Central Nervous System involvement in hereditary transthyretin amyloidosis (ATTRv) is present in liver transplanted patients with longstanding ATTRV30M amyloidosis, and in some rarer variants. The pathophysiology of brain involvement and its relationship with cognitive disturbances is unknown. This systematic review summarized the literature on brain and cognitive involvement in ATTRv amyloidosis and aimed to elucidate the reasons for such involvement. The literature search was performed using the following databases: Medline/PubMed, Embase via Elsevier, Scopus, and Web of Science. Two assessors independently screened titles and abstracts, examined full texts, extracted data, and assessed the risk of bias. The risk of bias assessment was carried out using the JBI critical appraisal tools. This review included studies that applied any neuroimaging exam or cognitive assessment in humans with genetic confirmation of any TTR mutation. 59 studies met the inclusion criteria. Overall, the studies were of good quality. 57 studies reported at least one brain MRI technique. Only six studies reported a formal neuropsychological assessment. The studies included 1218 ATTRv patients (mean 45.7 ± 11.8 years) and 169 asymptomatic TTR variant carriers (mean 30.6 ± 7.5 years). The most common TTR variant was V30M (n = 936), followed by V122I (n = 74). 42.4% of ATTRv patients presented abnormalities in the neuroimaging exam and 19.7% presented cognitive dysfunction. Based on the available evidence, brain involvement and cognitive symptoms can be present in ATTRv amyloidosis. Further research should explore the relationship of these symptoms with other complications (autonomic and cardiologic).

Patients with hereditary amyloidosis related to transthyretin (ATTRv amyloidosis) treated with liver transplant (LTx) often have central nervous system (CNS) manifestations, including cognitive dysfunction. The aim of this study was to explore the long-term outcome associated with neuropsychological test performance. A retrospective longitudinal review was conducted in a cohort of 289 ATTRv amyloidosis patients with the Val30Met mutation (ATTRV30M amyloidosis) who underwent a neuropsychological assessment (T1) 1-23 years (median = 11) post-LTx and 20-189 months (median = 81) prior to the study review. Clinical records were reviewed. The Kaplan-Meier and Cox regression methods were used to estimate survival and adjusted hazard ratios for all-cause mortality. Impaired performance on Dementia Rating Scale-2, Semantic Fluency, Phonemic Fluency and Trail Making Test Part B were predictive of shorter survival after neuropsychological assessment, even when demographic and clinical variables (i.e. education, age at disease onset ≥50, disease duration at LTx, interval between LTx and T1, age at T1, Modified Polyneuropathy Disability score at T1, and history of focal neurological episodes at T1) were taken into account. Measures of verbal learning and memory were not predictive of mortality. Study results demonstrate that cognitive impairment in ATTRV30M amyloidosis patients treated with LTx predicts long-term survival.

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an inherited disease, where the study of family history holds importance. This study evaluates the changes of age-of-onset (AOO) and other age-related clinical factors within and among families affected by ATTRv amyloidosis. We analysed information from 934 trees, focusing on family, parents, probands and siblings relationships. We focused on 1494 female and 1712 male symptomatic ATTRV30M patients. Results are presented alongside a comparison of current with historical records. Clinical and genealogical indicators identify major changes. Overall, analysis of familial data shows the existence of families with both early and late patients (1/6). It identifies long familial follow-up times since patient families tend to be diagnosed over several years. Finally, results show a large difference between parent-child and proband-patient relationships (20-30 years). This study reveals that there has been a shift in patient profile, with a recent increase in male elderly cases, especially regarding probands. It shows that symptomatic patients exhibit less variability towards siblings, when compared to other family members, namely the transmitting ancestors' age of onset. This can influence genetic counselling guidelines.

Introduction: Cardiac amyloidoses are the most fatal manifestation of systemic amyloidoses. It is believed the number of cases to be greatly underestimated mostly due to misdiagnosis. Particularly, the involvement of TTR V30M in the heart of ATTRV30M amyloidosis has not been completely understood specifically in terms of implicated cellular pathways, heart function and cardiac physiology. In the present work we proposed to characterize TTR V30M cardiac involvement particularly at the tissue cellular level in a mouse model. Methods: HSF ± hTTR V30M mice, a model that expresses human TTRV30M in a Ttr null background, widely used for the characterization and modulation of neurological features of ATTRV30M amyloidosis was used. SDS-PAGE of cardiac homogenates followed by Western blot was performed. Immunohistochemistry and double immunofluorescence analyses were carried out to determine TTR deposition pattern and sub-localization. Results: Western blots were able to detect TTR in its monomeric state at ∼14 kDa. Immunofluorescent images showed TTR was found mostly in the intercellular spaces. Blood contamination was excluded by CD31 staining. Tissues were Congo Red negative. Upon TTR and macrophages (CD68) staining in the cardiac tissue a clear tendency of macrophage convergence to the tissue regions where TTR was more abundant was observed. Moreover, in some instances it was possible to detect co-localization of both fluorophores. Cardiac fibroblasts were stained with PDGFr-alpha, and here the co-localization was not so evident although there was some degree of co-occurrence. The hearts of transgenic mice revealed higher content of Galectin-3. Conclusion: This animal model and associated features observed as result of cardiac TTR deposition provide a promising and invaluable research tool for a better understanding of the implicated pathways that lead to the lethality associated to TTR cardiac amyloidosis. New therapeutic strategies can be tested and ultimately this will lead to improved treatment alternatives capable of increasing patient's quality of life and life expectancy and, hopefully to eradicate a condition that is silently spreading worldwide.

Quantitative sensory testing (QST) has been one of the neurophysiological tools used for follow-up and disease progression assessment in ATTRv amyloidosis. We aimed to detect the utility of QST in identifying subclinical neuropathic involvement in ATTRV30M amyloidosis carriers. A cohort of ATTRV30M amyloidosis carriers were assessed with vibratory (VDT) and cooling (CDT) detection thresholds and heat pain responses. Subjects were divided into asymptomatic carriers (Group 1), paucisymptomatic carriers (Group 2) and stage 1 ATTRv-PN patients (Group 3). Nonparametric statistics were used for group comparisons. A total of 207 ATTRV30M amyloidosis carriers (83 males) were included. Of these, 113 subjects were asymptomatic and 94 symptomatic carriers. In asymptomatic carriers, CDT and Heat Pain (HP 5.0 and HP 0.5) were significantly lower when compared to both group of symptomatic carriers (p ≤ 0.005). In Group 3, VDT, CDT and HP 5.0 were significantly higher, when compared to Group 2 (p < 0.05). QST, in particular CDT, HP 5 and HP 0.5 modalities, seems a good tool to identify subclinical neuropathy in ATTRv amyloidosis carriers, with CDT showing a higher sensitivity to detect and early neuropathic involvement.