title: CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings.
abstract: OBJECTIVE
  Since liver transplant (LT) was introduced to treat patients with familial amyloid polyneuropathy carrying the V30M mutation (ATTR-V30M), ocular and cardiac complications have developed. Long-term central nervous system (CNS) involvement was not investigated. Our goals were to: (1) identify and characterise focal neurological episodes (FNEs) due to CNS dysfunction in ATTR-V30M patients; (2) characterise neuropathological features and temporal profile of CNS transthyretin amyloidosis.
  
  
  METHODS
  We monitored the presence and type of FNEs in 87 consecutive ATTR-V30M and 35 non-ATTR LT patients. FNEs were investigated with CT scan, EEG and extensive neurovascular workup. MRI studies were not performed because all patients had cardiac pacemakers as part of the LT protocol. We characterised transthyretin amyloid deposition in the brains of seven ATTR-V30M patients, dead 3-13 years after polyneuropathy onset.
  
  
  RESULTS
  FNEs occurred in 31% (27/87) of ATTR-V30M and in 5.7% (2/35) of the non-ATTR transplanted patients (OR=7.0, 95% CI 1.5 to 33.5). FNEs occurred on average 14.6 years after disease onset (95% CI 13.3 to 16.0) in ATTR-V30M patients, which is beyond the life expectancy of non-transplanted ATTR-V30M patients (10.9, 95% CI 10.5 to 11.3). ATTR-V30M patients with FNEs had longer disease duration (OR=1.24; 95% CI 1.07 to 1.43), renal dysfunction (OR=4.65; 95% CI 1.20 to 18.05) and were men (OR=3.57; 95% CI 1.02 to 12.30). CNS transthyretin amyloidosis was already present 3 years after polyneuropathy onset and progressed from the meninges and its vessels towards meningocortical vessels and the superficial brain parenchyma, as disease duration increased.
  
  
  CONCLUSIONS
  Our findings indicate that CNS clinical involvement occurs in ATTR-V30M patients regardless of LT. Longer disease duration after LT can provide the necessary time for transthyretin amyloidosis to progress until it becomes clinically relevant. Highly sensitive imaging methods are needed to identify and monitor brain ATTR. Disease modifying therapies should consider brain TTR as a target.
authors.affiliation: Unidade Corino de Andrade, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal Serviço de Neurologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Luís F
authors.initials: LF
authors.lastname: Maia
authors.affiliation: Departamento de Estudos Populacionais, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Magalhães
authors.affiliation: Serviço de Neurologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Joel
authors.initials: J
authors.lastname: Freitas
authors.affiliation: Unidade de Neuropatologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Taipa
authors.affiliation: Unidade de Neuropatologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuel Melo
authors.initials: MM
authors.lastname: Pires
authors.affiliation: Instituto de Patologia e Imunologia Molecular da Universidade do Porto, IPATIMUP, Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Osório
authors.affiliation: Serviço de Neuroradiologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dias
authors.affiliation: Departamento de Medicina, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Helena
authors.initials: H
authors.lastname: Pessegueiro
authors.affiliation: Serviço de Neurologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Correia
authors.affiliation: Unidade Corino de Andrade, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal Serviço de Neurofisiologia, Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Teresa
authors.initials: T
authors.lastname: Coelho
mesh_terms: D000328:Adult; D000682:Amyloid / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D028227:Amyloid Neuropathies, Familial / Q000097:blood / Q000134:cerebrospinal fluid / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D018450:Disease Progression; D004569:Electroencephalography; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016031:Liver Transplantation / Q000401:mortality / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011228:Prealbumin / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D011859:Radiography; D012189:Retrospective Studies; D063189:Symptom Assessment
chemical_list: D000682:Amyloid; D011228:Prealbumin; C041120:amyloid prealbumin
keywords: Amyloid; Clinical Neurology; Neuropathology; Neuropathy