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1.
Brain ; 143(3): 1010-1026, 2020 03 01.
Article in English | MEDLINE | ID: mdl-32179883

ABSTRACT

The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-ß protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.


Subject(s)
Frontotemporal Dementia/metabolism , Inflammation/metabolism , Protein Aggregates , Aged , Carbolines/metabolism , Carbon Radioisotopes/metabolism , Case-Control Studies , DNA-Binding Proteins/metabolism , Female , Frontotemporal Dementia/complications , Humans , Inflammation/complications , Isoquinolines/metabolism , Male , Microglia/metabolism , Middle Aged , Positron-Emission Tomography , Protein Binding , Tauopathies/metabolism
2.
Sex Transm Infect ; 88(6): 422-6, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22692276

ABSTRACT

OBJECTIVES: To conduct a case-control study of abnormalities in the semen of genitourinary (GU) medicine clinic attendees compared with general practice (GP) controls and in patients with asymptomatic and symptomatic non-specific urethritis (NSU) before and after the urethritis resolves. METHODS: Rates of semen abnormalities were compared between the different groups (19 with symptomatic and 27 with asymptomatic NSU, seven with symptomatic non-NSU and 64 clinic controls) and between clinic attendees and 417 patients attending GP for the first investigation of possible infertility. Those with symptomatic or asymptomatic NSU gave repeat semen samples on resolution of the NSU. RESULTS: The study included 117 clinic volunteers. They were shown to have statistically significantly worse total sperm counts (p=0.002), volume of semen (p<0.001) and percentage of abnormal forms (p<0.04) compared with 417 GP controls. Compared with the rest of the clinic volunteers, asymptomatic NSU patients had statistically significantly lower total sperm counts (p<0.02). Asymptomatic NSU patients had statistically significantly lower total sperm counts compared with symptomatic NSU patients (p<0.02). Compared with GP controls, clinic controls had statistically significantly inferior total sperm counts (p=0.009) and semen volume (p<0.001). CONCLUSIONS: GU clinic attendees are more likely to have abnormalities of semen than patients attending GP for the first check for possible infertility. A high rate of abnormal semen findings are found in patients with and without NSU but the highest rate occurred in those with asymptomatic NSU. Is asymptomatic NSU therefore pathogenic and does it require treatment like symptomatic NSU?


Subject(s)
Oligospermia/diagnosis , Oligospermia/epidemiology , Urethritis/complications , Adult , Case-Control Studies , Humans , Male , Prevalence
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