Pathogenesis of degenerative dementia: Emerging role for inflammation

Abstract

AbstractBackgroundRecent evidence proposes a role for immune‐mediated mechanisms in pathogenesis of neurodegenerative dementias. Contribution of inflammatory processes to the progression of neurodegeneration has also been hypothesized. While deposition of various proteins is recognised as the pathological hallmark for the neurodegenerative dementias, Alzheimer’s disease (AD) and Frontotemporal dementia (FTD), the role of inflammation secondary to immune dysregulation in neurodegeneration remains to be determined. In this study, we aimed to investigate the profile of autoantibodies in patients diagnosed to have neurodegenerative dementia and compare the association between the different subtypes.MethodWe performed immunological screening in a large cohort of neurodegenerative dementias. Diagnosis was based on standard criteria, on review of clinical, MR imaging and laboratory features. Dementia types comprised of Alzheimer’s disease (AD), Frontotemporal dementia (FTD), and Dementia with Lewy Bodies (DLB). The immunological screening consisted of antinuclear antibody (ANA) profile, paraneoplastic and autoimmune encephalitis profile.ResultOf 274 consecutive patients with degenerative dementia evaluated in the Cognitive Disorders Clinic (AD = 62, FTD = 202, DLB = 10), autoantibody profile was done in 174(63.5%). ANA profile was positive in 18.3%, paraneoplastic panel in 8.3% and autoimmune panel in 2.1% of patients. We observed a significantly higher frequency of immunopositivity in patients with FTD (34.4%) compared to AD(10.4%) and DLBD(14.2%). The range of antibodies detected included antibodies against anti‐Ro 52(SS‐A), anti‐La(SS‐B), PM‐Scl, centromere protein B(CENP‐B), dsDNA, histones and ribosomal P‐proteins in the ANA profile; anti‐Hu, anti‐Ri, anti‐Yo, anti‐CV‐2, PNMA2 (Ma2/Ta), Anti‐amphiphysin, Anti‐ SOX1, anti‐glial nuclear antibody(AGNA), anti‐Tr, Anti‐GAD65, anti‐Zic4, anti‐titin and anti‐recoverin in paraneoplastic and in the autoimmune profile autoantibodies present were N‐methyl‐D‐asparate(NMDA), alpha‐amino‐3‐hydroxy‐5 methyl‐4‐isoxazoleproprionic acid (AMPA), Leucine rich glioma‐inactivated protein‐1(LGI1), Contactin‐associated protein‐2(CASPR2), and GABAB receptor antibody. There were no significant systemic complaints in majority of patients, and no difference was observed in the mean age, gender and duration of illness between immune‐positive and immune‐negative patients.ConclusionOur findings further substantiate the emerging role for neuroinflammation secondary to immune dysregulation, in patients with classical neurodegenerative dementias. Establishing the profile of specific autoantibodies that occur in association with dementia subtypes, especially FTD, may aid in understanding mechanisms that underlie role of autoimmunity in neurodegenerative dementias, with therapeutic implications.