X-linked Myotubular Myopathy Manifesting Carrier with Central and Peripheral Nervous System Involvement.

X-linked myotubular myopathy (XLMTM) is a rare genetic disorder caused by X-linked mutations in the MTM1 gene. Although heterozygous females are typically asymptomatic, affected cases have recently been reported. We herein report a case of XLMTM manifesting carrier of the pathogenic c.206dupG mutation in MTM1 with uncommon extramuscular symptoms. She developed gaze nystagmus and cognitive impairment in addition to muscle weakness. Electrophysiological studies and brain magnetic resonance imaging indicated the involvement of the central and peripheral nervous systems. XLMTM manifesting carriers may have a wider spectrum of clinical phenotypes than currently assumed. Appropriate follow-up of extramuscular and conventional muscular manifestations is important in such cases.

Efficacy of Computed Tomography-Based Evaluation of Myocardial Extracellular Volume Combined With Red Flags for Early Screening of Concealed Cardiac Amyloidosis in Patients With Atrial Fibrillation.

BACKGROUND: The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed tomography-based myocardial extracellular volume (CT-ECV) combined with red flags for the early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.Methods and Results: Patients referred for AF ablation at Oita University Hospital were prescreened using the red-flag signs defined by echocardiographic or electrocardiographic findings, medical history, symptoms, and blood biochemical findings. Myocardial CT-ECV was quantified in red flag-positive patients using routine pre-AF ablation planning cardiac CT with the addition of delayed-phase cardiac CT scans. Patients with high (>35%) ECV were evaluated using technetium pyrophosphate (99 mTc-PYP) scintigraphy. A cardiac biopsy was performed during the planned AF ablation procedure if 99 mTc-PYP scintigraphy was positive. Between June 2022 and June 2023, 342 patients were referred for AF ablation. Sixty-seven (19.6%) patients had at least one of the red-flag signs. Myocardial CT-ECV was evaluated in 57 patients because of contraindications to contrast media, revealing that 16 patients had high CT-ECV. Of these, 6 patients showed a positive 99 mTc-PYP study, and 6 patients were subsequently diagnosed with wild-type ATTR-CM via cardiac biopsy and genetic testing. CONCLUSIONS: CT-ECV combined with red flags could contribute to the systematic early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.

Cognitive Impairment and Early-onset Cerebral Amyloid Angiopathy in a Middle-aged Man with a History of Childhood Traumatic Brain Injury.

We herein report the a 42-year-old man with early-onset cerebral amyloid angiopathy (CAA) and a history of traumatic brain injury and neurosurgery in childhood. Computed tomography revealed cognitive impairment and recurrent lobar intracerebral hemorrhaging. Magnetic resonance imaging indicated cerebral microbleeds, and Pittsburgh compound B positron emission tomography detected brain amyloid deposition, mainly in the region of trauma and occipital lobes. Interestingly, the patient had no genetic predispositions or relevant family history. This case suggests that a single traumatic brain injury or neurosurgery in childhood can cause early-onset CAA.

Objectively measured prolonged sleep is associated with plasma cytokines in older adults with mild cognitive impairment.

This study aimed to determine whether objective sleep time is associated with the concentrations of various plasma cytokines in older adults with mild cognitive impairment (MCI). In total, 118 adults with MCI (66 women; mean age: 75.7 years) participated in this prospective cohort study. All participants were required to wear a wristband sensor for 7.8 days, on average, every 3 months for 1 year and undergo measurement of 27 plasma cytokines using multiplex immunoassays. After adjusting for potential confounders, the associations of total sleep time with cytokine concentrations were assessed by multiple linear regression analysis. The total sleep time was significantly correlated with plasma interleukin (IL)-9 and macrophage inflammatory protein (MIP)-1ß levels (r = 0.239, p = 0.009, and r = 0.242, p = 0.008, respectively). Moreover, these associations remained significant after adjusting for covariates, including demographic characteristics, lifestyle-related diseases, and apolipoprotein E status (ß = 0.272, 95% confidence interval: 0.095-0.448, p = 0.003, and ß = 0.27, 95% confidence interval: 0.092-0.449, p = 0.003, respectively). Thus, this study is the first to demonstrate the association between objective prolonged sleep and higher plasma IL-9 and MIP-1ß levels in older adults with MCI.

