Origin of Transthyretin in Cerebral Amyloid Angiopathy.

This case series evaluates the correlation between transthyretin and cerebral amyloid angiopathy progression in individuals with hereditary transthyretin amyloidosis.

Correlation between a commercial electrophysiological test of sudomotor function and intraepidermal nerve fiber density in hereditary transthyretin amyloidosis.

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.

Disease-Modifying Drugs Extend Survival in Hereditary Transthyretin Amyloid Polyneuropathy.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, fatal systemic disease, associated with polyneuropathy and cardiomyopathy, that is caused by mutant transthyretin (TTR). In addition to liver transplantation, several groundbreaking disease-modifying drugs (DMDs) such as tetrameric TTR stabilizers and TTR gene-silencing therapies have been developed for ATTRv amyloid polyneuropathy. They were based on a working hypothesis of the mechanisms of ATTRv amyloid formation. In this retrospective cohort study, we investigated survival of all 201 consecutive patients with ATTRv amyloidosis in our center. The effects of DMDs on survival improvements were significant not only in early-onset patients but also in late-onset patients. ANN NEUROL 2024;95:230-236.

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.

Binding of serum-derived amyloid-associated proteins to amyloid fibrils.

BACKGROUND: Amyloid signature proteins such as serum amyloid P component, apolipoprotein E (ApoE), and ApoA-IV generally co-localise with amyloid, regardless of the types of amyloid precursor protein or the organs. Most of these proteins derive from serum and have reportedly been involved in amyloid fibril formation and stabilisation, as well as in excretion and degradation of amyloid precursor proteins. However, the processes and mechanisms by which these specific proteins deposit together with amyloid fibrils have not been clarified. METHODS: We analysed the binding of serum proteins to amyloid fibrils derived from amyloid ß and insulin in vitro by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Specific serum proteins including ApoA-I, ApoE, ApoA-IV, ApoC-III and vitronectin adhered to amyloid fibrils at high concentrations in vitro. In addition, the profile of these proteins commonly occurred in both amyloid ß and insulin amyloid fibrils and was mostly consistent with the composition of amyloid signature proteins. We also showed that high concentrations of serum proteins can adhere to amyloid fibrils in a short time. CONCLUSIONS: Our in vitro results suggest that amyloid signature proteins coexist with amyloid primarily dependent on the binding of each serum protein, in the extracellular fluid, to amyloid fibrils.

Age-related amyloidosis outside the brain: A state-of-the-art review.

Inside and outside the brain, accumulation of amyloid fibrils plays key roles in the pathogenesis of fatal age-related diseases such as Alzheimer's and Parkinson's diseases and wild-type transthyretin amyloidosis. Although the incidence of all amyloidoses increases with age, for some types of amyloidosis aging is known as the main direct risk factor, and these types are typically diseases of elderly people. More than 10 different precursor proteins are known to cause age-associated amyloidosis; these proteins include amyloid ß protein, α-synuclein, transthyretin, islet amyloid polypeptide, atrial natriuretic factor, and the newly discovered epidermal growth factor-containing fibulin-like extracellular matrix protein 1. Except for intracerebral amyloidoses, most age-related amyloidoses have been little studied. Indeed, in view of the increasing life expectancy in our societies, understanding how aging is involved in the process of amyloid fibril accumulation and the effects of amyloid deposits on the aging body is extremely important. In this review, we summarize current knowledge about the nature of amyloid precursor proteins, the prevalence, clinical manifestations, and pathogenesis of amyloidosis, and recent advances in our understanding of age-related amyloidoses outside the brain.

Apolipoprotein AI amyloid deposits in the ligamentum flavum in patients with lumbar spinal canal stenosis.

Amyloidosis is a protein-misfolding disease characterised by insoluble amyloid deposits in the extracellular space of various organs and tissues, such as the brain, heart, kidneys, and ligaments. We previously reported the frequent occurrence of amyloid deposits in the ligament flavum in the presence of lumbar spinal canal stenosis (LSCS), which is a common spinal disorder in older individuals. Our earlier clinicopathological studies revealed that amyloid deposits derived from transthyretin (TTR) were involved in the pathogenesis of LSCS. ATTR amyloid was the most common form in the ligamentum flavum, but amyloid deposits that were not identified still existed in more than 50% of patients with LSCS. In this study, we found apolipoprotein AI (AApoAI) amyloid deposits in the ligamentum flavum of patients with LSCS. The deposits occurred in 12% of patients with LSCS. Biochemical studies revealed that the amyloid deposits consisted mainly of full-length ApoAI. As a notable finding, the lumbar ligamentum flavum of patients who had LSCS with double-positive amyloid deposits-positive for both ATTR and AApoAI-was significantly thicker than that of patients who had LSCS with single-positive-that is, positive for either ATTR or AApoAI-amyloid deposits. We thus suggest that lumbar AApoAI amyloid formation may enhance the pathological changes of lumbar ATTR amyloidosis in patients with LSCS.

