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INTRODUCTION/AIMS: In the early stage, hereditary transthyretin (ATTRv) amyloidosis predominantly affects small nerve fibers, resulting in autonomic dysfunction and impaired sensation of pain and temperature. Evaluation of small fiber neuropathy (SFN) is therefore important for early diagnosis and treatment of ATTRv amyloidosis. Herein, we aimed to investigate the accuracy of a quick and non-invasive commercial sudomotor function test (SFT) for the assessment of SFN in ATTRv amyloidosis. METHODS: We performed the SFT in 39 Japanese adults with ATTRv amyloidosis, and we analyzed the correlations between electrochemical skin conductance (ESC) values obtained via the SFT and the parameters of other neuropathy assessment methods. RESULTS: ESC in the feet demonstrated significant, moderate correlations with intraepidermal nerve fiber density (IENFD) results (Spearman's rank correlation coefficient [rs ], 0.58; p < .002) and other neuropathy assessment methods including the sensory nerve action potential amplitude in the nerve conduction studies (rs , 0.52; p < .001), the Neuropathy Impairment Score (rs , -0.45; p < .01), the heat-pain detection threshold (rs , -0.62; p < .0001), and the autonomic section of the Kumamoto ATTRv clinical score (rs , -0.53; p < .0001). DISCUSSION: In this study, we found that ESC values in the feet via the SFT demonstrated significant, moderate correlations with IENFD and other SFN assessment methods in patients with ATTRv amyloidosis, suggesting that the SFT appears to be an appropriate method for assessment of SFN in this disease.
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Neuropatías Amiloides Familiares , Neuropatía de Fibras Pequeñas , Adulto , Humanos , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides Familiares/patología , Fenómenos Electrofisiológicos/fisiología , Fibras Nerviosas/fisiología , Neuropatía de Fibras Pequeñas/diagnóstico , Neuropatía de Fibras Pequeñas/etiología , Recuento de Células , Piel/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , JapónRESUMEN
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.
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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. METHODSâANDâRESULTS: 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.
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Neuropatías Amiloides Familiares , Fibrilación Atrial , Cardiomiopatías , Ablación por Catéter , Miocardio , Humanos , Fibrilación Atrial/cirugía , Fibrilación Atrial/diagnóstico por imagen , Masculino , Femenino , Anciano , Persona de Mediana Edad , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/cirugía , Cardiomiopatías/diagnóstico por imagen , Miocardio/patología , Tomografía Computarizada por Rayos X , Diagnóstico PrecozRESUMEN
Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid ß (Aß) deposits and causes dementia and cerebral hemorrhage. Although α-enolase (ENO1) was shown to possess multifunctional roles, its exact functions in CAA pathogenesis have not been determined. In this study, we focused on ENO1, a well-known glycolytic enzyme, which was previously identified via a proteomic approach as an upregulated protein in brain samples from patients with Alzheimer's disease (AD). We utilized the thioflavin T fluorescence assay and transmission electron microscopy to monitor the effects of ENO1 on amyloid formation by Aß peptides. We also cultured murine primary cerebrovascular smooth muscle cells to determine the effects of ENO1 on Aß cytotoxicity. To investigate the effects of ENO1 in vivo, we infused ENO1 or a vehicle control into the brains of APP23 mice, a transgenic model of AD/CAA, using a continuous infusion system, followed by a cognitive test and pathological and biochemical analyses. We found that novel functions of ENO1 included interacting with Aß and inhibiting its fibril formation, disrupting Aß fibrils, and weakening the cytotoxic effects of these fibrils via proteolytic degradation of Aß peptide. We also demonstrated that infusion of ENO1 into APP23 mouse brains reduced cerebrovascular Aß deposits and improved cognitive impairment. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aß fibril formation and fibril disruption. The proteolytic activity of ENO1 may thus underlie the enzyme's cytoprotective effect and clearance of Aß from the brain, and ENO1 may be a therapeutic target in CAA.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/patología , Ratones , Ratones Transgénicos , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/metabolismo , ProteómicaRESUMEN
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.