Predicting positron emission tomography brain amyloid positivity using interpretable machine learning models with wearable sensor data and lifestyle factors.

BACKGROUND: Developing a screening method for identifying individuals at higher risk of elevated brain amyloid burden is important to reduce costs and burden to patients in clinical trials on Alzheimer's disease or the clinical setting. We developed machine learning models using objectively measured lifestyle factors to predict elevated brain amyloid burden on positron emission tomography. METHODS: Our prospective cohort study of non-demented, community-dwelling older adults aged ≥ 65 years was conducted from August 2015 to September 2019 in Usuki, Oita Prefecture, Japan. One hundred and twenty-two individuals with mild cognitive impairment or subjective memory complaints (54 men and 68 women, median age: 75.50 years) wore wearable sensors and completed self-reported questionnaires, cognitive test, and positron emission tomography imaging at baseline. Moreover, 99 individuals in the second year and 61 individuals in the third year were followed up. In total, 282 eligible records with valid wearable sensors, cognitive test results, and amyloid imaging and data on demographic characteristics, living environments, and health behaviors were used in the machine learning models. Amyloid positivity was defined as a standardized uptake value ratio of ≥ 1.4. Models were constructed using kernel support vector machine, Elastic Net, and logistic regression for predicting amyloid positivity. The mean score among 10 times fivefold cross-validation repeats was utilized for evaluation. RESULTS: In Elastic Net, the mean area under the receiver operating characteristic curve of the model using objectively measured lifestyle factors alone was 0.70, whereas that of the models using wearable sensors in combination with demographic characteristics and health and life environment questionnaires was 0.79. Moreover, 22 variables were common to all machine learning models. CONCLUSION: Our machine learning models are useful for predicting elevated brain amyloid burden using readily-available and noninvasive variables without the need to visit a hospital. TRIAL REGISTRATION: This prospective study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of Oita University Hospital (UMIN000017442). A written informed consent was obtained from all participants. This research was performed based on the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.

Objective sleep was longitudinally associated with brain amyloid burden in mild cognitive impairment.

OBJECTIVE: Understanding the longitudinal association of objective sleep and physical activity with brain amyloid burden and cortical glucose metabolism has critical clinical and public health implications for dementia prevention in later life. METHODS: We enrolled 118 individuals aged ≥65 years with mild cognitive impairment, who were followed up on from August 2015 to September 2019. All participants continuously wore an accelerometer sensor for 7 consecutive days every 3 months and received annual 11 C-Pittsburgh compound-B and 18 F-fluorodeoxyglucose positron emission tomography (PET). Sleep and physical activity parameters were assessed using accelerometer sensor data and PET imaging was quantified using a standardized uptake-value ratio. Fifty-seven participants (48.3%) completed a lifestyle factor assessment and PET imaging over the 3-year period. A linear mixed-effects model was applied to examine the longitudinal association of sleep and physical activity parameters with PET imaging over the 3-year period, controlling for potential confounders. RESULTS: Sleep efficiency was inversely associated with amyloid uptake in the frontal lobe. Although sleep duration was positively associated with global amyloid uptake, particularly in the frontal lobe, their impact was extremely small. However, physical activity parameters were not significantly associated with the 11 C-Pittsburgh compound-B-uptake. Furthermore, sleep and physical activity parameters were not significantly associated with cortical glucose metabolism. INTERPRETATION: Lower sleep efficiency could be an early symptom of greater brain amyloid burden at the mild cognitive impairment stage. Therefore, the assessment of sleep may be useful for identifying individuals at higher risk for brain amyloid burden. Future longer term observational studies are required to confirm these findings.

Lifestyle factors that affect cognitive function-a longitudinal objective analysis.

