The frequency of central nervous system complications in the Cypriot cohort of ATTRV30M neuropathy transplanted patients.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is a hereditary, sensorimotor and autonomic neuropathy caused by deposits of mutated transthyretin (TTR). The commonest TTR mutation is V30M (ATTRV30M) with patients usually living for about 10 years after disease onset. Liver transplantation (LT) until recently was considered the standard treatment. OBJECTIVE AND METHODS: This study aims to assess the frequency of CNS complications in post-LT patients from the Cypriot cohort. Epidemiological data were collected for all genetically confirmed ATTRV30M neuropathy patients diagnosed at CING since 1992, and CNS-associated symptoms were assessed and evaluated by two neurology specialists. RESULTS: Out of the 48 transplanted patients, 10 (20.8%) presented with a CNS complication. All patients had ocular involvement, mainly glaucoma (7/10). Eight presented with transient focal neurological episodes (TFNEs), with expressive dysphasia being reported by four of them. The mean time of TFNE-emergence was 16.6 years after the LT. Three died from cerebral hemorrhage. CONCLUSIONS: CNS complications in post-LT ATTRV30M patients are not rare and usually manifest themselves at a time that surpasses the mean time the patients would have survived without a LT. CNS involvement is associated with increased mortality, due to cerebral hemorrhage.

C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aß amyloid and preserves memory in a mouse model of familial Alzheimer's disease.

According to the amyloid hypothesis of Alzheimer's disease (AD) the deposition of prefibrillar and fibrillar Aß peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aß peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aß peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aß peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aß, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease.

Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset.

BACKGROUND: ATTRV30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by amyloid deposition composed of aggregated misfolded TTR monomers with the V30M mutation. The age of onset in patients with ATTRV30M varies in different foci and the mechanism behind it is still unknown. METHODS: The tertiary neurology center following all ATTRV30M patients in Cyprus was used to collect demographic data to estimate; prevalence, incidence, penetrance, anticipation, time from disease onset to diagnosis and transplantation. Ocular, cardiac and leptomeningeal involvement in transplanted patients was explored. Correlation of C1q tagging SNPs with age of disease onset was carried out. RESULTS: Prevalence and incidence for ATTRV30M neuropathy in Cyprus are 5.4/100,000 and 0.3/100,000 respectively. Mean age of onset is 40.6 years and anticipation is 8.3 years. Penetrance reaches 51% and 75% by the ages of 50 and 80 years respectively. In liver transplanted patients rates of ocular, cardiac and leptomeningeal involvement were estimated to be 60%, 20% and 16%, respectively. C1q polymorphisms correlated with age of disease onset. CONCLUSIONS: ATTRV30M neuropathy has a rising prevalence in Cyprus due to improved survival of patients. Late onset complications are becoming a major problem. Complement C1q appears to be a modifier in this disease.