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Carcinoma de Células Renales , Neoplasias Renales , Meningoencefalitis , Anciano , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico , Interleucina-6 , Ipilimumab/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Leucocitosis/inducido químicamente , Meningoencefalitis/líquido cefalorraquídeo , Meningoencefalitis/inducido químicamente , Meningoencefalitis/diagnóstico , Metilprednisolona , Persona de Mediana Edad , Nivolumab/efectos adversos , Reflejo AnormalRESUMEN
Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81-127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81-127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81-127-based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis.
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Amiloide/metabolismo , Ensayos Analíticos de Alto Rendimiento/métodos , Prealbúmina/metabolismo , Amiloide/efectos de los fármacos , Neuropatías Amiloides Familiares/metabolismo , Apomorfina/farmacología , Células Cultivadas , Reposicionamiento de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Inflamación/genética , Neuroglía/metabolismo , Neuronas/metabolismo , Prealbúmina/química , Conformación Proteica , Proteolisis , Compuestos de Pirvinio/farmacología , Tripsina/metabolismoRESUMEN
Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Amiloidosis/etiología , Proteínas de la Matriz Extracelular/metabolismo , Enfermedades Vasculares/etiología , Anciano de 80 o más Años , Biomarcadores/metabolismo , Proteínas de Unión al Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Factor de Crecimiento Epidérmico/metabolismo , Proteínas de la Matriz Extracelular/fisiología , Femenino , Hemorragia Gastrointestinal/etiología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Intestino Grueso/irrigación sanguínea , Venas/metabolismoRESUMEN
INTRODUCTION/OBJECTIVE: In most cases, abnormal cardiac 123I-meta-iodobenzylguanidine (MIBG) scintigraphy increases the probability of a diagnosis of Parkinson's disease (PD) in patients with parkinsonian features. In our study, we validated the additional value of 123I-MIBG scintigraphy beyond providing information on neurological findings and response to dopaminergic therapy for the diagnosis of PDin the early phase. METHODS: We investigated 77 cases of PD (Hoehn and Yahr Stages I-III) and 73 cases of atypical parkinsonian disorder (APD), including 35 patients with multiple system atrophy, 19 with corticobasal syndrome, and 19 with progressive supranuclear palsy. Two multiple logistic regression models were developed to predict the probability of PD based on APD. Common covariates were resting tremor, vertical supranuclear palsy, apraxia, cerebellar symptoms, and response to dopaminergic therapy with MIBG scintigraphy (reference model) or without it (MIBG-added model). The net reclassification index (NRI) was examined and net benefit using decision curve analysis was performed to examine the additional clinical value of MIBG scintigraphy. Finally, we estimated the cost-effectiveness of MIBG scintigraphy. RESULTS: The MIBG-added model significantly improved the ability to classify PD or APD compared with the reference model (NRI index 1.390, p < 0.001). However, the decision curve of the reference model ranked equally with the MIBG-added model up to a risk threshold of 0.8. In addition, MIBG scintigraphy was not cost-effective. CONCLUSIONS: Although MIBG scintigraphy has statistical usefulness for PD diagnosis, there may be little additional benefit in the early phase of PD beyond the neurological findings and response to dopaminergic therapy regarding clinical effectiveness and cost-effectiveness. It may be of greatest value when neurological findings that do not match PD are observed during the clinical course.
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Enfermedad de Parkinson/diagnóstico por imagen , Trastornos Parkinsonianos/diagnóstico por imagen , 3-Yodobencilguanidina , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cintigrafía , Estudios RetrospectivosRESUMEN
We aimed to assess the possibility of using a noninvasive screening method for hereditary transthyretin amyloidosis by means of abdominal fat ultrasonography. Quantitative analysis of ultrasound B-mode images demonstrated a significant increase in mean echogenicity and a loss of the normal structure of the layers of fat tissue in patients with hereditary transthyretin amyloidosis (n = 19). The ultrasound features of the fat tissue and the degree of amyloid deposition seen histopathologically showed a significant correlation. These results suggest that abdominal fat ultrasonography may be a valuable method for screening for hereditary transthyretin amyloidosis. Ann Neurol 2017;81:604-608.
