RESUMEN
BACKGROUND: Peripheral neuropathy is one of the manifestations of primary or familial amyloidosis. Published studies from India are limited. MATERIALS AND METHODS: We reviewed the clinical and pathological features of amyloid neuropathy diagnosed at our Institute over the last 39 years. RESULTS: Fifty-five cases of amyloid neuropathies were diagnosed between 1981 and 2019, constituting 0.28% of peripheral nerve biopsies (55/19,081). Age at presentation ranged from 24 to 81 years (mean-48 years) with male preponderance [M:F = 3.58:1]. Duration of symptoms at presentation varied from 3 months to 10 years (mean-2.31 years). Majority presented with small fiber neuropathy (85%). Pure sensory symptoms predominated in 23%, while 72% had sensorimotor neuropathy and 35.8% had autonomic involvement, with isolated autonomic failure in one patient. Amyloid neuropathy was clinically suspected in 22.6% of nonfamilial cases. Familial amyloid neuropathy was suspected in eight patients. Genetic testing detected ATTR and gelsolin mutation in one each of tested patients. Nerve biopsies revealed characteristic birefringent amyloid deposits stained mahogany brown by Congo red predominantly surrounding endoneurial microvessels (34.5%), also in perineurium and epineurium in 25.45% cases. Preferential loss of small diameter myelinated fibers was noted. Axonal degeneration or regeneration was conspicuously absent. CONCLUSION: Amyloid neuropathy is uncommon (0.28% of nerve biopsies in our series). Nerve biopsy is essential for the diagnosis. We report our experience of amyloid neuropathy and underscore the importance of making an assiduous search for amyloid deposits in the appropriate setting. Awareness of this entity is important for early diagnosis in the light of emerging therapeutic advances.
Asunto(s)
Neuropatías Amiloides , Humanos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Neuropatías Amiloides/patología , Neuropatías Amiloides/diagnóstico , Anciano de 80 o más Años , Adulto Joven , Neuropatías Amiloides Familiares/patología , Neuropatías Amiloides Familiares/genética , India , BiopsiaRESUMEN
OBJECTIVE: The present study was intended to analyze the characteristics of myelinated nerve fibers density (MFD) of transthyretin amyloid polyneuropathy (ATTR-PN) and other similar neuropathies. METHODS: A total of 41 patients with ATTR-PN, 58 patients of other common peripheral neuropathies, and 17 age-and gender-matched controls who visited the First Hospital of Peking University and performed sural nerve biopsy between June 2007 and August 2021 were included for analysis of MFD. RESULTS: Except the vasculitic neuropathy group, the total and small MFD of patients in the ATTR-PN group were significantly lower than those of other disease groups. There was an obvious negative correlation between the total MFD and the disease course in the ATTR-PN group. The disease course of early-onset and late-onset symptoms was similar, but the loss of large myelinated nerve fibers (MF) was more severe for the latter. In addition, all late-onset and most early-onset patients had severely reduced MFD after a 2 years' disease course. The MFD in ATTR-PN patients was negatively correlated with Neuropathy Impairment Score (NIS) and Norfolk Quality of life-diabetic neuropathy (Norfolk QOL-DN) score. CONCLUSION: MF is lost differently in ATTR-PN and in other common peripheral neuropathies. The late-onset and early-onset ATTR-PN patients have different patterns of loss of large and small MF.
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Neuropatías Amiloides Familiares , Neuropatías Amiloides , Neuropatías Amiloides/patología , Neuropatías Amiloides Familiares/diagnóstico , Progresión de la Enfermedad , Humanos , Fibras Nerviosas Mielínicas/patología , Prealbúmina , Calidad de VidaRESUMEN
Light-chain (AL) amyloidosis is characterized by deposition of immunoglobulin light chains (LC) as fibrils in target organs. Alongside the full-length protein, abundant LC fragments are always present in AL deposits. Herein, by combining gel-based and mass spectrometry analyses, we identified and compared the fragmentation sites of amyloid LCs from multiple organs of an AL λ amyloidosis patient (AL-55). The positions pinpointed here in kidney and subcutaneous fat, alongside those previously detected in heart of the same patient, were aligned and mapped on the LC's dimeric and fibrillar states. All tissues contain fragmented LCs along with the full-length protein; the fragment pattern is coincident across organs, although microheterogeneity exists. Multiple cleavage positions were detected; some are shared, whereas some are organ-specific, likely due to a complex of proteases. Cleavage sites are concentrated in 'proteolysis-prone' regions, common to all tissues. Several proteolytic sites are not accessible on native dimers, while they are compatible with fibrils. Overall, data suggest that the heterogeneous ensemble of LC fragments originates in tissues and is consistent with digestion of preformed fibrils, or with the hypothesis that initial proteolytic cleavage of the constant domain triggers the amyloidogenic potential of LCs, followed by subsequent proteolytic degradation. This work provides a unique set of molecular data on proteolysis from ex vivo amyloid, which allows discussing hypotheses on role and timing of proteolytic events occurring along amyloid formation and accumulation in AL patients.
