Akinori Nakamura

Here we report a case of a 77-year-old Japanese woman who carries the heterozygous APP p.Tyr681His variant. This variant lies within the amyloid-β region, precisely at the β′-site of the β-secretase cleavage. She presented with preserved cognition despite a prior left frontal hemorrhage at age 70, MRI findings suggestive of cerebral amyloid angiopathy, and a family history of intracerebral hemorrhage, later developing recurrent hemorrhage at age 78.

Background: Epileptic seizures and subclinical epileptiform activity are increasingly recognized as comorbidities in Alzheimer's disease (AD) and have been associated with accelerated cognitive decline. Whether antiseizure medication (ASM) therapy favorably influences cognitive trajectories in AD remains unclear. Objective: To assess the effects of ASM therapy on cognitive trajectories in patients with AD with comorbid epilepsy, and to identify patient subgroups most likely to benefit. Methods: We retrospectively studied 538 patients (403 AD only; 135 AD with comorbid epilepsy) treated with newer-generation ASMs between 2020 and 2025. Cognitive change over 24 months was assessed using the Mini-Mental State Examination (MMSE). Analyses included linear mixed-effects modeling, sliding window interaction analysis across baseline MMSE scores (11–29), and 1:1 propensity score matching stratified by baseline MMSE (≤21, 22–26, and ≥27). Results: After propensity score matching, baseline MMSE scores were well balanced between the groups. The sliding window analysis suggested a subgroup-specific interaction between group and time in the MMSE (range 22–26), peaking at MMSE 25. In the 22–26 stratum, MMSE at 12 months was higher in the AD with comorbid epilepsy group than in the AD-only group (23.23 ± 0.46 versus 20.33 ± 0.52, p < 0.001). The 24-month difference (22.92 ± 1.37 versus 19.36 ± 0.99, p = 0.047) was borderline and considered exploratory. Conclusions: Antiseizure therapy was associated with favorable cognitive trajectories in patients with AD and comorbid epilepsy, particularly with baseline MMSE 22–26. These exploratory findings suggest a potential therapeutic window that warrants confirmation in prospective studies.

Background: Alzheimer's disease (AD) frequently causes epilepsy and myoclonus. These symptoms are thought to be associated with neuronal hyperexcitability, highlighting the need for biomarkers that reflect synaptic functional alterations. Objective: We aimed to examine changes in neuronal excitability associated with AD progression using magnetoencephalography (MEG). Furthermore, we investigated the relationship between alterations in electromagnetic signals and other neuroimaging biomarkers. Methods: We measured middle-latency somatosensory evoked magnetic fields (m-SEFs) following right median nerve stimulation in 45 individuals, comprising 6, 8, and 31 individuals with AD dementia (ADD), mild cognitive impairment (MCI), and cognitively healthy older adults, respectively. Cortical reactivity relative to the primary somatosensory response (N20 m) was assessed using normalized m-SEF waveforms. Additionally, we analyzed associations between these waveforms and amyloid-β (Aβ) deposition, regional glucose metabolism, and gray matter volume using positron-emission tomography and magnetic resonance imaging. Results: The m-SEF waveform exhibited six components (M2–M7) within 150 ms of the N20 m (M1) response. The m-SEF waveforms tended to be enlarged in ADD and MCI, with a significant enhancement of M2 in ADD. The amplitude of M7 at approximately 100 ms latency was significantly and positively correlated with local Aβ deposition in the sensorimotor cortex. Moreover, regional glucose hypometabolism in the hippocampus and pulvinar was significantly associated with enlargement of the M4, M6, and M7 components. Conclusions: These findings indicate that cortical responses to somatosensory stimulation are modulated by AD progression. M-SEF may serve as a potential marker for evaluating cortical excitability in the sensorimotor cortex.

