The basis of anti-Aß antibody therapy: The toxicity of Aß aggregates and the mechanism of action of anti-Aß antibodies.

In the pathophysiology of Alzheimer's disease (AD), the amyloid hypothesis, which posits that amyloid ß-protein (Aß) abnormally aggregates and damages neurons with tau, has been proposed. It was originally thought that the accumulation of insoluble amyloid fibrils in the brain leads to AD-inducing neurotoxicity; however, in recent years, the positioning of early and intermediate aggregates has also been emphasized. In particular, following the positive results of phase 3 clinical trials of lecanemab and its approval in Japan and the United States, the pathology of protofibrils, which are the target molecules of lecanemab, has attracted attention. Using high-speed atomic force microscopy, we have previously reported that lecanemab, which has a high affinity for protofibrils, binds to and surrounds them. Donanemab, a recombinant monoclonal antibody that primarily targets fibrils composed of N3pG Aß, has also attracted attention because of its efficacy in phase 3 clinical trials in patients with early stage AD.

[Anti-Amyloid Antibody Therapy for Alzheimer's Disease].

Alzheimer's disease (AD) is pathologically characterized by deposition of amyloid plaques (comprising amyloid ß [Aß] protein) and neurofibrillary tangles (comprising tau protein), and neuronal death. Aß monomers aggregate to form oligomers, protofibrils, and mature fibrils. Previously, the mature fibrils and plaques were implicated as contributors to neurotoxicity and neurodegeneration. However, a growing body of evidence proves stronger toxicity of oligomers and protofibrils. Among the many recent phase 3 clinical trials that have investigated the role of anti-Aß antibodies in AD, some have shown the clinical efficacy of aducanumab, lecanemab, and donanemab in these patients. Lecanemab showed selectivity towards protofibrils over fibrils, and donanemab was specifically directed against Aß only in brain-specific amyloid plaques. In contrast, other anti-Aß antibodies did not show efficacy in AD.

Anti-amyloid ß Antibody Therapies for Alzheimer's Disease: Association between the Target of Amyloid ß Aggregates and the Clinical Efficacy of Anti-amyloid ß Antibody.

Phase 3 clinical trials have validated the clinical efficacy of some anti-amyloid ß (Aß) antibody therapies, such as lecanemab and donanemab. To date, several clinical trials of anti-Aß drugs have been conducted. However, most of these methods have been unsuccessful. Various Aß aggregates are present during Aß aggregation. The difference in the clinical efficacy of anti-Aß antibody therapy may be attributed to variations in the Aß aggregates targeted. Lecanemab primarily targets protofibrils, and donanemab targets plaques. Solanezumab and bapinezumab target Aß aggregates of monomers alone or from monomers to low molecular weight oligomers. Anti-Aß antibody therapies with clinical cognitive efficacy are thus characterized by targeting large-molecular-weight Aß aggregates, such as protofibrils and plaques. In addition, a positive association was observed between the reduction in amyloid deposition and the inhibition of cognitive decline.

Glucose metabolism and smaller hippocampal volume in elderly people with normal cognitive function.

We investigated associations of glycemic measures, and insulin resistance and secretion measures with hippocampal and subfield volumes. In this cross-sectional study, 7400 community-dwelling participants underwent brain MRI and health checkups between 2016 and 2018. Hemoglobin A1c (HbA1c), glycated albumin (GA), homeostasis model assessment for insulin resistance (HOMA-IR), and HOMA of percent ß-cell function (HOMA-ß) were evaluated. The associations of each measure with a smaller volume of the hippocampus and twelve hippocampal subfields were investigated. As a result, higher HbA1c or GA and lower HOMA-ß levels were significantly associated with smaller volumes in multiple hippocampal subfields. Furthermore, even when we analyzed non-diabetic individuals, substantial associations remained between higher GA or lower HOMA-ß levels and smaller volumes of the whole hippocampus or the fimbria. Our findings indicate that postprandial glucose fluctuations, postprandial hyperglycemia, and low insulin secretion have a specific effect on the development of smaller hippocampal volume, suggesting that primary prevention of diabetes and/or sufficient glucose control are important for the prevention of dementia.

