Authors: Sato, Tomohiko | Hanyu, Haruo | Koyama, Yumi | Horita, Haruka | Aoki, Toshinori | Hirao, Kentaro | Kanetaka, Hidekazu | Shimizu, Soichiro
Article Type: Research Article
Abstract: Background: In Alzheimer’s disease (AD) patients, the severity of cognitive impairment is thought to correlate with the degree of brain imaging abnormalities. However, some patients show only mild cognitive deficit, despite severe brain atrophy on magnetic resonance imaging (MRI) or marked hypoperfusion in the cerebral cortices on single-photon emission computed tomography (SPECT). This suggests that cognitive reserve (CR) can compensate for the clinical manifestations of AD in patients with extensive brain pathology. Objective: We aimed to determine whether this discrepancy between cognitive and imaging findings is associated with CR. Methods: Factors associated with the discrepancy between the degree of cognitive …impairment and MRI (medial temporal lobe atrophy) and SPECT (posterior cerebral hypoperfusion) findings were analyzed in 135 patients with probable AD. Factors as proxies for CR included education, occupation, leisure activity, comorbidities, frailty, and other demographics. The discrepancy index (DI) was calculated as the difference between the degree of imaging abnormalities and the degree of cognitive dysfunction. Results: Multiple regression analysis showed that leisure activity and education were significantly associated with the discrepancy between cognitive and imaging findings. When the level of CR was determined based on leisure activity and education, the high-CR group showed a significantly larger DI than the moderate- and low-CR groups. Conclusion: The discrepancy between cognitive and imaging findings in patients with AD is associated with CR, measured using a combination of two indicators, i.e., leisure activity and education. Therefore, lifestyle interventions may delay the appearance of clinical symptoms resulting from underlying AD pathology, by increasing CR. Show more
Keywords: Alzheimer’s disease, brain imaging, cognition, cognitive reserve, education, leisure activity
DOI: 10.3233/JAD-210728
Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 273-281, 2021
Authors: Hanyu, Haruo | Koyama, Yumi | Umekida, Kazuki | Watanabe, Sadayoshi | Matsuda, Hiroshi | Koike, Riki | Takashima, Akihiko
Article Type: Research Article
Abstract: Background: The entorhinal cortex is the very earliest involvement of Alzheimer’s disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. Objective: We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Methods: Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of …AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI–). Results: Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI–. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Conclusions: Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12–15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD. Show more
Keywords: Alzheimer’s disease, mild cognitive impairment, path integration, prodromal Alzheimer’s disease, progression, virtual reality
DOI: 10.3233/JAD-240347
Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 651-660, 2024
Authors: Hanyu, Haruo | Koyama, Yumi | Horita, Haruka | Aoki, Toshinori | Sato, Tomohiko | Takenoshita, Naoto | Kanetaka, Hidekazu | Shimizu, Soichiro | Hirao, Kentaro | Watanabe, Sadayoshi
Article Type: Research Article
Abstract: Background: Alzheimer’s disease (AD) is a biologically heterogenous disease. Previous studies have reported the existence of various AD subtypes, and the various clinical features of the subtypes. However, inconsistent results have been obtained. Objective: To clarify the clinical characteristics of the various AD subtypes, by classifying probable AD into subtypes based on magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) findings. Methods: A total of 245 patients with probable AD were classified into the typical AD (TAD) subtype, limbic-predominant (LP) subtype, hippocampal-sparing (HS) subtype, and minimal-change (MC) subtype, based on the presence of medial temporal lobe atrophy on …MRI and posterior cerebral hypoperfusion on SPECT. Demographics, including age, sex, body mass index, disease duration, education years, comorbidities, frailty, leisure activity, and neuropsychological findings were compared between the AD subtypes. Results: he frequency of TAD, LP, HS, and MC subtypes was 49%, 20%, 18%, and 13%, respectively. Patients with the LP subtype were older and characterized by fewer major comorbidities, higher frailty, and slower progression of disease. Patients with the HS subtype were younger and characterized by shorter disease duration, lower frailty, and preserved memory, but had prominent constructional dysfunction. Patients of the MC subtype were characterized by shorter disease duration, lower education level, less leisure activity, less impaired memory and orientation, and slower progression. Conclusion: Patients with different AD subtypes differed in their demographic and clinical features. The characterization of patients’ AD subtypes may provide effective support for the diagnosis, treatment, and care of AD patients. Show more
