A circulating, disease-specific, mechanism-linked biomarker for ATTR polyneuropathy diagnosis and response to therapy prediction.

The transthyretin (TTR) amyloidoses (ATTR) are progressive, degenerative diseases resulting from dissociation of the TTR tetramer to monomers, which subsequently misfold and aggregate, forming a spectrum of aggregate structures including oligomers and amyloid fibrils. To determine whether circulating nonnative TTR (NNTTR) levels correlate with the clinical status of patients with V30M TTR familial amyloid polyneuropathy (FAP), we quantified plasma NNTTR using a newly developed sandwich enzyme-linked immunosorbent assay. The assay detected significant plasma levels of NNTTR in most presymptomatic V30M TTR carriers and in all FAP patients. NNTTR was not detected in age-matched control plasmas or in subjects with other peripheral neuropathies, suggesting NNTTR can be useful in diagnosing FAP. NNTTR levels were substantially reduced in patients receiving approved FAP disease-modifying therapies (e.g., the TTR stabilizer tafamidis, 20 mg once daily). This NNTTR decrease was seen in both the responders (average reduction 56.4 ± 4.2%; n = 49) and nonresponders (average reduction of 63.3 ± 4.8%; n = 32) at 12 mo posttreatment. Notably, high pretreatment NNTTR levels were associated with a significantly lower likelihood of clinical response to tafamidis. Our data suggest that NNTTR is a disease driver whose reduction is sufficient to ameliorate FAP so long as pretreatment NNTTR levels are below a critical clinical threshold.

Treatment of cardiac transthyretin amyloidosis: an update.

Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver. As a result of gene mutations or as an ageing-related phenomenon, TTR molecules may misfold and deposit in the heart and in other organs as amyloid fibrils. Cardiac involvement in TTR-related amyloidosis (ATTR) manifests typically as left ventricular pseudohypertrophy and/or heart failure with preserved ejection fraction. ATTR is an underdiagnosed disorder as well as a crucial determinant of morbidity and mortality, thus justifying the current quest for a safe and effective treatment. Therapies targeting cardiac damage and its direct consequences may yield limited benefit, mostly related to dyspnoea relief through diuretics. For many years, liver or combined heart and liver transplantation have been the only available treatments for patients with mutations causing ATTR, including those with cardiac involvement. The therapeutic options now include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Following the positive results of a phase 3 trial on tafamidis, and preliminary findings on patisiran and inotersen in patients with ATTR-related neuropathy and cardiac involvement, we provide an update on this rapidly evolving field, together with practical recommendations on the management of cardiac involvement.

Demyelinating Neuropathy in a Patient Treated With Revusiran for Transthyretin (Thr60Ala) Amyloidosis.

Transthyretin amyloidosis patients develop length-dependent peripheral neuropathy, autonomic dysfunction, and restrictive cardiomyopathy associated with deposition of amyloid fibrils in these tissues. Despite advances in management over the past decade, this disorder causes profound debilitation and ultimately proves fatal. In this report, we describe a man with late-onset cardiac amyloidosis due to a transthyretin Thr60Ala mutation who was treated with an investigational RNAi therapeutic, revusiran, which targets hepatic transthyretin production. Sixteen months into treatment, he developed bilateral lower-extremity weakness and numbness, worsening balance, difficulty manipulating objects with his hands, and finger numbness. Nerve conduction studies were consistent with multifocal demyelinating neuropathy. Intravenous immunoglobulin therapy improved sensation in his hands and feet, and improved hand dexterity. A sural nerve biopsy demonstrated demyelination with substantial axonal loss in the absence of histologically detectable endoneurial amyloid deposition. This case expands the clinicopathologic spectrum of transthyretin amyloidosis and may represent complex disease and treatment effects.

Amyloid pathology and axonal injury after brain trauma.