Urinary D-asparagine level is decreased by the presence of glioblastoma.

Gliomas, particularly glioblastomas (GBMs), pose significant challenges due to their aggressiveness and poor prognosis. Early detection through biomarkers is critical for improving outcomes. This study aimed to identify novel biomarkers for gliomas, particularly GBMs, using chiral amino acid profiling. We used chiral amino acid analysis to measure amino acid L- and D-isomer levels in resected tissues (tumor and non-tumor), blood, and urine from 33 patients with primary gliomas and 24 healthy volunteers. The levels of D-amino acid oxidase (DAO), a D-amino acid-degrading enzyme, were evaluated to investigate the D-amino acid metabolism in brain tissue. The GBM mouse model was created by transplanting GBM cells into the brain to confirm whether gliomas affect blood and urine chiral amino acid profiles. We also assessed whether D-amino acids produced by GBM cells are involved in cell proliferation. D-asparagine (D-Asn) levels were higher and DAO expression was lower in glioma than in non-glioma tissues. Blood and urinary D-Asn levels were lower in patients with GBM than in healthy volunteers (p < 0.001), increasing after GBM removal (p < 0.05). Urinary D-Asn levels differentiated between healthy volunteers and patients with GBM (area under the curve: 0.93, sensitivity: 0.88, specificity: 0.92). GBM mouse model validated the decrease of urinary D-Asn in GBM. GBM cells used D-Asn for cell proliferation. Gliomas induce alterations in chiral amino acid profiles, affecting blood and urine levels. Urinary D-Asn emerges as a promising diagnostic biomarker for gliomas, reflecting tumor presence and severity.

A Supramolecular Biosensor for Rapid and High-Throughput Quantification of a Disease-Associated Niacin Metabolite.

Metabolic abnormalities play a pivotal role in various pathological conditions, necessitating the quantification of specific metabolites for diagnosis. While mass spectrometry remains the primary method for metabolite measurement, its limited throughput underscores the need for biosensors capable of rapid detection. Previously, we reported that pillar[6]arene with 12 carboxylate groups (P6AC) forms host-guest complexes with 1-methylnicotinamide (1-MNA), which is produced in vivo by nicotinamide N-methyltransferase (NNMT). P6AC acts as a biosensor by measuring the fluorescence quenching caused by photoinduced electron transfer upon 1-MNA binding. However, the low sensitivity of P6AC makes it impractical for detecting 1-MNA in unpurified biological samples. In this study, we found that P6A with 12 sulfonate groups (P6AS) is a specific and potent supramolecular host for 1-MNA interactions even in biological samples. The 1-MNA binding affinity of P6AS in water was found to be (5.68 ± 1.02) × 106 M-1, which is approximately 700-fold higher than that of P6AC. Moreover, the 1-MNA detection limit of P6AS was determined to be 2.84 × 10-7 M, which is substantially lower than that of P6AC. Direct addition of P6AS to culture medium was sufficient to quantify 1-MNA produced by cancer cells. Furthermore, this sensor was able to specifically detect 1-MNA even in unpurified human urine. P6AS therefore enables rapid and high-throughput quantification of 1-MNA, and further improvement of our strategy will contribute to the establishment of high-throughput screening of NNMT inhibitors, diagnosis of liver diseases, and imaging of human cancer cells in vivo.

[A case of left posterior cortical atrophy presenting with kana-predominant reading impairment].

The patient was an 85-year-old man with a one-year history of difficulty reading kana. Neuropsychological evaluation revealed kana (phonogram)-selective reading impairment and kanji (ideogram)-dominant writing impairment. MRI revealed significant cerebral atrophy in the left occipital cortex, leading to the clinical diagnosis of posterior cortical atrophy (PCA). Cerebrospinal fluid amyloid ß1-42 levels were reduced, and amyloid PET showed accumulation in the posterior cingulate cortex, precuneus, and frontal lobe. In contrast, tau PET showed no accumulation in the atrophied brain areas. Episodes of REM sleep behavior disorder and decreased uptake on meta-iodobenzylguanidine (MIBG) myocardial scintigraphy suggested the involvement of Lewy body pathology. PCA with distinct laterality has been rarely reported, and |this is the first case to present Kana-selective reading impairment and Kanji-dominant writing impairment with neurodegenerative background.

