Distribution and progression of cerebral amyloid angiopathy in early-onset V30M (p.V50M) hereditary ATTR amyloidosis.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is becoming the most common and serious complications in long-lived hereditary ATTR amyloidosis patients. It is therefore imperative to elucidate the characteristics of ATTR-type CAA and develop useful biomarkers. METHODS: We enrolled 34 ATTRv amyloidosis patients with the V30M (p.V50M) variant for analysis with three-dimensional stereotactic surface projection z score imaging of Pittsburgh compound B (PiB)-PET. RESULTS: Eight patients exhibited central nervous system (CNS) symptoms. Seven patients suffered transient focal neurologic episodes, and 2 patients each experienced cerebellar haemorrhages or cognitive decline. The amount of 11C-PiB accumulation increased as a function of disease duration. 11C-PiB-PET abnormalities were seen at 8 years from onset and were associated with CNS manifestations from 12 years. The annual increase rate of the standardised uptake value ratio (SUVR) in female patients was significantly higher than in male patients. CNS amyloid deposition started in the upper middle surface of the cerebellar cortex, and then spread out over the entire surface of the cerebellum, Sylvian fissure, and anterior part of the longitudinal fissure of the cerebrum. CONCLUSIONS: PiB-PET is a useful biomarker for the early detection and treatment evaluation of ATTR-type CAA. Female gender is associated with more rapid progression of ATTR-type CAA.

CSF/plasma levels, transthyretin stabilisation and safety of multiple doses of tolcapone in subjects with hereditary ATTR amyloidosis.

PURPOSE: To investigate the effect of tolcapone on cerebrospinal fluid (CSF) transthyretin (TTR) tetramer stability in patients with hereditary transthyretin (ATTRv) amyloidosis. METHODS: A total of 9 patients were enrolled in the study (3 men, 50.3 ± 14.4 years old). Three patients had central nervous system (CNS) involvement. Patients were assigned to receive tolcapone 300 mg/day or 600 mg/day for 7 days. Plasma and CSF were collected at baseline and 2 h after the final tolcapone dose. RESULTS: The mean CSF tolcapone and 3-O-Methyltolcapone (3-OMT) concentration were 39.4 ± 36.3 ng/mL and 26.0 ± 4.9 ng/mL, respectively, after 7 days of tolcapone dosing. Tolcapone and 3-OMT were detected in the CSF of patients with or without CNS symptoms. The mean total study drug (tolcapone + 3-OMT) to TTR molar ratio in CSF was 1.15 ± 0.59. Orally administered tolcapone significantly increased CSF TTR concentration and decreased monomer content under semi-denaturing conditions. Eight adverse events (AEs) were reported in 6 patients. All AEs were mild in severity and resolved. CONCLUSIONS: Tolcapone was able to cross the blood brain-barrier, highlighting its potential to decrease CNS manifestations of ATTRv amyloidosis. Tolcapone was well tolerated by patients with ATTRv amyloidosis.

Distribution of amyloidosis subtypes based on tissue biopsy site - Consecutive analysis of 729 patients at a single amyloidosis center in Japan.

This study was performed to elucidate the distribution of amyloidosis subtypes based on tissue biopsy site. Samples obtained from 729 consecutive patients with amyloidosis were analyzed by immunohistochemical staining (IHC) and supplemental mass spectrometry (MS). The correlations between the type of organs from which samples were obtained and amyloidosis subtypes were investigated retrospectively. Among the patients, 95.1% were diagnosed by IHC and 4.9% were diagnosed by MS. The distribution of amyloidosis subtypes was as follows: AL, 59.1%; ATTR, 32.9%; AA, 4.0%; AH, 1.4%; Aß2M, 0.8%; and others, 0.9%. AL was the most common subtype in most organs, including the liver, lung, kidney, lower urinary tract, bone marrow, gastrointestinal tract, and skin/subcutaneous tissue. ATTR was the most common subtype in the heart, carpal tunnel, and peripheral nerves. AH was the second most common subtype in renal biopsy. Three or more amyloidosis subtypes were detected in each organ. In conclusion, AL was the most common subtype in most biopsy sites except the heart, carpal tunnel, and peripheral nerve, in which ATTR was more common. Because several types of amyloidogenic protein were detected in each organ, amyloid typing must be pursued, no matter the site from where biopsy was obtained.