OBJECTIVE: To image ß-amyloid (Aß) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aß are correlated, and compare the spatial distribution of Aß to Alzheimer disease (AD). METHODS: Patients 11 months to 17 years after moderate-severe TBI underwent (11)C-Pittsburgh compound B ((11)C-PiB)-PET, structural and diffusion MRI, and neuropsychological examination. Healthy aged controls and patients with AD underwent PET and structural MRI. Binding potential (BPND) images of (11)C-PiB, which index Aß plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy, was estimated and correlated with (11)C-PiB BPND. RESULTS: Twenty-eight participants (9 with TBI, 9 controls, 10 with AD) were assessed. Increased (11)C-PiB BPND was found in TBI vs controls in the posterior cingulate cortex and cerebellum. Binding in the posterior cingulate cortex increased with decreasing fractional anisotropy of associated white matter tracts and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions but increased in the cerebellum. CONCLUSIONS: Increased Aß burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathologic features of dementia, which may relate to axonal damage produced by the injury.

Clinical and prognostic differences among patients with light chain deposition disease, myeloma cast nephropathy and both.

In some patients with light chain deposition disease (LCDD) there is also evidence of myeloma cast nephropathy (MCN) on renal biopsy. The purpose of this study was to evaluate the renal and survival outcome of patients with concomitant diagnosis of MCN and LCDD to LCDD and MCN alone. Eighty seven patients were identified and divided into LCDD (n=45), MCN (n=29), and LCDD+ MCN (n=13). Patients with LCDD+ MCN had a worse overall survival (OS) compared to patients with LCDD (p=0.03), but similar to patients with MCN (p=0.4). Death-censored renal survival was no different amongst the groups. Presenting with acute renal failure at time of renal biopsy (HR 7.2, p=0.0002) was an independent poor renal prognostic factor while older age (HR 1.06, p=0.0002), presence of osteolytic lesions (HR 4.4, p<0.0001), and requirement for dialysis or creatinine≥5 mg/dL (HR 3.2, p=0.0006) at time of renal biopsy were independent poor prognostic factors for OS.

Reversibility of acquired amyloid polyneuropathy after liver retransplantation.

Domino liver transplantation (DLT) has become an accepted procedure designed to address problems with organ limited supply. However, cases of acquired amyloid neuropathy are increasingly being recognized following this procedure. Until now, only one patient had undergone liver retransplantation and follow-up findings were not reported. We describe the case of a 72-year-old patient with partial recovery from acquired amyloid neuropathy following retransplantation with a deceased donor 7 years after DLT performed for end-stage liver disease. His clinical and paraclinical improvement is described, and the impact of this case on the indication for a domino procedure and the challenges linked to retransplantation are discussed.

Amyloid neuropathies.

Peripheral neuropathy is a common complication of many of the systemic amyloidoses. Although the cause of neuropathy is not entirely clear, it is likely related to amyloid deposition within the nerve. This may lead to focal, multifocal, or diffuse neuropathies involving sensory, motor and/or autonomic fibers. The presenting symptoms depend on the distribution of nerves affected. One of the most common phenotypes is sensorimotor polyneuropathy, which is characterized by symptoms of neuropathic pain, numbness, and in advanced cases weakness. Symptoms begin in the feet and ultimately progress to the proximal legs and hands. The most common focal neuropathy is a median neuropathy at the wrist, clinically known as carpal tunnel syndrome. Carpal tunnel symptoms may include pain and sensory disturbances in the lateral palm and fingers; hand weakness may ensue if the focal neuropathy is severe. Autonomic neuropathy may affect a variety of organ systems such as the cardiovascular, gastrointestinal, and genitourinary systems. Symptoms may be non-specific making the diagnosis of autonomic neuropathy more difficult to identify. However, it is important to recognize and distinguish autonomic neuropathy from diseases of the end-organs themselves. This article reviews the inherited and acquired amyloidoses that affect the peripheral nervous system including familial amyloid polyneuropathy, and primary, secondary and senile amyloidosis. We emphasize the clinical presentation of the neurologic aspects of these diseases, physical examination findings, appropriate diagnostic evaluation, treatment and prognosis.

Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology.

BACKGROUND: A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated. METHODS AND RESULTS: To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway. CONCLUSIONS: Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.

[Original articles on axonal neuropathy in 2010]. / Les actualités sur les polyneuropathies axonales en 2010.

During 2010, 15 articles were published which focused on chronic sensorimotor axonal neuropathy; some will be discussed in this review. Clinical diagnosis from signs and symptoms seems to be excessively variable, often overestimating the incidence of diabetic sensorimotor polyneuropathy. Long-term use of Metformin is associated with malabsorption of vitamin B12. Metformin exposure may be a iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. The neuroprotective role of vitamin E against cisplatinperipheral neurotoxicity has been suggested by a phase III study. Metallosis after hip arthroplasty with a cobalt-chromium alloy prosthesis can cause progressive sensory disturbance, hearing loss and hypothyroidism. The effects of electrical stimulation on neuromuscular recovery after nerve crush injury in rats do not support a benefit of the tested protocol using electrical stimulation during the period of motor nerve recovery following injury. The rate of motor vehicle accidents in patients with neuropathy, based on surveys from 260 subjects, demonstrated that 40.6% were involved in traffic accidents. Accident frequency and discomfort with driving are higher in neuropathy patients compared to age-matched national statistics. Peripheral neuropathy in primary (AL) amyloidosis may be the cause of stepwise progressive, multiple upper limb mononeuropathies.

[New elements in the diagnosis and the treatment of primary AL amyloid polyneuropathy and neuropathy due to POEMS syndrome]. / Nouveautés dans le diagnostic et le traitement des neuropathies périphériques liées à l'amylose AL et au syndrome POEMS.

INTRODUCTION: Primary AL amyloid polyneuropathy (AL-PN) and neuropathy due to POEMS syndrome (POEMS-N) are rare, associated with a monoclonal gammopathy (MG) IgGλ or IgAλ at a low rate and systemic manifestations. They are invalidating and life-threatening. STATE OF THE ART: AL-PN usually mimics small fiber length-dependent axonal polyneuropathies, but also multifocal or painful neuropathies, POEMS-N corresponds to a rapid ascending CIDP with MG. To confirm the diagnosis of AL-PN, initial investigations should identify amyloidosis on nerve or accessory salivary glands, to establish the type of amyloid after serum free light-chain (FLC) measurements. For the diagnosis of N-POEMS, diagnosis is based on the presence of four criteria proposed by Dispenzieri. These neuropathies are associated with biomarkers, useful for diagnosis and treatment monitoring: elevated serum level of FLC monoclonal in (AL-PN) or VEGF (N-POEMS). PERSPECTIVES: Early diagnosis of these neuropathies and early treatment using high-dose melphalan associated with an autologous hematopoietic stem cell graft or low monthly doses can improve the clinical manifestations and patient survival. CONCLUSIONS: Systematic search for monoclonal gammopathy by immunofixation and serum free light chains is very useful for the management of progressive peripheral neuropathies of unknown origin.

Acquired amyloid neuropathy in a Portuguese patient after domino liver transplantation.

Familial amyloid polyneuropathy (FAP) is a progressive neuropathy with autonomic dysfunction. Domino liver transplantation (DLT), in which the liver of an FAP patient is transplanted into another patient, is routinely applied to compensate for the shortage of available organs. We report a patient who developed a clinical picture of FAP 9 years after a DLT from an FAP donor. Electrophysiological, neuropathological, and autonomic tests were administered. The patient presented with typical clinical features of FAP. Electrophysiological investigation confirmed a moderate sensorimotor axonal and autonomic neuropathy. Sural nerve biopsy confirmed the presence of amyloid deposits in the endoneurium. Skin biopsy at the ankle showed reduced intraepidermal nerve fiber density. Our report shows that FAP can develop in a recipient of an FAP liver. This suggests that careful longitudinal study is required to evaluate the risk of FAP polyneuropathy in patients who undergo domino liver transplantation.