Lutein from Chicken Eggs Prevents Amyloid ß-Peptide Aggregation In Vitro and Amyloid ß-Induced Inflammation in Human Macrophages (THP-1).

Epidemiological studies predict that chicken eggs contain constituents other than proteins that prevent Alzheimer's disease. This study screened for constituents that inhibit the aggregation of amyloid ß peptide (Aß)1-42 and elucidated their mechanisms to explore the active components of chicken eggs. Thioflavin T assays and transmission electron microscopy observations showed that arachidonic acid (ARA), lysophosphatidylcholine, lutein (LTN), palmitoleic acid, and zeaxanthin inhibited Aß aggregation. Among these, ARA and LTN showed the highest activity. Photoinduced cross-linking of unmodified protein assays and infrared absorption spectrometry measurements showed that LTN strongly inhibited highly toxic Aß1-42 protofibril formation. Furthermore, LTN suppressed Aß1-42-induced IL 1B and TNF expression in human macrophage-like cells. In summary, LTN plays a crucial role in the AD-preventive effect of chicken eggs by suppressing Aß1-42 aggregation and Aß1-42-induced inflammation.

Sympathetic 123I-metaiodobenzylguanidine index for Lewy body disease: probability-based diagnosis and identifying patients exempt from late imaging.

OBJECTIVE: We aimed to establish a practical diagnostic index for Lewy body diseases (LBD), such as Parkinson's disease and dementia, with Lewy bodies in outpatient settings and criteria for exempting patients from late imaging. METHODS: We acquired early and late 123I-metaiodobenzylguanidine (MIBG) images from 108 consecutive patients with suspected LBD and standardized heart-to-mediastinum (H/M) ratios for collimator conditions. Exclusions included young-onset Parkinson's disease (age < 50 years) and genetic transthyretin-type amyloidosis. We developed logistic models incorporating H/M ratios with or without age (n = 92). The sympathetic MIBG index for LBD (SMILe index), categorized LBD likelihood from 0 (lowest) to 1 (highest). Diagnostic accuracy was assessed as the area under the receiver operating characteristic (ROC) curve (AUC). The characteristics of the new index were compared with H/M ratios. The need for late imaging was explored using the SMILe index. RESULTS: Early or late SMILe indexes using a single H/M ratio variable discriminated LBD from non-LBD. The AUC values for early and late SMILe indexes were 0.880 and 0.894 (p < 0.0001 for both), identical to those for early and late H/M ratios. The sensitivity and the specificity of early SMILe indexes with a 0.5 threshold were 76% and 90%, achieving accuracy of accuracy 86%. Similarly, the late SMILe index demonstrated a sensitivity of 76% and specificity of 87%, with an accuracy of 84%. Early SMILe indexes < 0.3 or > 0.7 (representing 84% patients) indicated a diagnosis without a late MIBG study. CONCLUSION: The 123I-MIBG-derived SMILe indexes provide likelihood of LBD, and those with a 50% threshold demonstrated optimal diagnostic accuracy for LBD. The index values of either < 0.3 or > 0.7 accurately selected patients who do not need late imaging.

Absolute quantitation of sympathetic nerve activity using [123I] metaiodobenzylguanidine SPECT-CT in neurology.