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Neuropatías Amiloides Familiares/diagnóstico por imagen , Amiloide/metabolismo , Grasa Subcutánea Abdominal/diagnóstico por imagen , Grasa Subcutánea Abdominal/metabolismo , Ultrasonografía/métodos , Adulto , Anciano , Neuropatías Amiloides Familiares/metabolismo , Biopsia con Aguja Fina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ultrasonografía/normasRESUMEN
Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aß) deposits and causes cerebral hemorrhage and dementia. The exact molecules that co-accumulate with cerebrovascular Aß deposits are still not fully known. In our study here, we performed proteomic analyses with microdissected leptomeningeal arteries and cerebral neocortical arterioles from 8 cases with severe CAA, 12 cases with mild CAA, and 10 control cases without CAA, and we determined the levels of highly expressed proteins in cerebral blood vessels in CAA. We focused on sushi repeat-containing protein 1 (SRPX1), which is specifically expressed in CAA-affected cerebral blood vessels. Because SRPX1, which is known as a tumor suppressor gene, reportedly induced apoptosis in tumor cells, we hypothesized that SRPX1 may play an important role in Aß-induced apoptosis in CAA. Immunohistochemical studies revealed that SRPX1 co-accumulated with Aß deposits in cerebral blood vessels of all autopsied cases with severe CAA. In contrast, no SRPX1 co-accumulated with Aß deposits in senile plaques. Furthermore, we demonstrated that both Aß40 and Aß42 bound to SRPX1 in vitro and enhanced SRPX1 expression in primary cultures of cerebrovascular smooth muscle cells. SRPX1 enhanced caspase activity induced by Aß40. Knockdown of SRPX1, in contrast, reduced the formation of Aß40 accumulations and the activity of caspase in cultured cerebrovascular smooth muscle cells. SRPX1 may thus be a novel molecule that is up-regulated in cerebrovascular Aß deposits and that may increase Aß-induced cerebrovascular degeneration in CAA.
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Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Proteínas de la Membrana/metabolismo , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteínas E/genética , Encéfalo/patología , Células Cultivadas , Angiopatía Amiloide Cerebral/genética , Angiopatía Amiloide Cerebral/patología , Femenino , Humanos , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Persona de Mediana Edad , Miocitos del Músculo Liso/metabolismo , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Fragmentos de Péptidos/metabolismo , Unión Proteica , Proteoma , ARN Interferente PequeñoRESUMEN
Multiple system atrophy (MSA) is a progressive neurodegenerative disease that often causes vocal cord paralysis (VCP), Parkinsonism, cerebellar ataxia, and autonomic dysfunction. VCP is the most fatal symptom that affects the prognosis of patients with MSA. Coronavirus disease 2019 (COVID-19) is often associated with neurological complications and it has recently been reported to induce VCP in patients without neurodegenerative diseases. We herein present two cases of patients with MSA in whom VCP worsened after COVID-19 and this led to the need to perform emergency tracheostomies. As VCP may deteriorate after COVID-19 in patients with MSA, it is important to prevent COVID-19 in these patients and closely monitor such patients for any signs of VCP deterioration post-infection to improve their prognosis.
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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.
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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 (pâ<â0.001 and pâ<â0.001, respectively). The mean FDG uptake value in the clinic-based MCI cohort was significantly lower than that in the community-based MCI cohort (pâ<â0.001). 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.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Fluorodesoxiglucosa F18/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Estudios Prospectivos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Tomografía de Emisión de Positrones/métodos , Compuestos de Anilina/metabolismo , Glucosa/metabolismo , Amiloide/metabolismoRESUMEN
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.
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Factor Activador de Células B , Sarcoidosis , Humanos , Factor Activador de Células B/líquido cefalorraquídeo , Calidad de Vida , Biomarcadores , Sarcoidosis/diagnóstico por imagen , Sarcoidosis/líquido cefalorraquídeoRESUMEN
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.