Patient with amyloidoma of the ulnar nerve and salivary glands.

Amyloidomas of the peripheral nervous system have been reported rarely. We describe a patient with a history of localized amyloidosis of the salivary glands who presented a few years later with paresthesias of her left medial arm, forearm, and fifth digit. A mass affecting the left ulnar nerve was confirmed by MRI studies. It was excised and proven on pathological examination to be an amyloidoma. The benign course of this patient's illness is consistent with localized amyloidosis affecting two different organs.

[Amyloid neuropathy resulting from an unknown protein]. / Neuropathie amyloïde liée à une protéine non identifiée.

Amyloid neuropathy is related to acquired or hereditary forms of amyloidosis resulting from transthyretin variants. We reported a 42-year-old man suffering from a peripheral neuropathy not related to transthyretin mutations. Mass spectrometry may be useful to identify this rare form of amyloid neuropathy.

[Case of rheumatoid arthritis with various histological lesions of the kidney].

We experienced a case of rheumatoid arthritis with nephrotic syndrome. A renal biopsy specimen from this patient showed various renal histological changes. The patient was a 50-year-old man who was diagnosed as having rheumatoid arthritis in 1987. We performed a renal biopsy because he had persistent proteinuria from March in 2002. The renal biopsy specimen showed amyloid AA and P protein deposition in the glomeruli. Moreover mild mesangial proliferation was recognized. IgA-deposition in the mesangial area, and granular-deposition of IgG along the glomerular capillary wall were also observed. In electron microscopy, electron dense deposits were recognized in the mesangial area and subepithelium of the glomerular basement membrane. From these findings, we diagnosed amyloid nephropathy, IgA nephritis and membranous nephropathy. Renal biopsy of patients with RA is useful not only for precise diagnosis, but also for selection of the appropriate treatment.

[Multisystemic amyloidosis. Clinical study of 39 patients in Lebanon]. / Amyloses multisystémiques. Etude clinique de 39 patients au Liban.

OBJECTIVE: Clinical analysis of multisystem amyloidosis in Lebanon, by histological type. METHOD: Retrospective study of 39 cases of multisystem amyloidosis diagnosed histologically in a university hospital center between 1991 and 2002. It analyzed the following clinical data: age, gender, type of presentation, time from symptom onset to diagnosis, clinical features, concomitant diseases, family history of amyloidosis, biopsy sites, presence of urinary or serum monoclonal gammopathy, immunohistochemical type, prognosis and treatment. RESULTS: Median age at diagnosis was 56+/-18 years. The overall ratio of men to woman was 1.4. AL amyloidosis (amyloid light chain) accounted for 54% (21/39) of the cases, AA (amyloid-associated) amyloidosis 36% (14/39), while 10% (4/39) were not typed. Among the 21 cases of AL amyloidosis, 12 were idiopathic (57%) and 9 (43%) were associated with multiple myeloma; among the 14 cases of AA amyloidosis, 7 were associated with familial Mediterranean fever and 5 with chronic disorders. Proteinuria was often the first symptom. The initial manifestations in AL amyloidosis patients with myeloma were more often related to amyloidosis than to myeloma. Renal involvement was seen in 95% (37/39) of all cases (95% of AL versus 93% of AA), proteinuria in 87% of cases and renal failure in 72%. Cardiac amyloidosis (57% of AL versus 7% of AA; p>0.05), infiltration of the tongue (19% of AL versus 0% of AA; p>0.05) and neurological manifestations (24% of AL versus 7% of AA; p>0.05) were more frequent in AL amyloidosis. The 7 patients who died (18%) had AL amyloidosis (5 of them had myeloma). Heart failure was the most frequent cause of death related to amyloid. CONCLUSION: Multisystem amyloidosis is frequent in Lebanon and familial Mediterranean fever is still frequently associated with the secondary type. Accurate diagnosis and classification are essential for the prognosis and treatment of the disease. Poor prognosis was associated with the AL type, especially when accompanied by myeloma, and with cardiac amyloidosis.