BACKGROUND AND PURPOSE: The ability of [123I]metaiodobenzylguanidine (MIBG) sympathetic nerve imaging with three-dimensional (3D) quantitation to clinically diagnose neurological disorders has not been evaluated. This study compared absolute heart counts calculated as mean standardized uptake values (SUVmean) using conventional planar imaging and assessed the contribution of [123I]MIBG single-photon emission computed tomography (SPECT)-CT to the diagnosis of neurological diseases. METHODS: Seventy-two patients with neurological diseases were consecutively assessed using early and delayed [123I]MIBG SPECT-CT and planar imaging. Left ventricles were manually segmented in early and delayed SPECT-CT images, then the SUVmean and washout rates (WRs) were calculated. Heart-to-mediastinum ratios (HMRs) and WRs on planar images were conventionally computed. We investigated correlations between planar HMRs and SPECT-CT SUVmeans and between WRs obtained from planar and SPECT-CT images. The cutoff for SPECT-CT WRs defined by linear regression and that of normal planar WRs derived from a database were compared with neurological diagnoses of the patients. We assigned the patients to groups according to clinical diagnoses as controls (n = 6), multiple system atrophy (MSA, n = 7), progressive supranuclear palsy (PSP, n = 17), and Parkinson's disease or dementia with Lewy bodies (PD/DLB, n = 19), then compared SPECT-CT and planar image parameters. RESULTS: We found significant correlations between SPECT-CT SUVmean and planar HMR on early and delayed images (R2 = 0.69 and 0.82, p < 0.0001) and between SPECT-CT and planar WRs (R2 = 0.79, p < 0.0001). A threshold of 31% for SPECT-CT WR based on linear regression resulted in agreement between planar and SPECT-CT WR in 67 (93.1%) of 72 patients. Compared with controls, early and delayed SUVmean in patients with PSP and MSA tended more towards significance than planar HMR. This trend was similar for SPECT-CT WRs in patients with PSP. CONCLUSIONS: Absolute heart counts and SUVmean determined using [123I]MIBG SPECT-CT correlated with findings of conventional planar images in patients with neurological diseases. Three-dimensional quantitation with [123I]MIBG SPECT-CT imaging might differentiate patients with PSP and MSA from controls.

Plasma biomarkers for predicting the development of dementia in a community-dwelling older Japanese population.

AIM: To assess the association between plasma amyloid ß (Aß) 42/40, phosphorylated tau (p-τ)181, glial fibrillary acidic protein (GFAP), or neurofilament light chain (NfL) and the risk of dementia and to determine whether these plasma biomarkers could improve the ability to predict incident dementia in a general older population. METHODS: A total of 1346 Japanese community-dwelling individuals aged ≥65 years without dementia were followed prospectively for 5.0 years. Plasma biomarkers were quantified using a Simoa HD-X analyzer. A Cox proportional hazards model was used to estimate the hazard ratios of each plasma biomarker level for the risk of dementia. RESULTS: During the follow-up, 151 participants developed dementia, of whom 108 had Alzheimer disease (AD) and 43 non-Alzheimer dementia (non-AD). Lower plasma Aß42/40 levels and higher plasma p-τ181 levels were significantly associated with developing AD but not non-AD, whereas significant associations were observed between higher plasma levels of GFAP and NfL and risk of both AD and non-AD (all P for trend <0.05). In addition, adding these four plasma biomarkers into a model consisting of the total score of the dementia risk model significantly improved the predictive ability for incident dementia. CONCLUSION: Our findings suggest that plasma Aß42/40 and p-τ181 are specific markers of AD, and plasma GFAP and NfL are potential biomarkers for all-cause dementia in the general Japanese older population. In addition, the measurement of these plasma biomarkers may be a useful and relatively low-invasive procedure for identifying individuals at high risk for developing dementia in clinical practice.

[The Roles of Aß in Alzheimer's Disease: In Light of the Latest Findings].

The 'amyloid hypothesis', initially put forward in 1992, posits that amyloid ß protein (Aß) contributes to neurodegeneration through aberrant aggregation. In the process of this aberrant aggregation, Aß forms oligomers, protofibrils, and mature fibrils, ultimately developing plaques. These mature fibrils and plaques were believed to be the culprits behind the neurotoxicity and neurodegeneration seen in Alzheimer's disease (AD). However, growing evidence in recent years has led to the 'Aß oligomer hypothesis', which suggests that the intermediate forms of aggregates, such as oligomers and protofibrils, exhibit stronger neurotoxicity than the mature forms. Consequently, efforts have been made to develop anti-Aß antibody drugs that specifically target these intermediate aggregates. Such interventions hold promise as disease-modifying treatments for AD.

Serum high-sensitivity C-reactive protein and dementia in a community-dwelling Japanese older population (JPSC-AD).

