Cerebellar and Cerebral Amyloid Visualized by [18F]flutemetamol PET in Long-Term Hereditary V30M (p.V50M) Transthyretin Amyloidosis Survivors

Abstract

Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS.

Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8-25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [¹⁸F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls.

Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD.

Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.

Keywords: [18F]flutemetamol; amyloid angiopathy; amyloidosis-hereditary; positron emission tomography; transthyretin.

Figure 1

PET/CT examination of [¹⁸F]flutemetamol shown as Z-score in the brain in relation to pons from a left lateral view of the brain. The intensity of the uptakes is visualized on the left panel and is graded from low increased uptake in blue (Z-score +2SD) to high increased uptake in red (Z-score +8SD). (A) An ATTR V30M patient with 15 years of disease showing no increased uptake; (B) an ATTR V30M patient with 16 years of disease showing increased uptake in the cerebellum, (C) an ATTR V30M patient with 27 years of disease showing diffuse increased uptake in the brain, and (D) an Alzheimer's patient with generalized increased uptake in the frontoparietotemporal regions.

Figure 2

Scatter plot of the relationship between (A) composite Z-score and duration of disease from diagnosis (r_S = −0.20; NS) and (B) relationship between Z-score cerebellum and age at onset (r_S = −0.45; P < 0.05).

Figure 3

Fraction of patients with pathological Z-score (>2) in different brain regions. Curves represent patient groups: AD (orange), ATTR V 30M age <40 (gray), and ATTR V30M age >40 years (yellow).