TDP-43 frontotemporal lobar degeneration and autoimmune disease.

BACKGROUND: The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. OBJECTIVE: To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls. DESIGN: Case control. SETTING: Academic medical centres. PARTICIPANTS: 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels. OUTCOME MEASURES: χ(2) Comparison of autoimmune prevalence and follow-up logistic regression. RESULTS: There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC. CONCLUSIONS: svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.

Maternal transmission of Alzheimer disease.

Some researchers propose maternal Alzheimer disease (AD) inheritance. We compared dementia family histories in AD cases and cognitively normal controls. We expected more mothers to have AD in both groups. If maternal risk was not only due to female longevity, more AD cases' than controls' mothers should have dementia. We matched 196 AD cases to 200 controls by sex and age. We obtained parent dementia status and age of death for 348 AD and 319 control parents. Twenty-four (12%) controls' fathers, 26 (13%) AD patients' fathers, 58 (29%) controls' mothers, and 55 (28%) AD mothers had memory difficulty. More mothers than fathers had memory problems in both groups and the statistical significance persisted after adjusting for parent age at death and APOE for controls [odds ratios (OR)=2.40, P=0.004] but not cases (OR=1.63, P=0.14), although the results are qualitatively similar. There was no evidence of a real difference between the 2 groups in interaction analysis (P=0.41). Mothers of both cases and controls were more often affected than fathers, even after adjusting for age. Cases' mothers no more often had dementia than controls' mothers, which does not support maternal AD transmission. Rather, the increased number of affected mothers relates, at least in part, to female longevity.

C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic.

Alzheimer disease (AD) and frontotemporal dementia (FTD) are two frequent forms of primary neurodegenerative dementias with overlapping clinical symptoms. Pathogenic mutations of the amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) genes have been linked to familial early-onset forms of AD; however, more recently mutations in the common FTD genes encoding the microtubule associated protein tau (MAPT), progranulin (GRN) and C9ORF72, have also been reported in clinically diagnosed AD patients. To access the contribution of mutations in a well-characterized series of patients, we systematically performed genetic analyses of these EOAD and FTD genes in a novel cohort of 227 unrelated probands clinically diagnosed as probable AD which were ascertained at Mayo Clinic Florida between 1997 and 2011. All patients showed first symptoms of dementia before 70 years. We identified 9 different pathogenic mutations in the EOAD genes in a total of 11 patients explaining 4.8% of the patient population. Two mutations were novel: PSEN1 p.Pro218Leu and PSEN2 p.Phe183Ser. Importantly, mutations were also identified in all FTD genes: one patient carried a MAPT p.R406W mutation, one patient carried the p.Arg198Glyfs19X loss-of-function mutation in GRN and two patients were found to carry expanded GGGGCC repeats in the non-coding region of C9ORF72. Together the FTD genes explained the disease in 1.8% of our probable AD population. The identification of mutations in all major FTD genes in this novel cohort of clinically diagnosed AD patients underlines the challenges associated with the differential diagnosis of AD and FTD resulting from overlapping symptomatology and has important implications for molecular diagnostic testing and genetic counseling of clinically diagnosed AD patients. Our findings suggest that in clinically diagnosed AD patients, genetic analyses should include not only the well-established EOAD genes APP, PSEN1 and PSEN2 but also genes that are usually associated with FTD. Finally, the overall low frequency of mutation carriers observed in our study (6.6%) suggests the involvement of other as yet unknown genetic factors associated with AD.