Needle-shaped amyloid deposition in rat mammary gland: evidence of a novel amyloid fibril protein.

Amyloidosis is an extremely rare event in rats. In this study, we report that lipopolysaccharide binding protein (LBP) is the most likely amyloidogenic protein in rat mammary amyloidosis. Histologically, corpora amylacea (CA) and stromal amyloid (SA) were observed in rat mammary glands, and needle-shaped amyloid (NA) was also observed on the surface or gap of CA and SA. Following surveillance in aged rats, NA was observed in 62% of mammary tumours, 25% of male mammary glands and 83% of female mammary glands. Proteomic analysis showed that lactadherin was a major constitutive protein of CA and SA, and both were positive following immunohistochemistry with anti-lactadherin antibodies. In the same analysis, LBP was detected as a prime candidate protein in NA, and NA was positive following immunohistochemistry and immunoelectron microscopy with anti-LBP antibody. Furthermore, synthetic peptides derived from rat LBP formed amyloid fibrils in vitro. Overall, these results provide evidence that LBP is an amyloid precursor protein of NA in rat mammary glands.

Characteristics of acquired transthyretin amyloidosis: A case series and review of the literature.

OBJECTIVE: To elucidate the clinical characteristics of acquired ATTR amyloidosis after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary variant ATTR (ATTRv) amyloidosis. METHODS: We evaluated the presence of amyloid deposits and clinical symptoms in 30 recipients of domino liver transplants (24 men and 6 women) who underwent DLT with liver grafts explanted from patients with ATTRv amyloidosis. We analyzed symptoms and measures of 7 cases of symptomatic acquired ATTR amyloidosis and compared those with 30 patients with ATTRv amyloidosis who were the domino liver donors. We also reviewed the literature on case studies of acquired ATTR amyloidosis. RESULTS: We found amyloid deposition in 13 of our 30 domino liver recipients. A Kaplan-Meier analysis estimated that the median time from DLT to the first detection of amyloid was 8.5 years. In the literature review, the mean time was 7.3 years, with a wide range of 0.5-13 years. Our 7 symptomatic cases and the literature cases with acquired ATTR amyloidosis presented with clinical features that differed from patients with ATTRv amyloidosis who were the domino liver donors. Patients with acquired ATTR amyloidosis showed markedly milder autonomic disturbance, which is one of the main symptoms of ATTRv amyloidosis. CONCLUSIONS: Careful monitoring is required for DLT recipients of ATTRv liver grafts because the time from DLT to disease onset has a wide range and the clinical picture of these DLT recipients is distinct from that of liver donors.

Hereditary ATTR Amyloidosis with Cardiomyopathy Caused by the Novel Variant Transthyretin Y114S (p.Y134S).

We report the clinical features of a patient with hereditary transthyretin (ATTR) amyloidosis associated with a novel mutation (Y114S, p.Y134S). A 65-year-old Japanese man was admitted to our hospital after a 3-year history of progressive dyspnea on exertion. Five years previously, he presented dysesthesia in both hands caused by carpal tunnel syndrome. A genetic analysis revealed a base pair substitution of adenine to cytosine in the second codon of exon 4, residue 114, in the TTR gene (c.401A>C). The clinical characteristics were progressive cardiomyopathy with a poor vital prognosis, late onset, sporadic case, bilateral carpal tunnel syndrome, hypothyroidism, and small fiber neuropathy.

New simple and quick method to analyze serum variant transthyretins: direct MALDI method for the screening of hereditary transthyretin amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is caused by a variant transthyretin (TTR), which is a serum protein secreted by the liver. Mass spectrometry (MS) is a useful tool that can detect variant TTRs in serum samples from patients with ATTRv amyloidosis. We previously reported several mass spectrometric methods to detect variant TTRs in serum samples. Those methods require cumbersome immunoprecipitation with anti-TTR antibodies and significant time to analyze the variant TTRs. In our study here, we developed a new simple and quick method to detect variant TTRs in serum samples by means of matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) MS without immunoprecipitation (direct MALDI). METHODS: By using direct MALDI, we analyzed 288 serum samples obtained from patients who were clinically suspected having amyloidosis to investigate the usefulness of this direct MALDI method to detect variant TTRs in serum samples. RESULTS: The method completed the process within 30 min. We successfully identified variant TTRs in serum samples from patients, except for a few patients with TTR Glu61Lys and Glu89Gln mutations because of the small mass shift of those variant TTRs from wild-type TTR. We also found that the mass shifts of variant TTRs measured by direct MALDI corresponded to theoretical mass changes. CONCLUSION: Our results suggest that the direct MALDI method is useful for the screening of ATTRv amyloidosis.

A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1.

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.