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Neuropatías Amiloides/genética , Amiloide/genética , Proteínas Amiloidogénicas/genética , Amiloidosis/genética , Cadenas Ligeras de Inmunoglobulina/genética , Amiloide/metabolismo , Neuropatías Amiloides/metabolismo , Neuropatías Amiloides/patología , Amiloidosis/metabolismo , Amiloidosis/patología , Endopeptidasas/genética , Humanos , Cadenas Ligeras de Inmunoglobulina/metabolismo , Cinética , Péptido Hidrolasas/genética , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , Proteolisis , TermodinámicaRESUMEN
The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Modelos Estadísticos , Enfermedad de Alzheimer/psicología , Neuropatías Amiloides/metabolismo , Neuropatías Amiloides/patología , Péptidos beta-Amiloides , Animales , Humanos , Proteínas tau/metabolismoRESUMEN
Salmon calcitonin is a good model for studying amyloid behavior and neurotoxicity. Its slow aggregation rate allows the purification of low molecular weight prefibrillar oligomers, which are the most toxic species. It has been proposed that these species may cause amyloid pore formation in neuronal membranes through contact with negatively charged sialic acid residues of the ganglioside GM1. In particular, it has been proposed that an electrostatic interaction may be responsible for the initial contact between prefibrillar oligomers and GM1 contained in lipid rafts. Based on this evidence, the aim of our work was to investigate whether the neurotoxic action induced by calcitonin prefibrillar oligomers could be counteracted by treatment with neuraminidase, an enzyme that removes sialic acid residues from gangliosides. Therefore, we studied cell viability in HT22 cell lines and evaluated the effects on synaptic transmission and long-term potentiation by in vitro extracellular recordings in mouse hippocampal slices. Our results showed that treatment with neuraminidase alters the surface charges of lipid rafts, preventing interaction between the calcitonin prefibrillar oligomers and GM1, and suggesting that the enzyme, depending on the concentration used, may have a partial or total protective action in terms of cell survival and modulation of synaptic transmission.
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Neuropatías Amiloides , Calcitonina/toxicidad , Proteínas de Peces/toxicidad , Neuraminidasa/farmacología , Salmón , Neuropatías Amiloides/inducido químicamente , Neuropatías Amiloides/metabolismo , Neuropatías Amiloides/patología , Neuropatías Amiloides/prevención & control , Animales , Gangliósido G(M1)/metabolismo , Masculino , Microdominios de Membrana/metabolismo , Microdominios de Membrana/patología , Ratones , Ratones Endogámicos BALB C , Electricidad EstáticaRESUMEN
BACKGROUND: Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle). METHODS: The patient underwent magnetic resonance imaging (MRI) and whole body 18 F-florbetapir positron emission tomography (PET)/MRI. RESULTS: Whole body 18 F-florbetapir PET/MRI revealed abnormal low-level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis. CONCLUSIONS: 18 F-florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.
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Neuropatías Amiloides/patología , Amiloidosis/patología , Compuestos de Anilina/farmacología , Glicoles de Etileno/farmacología , Mononeuropatías/patología , Neuropatías Amiloides/diagnóstico , Amiloidosis/diagnóstico , Biopsia/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Mononeuropatías/diagnóstico , Procedimientos Neuroquirúrgicos , Tomografía de Emisión de Positrones/métodosRESUMEN
We describe three cases, two 70-year-old males with mainly cardiac symptoms and a 34-year-old male with gastro-intestinal and neurologic symptoms. Each patient was shown to have a distinctive type of transthyretin-mediated amyloidosis (ATTR). ATTR amyloidosis is a life-threatening disease characterised by the extracellular deposition of pathogenic transthyretin (TTR). A distinction is made between hereditary ATTR (ATTRv), in case of a pathogenic TTR mutation, and the acquired wild-type ATTR (ATTRwt). The prevalence of ATTR amyloidosis is probably underestimated. The variety of symptoms means that patients often visit several specialists, resulting in an average diagnostic delay of two to three years. Because of the development of new therapeutic possibilities, early diagnosis becomes more important to allow initiation of therapy at an early stage of the disease. Family members should be screened and asymptomatic carriers should undergo follow-up.
