Loss of TREM2 function impairs phagocytosis and correlates with decreased soluble TREM2 in biological fluids of patients with neurodegenerative disorders.

To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD) patients with long follow-up. Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerative syndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center between November 1991 and July 2013. The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up of four years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years, 75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4%) were dementia with Lewy bodies (DLB) in 29 subjects, Parkinson disease (PD) in 22, multiple system atrophy (MSA) in two, and mild cognitive impairment (MCI) in 12. In six cases, in whom postmortem was performed, neuropathological examination disclosed neuronal loss and widespread Lewy-type pathology in the brain in each case. In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that the majority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBD represented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice, in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventions with potential disease-modifying agents.

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss‐of‐function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type‐1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross‐sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non‐AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho‐tau_181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.

Background: Preliminary studies suggested that anti-Tr antibodies identify patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin disease (HD). Objective: To extend the clinical–immunologic analysis to 28 patients with anti-Tr antibodies. Methods: Anti-Tr antibodies were detected by immunohistochemistry. A competitive inhibition assay was used to ascertain if anti-Tr antibodies of different sera identify common epitopes. Anti-Tr immunoglobulin G (IgG) subclass distribution was determined by immunohistochemistry using monoclonal antibodies against human IgG isotypes. Tr immunoreactivity was analyzed in tumor sections using biotinylated anti-Tr IgG. Results: Median age of the 28 patients was 61 years (range 14 to 75 years) and 22 were male. A cerebellar syndrome was present in 27 patients and a possible limbic encephalitis in one. HD was diagnosed in 25 patients. No tumor was found in three patients; the autopsy of one of them disclosed severe loss of Purkinje cells without inflammatory infiltrates. Anti-Tr antibodies spontaneously disappeared in all patients without tumor and in 10/10 patients after successful HD treatment. Anti-Tr antibodies were absent in the serum but positive in the CSF of two patients. All positive anti-Tr sera inhibited the immunoreactivity of biotinylated anti-Tr IgG. The predominant isotypes of anti-Tr were IgG1 and IgG3. Only 1 out of the 15 HD samples studied presented anti-Tr positivity that was localized in some Reed-Sternberg cells. Conclusions: This study confirms the strong association between anti-Tr antibodies and PCD associated with HD. Anti-Tr antibodies from different patients recognize similar epitopes. Unlike other antineuronal antibodies, anti-Tr antibodies can be detected in the CSF but not in the serum and may spontaneously disappear during the follow-up, and Tr immunoreactivity is usually lacking in the tumor.