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  • 1
    Online Resource
    Online Resource
    Pure tone audiometry and cerebral pathology in healthy older adults
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 2 ( 2020-02), p. 172-176
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 2 ( 2020-02), p. 172-176
    Abstract: Hearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations. Methods Data from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2–71.9 years), who underwent structural MRI, 18 F-florbetapir positron emission tomography, pure tone audiometry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults. Results There was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo β-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer’s disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase. Conclusion Pure tone audiometry performance did not predict concurrent β-amyloid deposition, small vessel disease or Alzheimer’s disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-321897
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1480429-3
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  • 2
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    Incidental findings on brain imaging and blood tests: results from the first phase of Insight 46, a prospective observational substudy of the 1946 British birth cohort
    BMJ ; 2019
    In:  BMJ Open Vol. 9, No. 7 ( 2019-07), p. e029502-
    Details
    In: BMJ Open, BMJ, Vol. 9, No. 7 ( 2019-07), p. e029502-
    Abstract: To summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study. Design Prospective observational sub-study of a birth cohort. Setting Single-day assessment at a research centre in London, UK. Participants 502 individuals were recruited from the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, based on pre-specified eligibility criteria; mean age was 70.7 (SD: 0.7) and 49% were female. Outcome measures Data regarding the number and types of incidental findings were summarised as counts and percentages, and 95% confidence intervals were calculated. Results 93.8% of participants completed a brain scan (n=471); 4.5% of scanned participants had a pre-defined reportable abnormality on brain MRI (n=21); suspected vascular malformations and suspected intracranial mass lesions were present in 1.9% (n=9) and 1.5% (n=7) respectively; suspected cerebral aneurysms were the single most common vascular abnormality, affecting 1.1% of participants (n=5), and suspected meningiomas were the most common intracranial lesion, affecting 0.6% of participants (n=3); 34.6% of participants had at least one abnormality on clinical blood tests (n=169), but few reached the prespecified threshold for urgent action (n=11). Conclusions In older adults, aged 69-71 years, potentially serious brain MRI findings were detected in around 5% of participants, and clinical blood test abnormalities were present in around one third of participants. Knowledge of the expected prevalence of incidental findings in the general population at this age is useful in both research and clinical settings.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    DOI: 10.1136/bmjopen-2019-029502
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 2599832-8
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  • 3
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    Population-based blood screening for pre-clinical Alzheimer’s disease: a British birth cohort at age 70
    BMJ ; 2022
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 93, No. 6 ( 2022-06), p. A91.2-A91
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 93, No. 6 ( 2022-06), p. A91.2-A91
    Abstract: In pre-clinical Alzheimer’s disease, cerebral amyloid-β (Aβ) deposition precedes symptoms; Aβ-targeted therapies may have maximum benefits at this stage. Existing Aβ status measurement techniques, including amyloid PET and CSF testing, are difficult to upscale. We therefore compared the concordance of three different blood-based techniques (liquid chromatography-mass spectrometry (LC¬-MS) measures of plasma Aβ, and single molecule array (Simoa) measures of plasma Aβ and phospho-tau181 (p-tau181)) with amyloid PET-positivity in dementia-free members of Insight 46, a sub-study of the British 1946 birth cohort. Of 441 dementia-free individuals with complete data, 82 (18.6%) were amyloid PET-positive. The area under the receiver operating characteristics curve for amyloid PET status using a base model comprising age, sex and APOE ε4 carrier status was 0.695 (95% confidence interval: 0.628–0.762). The best perform- ing Simoa biomarker was p-tau181 (0.707; 0.646–0.768). LC-MS Aβ1–42/1–40 performed significantly better (0.817; 0.770–0.864), with a Youden’s index cut-point of 0.095 detecting amyloid PET-positivity with 86.6% sensitivity and 71.9% specificity. Without screening, 543 individuals would need PET scans, to obtain 100 PET-positive individuals. Screening using the base model would require 940 individuals, with 266 proceeding to scan. Using LC-MS Aβ1–42/1–40 alone would reduce these numbers to 623 and 243 respectively. Across a theoretical range of amyloid PET-positivity prevalence of 10–50%, LC-MS Aβ1–42/1–40 would consistently reduce scan numbers, with greater cost savings at lower prevalence. ashvini.keshavan@nhs.net