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Neuropatías Amiloides Familiares/diagnóstico , Neuropatías Amiloides/diagnóstico , Adulto , Anciano , Neuropatías Amiloides/patología , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/patología , Diagnóstico Tardío , Humanos , MasculinoAsunto(s)
Neuropatías Amiloides , Cadenas Ligeras de Inmunoglobulina/metabolismo , Mieloma Múltiple , Proteínas de Neoplasias/metabolismo , Nervio Sural , Anciano , Neuropatías Amiloides/metabolismo , Neuropatías Amiloides/patología , Femenino , Humanos , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Nervio Sural/metabolismo , Nervio Sural/patologíaRESUMEN
BACKGROUND: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood. OBJECTIVE: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults. METHODS: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. RESULTS: WMH burden in the whole group was associated with both vascular and Alzheimer's disease (AD) pathologies: arteriolosclerosis (pâ<â10-4), gross (pâ<â10-4), and microscopic infarcts (pâ=â0.04), and amyloid-ß plaques (pâ=â0.028). In non-demented participants (mild or no cognitive impairment) (Nâ=â332), WMH burden was related to gross infarcts (pâ=â10-4) and arteriolosclerosis (pâ<â10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (Nâ=â178), WMH burden was related to gross infarcts (pâ=â8×10-4) and arteriolosclerosis (pâ=â0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (pâ=â0.038) and non-demented (pâ=â0.006) groups. CONCLUSION: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.
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Enfermedades del Sistema Nervioso/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Neuropatías Amiloides/diagnóstico por imagen , Neuropatías Amiloides/patología , Neuropatías Amiloides/psicología , Autopsia , Infarto Cerebral/diagnóstico por imagen , Infarto Cerebral/patología , Infarto Cerebral/psicología , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/patología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Disfunción Cognitiva/psicología , Estudios de Cohortes , Costo de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/patología , Arteriosclerosis Intracraneal/psicología , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/psicología , Pruebas Neuropsicológicas , Sustancia Blanca/patologíaRESUMEN
With the first RNA interference (RNAi) drug (ONPATTRO (patisiran)) on the market, we witness the RNAi therapy field reaching a critical turning point, when further improvements in drug candidate design and delivery pipelines should enable fast delivery of novel life changing treatments to patients. Nevertheless, ignoring parallel development of RNAi dedicated in vitro pharmacological profiling aiming to identify undesirable off-target activity may slow down or halt progress in the RNAi field. Since academic research is currently fueling the RNAi development pipeline with new therapeutic options, the objective of this article is to briefly summarize the basics of RNAi therapy, as well as to discuss how to translate basic research into better understanding of related drug candidate safety profiles early in the process.
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Neuropatías Amiloides/terapia , Interferencia de ARN , ARN Mensajero/genética , ARN Interferente Pequeño/uso terapéutico , Tratamiento con ARN de Interferencia/métodos , Neuropatías Amiloides/genética , Neuropatías Amiloides/metabolismo , Neuropatías Amiloides/patología , Animales , Técnicas de Transferencia de Gen , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/genética , MicroARNs/metabolismo , Terapia Molecular Dirigida/métodos , Estabilidad del ARN , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , ARN no Traducido/antagonistas & inhibidores , ARN no Traducido/genética , ARN no Traducido/metabolismo , Complejo Silenciador Inducido por ARN/genética , Complejo Silenciador Inducido por ARN/metabolismoRESUMEN
BACKGROUND: Aggregation of abnormal phosphorylated tau in brain stem areas may be a possible early pathological manifestation of Alzheimer's disease (AD). OBJECTIVE: This study aimed to explore the prevalence of cases with AD-related pathology in subjects <40 years of age and to explore the association of such pathology, neuropsychiatric symptoms, and APOE genotype. METHOD: We conducted brain immunohistochemistry for 189 cases <40 years of age (mean±standard deviation age 25.3±13.1 years). Tau positive cases were then assessed for the distribution of tau pathology in the locus ceruleus (LC), raphe nucleus (RN), and entorhinal cortex (ErC), and the distinction between neuronal threads and cellular inclusions. Apolipoprotein E (APOE) genotype was also examined. RESULTS: Tau pathology was detected in 135 cases (71.4%; 13-39 years; only LC, 23 cases; only RN, 4 cases; only ErC, 35 cases; LC+RN, 3 cases; LC+ErC, 57 cases; all three regions, 10 cases). The prevalence of thread pathology was higher than that of cellular inclusions. Significantly higher prevalence of the APOEÉ2 allele were found in 10-39 years of age natural death cases (pâ<â0.05). Amyloid-ß deposition was found in only 7 cases, along with a significantly high frequency of the É4 allele (pâ<â0.05). While a past history of psychiatric disease was a significant risk factor for suicide, AD-related pathology was not associated with suicide. CONCLUSIONS: Both the brain stem and entorhinal cortex was the initial site of tau pathology in many younger subjects. AD-related pathology may not be a significant accelerating factor for suicide in younger subjects.