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Cognición , Disfunción Cognitiva , Humanos , Anciano , Estudios Prospectivos , Estilo de Vida , SueñoRESUMEN
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.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Amiloide/metabolismo , Sueño , Glucosa/metabolismoRESUMEN
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.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Dispositivos Electrónicos Vestibles , Masculino , Humanos , Femenino , Anciano , Estudios Prospectivos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones , Amiloide/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/psicología , Proteínas Amiloidogénicas , Estilo de Vida , Aprendizaje Automático , Péptidos beta-Amiloides/metabolismoRESUMEN
Transthyretin (TTR), the precursor protein for amyloidogenic TTR (ATTR) amyloidosis, forms tetramers and escapes glomerular filtration by binding with thyroxine and retinol-binding protein. However, variant TTRs are unstable as tetramers, so monomeric TTR has become the precursor protein of amyloid deposits, via protein misfolding. The aim of the study was to evaluate the utility of urinary TTR in the diagnosis of ATTRv amyloidosis. Urinary samples from healthy volunteers, ATTRv V50M amyloidosis patients, and asymptomatic carriers of the ATTRv V50M gene were analysed using ELISA. To analyse the different forms of TTR secreted to the urine, we performed Western blotting and mass spectrometry. Urinary TTR concentrations were significantly higher in the ATTRv V50M amyloidosis patients than they were in the healthy volunteers and asymptomatic carriers of the gene. Although the TTR concentrations were negligible in the healthy volunteers, they were correlated with disease progression and urinary albumin concentrations in the ATTRv V50M amyloidosis patients. The Western blotting and mass spectrometry revealed the presence of monomeric wild-type and variant TTRs in the urine. Urinary TTR concentrations may become a more sensitive biomarker of ATTRv progression than albumin.
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A 59-year-old man with progressive cognitive decline and mood disturbances was admitted to the hospital. Brain magnetic resonance imaging revealed marked white matter hyperintensity (WMH) and widespread lobar cerebral microbleeds. Because he had untreated hypertension, we started antihypertensive treatment and found a significantly improved cognitive function and WMH regression. We diagnosed him with cerebral amyloid angiopathy (CAA) based on the modified Boston Criteria with the rare apolipoprotein E (ApoE) ε2/ε4 genotype. The mechanism underlying reversible leukoencephalopathy in CAA may be related to the loss of autoregulation of brain circulation: cerebrovascular amyloid ß deposits damaged the blood-brain barrier of the capillaries, which led to vasogenic edema induced by blood pressure surges.
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Péptidos beta-Amiloides , Angiopatía Amiloide Cerebral , Masculino , Humanos , Persona de Mediana Edad , Angiopatía Amiloide Cerebral/diagnóstico , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/efectos adversos , Inflamación/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/etiologíaRESUMEN
Transthyretin (TTR)-related hereditary amyloidosis (ATTRv) is a rare autosomal dominant disorder that is caused by pathogenic missense mutation of the TTR gene. As of today, more than 150 TTR gene variants have been reported to occur as causal mutations. Herein, we present three familial patients of ATTRv caused by the Thr49Ser (p.Thr69Ser) variant, including their phenotypes and penetrance. The first patient was a 68-year-old woman with a history of carpal tunnel syndrome, who was referred to our department with heart failure symptoms. Echocardiography, 99mTechnetium (Tc)-pyrophosphate scintigraphy, and myocardial biopsy confirmed her diagnosis as TTR-related amyloidosis. Genetic testing for the TTR gene was performed, which confirmed the presence of a Thr49Ser (p.Thr69Ser) variant. The second patient, a 45-year-old woman, who was the niece of the first patient, presented with dyspnea on exertion. Her clinical manifestations included cardiac symptoms in addition to polyneuropathy. Similarly, myocardial biopsy showed TTR amyloid deposition within cardiac tissues, and TTR gene sequencing detected the presence of a Thr49Ser (p.Thr69Ser) variant. The final patient was a 42-year-old man, who was the nephew of the first patient, presented with numbness in his hands. Abdominal wall fat pad biopsy showed TTR amyloid deposition, and TTR gene sequencing was performed considering the familial history to confirm the presence of Thr49Ser (p.Thr69Ser) variant. No cardiac symptoms or dysfunctions have been observed yet, but imaging has detected TTR amyloid deposition in the heart. The present three patients with Thr49Ser (p.Thr69Ser) variant showed variation in phenotypes including cardiac and neurological manifestations at a fairly young age. In addition, the familial relationship in this report suggested that this variant is highly penetrant. Early genetic diagnosis due to collecting the genetic information from family medical history may be beneficial to improve patient prognosis via early therapeutic intervention.