Background: Identifying lifestyle factors associated with cognitive decline has critical clinical and public health implications for dementia prevention in later life. The longitudinal associations of sleep and physical activity with cognitive function remain unclear. This study examined whether objectively measured sleep and physical activity were longitudinally associated with cognitive function in older adults over a three-year period. Methods: This prospective cohort study enrolled 855 community-dwelling adults aged 65 and older, who were followed from 2015 to 2019. All participants were required to wear a wearable sensor for 7 consecutive days every 3 months and had annual cognitive assessments. Wearable sensor data (August 2015-September 2019) and Mini-Mental State Examination (MMSE) scores (August 2015-April 2019) were collected over 3 years of follow-up. First, principal component analysis was conducted to reduce the dimensions of the sleep and physical activity variables to two principal components for inclusion in a mixed-effects model. The sleep index consisted of sleep efficiency, time awake after sleep onset, and waking frequency. The physical activity index was composed of walking comprised steps per day and time devoted to light or moderate-to-vigorous physical activity. A higher sleep index indicated poor sleep quality, whereas a lower physical activity index indicated less physical activity. Second, a linear mixed effect model was used to examine the longitudinal association of sleep and physical activity indices with cognitive decline over time. Results: In total, 855 adults were recruited for this study at baseline. Of these, 729 adults (85.3%) completed a measurement of lifestyle factors and an annual cognitive testing, whereas 126 were excluded because of death or loss during follow-up. After adjusting for age, sex, education level, and time, the sleep index was inversely associated with MMSE scores (estimate, -0.06229; standard error, 0.02202; p = 0.0047) and the physical activity index was positively associated with MMSE scores (estimate, 0.06699; standard error, 0.03343; p = 0.0453). Conclusion: Poor sleep quality and lower physical activity were significant risk factors for subsequent cognitive decline in older adults. The present study facilitates the development of novel evidence-based interventions for physical activity and sleep quality to delay cognitive decline.

Comparison of Brain Amyloid Deposition and Cortical Glucose Metabolism Between Clinic- and Community-Based Cohort.

BACKGROUND: The differences in positron emission tomography (PET) imaging among older adults with mild cognitive impairment (MCI), according to the recruitment source, remain unclear. OBJECTIVE: To investigate the differences in brain amyloid deposition and cortical glucose metabolism according to recruitment source among older adults with MCI. METHODS: Participants in the clinic-based MCI cohort, who were referred to Oita University Hospital for cognitive decline, consisted of 90 adults with MCI. The community-based MCI cohort, which participated in a prospective cohort study, consisted of 118 adults with MCI. Participants underwent cognitive function evaluation, 11C-Pittsburgh compound B (PiB)-PET, and 18F-fluorodeoxyglucose (FDG)-PET. The prevalence of amyloid positivity and mean PiB and FDG uptake values were compared between the cohorts. Moreover, a voxel-by-voxel group study was performed to determine the areas with significant differences between the clinic- and community-based MCI cohorts. RESULTS: The prevalence of amyloid positivity and mean PiB uptake value in the clinic-based MCI cohort were significantly higher than those in the community-based MCI cohort (p < 0.001 and p < 0.001, respectively). The mean FDG uptake value in the clinic-based MCI cohort was significantly lower than that in the community-based MCI cohort (p < 0.001). SPM 8 analysis showed significantly increased PiB uptake in the precuneus and parietotemporal lobe and significantly decreased FDG uptake in the posterior cingulate in the clinic-based MCI cohort compared to the community-based MCI cohort. CONCLUSION: The prevalence and severity of amyloid pathology in older adults with MCI varied depending on the recruitment source.

Cerebrospinal fluid B-cell activating factor levels as a novel biomarker in patients with neurosarcoidosis.