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Neuropatías Amiloides/epidemiología , Neuropatías Amiloides/patología , Péptidos beta-Amiloides , Apolipoproteínas E/genética , Patologia Forense , Suicidio/estadística & datos numéricos , Tauopatías/epidemiología , Tauopatías/patología , Adolescente , Adulto , Factores de Edad , Alelos , Autopsia , Tronco Encefálico/patología , Niño , Corteza Entorrinal/patología , Femenino , Genotipo , Humanos , Inmunohistoquímica , Japón/epidemiología , Locus Coeruleus/patología , Masculino , Prevalencia , Núcleos del Rafe/patología , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Commercial solutions of human serum albumin (HSA) are administered to critically ill patients for the treatment of shock, restoration of blood volume, and the acute management of burns. Previously, conflicting results on the effects of HSA administration have been reported varying from a favorable increase in total plasma antioxidant capacity to a higher mortality rate in traumatic brain injury (TBI) patients. These results could be partially explained due to the known heterogeneity of HSA solutions. We report the discovery of S-sulfonated human transthyretin (hTTR) in HSA solutions. METHODS: Proteomics was performed on commercially available solutions of 5% HSA by LC-MS analysis. The MS charge envelope for hTTR was deconvolved to the uncharged native hTTR parent mass (13,762â¯Da). The parent mass was then integrated, and relative proportions of the 2 major species of hTTR, native and S-sulfonated hTTR (13,842â¯Da), were calculated. RESULTS: The majority of hTTR found in 5% commercial HSA solutions is in the S-sulfonated form regardless of the age of the HSA solution. S-sulfonation of hTTR at the free cysteine residue in position 10 appears to be the result of a mixed disulfide exchange possibly with S-cysteinylated hTTR or S-cysteinylated HSA. hTTR is a tetramer composed of four identical monomers each containing a reduced cysteine residue in position 10. S-sulfonation of hTTR at this cysteine residue can destabilize the hTTR tetramer, an important step in the formation of TTR-related amyloid fibrils. CONCLUSIONS: Administration of a commercial HSA solution that already contains S-sulfonated hTTR could potentially contribute to the development of amyloid-related/polyneuropathy in the critically ill.
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Neuropatías Amiloides/metabolismo , Prealbúmina/análisis , Albúmina Sérica Humana/química , Soluciones/química , Soluciones/economía , Neuropatías Amiloides/patología , Cromatografía Liquida , Cisteína/química , Cisteína/metabolismo , Humanos , Espectrometría de Masas , Oxidación-Reducción , Prealbúmina/metabolismo , Proteómica , Albúmina Sérica Humana/metabolismoRESUMEN
We demonstrated that an antibiotic cocktail (ABX)-perturbed gut microbiome is associated with reduced amyloid-ß (Aß) plaque pathology and astrogliosis in the male amyloid precursor protein (APP)SWE /presenilin 1 (PS1)ΔE9 transgenic model of Aß amyloidosis. We now show that in an independent, aggressive APPSWE/PS1L166P (APPPS1-21) mouse model of Aß amyloidosis, an ABX-perturbed gut microbiome is associated with a reduction in Aß pathology and alterations in microglial morphology, thus establishing the generality of the phenomenon. Most importantly, these latter alterations occur only in brains of male mice, not in the brains of female mice. Furthermore, ABX treatment lead to alterations in levels of selected microglial expressed transcripts indicative of the "M0" homeostatic state in male but not in female mice. Finally, we found that transplants of fecal microbiota from age-matched APPPS1-21 male mice into ABX-treated APPPS1-21 male restores the gut microbiome and partially restores Aß pathology and microglial morphology, thus demonstrating a causal role of the microbiome in the modulation of Aß amyloidosis and microglial physiology in mouse models of Aß amyloidosis.
