathology should not necessarily be excluded by normal myocardial scintigraphy results, especially when other biomarkers suggest the presence of comorbid Alzheimer disease pathology. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that 123I-MIBG myocardial scintigraphy accurately identifies patients with LBD.

Detectability of Breast Tumors in Excised Breast Tissues of Total Mastectomy by IR-UWB-Radar-Based Breast Cancer Detector.

The objective of this paper is to investigate the detectability of breast tumors having various histological types in excised breast tissues of total mastectomy. The tumor images measured by a portable impulse-radio-ultra-wideband (IR-UWB)-radar-based breast cancer detector are compared with both pathological images and images of dedicated breast positron emission tomography. It is found that the detector can detect invasive-ductal-carcinomas and extensive intraductal component in the dense breast. The density of the breast has a correlation to the effective permittivity derived from the reconstructed confocal images. The results show that the IR-UWB-radar-based breast cancer detector has a potential as a portable modality for early-stage breast cancer screening.

KRAS fluorescence in situ hybridisation testing for the detection and diagnosis of pancreatic adenocarcinoma.

AIMS: The aim of our study was to analyse correlations between KRAS mutation status, chromosomal changes that affect KRAS status in cells from pancreatic tumours. METHODS: We collected 69 cases of surgically resected pancreatic ductal adenocarcinoma (PDA) and seven cases of chronic pancreatitis (CP). Chromosomal abnormalities of KRAS and CEP12 were detected using fluorescence in situ hybridisation (FISH). RESULTS: The number of CEP12 signals per cell ranged from 1.78 to 2.04 and 1.46 to 4.88 in CP and PDA samples, respectively, while the number of KRAS signals per cell ranged from 1.94 to 2.06 and 1.88 to 8.18 in CP and PDA samples, respectively. The 'chromosomal instability index', which was defined as the percentage of cells with any chromosomal abnormality, was over 5.7 times greater in PDA than in CP. We performed KRAS mutation analysis by direct sequencing and found that tumours with KRAS mutations have a significantly higher mean KRAS signal per cell from PDA samples compared with tumours with wild-type KRAS. KRAS amplification was noted in 10% of cases. Although we found that lymph node metastasis and distal metastasis of PDA were more frequent in cases with KRAS amplification, this was not correlated with overall survival. Using a threshold of 40%, we found that the chromosomal instability index robustly discriminated PDA cells from CP cells. CONCLUSIONS: Based on these findings, we concluded that FISH testing of KRAS using cytology samples may represent an accurate approach for the diagnosis of PDA.