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.

Background and Objectives: CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer’s disease (AD) and has recently been regarded to reflect amyloid-beta 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 (Aβ42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with Alzheimer’s 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 six NIID patients. Results: The mean age of patients with NIID, AD, DLB, FTD, PSP, and CBS were 71.3, 74.6, 76.8, 70.2, 75.5, and 71.9 years old, respectively. CSF p-tau181 was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared to 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 NIID patients (91.7%). Within these patients, only two patients showed decreased CSF Aβ42, 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 Aβ42 (A−T+) was significantly higher in NIID (75%) compared to 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 to 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, molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.