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Neuropatías Amiloides/patología , Encefalopatías/patología , Microbioma Gastrointestinal , Microglía/patología , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Antibacterianos/efectos adversos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Masculino , Ratones , Placa Amiloide/metabolismo , Factores SexualesRESUMEN
OBJECTIVE: To describe an expanded teased nerve fibre classification in disease association. METHODS: We reviewed four newly proposed teased nerve fibre types (Types J-M): Type J, rope-like fibres; K, fibril-like clumps of osmium positivity; L, cellular debris along and within nerve fibres; M, circular axonal inclusions surrounded by thin myelin. Different clinical pathological entities were studied for these fibre types including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP: N=20); amyloid polyneuropathy (N=20); intraneural B-cell lymphoma (N=20) or adult-onset polyglucosan body disease (APBD: N=6) in comparison with 112 disease controls. Student's t-test was used to test significance of association between the identified fibre types and the specific clinical diagnosis. RESULTS: Each fibre type significantly associated (p<0.001) with particular disease categories: Type J, 60% of CIDP cases; Type K, 75% of amyloid cases; Type L, 75% of intraneural lymphoma cases; Type M, 100% of APBD cases. Rarely were these fibres found in the other disease control cases ≤3% of cases. In three cases, the teased fibre findings were so striking additional paraffin nerve preparations were made to make the pathological diagnosis when initial paraffin sections were non-diagnostic. CONCLUSIONS: Teased nerve fibre Types J-M associate with commonly seen pathological diagnosis and are helpful in the consideration of specific neuropathy diagnoses.
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Neuropatías Amiloides/patología , Enfermedad del Almacenamiento de Glucógeno/patología , Linfoma de Células B/patología , Fibras Nerviosas/patología , Enfermedades del Sistema Nervioso/patología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/patología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
In this study, we investigated the effects of chronic administration of an inhibitor of the ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-ß pathology were obtained through small-animal PET imaging with 18F-FDG, 18F-peripheral benzodiazepine receptor (18F-PBR), and 18F-florbetapir (18F-AV45), respectively. Baseline scans were acquired at 6-7 wk of age and follow-up scans at 4, 7, and 12 mo. 18F-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-ß (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in 18F-AV45 uptake. An effect of treatment was observed in the cortex (P = 0.0014), hippocampus (P = 0.0005), and thalamus (P < 0.0001). Histology confirmed reduction of amyloid-ß pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18F-FDG uptake than WT mice in the thalamus (P = 0.0004) and hippocampus (P = 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. 18F-PBR111 detected a significant age-related increase in TG mice (P < 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. Conclusion: Although 18F-FDG, 18F-PBR111, and 18F-AV45 all detected pathologic alterations between TG and WT mice, only 18F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18F-AV45 undermine the specificity of this effect.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Envejecimiento , Enfermedad de Alzheimer/patología , Neuropatías Amiloides/patología , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Química Encefálica , Inhibidores Enzimáticos/uso terapéutico , Glicoles de Etileno , Fluorodesoxiglucosa F18 , Humanos , Inflamación/patología , Ratones , Ratones Transgénicos , Tomografía de Emisión de Positrones , Radiofármacos , Resultado del TratamientoRESUMEN
OBJECTIVE: To elucidate early skin denervation in hereditary transthyretin (TTR) amyloidosis and iatrogenic TTR amyloidosis. METHODS: We investigated intraepidermal nerve fiber density (IENFD) and clinical findings in 32 patients with hereditary TTR amyloidosis, 11 asymptomatic mutation carriers, 6 patients with iatrogenic TTR amyloidosis, and 23 healthy volunteers. RESULTS: IENFD values were reduced in patients with the V30M mutation (1.9 ± 2.1 per 1 mm), patients with non-V30M mutations (5.8 ± 3.2 per 1 mm), and patients with iatrogenic TTR amyloidosis (3.5 ± 1.8 per 1 mm) compared with healthy volunteers (11.8 ± 3.2 per 1 mm) (p < 0.01). Skin denervation also occurred, even in presymptomatic V30M mutation carriers (5.0 ± 2.2 per 1 mm). The IENFD was correlated with disease duration (ρ = -0.533, p = 0.002) and various peripheral neuropathy parameters such as sensory impairment in the Kumamoto clinical score (ρ = -0.575, p = 0.001), heat-pain detection threshold (ρ = -0.704, p < 0.001), and sural sensory nerve action potential (ρ = 0.481, p = 0.005). TTR amyloid deposits frequently occurred in connective tissues and vessels of the dermal reticular layer in patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis. CONCLUSIONS: Patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis may show early skin denervation even in the presymptomatic stage. IENFD may thus be useful for early diagnosis and may serve as a biomarker in clinical trials for hereditary and iatrogenic TTR amyloidosis.