OBJECTIVES: Neurosarcoidosis (NS) is a severe complication of sarcoidosis. Patients with NS often have poor outcomes. To improve both the quality of life and prognosis in patients with NS, accurate and reliable methods for early diagnosis and determining the efficacy of treatment are needed. This study aims to investigate B-cell-activating factor of the tumor necrosis factor family (BAFF) in cerebrospinal fluid (CSF) and elucidate the relationship between CSF BAFF levels and various parameters of NS. METHODS: We studied 20 patients with NS and 14 control subjects. We measured CSF BAFF levels in all subjects and investigated the relationship with clinical findings, serum and CSF measures, and magnetic resonance imaging (MRI) findings. RESULTS: CSF BAFF levels were significantly increased in patients with NS compared with controls (median 0.089 vs 0.04 ng/mL, p = 0.0005). CSF BAFF values were correlated with CSF findings-cell count, protein, angiotensin-converting enzyme, lysozyme, soluble interleukin-2 receptor, and immunoglobulin G-but not with serum parameters. CSF BAFF levels were especially higher in patients with abnormal intraparenchymal lesions of the brain and abnormal spinal MRI findings. CSF BAFF levels decreased significantly after immunosuppressive therapy. CONCLUSION: CSF BAFF may aid the quantitative evaluation of NS and may serve as a biomarker for this disease.

A Case of Miller Fisher Syndrome with Cerebellar Hypoperfusion.

We report a case of a 76-year-old man with Miller Fisher syndrome presenting with acute ophthalmoplegia and ataxia. Cerebrospinal fluid analysis showed normocytosis with an increased protein level. Serum anti-GQ1b IgG and anti-GT1a IgG antibodies were positive. Based on these results, the patient was diagnosed with Miller Fisher syndrome. He was treated with two courses of intravenous immunoglobulin, which improved his neurological symptoms. Brain perfusion single-photon emission computed tomography showed that cerebellar blood flow was decreased in the acute stage of the disease and improved after treatment. Although the prevailing view is that ataxia in Miller Fisher syndrome patients is of a peripheral origin, this case suggests that cerebellar hypoperfusion contributes to the development of ataxia in Miller Fisher syndrome.

Peripheral administration of nanomicelle-encapsulated anti-Aß oligomer fragment antibody reduces various toxic Aß species in the brain.

BACKGROUND: Although a large amount of evidence has revealed that amyloid ß (Aß), especially Aß oligomers, protofibrils, and pyroglutamated Aßs, participate primarily in the pathophysiological processes of Alzheimer's disease, most clinical trials of anti-Aß antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aß oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer's disease pathology in Alzheimer's disease model mice at the age of emergence of early Alzheimer's disease pathology. RESULTS: During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aß species, such as Aß oligomers, toxic Aß conformers, and pyroglutamated Aßs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aß plaques, Aß-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimer's disease. CONCLUSIONS: The results indicated that the strategy of reducing toxic Aß species in early dementia owing to Alzheimer's disease by providing sufficient antibodies in the brain may modify Alzheimer's disease progression.

Cerebrospinal Fluid Interleukin-6 in Immune Checkpoint Inhibitor-Induced Autoimmune Meningoencephalitis.

Immune checkpoint inhibitors (ICIs) have proven clinical benefits in various advanced cancers. However, despite their significant therapeutic efficacy, ICIs induce immune-related adverse events. Among these events, autoimmune meningoencephalitis often has severe effects on patients' outcomes, but its specific clinical features are still unclear. Here, we report two cases of ICI-associated meningoencephalitis with elevated interleukin-6 (IL-6) levels in the cerebrospinal fluid (CSF). A 47-year-old woman (Case 1) with renal cell carcinoma developed severe headache after a seventh nivolumab administration. A neurological examination revealed jolt accentuation signs and hyperreflexia in all extremities. CSF analysis revealed a high IL-6 value (6,620 pg/mL) with marked pleocytosis. A 70-year-old woman (Case 2) who received an initial administration of nivolumab plus ipilimumab for renal cell carcinoma developed alterations of consciousness. She presented with impaired consciousness, neck stiffness, and hyperreflexia in all extremities. CSF analysis demonstrated a high IL-6 value (49.3 pg/mL) with mild pleocytosis. Both patients were treated with steroid pulse therapy (methylprednisolone 1,000 mg/day, 3 days), followed by the administration of oral predonisolone. The symptoms and laboratory findings improved in both cases. CSF IL-6 values were proportional to the severity of meningoencephalitis and other clinical parameters. These findings may help elucidate the mechanisms of central nervous system complications that are caused by ICIs.

Changes in objectively measured lifestyle factors during the COVID-19 pandemic in community-dwelling older adults.