Background: The relationship between physical activity and hippocampal volume is important; however, most studies have used questionnaires to measure physical activity. We aimed to determine whether maintaining high levels of daily physical activity measured by an accelerometer reduces hippocampal atrophy in community-dwelling adults. Methods: This cohort study used data from community-dwelling adults aged ≥60 years who participated in the National Institute for Longevity Sciences Longitudinal Study of Aging, which is a population-based prospective cohort study of approximately 2,300 Japanese adults. Tertiles of step count, light-intensity physical activity, and moderate-to-vigorous-intensity physical activity (MVPA) were measured using accelerometers. Changes in the hippocampal and total grey matter volumes over approximately 10 years were obtained from high-resolution 3D T1-weighted Magnetic Resonance Imaging (MRI) images. Results: The analysis included 287 men and 264 women, with no history of head surgery, dementia, or stroke at baseline, who completed the MRI scans and follow-up surveys. Significant interactions between MVPA and years since baseline with whole and right hippocampal volumes were observed only in men (p<.05). Annual whole hippocampal atrophy volumes in the lowest, intermediate, and highest MVPA groups were -72.11, -58.25, and -59.53 mm3, respectively. Right hippocampal atrophy volumes were -36.93, -28.47, and -28.53 mm3, respectively. The total and right hippocampal volumes in the lowest MVPA group declined more rapidly than those in the other groups. Conclusions: Lower MVPA levels in men were associated with higher rates of both total and right hippocampal atrophy. The relationship between MVPA and atrophy may help develop dementia prevention strategies.

Background: It is known that eyes-open (EO) and eyes-closed (EC) conditions invoke different organizations of brain functional networks, such as sensorimotor, attention, and salience networks in healthy participants. Functional connectivity (FC) extracted from resting-state functional magnetic resonance imaging data, under either EO or EC conditions, has been widely applied to explore the neural substrates of Alzheimer's disease (AD). However, the impact of eye conditions on FC within the AD continuum remains not fully understood. Objective: This study aims to investigate the effects of eye conditions on FC across the AD continuum. Methods: FC with the primary visual cortex (V1) seed was analyzed for both EO and EC conditions in 59 amyloid-β (Aβ)-positron emission tomography (PET)-negative cognitively normal (CN−), 14 Aβ-PET-positive CN+, 24 mild cognitive impairment (MCI+), and 15 AD individuals. Results: EO and EC differently modulated FC between the V1 and cerebellum, especially the posterior vermis, in all groups. In CN−, CN+, and MCI+ groups, EO significantly facilitated FC between V1 and the cerebellum compared with the EC condition. However, the AD group showed the reverse pattern. Moreover, a sub-analysis demonstrated that the FC significantly correlated with a truncal balance measure under EO, but not EC, in participants with MCI+ and AD. Conclusions: The results show that the FC between the V1 and cerebellum changed in AD. This finding may partially explain the impaired truncal balance and tendency to fall down in AD. This study suggests that analyzing FC under EO and EC conditions may provide a new functional biomarker for AD.

Background: Comorbid Alzheimer’s disease (AD) neuropathology is common in Lewy body disease (LBD); however, AD comorbidity in the prodromal phase of LBD remains unclarified. This study investigated AD comorbidity in the prodromal and symptomatic phases of LBD by analysing plasma biomarkers in patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) and at-risk individuals of LBD (NaT-PROBE cohort). Methods: Patients with PD (PD group, n=84) and DLB (DLB group, n=16) and individuals with LBD with ≥2 (high-risk group, n=82) and without (low-risk group, n=37) prodromal symptoms were enrolled. Plasma amyloid-beta (Aβ) composite was measured using immunoprecipitation-mass spectrometry assays. Plasma phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and alpha-synuclein (aSyn) were measured using a single-molecule array. Results: p-tau181 levels were higher in the PD and DLB groups than in the low-risk group. Aβ composite level was higher in the DLB group than in the high-risk group. AD-related biomarker levels were not elevated in the high-risk group. NfL levels were higher in the high-risk, PD, and DLB groups than in the low-risk group. In the PD group, Aβ composite was associated with cognitive function, p-tau181 with motor function and non-motor symptoms, and NfL with cognitive and motor functions and non-motor symptoms. In the high-risk group, NfL was associated with metaiodobenzylguanidine scintigraphy abnormalities. Conclusions: The PD and DLB groups exhibited comorbid AD neuropathology, though not in the prodromal phase. Elevated plasma NfL levels, even without elevated AD-related plasma biomarker levels, may indicate aSyn-induced neurodegeneration in the prodromal phase of LBD. What is already known on this topic: Comorbid Alzheimer’s disease (AD) neuropathology is common in Parkinson’s disease (PD) dementia and dementia with Lewy bodies (DLB); however, AD comorbidity in the prodromal phase of Lewy body disease (LBD) is yet to be clarified. What this study adds: Four plasma biomarkers (amyloid-beta (Aβ) composite, phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and alpha-synuclein (aSyn)) were measured in patients with PD and DLB and high– and low-risk individuals with ≥2 and without LBD prodromal symptoms. Increased plasma levels of p-tau181 indicated AD comorbidity in patients with PD and DLB, while no elevation of AD-related biomarkers was found in the high-risk individuals. Plasma NfL levels were higher in the high-risk, PD, and DLB groups than in the low-risk group and were associated with a higher rate of abnormalities in metaiodobenzylguanidine (MIBG) scintigraphy in the high-risk group. How this study might affect research, practice or policy: This study demonstrated that comorbid AD neuropathology exists in the symptomatic phase of LBD, though not in its prodromal phase. Plasma p-tau181 may be more sensitive for detecting comorbid AD neuropathology than plasma Aβ composite. Elevated plasma NfL levels may indicate aSyn-induced neurodegeneration in the prodromal phase of LBD.