Keywords: Alzheimer’s disease, atrophy, hypoperfusion, magnetic resonance imaging, neuropsychology, single-photon emission computed tomography
DOI: 10.3233/JAD-215674
Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 781-789, 2022
Authors: Hirose, Daisuke | Shimizu, Soichiro | Hirao, Kentaro | Ogawa, Yusuke | Sato, Tomohiko | Kaneko, Yoshitsugu | Takenoshita, Naoto | Namioka, Nayuta | Fukasawa, Raita | Umahara, Takahiko | Sakurai, Hirofumi | Watanabe, Ryo | Hanyu, Haruo
Article Type: Research Article
Abstract: Background/Objective: Although frailty is closely linked to dementia, particularly Alzheimer’s disease (AD), underlying pathophysiology of frailty associated with AD remains uncertain. This study aimed to investigate differences in structural and functional brain imaging abnormalities between AD with and without frailty. Methods: A total of 191 outpatients with probable AD (men: 91; women: 100; age: 80.7±6.3 years) who underwent both magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) were enrolled in this study. Frailty was determined in accordance with the Obu study Health Promotion for the Elderly. We compared numbers of small infarctions in the subcortical gray and white …matter and severity of white matter abnormalities (periventricular hyperintensity [PVH] and deep white matter hyperintensity [DWMH]) on MRI, and regional cerebral blood flow (rCBF) changes on SPECT between AD with and without frailty. Results: The prevalence of frailty was 43.4% in patients with AD. PVH and DWMH scores were significantly higher in AD with frailty compared to those without frailty. AD with frailty had a trend of decreased rCBF in the bilateral anterior cingulate gyrus, whereas those without frailty tend to have decreased rCBF in the left dominant parietal lobe and precuneus. Conclusion: Our MRI and SPECT imaging studies suggest different underlying pathophysiology in the brain between AD with frailty and without frailty. Show more
Keywords: Alzheimer’s disease, frailty, magnetic resonance imaging, single-photon emission computed tomography
DOI: 10.3233/JAD-180701
Citation: Journal of Alzheimer's Disease, vol. 67, no. 4, pp. 1201-1208, 2019
Authors: Hirao, Kentaro | Yamashita, Fumio | Tsugawa, Akito | Haime, Rieko | Fukasawa, Raita | Sato, Tomohiko | Kanetaka, Hidekazu | Umahara, Takahiko | Sakurai, Hirofumi | Hanyu, Haruo | Shimizu, Soichiro
Article Type: Research Article
Abstract: Background: White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date. Objective: To investigate the association between WMH progression and cognitive decline in amnestic MCI patients. Methods: Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and …deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated. Results: An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item. Conclusion: DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients. Show more
Keywords: Deep white matter hyperintensities, mild cognitive impairment, periventricular hyperintensities
DOI: 10.3233/JAD-201451
Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 877-883, 2021
Authors: Takenoshita, Naoto | Shimizu, Soichiro | Kanetaka, Hidekazu | Sakurai, Hirofumi | Suzuki, Ryo | Miwa, Takashi | Odawara, Masato | Ishii, Kenji | Shimada, Hitoshi | Higuchi, Makoto | Suhara, Tetsuya | Hanyu, Haruo
Article Type: Research Article
Abstract: Background/Objective: Although type 2 diabetes mellitus (DM) is a risk factor for the development of dementia, the underlying brain pathologies and mechanisms vary among patients. In this study, we classified patients with clinically diagnosed Alzheimer’s disease (AD) associated with DM into subgroups based on their amyloid and tau accumulation patterns on positron emission tomography (PET), and analyzed the differences in clinical features and brain imaging findings between the subgroups. Methods: Sixty-four patients with probable or possible AD associated with DM were classified using PiB (detects amyloid, A) and PBB3 (detects tau, T) PET studies. Patients were classified into the A+/T+ …group (n = 35, AD pathology), the A– /T+ group (n = 19, tauopathy), and the A– /T– group (n = 10, non-amyloid/non-tau neuronal damage). Results: Compared with the A+/T+ group, the A– /T+ group showed less-well controlled glycemia, longer duration of diabetes, more glucose variability, higher frequency of insulin therapy and biochemical hypoglycemia, and greater impairment of frontal lobe function, slower progression of cognitive decline, fewer APOE4 carriers, less severe medial temporal lobe atrophy, and lower frequency of posterior cerebral hypoperfusion. This subgroup showed different clinical and radiological features from AD. Conclusion: Among patients with clinically diagnosed AD with DM, there are subgroups with neuronal damage independent of AD pathology. A subgroup of dementia patients suspected of having tauopathy is strongly associated with DM-related metabolic abnormalities. This study highlights the identification of a novel dementia subgroup (diabetes-related dementia), which is important for considering appropriate therapies and care in clinical practice. Show more
Keywords: Alzheimer’s disease, amyloid, diabetes mellitus, diabetes-related dementia, positron emission tomography, tau
DOI: 10.3233/JAD-190620
Citation: Journal of Alzheimer's Disease, vol. 71, no. 1, pp. 261-271, 2019
Authors: Shimizu, Soichiro | Takenoshita, Naoto | Inagawa, Yuta | Tsugawa, Akito | Hirose, Daisuke | Kaneko, Yoshitsugu | Ogawa, Yusuke | Serisawa, Shuntaro | Sakurai, Shu | Hirao, Kentaro | Kanetaka, Hidekazu | Kanbayashi, Takashi | Imanishi, Aya | Sakurai, Hirofumi | Hanyu, Haruo
Article Type: Research Article
Abstract: Background: Recently, many studies have investigated the association between orexin A and Alzheimer’s disease (AD). However, it remains to be determined whether the observed changes in orexin A levels are associated with pathological changes underlying AD, or cognitive function. In particular, a direct association between cerebrospinal fluid (CSF) orexin A levels and cognitive function has not been reported to date. Objective: The aim of this study was to identify whether there is a direct association between the orexinergic system and cognitive function in AD. Methods: For this study, we included 22 patients with AD and 25 control subjects who underwent …general physical, neurological, and psychiatric examinations, neuroimaging, and CSF collection by lumbar puncture were enrolled. Correlations between CSF orexin A levels and CSF AD biomarker levels (i.e., levels of phosphorylated tau [p-tau], Aβ42 , and Aβ42 /Aβ40 ) were assessed to confirm the results of previous studies. Moreover, the correlation between CSF orexin A levels and Mini-Mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores were analyzed. Results: There was a significant positive correlation between CSF orexin-A levels and cognitive function (MMSE scores: r = 0.591, p = 0.04, MoCA score: r = 0.571, p = 0.006) in AD patients. Conclusion: This is the first study to our knowledge demonstrating an association between cognitive function and CSF orexin A levels in AD. Our results suggest the possibility that orexinergic system overexpression is not always a negative factor for cognitive function In AD. Show more
Keywords: Alzheimer’s disease, cerebrospinal fluid Alzheimer’s disease biomarker, cognitive function, hypocretin 1, orexin A
DOI: 10.3233/JAD-190958
Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 117-123, 2020
Authors: Miyashita, Akinori | Wen, Yanan | Kitamura, Nobutaka | Matsubara, Etsuro | Kawarabayashi, Takeshi | Shoji, Mikio | Tomita, Naoki | Furukawa, Katsutoshi | Arai, Hiroyuki | Asada, Takashi | Harigaya, Yasuo | Ikeda, Masaki | Amari, Masakuni | Hanyu, Haruo | Higuchi, Susumu | Nishizawa, Masatoyo | Suga, Masaichi | Kawase, Yasuhiro | Akatsu, Hiroyasu | Imagawa, Masaki | Hamaguchi, Tsuyoshi | Yamada, Masahito | Morihara, Takashi | Takeda, Masatoshi | Takao, Takeo | Nakata, Kenji | Sasaki, Ken | Watanabe, Ken | Nakashima, Kenji | Urakami, Katsuya | Ooya, Terumi | Takahashi, Mitsuo | Yuzuriha, Takefumi | Serikawa, Kayoko | Yoshimoto, Seishi | Nakagawa, Ryuji | Saito, Yuko | Hatsuta, Hiroyuki | Murayama, Shigeo | Kakita, Akiyoshi | Takahashi, Hitoshi | Yamaguchi, Haruyasu | Akazawa, Kohei | Kanazawa, Ichiro | Ihara, Yasuo | Ikeuchi, Takeshi | Kuwano, Ryozo
Article Type: Short Communication
Abstract: Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002–0.0059); however, no significant association with LOAD was observed in these variants. Considering …low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese. Show more
Keywords: Alzheimer's disease, Japanese, rare variants, SNP, TREM2
DOI: 10.3233/JAD-140225
Citation: Journal of Alzheimer's Disease, vol. 41, no. 4, pp. 1031-1038, 2014