BACKGROUND: In this manuscript, we investigate whether objectively measured lifestyle factors, including walking steps, sedentary time, amount of unforced physical activity, level of slight and energetic physical activity, conversation time, and sleep parameters, were altered before and during the COVID-19 pandemic among community-dwelling older adults. METHODS: Data were obtained from a prospective cohort study conducted from 2015 to 2019 and a subsequent dementia prevention study undertaken in September 2020. Community-dwelling adults aged ≥ 65 years wore wearable sensors before and during the pandemic. RESULTS: A total of 56 adults were enrolled in this study. The mean age was 74.2 ± 3.9 years, and 58.9% (n = 33) of the participants were female. Moderate and vigorous physical activity time significantly decreased, and sedentary time significantly increased during the pandemic. CONCLUSIONS: This is the first study to demonstrate differences in objectively assessed lifestyle factors before and during the COVID-19 pandemic among community-dwelling older adults. The findings show that the pandemic has adversely affected physical activity among older adults living on their own in Japan.

Association of serum thyroid hormone levels with positron emission tomography imaging in non-demented older adults.

BACKGROUND: Although increasing evidence indicates that even variations in normal range thyroid function are associated with Alzheimer's disease (AD), the association between serum thyroid hormone levels within the reference range and AD biomarkers remains unclear. This study examined whether variations in thyroid hormones within the reference range are associated with brain amyloid burden and cortical glucose metabolism in older adults without dementia. METHODS: One hundred and two non-demented older adults underwent 11 C-Pittsburgh Compound B positron emission tomography (PiB-PET), 18 F-fluorodeoxyglucose (FDG)-PET, and measurement of serum thyroid-stimulating hormone (TSH), free triiodothyronine (T3), and free thyroxine (T4) levels. The discrimination between PiB-negative and PiB-positive subgroup was made on the basis of a subject's cortical uptake value ratio greater than 1.4. The association of serum thyroid hormone levels with global PiB or FDG uptake, and PiB or FDG uptake in each region of interest, including frontal and temporoparietal lobes and posterior cingulate gyrus, was analysed using a multiple regression model with adjustment for covariates, including age, gender, years of education, apolipoprotein E4 status or PiB uptake value. RESULTS: In the PiB-positive subgroup, the serum TSH levels positively associated with the global FDG uptake (ß = 0.471, P = 0.003) and FDG uptake in the frontal and temporoparietal lobes (ß = 0.466, P = 0.003, ß = 0.394, P = 0.012, respectively); the serum-free T3 levels negatively associated with the FDG uptake in the temporoparietal lobe and posterior cingulate region (ß = -0.351, P = 0.033, ß = -0.544, P = 0.002, respectively). The PiB-negative subgroup showed no significant associations. The serum thyroid hormone levels did not correlate with the global PiB uptake and PiB uptake in each region. CONCLUSIONS: The variations in the thyroid hormones within the reference ranges are associated with glucose metabolism, particularly in the specific regions affected by the neuropathologic changes of AD, in non-demented older adults with brain amyloid burden.

Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-ß (Aß) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aß, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-ß 42 (Aß42)/Aß40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aß clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Association between Benton Visual Retention Test Scores and PET Imaging in Elderly Adults.

BACKGROUND: The Benton Visual Retention Test (BVRT) is a well-validated and reliable test for assessing visual memory and visuospatial function. However, the association between the BVRT score and imaging biomarker of Alzheimer's disease (AD) remains unclear. OBJECTIVE: This study examined whether the BVRT score is associated with brain amyloid burden and cortical glucose metabolism in elderly adults without dementia. METHODS: A total of 69 elderly adults without dementia, including 45 subjects with amnestic mild cognitive impairment and 24 cognitively healthy adults, underwent the BVRT and 11C-Pittsburgh compound B (PiB) and 18F-fluorodeoxyglucose (FDG) positron emission tomography. The correct scores in the BVRT were used for analyses. A multiple linear regression analysis was conducted to investigate the relationship between BVRT scores and PiB or FDG uptake. Moreover, a voxel-wise linear regression analysis of the association between BVRT scores and PiB or FDG uptake was conducted using Statistical Parametric Mapping. RESULTS: After adjusting for age, sex, education, and ApoE4 status, the BVRT scores were inversely correlated with the mean PiB uptake (ß = -0.35, P = 0.003), whereas they were positively correlated with FDG uptake (ß = 0.266, P = 0.038). Moreover, the BVRT scores were inversely correlated with amyloid burden in the right superior temporal and superior frontal gyri and the left parietal lobe, whereas they were positively correlated with cortical glucose metabolism in the right posterior cingulate and milled temporal gyri, left temporoparietal lobe, and right superior frontal gyrus. CONCLUSION: BVRT scores are correlated with brain amyloid burden and cortical glucose metabolism, mainly in regions commonly affected in AD.

