A Longitudinal SPECT Study of Different Patterns of Regional Cerebral Blood Flow in Alzheimer's Disease with or without Diabetes

Aims: To determine the effect of diabetes mellitus (DM) on regional cerebral blood flow (rCBF) patterns in patients with Alzheimer’s disease (AD). Methods: We investigated the initial rCBF of 71 AD patients (36 without DM and 35 with DM) and the final rCBF of 23 AD patients (12 without DM and 11 with DM) after an average of 32 months. Single-photon emission computed tomography (SPECT) data were analyzed by statistical brain imaging. Results: The initial SPECT showed that AD patients without DM had lower rCBF in the left and right inferior temporal gyri than AD patients with DM. A follow-up SPECT demonstrated that rCBF decreased in more widespread regions, including the parietal, temporal, frontal, and limbic lobes, in AD patients without than with DM. Conclusion: This study suggests that functional brain abnormalities in AD differ depending on the DM status at baseline and during follow-up, reflecting neuropathologic differences

Sarcopenia and Muscle Functions at Various Stages of Alzheimer Disease

Although sarcopenia is closely linked to dementia, particularly Alzheimer disease (AD), there are few studies examining the prevalence and associated factors of sarcopenia in subjects with AD. This study aimed to investigate the prevalence of sarcopenia, factors associated with sarcopenia in elderly subjects with AD, and differences in muscle functions of the upper and lower extremities and gait speed at various stages of AD. We evaluated handgrip and knee extension strength, muscle mass, and gait speed in 285 elderly outpatients with probable AD (mean age 82. 0 ± 5.3 years), including early AD (n = 82), mild AD (n = 90), and moderate AD (n = 113), and 67 elderly outpatients with normal cognition (NC) (mean age 81.1 ± 4.7 years). Sarcopenia was defined according to the consensus of the Asian Working Group for Sarcopenia. The prevalence rate of sarcopenia was significantly higher in early AD, mild AD, and moderate AD than in NC (11% in NC, 36% in early AD, 45% in mild AD, and 60% in moderate AD of the female group, and 13% in NC, 41% in early AD, 47% in mild AD, and 47% in moderate AD of the male group). Age, body mass index, and Mini-mental state examination score were associated with sarcopenia in female or male AD groups. Decreased muscle strength without loss of muscle mass of the upper and lower extremities in the female AD group and those of the lower extremity in the AD male group were found in early and mild stages. Both muscle strength and mass decreased in the moderate AD. Low gait speed was also found in the early female and male AD which progressed with advancing dementia. Subjects with AD, even the early stages of AD, showed a high prevalence rate of sarcopenia. Higher age, lower BMI, and lower MMSE score were associated with sarcopenia in the female or male AD. There were differences in muscle functions and physical performance between the stages of the female and male AD

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Phosphorylated TDP-43 localizes to chronic cerebral infarctions in human brains

The transactivation response DNA-binding protein of 43 kDa (TDP-43) is a nuclear protein pivotal in RNA processing. Because phosphorylated TDP43 (pTDP-43) has been identified as a component of the ubiquitin-positive and tau-negative inclusions observed in the brains of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients, it is considered to play a major role in neurodegenerative processes. We previously reported that pTDP-43 is located in macrophages of atherosclerotic lesions of human carotid and major cerebral arteries. We hence hypothesized that pTDP-43 might be localized in the macrophages of other human brain lesions. Therefore, we investigated the immunolocalization of pTDP-43 in human brains with chronic cerebral infarction. Furthermore, we investigated the colocalization of pTDP-43 and the 14-3-3 eta isoform and found that pTDP-43 was localized in many macrophages located in chronic cerebral infarctions, in 6 out of the 15 human brains analyzed. pTDP-43 colocalized with the 14-3-3 eta isoform in these lesions. This is the first demonstration of pTDP-43 immunolocalization in chronic cerebral infarctions in human brains. We believe that our findings may be useful towards further understanding the pathophysiological roles of TDP-43 in various neurological disorders