Non-invasive detection and differentiation of cardiac amyloidosis using 99mTc-pyrophosphate scintigraphy and 11C-Pittsburgh compound B PET imaging.

PURPOSE: To investigate the utility of the combined use of 11C-Pittsburgh compound B (11C-PiB) positron emission tomography (PET) imaging and 99mTc-pyrophosphate (99mTc-PYP) scintigraphy for detection and differentiation of three major types of cardiac amyloidosis, i.e. immunoglobulin light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt) amyloidosis. METHODS: Whole-body 11C-PiB PET and 99mTc-PYP scintigraphy were performed in 17 patients with AL amyloidosis, 22 patients with ATTRv, and eight patients with ATTRwt amyloidosis. The correlations between organ involvement and the uptake of 11C-PiB and 99mTc-PYP were analyzed in each patient. RESULTS: Cardiac amyloidosis was detectable by 99mTc-PYP scintigraphy or 11C-PiB PET in all systemic amyloidosis patients with cardiac involvement. 99mTc-PYP scintigraphy and 11C-PiB PET showed an interesting complementary relation. Strict combination of positive 11C-PiB and negative 99mTc-PYP uptake (PiB pattern) was observed in all AL amyloidosis patients with cardiac involvement. In contrast, strict combination of positive 99mTc-PYP and negative 11C-PiB uptake (PYP pattern) was observed in all ATTRwt amyloidosis patients with cardiac involvement. ATTRv amyloidosis patients with cardiac involvement were divided into two groups: PiB pattern or PYP pattern. All of the early-onset V30M (p.V50M) ATTRv patients showed the PiB pattern, whereas all of the late-onset V30M and non-V30M ATTRv patients showed the PYP pattern. CONCLUSIONS: All three major types of cardiac amyloidosis can be detected and differentiated non-invasively by combined use of the two amyloid imaging methods and TTR gene testing.

A Late-onset and Relatively Rapidly Progressive Case of Pure Spinal Form Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene.

A 61-year-old Japanese man with the pure spinal form of cerebrotendinous xanthomatosis developed dysesthesia of the lower limbs and gait disturbance at 57 years of age. At 61 years old, he was unable to walk without support. A neurological examination showed spasticity and sensory disturbance in the lower limbs. Spinal MRI showed long hyperintense lesions involving the lateral and posterior funiculus in the cervical and thoracic cord on T2-weighted images. His serum cholestanol level was markedly elevated. A CYP27A1 gene analysis identified two missense variants, p.R474W, and a novel p.R262C variant. Combination therapy with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decreased his serum cholestanol level.

[A 36-year-old woman with primary central nervous system lymphoma diagnosed by twice brain biopsies, showing relapsing and remitting brain lesions].

A 36-year-old woman visited a local hospital suffering from acute onset dizziness. Brain MRI revealed multiple white matter lesions without gadolinium enhancement in the both hemispheres. Although she began to receive a treatment under a clinical diagnosis of multiple sclerosis, she developed newly emerging brain lesions and was referred to our hospital. Neurological examination detected intention tremor, right-sided dysdiadochokinesis, and gait ataxia. Both blood and cerebrospinal fluid tests were unremarkable but follow-up brain MRIs showed rapidly relapsing and remitting lesions. The first brain biopsy ended up showing non-specific changes but the second biopsy with five months interval confirmed primary central nervous system lymphoma (PCNSL). The patient was treated by chemotherapy and showed partial response. It is important to consider sequential brain biopsies if needed because PCNSL may present diverse brain lesions on MRI including non-neoplastic early lesions.