Relationship between Cerebrospinal Fluid Matrix Metalloproteinases Levels and Brain Amyloid Deposition in Mild Cognitive Impairment.

This study aimed to explore whether cerebrospinal fluid (CSF) levels of matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) were associated with brain amyloid deposition, cortical glucose metabolism, and white matter lesions (WMLs) in individuals with amnestic mild cognitive impairment (MCI). A total of 33 individuals with amnestic MCI (mean age, 75.6 years) underwent 11C-Pittsburgh compound B positron emission tomography (PiB-PET), 18F-fluorodeoxyglucose positron emission tomography, magnetic resonance imaging or computed tomography, and CSF analysis. PET uptake of the frontal and temporoparietal lobes and posterior cingulate gyrus was assessed using the cerebellar cortex as the reference region. WMLs were assessed by the Fazekas scale. CSF levels of MMPs and TIMPs were measured with bead-based multiplex assays. After adjusting for covariates, multiple linear regression analysis showed that CSF levels of MMP-2 were negatively correlated with global PiB uptake (p = 0.035), especially in the parietotemporal lobe and posterior cingulate gyrus (p = 0.016 and p = 0.041, respectively). Moreover, CSF levels of MMP-7 were positively correlated with the severity of WMLs (p = 0.033). CSF levels of MMP-2 and MMP-7 are associated with brain amyloid deposition and severity of WMLs, respectively. These findings provide valuable insights into the role of MMPs in amyloid ß catabolism and blood-brain barrier integration at the MCI stage.

Novel Serum Biomarkers of Neurovascular Unit Associated with Cortical Amyloid Deposition.

BACKGROUND: Whether blood biomarkers of neurovascular unit are associated with cortical amyloid deposition on positron emission tomography (PET) imaging remains unclear. OBJECTIVE: To investigate the association between novel serum biomarkers of neurovascular unit, such as protein tyrosine phosphatase receptor type B (PTPRB), gap junction protein alpha-5 (GJA5), adenosine triphosphate-sensitive inward rectifier potassium channel-8 (KCNJ8), and von Willebrand factor (vWF), and cortical amyloid deposition. METHODS: Between 2012 and 2018, 68 elderly individuals with amnestic mild cognitive impairment (32 men and 36 women; mean age 75.2 years) were enrolled. All participants underwent 11C-Pittsburgh compound-B (PiB)-PET, 18F-fluorodeoxyglucose-PET, and measurement of serum PTPRB, GJA5, KCNJ8, and vWF levels using commercially available human enzyme-linked immunosorbent assay kits. Based on the mean cortical standardized uptake value ratio, the participants were divided into two groups: PiB-negative group and PiB-positive group. Serum levels of PTPRB, GJA5, KCNJ8, and vWF were compared between the two groups. Multiple linear regression analysis was performed to investigate the relationship between serum PTPRB, GJA5, KCNJ8, and vWF levels and cortical amyloid deposition. RESULTS: PTPRB and GJA5 levels were significantly lower and KCNJ8 and vWF levels were significantly higher in the PiB-positive group than in the PiB-negative group. PTPRB and GJA5 levels inversely correlated with mean PiB uptake, whereas KCNJ8 and vWF levels positively correlated with mean PiB uptake. CONCLUSION: Serum levels of PTPRB, GJA5, KCNJ8, and vWF correlate with cortical amyloid deposition. These novel blood biomarkers of neurovascular unit are useful for identifying elderly individuals at risk of developing Alzheimer's disease.