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2022-ABN.297
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1480429-3
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  • 4
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    Knockout of the inhibitory receptor TIGIT enhances the antitumor response of ex vivo expanded NK cells and prevents fratricide with therapeutic Fc-active TIGIT antibodies
    BMJ ; 2023
    In:  Journal for ImmunoTherapy of Cancer Vol. 11, No. 12 ( 2023-12), p. e007502-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 11, No. 12 ( 2023-12), p. e007502-
    Abstract: Inhibitory receptor T-cell Immunoreceptor with Ig and ITIM domains (TIGIT) expressed by Natural Killer (NK) and T cells regulates cancer immunity and has been touted as the next frontier in the development of cancer immunotherapeutics. Although early results of anti-TIGIT and its combinations with antiprogrammed death-ligand 1 were highly exciting, results from an interim analysis of phase III trials are disappointing. With mixed results, there is a need to understand the effects of therapeutic anti-TIGIT on the TIGIT + immune cells to support its clinical use. Most of the TIGIT antibodies in development have an Fc-active domain, which binds to Fc receptors on effector cells. In mouse models, Fc-active anti-TIGIT induced superior immunity, while Fc receptor engagement was required for its efficacy. NK-cell depletion compromised the antitumor immunity of anti-TIGIT indicating the essential role of NK cells in the efficacy of anti-TIGIT. Since NK cells express TIGIT and Fc-receptor CD16, Fc-active anti-TIGIT may deplete NK cells via fratricide, which has not been studied. Methods CRISPR-Cas9-based TIGIT knockout (KO) was performed in expanded NK cells. Phenotypic and transcriptomic properties of TIGIT KO and wild-type (WT) NK cells were compared with flow cytometry, CyTOF, and RNA sequencing. The effect of TIGIT KO on NK-cell cytotoxicity was determined by calcein-AM release and live cell imaging-based cytotoxicity assays. The metabolic properties of TIGIT KO and WT NK cells were compared with a Seahorse analyzer. The effect of the Fc-component of anti-TIGIT on NK-cell fratricide was determined by co-culturing WT and TIGIT KO NK cells with Fc-active and Fc-inactive anti-TIGIT. Results TIGIT KO increased the cytotoxicity of NK cells against multiple cancer cell lines including spheroids. TIGIT KO NK cells upregulated mTOR complex 1 (mTORC1) signaling and had better metabolic fitness with an increased basal glycolytic rate when co-cultured with cancer cells compared with WT NK cells. Importantly, TIGIT KO prevented NK-cell fratricide when combined with Fc-active anti-TIGIT. Conclusions TIGIT KO in ex vivo expanded NK cells increased their cytotoxicity and metabolic fitness and prevented NK-cell fratricide when combined with Fc-active anti-TIGIT antibodies. These fratricide-resistant TIGIT KO NK cells have therapeutic potential alone or in combination with Fc-active anti-TIGIT antibodies to enhance their efficacy.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2023-007502
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2719863-7
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  • 5
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    Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia
    BMJ ; 2020
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 91, No. 3 ( 2020-03), p. 263-270
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 91, No. 3 ( 2020-03), p. 263-270
    Abstract: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions Raised GFAP concentrations appear to be unique to GRN -related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2019-321954
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1480429-3
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  • 6
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    Subjective cognitive complaints at age 70: associations with amyloid and mental health
    BMJ ; 2021
    In:  Journal of Neurology, Neurosurgery & Psychiatry Vol. 92, No. 11 ( 2021-11), p. 1215-1221
    Details
    In: Journal of Neurology, Neurosurgery & Psychiatry, BMJ, Vol. 92, No. 11 ( 2021-11), p. 1215-1221
    Abstract: To investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study. Methods Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to 18 F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant’s perspective on SCD was evaluated in relation to MyCog score. Results Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) −0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant’s perception of SCD was generally in accordance with that of the participant. Conclusions This cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer’s disease pathology and SCD.
    Type of Medium: Online Resource
    ISSN: 0022-3050 , 1468-330X
    URL: Article
    DOI: 10.1136/jnnp-2020-325620
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 1480429-3
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