Background: Abnormal amyloid‐β (Aβ) deposition in the brain has been defined as the earliest pathological change of Alzheimer disease (AD). We combined immunoprecipitation (IP) with MALDI‐TOF MS to develop IP‐MALDI‐MS, which is an analytical technique for plasma Aβ. This technique has previously revealed that APP669‐711/Aβ1‐42 ratio, Aβ1‐40/Aβ1‐42 ratio, and a combination of these two biomarkers (a composite biomarker) in human plasma correlates highly with SUVR obtained from amyloid PET (Nakamura et al., Nature, 2018). In this work, we validated a concordance between plasma Aβ biomarkers by IP‐MALDI‐MS and visual amyloid PET status with an independent dataset from the previous report.Method: Plasma samples were obtained from 41 Aβ+ and 55 Aβ‐ subjects classified using PET with PIB tracer in National Center for Geriatrics and Gerontology. Aβ‐related peptides were immunoprecipitated from the sample spiked by stable isotope‐labeled (SIL) Aβ1‐38 using beads coupled with anti‐Aβ antibody. After the IP was performed two times consecutively, Aβ‐related peptides eluted from the antibody beads were applied to MALDI‐TOF MS. SIL‐Aβ1‐38 was used as an internal standard for normalizing an intensity of each Aβ‐related peptide. APP669‐711/Aβ1‐42 ratio and Aβ1‐40/Aβ1‐42 ratio were calculated from those intensities and then the composite biomarker was generated as previous reported.Result: APP669‐711/Aβ1‐42 ratio, Aβ1‐40/Aβ1‐42 ratio and the composite biomarker were significantly higher in the Aβ+ group than the Aβ‐ group (p < 0.001). IP‐MALDI‐MS discriminated Aβ‐PET positivity with high AUC in APP669‐711/Aβ1‐42 ratio (92.8%), Aβ1‐40/Aβ1‐42 ratio (95.7%) and the composite biomarker (95.8%). Furthermore, an accuracy of the three biomarkers was 89.6‐92.7% in the Aβ+/‐ classification.Conclusion: Our results demonstrated high concordance of plasma Aβ biomarkers with visual amyloid PET status. The measurement by IP‐MALDI‐MS can provide the biomarker values highly associated with Aβ‐PET positivity.

Background: We recently developed a high‐performance plasma biomarker that reliably predicts individual brain status of amyloid‐β (Aβ) burden using immunoprecipitation‐mass spectrometry (IP‐MS). This study aimed to analyze performances of the plasma Aβ biomarker in a longitudinal dataset using J‐ADNI data.Method: There were 165 subjects, including 38 cognitively normal (CN), 61 MCI and 46 AD individuals who participated in the J‐ADNI study, and 132 of them had two times of follow‐up data within 36 months. The plasma composite biomarker was generated by combining plasma ratios of APP_669‐711/Aβ_1‐42 and Aβ_1‐40/Aβ_1‐42, which were measured by the IP‐MS assay. Using PiB‐PET as the standard of truth (Aβ+ or Aβ‐), plasma biomarker performances were analyzed using the ROC analysis. Relationships of plasma composite biomarker values and longitudinal changes in Aβ deposition (assessed by PiB‐SUVR), degree of medial temporal atrophy (assessed by VSRAD^® z‐scores of structural MRI), and cognitive decline (assessed by cognitive test scores) were analyzed.Result: The ROC analyses showed that the composite biomarker performs good both in base line data and follow up data with AUC greater than 90%. There were no significant changes in plasma composite biomarker values across longitudinal observations. The baseline composite biomarker values were significantly correlated with annual rate of Aβ deposition, especially within subjects whose baseline PiB‐SUVR was relatively small (less than 2.0). The baseline composite biomarker values were also significantly correlated with the rate of medial temporal atrophy and the rate of cognitive decline.Conclusion: Clinical utility of the plasma Aβ biomarker was validated in J‐ADNI longitudinal data, and it provided information for future disease progression.