In recent years, the association between neuroinflammatory markers and dementia, especially Alzheimer's disease (AD), has attracted much attention. However, the evidence for the relationship between serum-hs-CRP and dementia including AD are inconsistent. Therefore, the relationships of serum high-sensitivity CRP (hs-CRP) with dementia including AD and with regions of interest of brain MRI were investigated. A total of 11,957 community residents aged 65 years or older were recruited in eight sites in Japan (JPSC-AD Study). After applying exclusion criteria, 10,085 participants who underwent blood tests and health-related examinations were analyzed. Then, serum hs-CRP levels were classified according to clinical cutoff values, and odds ratios for the presence of all-cause dementia and its subtypes were calculated for each serum hs-CRP level. In addition, the association between serum hs-CRP and brain volume regions of interest was also examined using analysis of covariance with data from 8614 individuals in the same cohort who underwent brain MRI. After multivariable adjustment, the odds ratios (ORs) for all-cause dementia were 1.04 (95% confidence interval [CI] 0.76-1.43), 1.68 (95%CI 1.08-2.61), and 1.51 (95%CI 1.08-2.11) for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L, and those for AD were 0.72 (95%CI 0.48-1.08), 1.76 (95%CI 1.08-2.89), and 1.61 (95%CI 1.11-2.35), for 1.0-1.9 mg/L, 2.0-2.9 mg/L, and ≥ 3.0 mg/L, respectively, compared to < 1.0 mg/L. Multivariable-adjusted ORs for all-cause dementia and for AD prevalence increased significantly with increasing serum hs-CRP levels (p for trend < 0.001 and p = 0.001, respectively). In addition, the multivariable-adjusted temporal cortex volume/estimated total intracranial volume ratio decreased significantly with increasing serum hs-CRP levels (< 1.0 mg/L 4.28%, 1.0-1.9 mg/L 4.27%, 2.0-2.9 mg/L 4.29%, ≥ 3.0 mg/L 4.21%; p for trend = 0.004). This study's results suggest that elevated serum hs-CRP levels are associated with greater risk of presence of dementia, especially AD, and of temporal cortex atrophy in a community-dwelling Japanese older population.

Brain atrophy in normal older adult links tooth loss and diet changes to future cognitive decline.

Several studies have found associations between poor oral health, particularly tooth loss and cognitive decline. However, the specific brain regions affected by tooth loss and the probable causes remain unclear. We conducted a population-based longitudinal cohort study in Nakajima, Nanao City, Japan. Between 2016 and 2018, 2454 residents aged ≥60 participated, covering 92.9% of the local age demographics. This study used comprehensive approach by combining detailed dental examinations, dietary assessments, magnetic resonance imaging (MRI) analysis, and cognitive evaluations. Tooth loss, even in cognitively normal individuals, is associated with parahippocampal gyrus atrophy and increased WMH volume, both of which are characteristics of dementia. Tooth loss was associated with altered dietary patterns, notably a reduction in plant-based food intake and an increase in fatty, processed food intake. This study highlights a possible preventative pathway where oral health may play a significant role in preventing the early neuropathological shifts associated with dementia.

Extracellular high molecular weight α-synuclein oligomers induce cell death by disrupting the plasma membrane.

α-Synuclein (αS), the causative protein of Parkinson's disease and other α-synucleinopathies, aggregates from a low molecular weight form (LMW-αS) to a high molecular weight αS oligomer (HMW-αSo). Aggregated αS accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular αS aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-αSo or LMW-αS. Extracellular HMW-αSo was more cytotoxic than LMW-αS and was a crucial factor for inducing plasma membrane damage and cell death. HMW-αSo induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-αSo also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-αSo causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for α-synucleinopathies.

Diffuse glioma-induced structural reorganization in close association with preexisting syntax-related networks.

Glioma in the left frontal cortex has been reported to cause agrammatic comprehension and induce global functional connectivity alterations within the syntax-related networks. However, it remains unclear to what extent the structural reorganization is affected by preexisting syntax-related networks. We examined 28 patients with a diffuse glioma in the left hemisphere and 23 healthy participants. Syntactic abilities were assessed by a picture-sentence matching task with various sentence types. The lesion responsible for agrammatic comprehension was identified by region-of-interest-based lesion-symptom mapping (RLSM). Cortical structural alterations were examined by surface-based morphometry (SBM), in which the cortical thickness and fractal dimension were measured with three-dimensional magnetic resonance imaging (MRI). Fiber tracking on the human population-averaged diffusion MRI template was performed to examine whether the cortical structural alterations were associated with the syntax-related networks. The RLSM revealed associations between agrammatic comprehension and a glioma in the posterior limb of the left internal capsule. The SBM demonstrated that decreased cortical thickness and/or increased complexity of the right posterior insula were associated not only with agrammatic comprehension of the patients but also with the syntactic abilities of healthy participants. The fiber tracking revealed that the route between these two regions was anatomically integrated into the preexisting syntax-related networks previously identified. These results suggest a potential association between agrammatic comprehension in patients with diffuse glioma and structural variations in specific tracts and cortical regions, which may be closely related to the syntax-related networks.

IgG index of cerebrospinal fluid can reflect pathophysiology associated with Lewy bodies in Parkinson's disease.

BACKGROUND: Neuroinflammation is one of the pathophysiologies of Parkinson's disease (PD). Lewy bodies, the pathological hallmark of PD, emerge as a consequence of α-synuclein aggregation, and neuroinflammation is induced concurrently with this aggregation. Imaging and cerebrospinal fluid (CSF) biomarkers that reflect PD pathophysiology have been developed or are under investigation. The IgG index of CSF is a marker of inflammation, and may also reflect the pathophysiology of PD. AIM: We examined if the IgG index reflects the pathophysiology of PD in drug-naïve PD patients. METHOD: The subjects were 20 consecutive PD patients who underwent 123I-MIBG scintigraphy for assessment of the heart to mediastinum (H/M) ratio and wash out rate, 123I-Ioflupane SPECT for examination of the specific binding ratio in the striatum, and lumbar puncture before treatment. The CSF IgG index and levels of pathogenic proteins (total α-synuclein, oligomeric α-synuclein, total tau, phosphorylated tau and amyloid Aß1-42) were determined. The IgG index was compared with the other parameters using Spearman correlation analysis. RESULTS: The IgG index showed a significant correlation with the H/M ratio in early (r = -0.563, p = 0.010) and delayed (r = -0.466, p = 0.038) images in 123I-MIBG scintigraphy and with the CSF total tau level (r = -0.513, p = 0.021). CONCLUSION: Neuroinflammation is involved in PD pathophysiology in some patients, and a higher IgG index indicates the presence of neuroinflammation accompanied by emergence of Lewy bodies.

Gender and age influence the association between gait speed and mild cognitive impairment in community-dwelling Japanese older adults: from the Japan Prospective Studies Collaboration for Ageing and Dementia (JPSC-AD).

BACKGROUND: Studies have shown that decreased gait speed is associated with impaired cognitive function. However, whether this association is equivalent across ages or genders in the older population remains unclear. Thus, we examined the association between mild cognitive impairment (MCI) and gait speed emphasising the influence of age and gender. METHODS: Overall, 8233 Japanese participants aged ≥65 years were enrolled in this cross-sectional study between 2016 and 2018. After stratification by gender and age group, the participants' gait speeds were divided into quintiles, and the difference in MCI prevalence at each gait speed quintile was calculated. Logistic regression analyses were performed to assess the odds of MCI for each quintile and to assess the influence of age and gender. RESULTS: Males had a consistently higher prevalence of MCI than females. The odds of MCI were increased as gait speed decreased. Logistic regression analyses revealed that in the multivariable-adjusted model 2, the odds ratios (95% confidence interval; CI) for MCI were 2.02 (1.47-2.76) for females and 1.75 (1.29-2.38) for males in the slowest gait speed quintiles compared to the fastest quintile. In the stratified analyses, only males showed an age-dependent increase in the associations between gait speed and MCI, while females exhibited comparable associations across age groups. CONCLUSIONS: Reduced gait speed was associated with increased odds of MCI, and this association may vary according to gender and age. Therefore, gait speed could serve as a valuable screening tool for MCI, with gender- and age-dependent clinical implications.