Publications by authors named "Jonathan M Schott"

252 Publications

Grip strength from midlife as an indicator of later-life brain health and cognition: evidence from a British birth cohort.

BMC Geriatr 2021 08 31;21(1):475. Epub 2021 Aug 31.

MRC Unit for Lifelong Health and Ageing at UCL, University College London, London, United Kingdom.

Background: Grip strength is an indicator of physical function with potential predictive value for health in ageing populations. We assessed whether trends in grip strength from midlife predicted later-life brain health and cognition.

Methods: 446 participants in an ongoing British birth cohort study, the National Survey of Health and Development (NSHD), had their maximum grip strength measured at ages 53, 60-64, and 69, and subsequently underwent neuroimaging as part of a neuroscience sub-study, referred to as "Insight 46", at age 69-71. A group-based trajectory model identified latent groups of individuals in the whole NSHD cohort with below- or above-average grip strength over time, plus a reference group. Group assignment, plus standardised grip strength levels and change from midlife were each related to measures of whole-brain volume (WBV) and white matter hyperintensity volume (WMHV), plus several cognitive tests. Models were adjusted for sex, body size, head size (where appropriate), sociodemographics, and behavioural and vascular risk factors.

Results: Lower grip strength from midlife was associated with smaller WBV and lower matrix reasoning scores at age 69-71, with findings consistent between analysis of individual time points and analysis of trajectory groups. There was little evidence of an association between grip strength and other cognitive test scores. Although greater declines in grip strength showed a weak association with higher WMHV at age 69-71, trends in the opposite direction were seen at individual time points with higher grip strength at ages 60-64, and 69 associated with higher WMHV.

Conclusions: This study provides preliminary evidence that maximum grip strength may have value in predicting brain health. Future work should assess to what extent age-related declines in grip strength from midlife reflect concurrent changes in brain structure.
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http://dx.doi.org/10.1186/s12877-021-02411-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406895PMC
August 2021

Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.

EClinicalMedicine 2021 Aug 12:101070. Epub 2021 Aug 12.

Francis Crick Institute, London, UK.

Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear.

Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβGPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I βGPI (aD1β2GPI) IgG.

Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups ( < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO =-0.15  = 0.040) and was associated with venous thromboembolism ( = 0.043). In contrast, aCL IgA ( < 0.001) and IgG ( < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO.

Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management.
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http://dx.doi.org/10.1016/j.eclinm.2021.101070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358233PMC
August 2021

Serum and cerebrospinal fluid biomarker profiles in acute SARS-CoV-2-associated neurological syndromes.

Brain Commun 2021 12;3(3):fcab099. Epub 2021 May 12.

Advanced Pathogens Diagnostic Unit, University College London Hospitals NHS Foundation Trust, London WC1H 8NJ, UK.

Preliminary pathological and biomarker data suggest that SARS-CoV-2 infection can damage the nervous system. To understand what, where and how damage occurs, we collected serum and CSF from patients with COVID-19 and characterized neurological syndromes involving the PNS and CNS ( = 34). We measured biomarkers of neuronal damage and neuroinflammation, and compared these with non-neurological control groups, which included patients with ( = 94) and without ( = 24) COVID-19. We detected increased concentrations of neurofilament light, a dynamic biomarker of neuronal damage, in the CSF of those with CNS inflammation (encephalitis and acute disseminated encephalomyelitis) [14 800 pg/ml (400, 32 400)], compared to those with encephalopathy [1410 pg/ml (756, 1446)], peripheral syndromes (Guillain-Barré syndrome) [740 pg/ml (507, 881)] and controls [872 pg/ml (654, 1200)]. Serum neurofilament light levels were elevated across patients hospitalized with COVID-19, irrespective of neurological manifestations. There was not the usual close correlation between CSF and serum neurofilament light, suggesting serum neurofilament light elevation in the non-neurological patients may reflect peripheral nerve damage in response to severe illness. We did not find significantly elevated levels of serum neurofilament light in community cases of COVID-19 arguing against significant neurological damage. Glial fibrillary acidic protein, a marker of astrocytic activation, was not elevated in the CSF or serum of any group, suggesting astrocytic activation is not a major mediator of neuronal damage in COVID-19.
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http://dx.doi.org/10.1093/braincomms/fcab099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194666PMC
May 2021

Aducanumab: a new phase in therapeutic development for Alzheimer's disease?

EMBO Mol Med 2021 Aug 2;13(8):e14781. Epub 2021 Aug 2.

UK Dementia Research Institute at UCL, London, UK.

On 7 June the FDA approved aducanumab, the first new drug for Alzheimer's disease in almost 20 years-and notably, the first drug with a putative disease-modifying mechanism for the treatment of this devastating disorder, namely the removal of β-amyloid (or Aβ) plaques from the brain.
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http://dx.doi.org/10.15252/emmm.202114781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350893PMC
August 2021

Cerebrospinal fluid metallomics in cerebral amyloid angiopathy: an exploratory analysis.

J Neurol 2021 Jul 22. Epub 2021 Jul 22.

Department of Brain Repair and Rehabilitation, Stroke Research Centre, UCL Queen Square Institute of Neurology, Russell Square House, 10-12 Russell Square, London, WC1B 5EH, UK.

Introduction: Cerebral amyloid angiopathy (CAA) is associated with symptomatic intracerebral haemorrhage. Biomarkers of clinically silent bleeding events, such as cerebrospinal fluid (CSF) ferritin and iron, might provide novel measures of disease presence and severity.

Methods: We performed an exploratory study comparing CSF iron, ferritin, and other metal levels in patients with CAA, control subjects (CS) and patients with Alzheimer's disease (AD). Ferritin was measured using a latex fixation test; metal analyses were performed using inductively coupled plasma mass spectrometry.

Results: CAA patients (n = 10) had higher levels of CSF iron than the AD (n = 20) and CS (n = 10) groups (medians 23.42, 15.48 and 17.71 μg/L, respectively, p = 0.0015); the difference between CAA and AD groups was significant in unadjusted and age-adjusted analyses. We observed a difference in CSF ferritin (medians 10.10, 7.77 and 8.01 ng/ml, for CAA, AD and CS groups, respectively, p = 0.01); the difference between the CAA and AD groups was significant in unadjusted, but not age-adjusted, analyses. We also observed differences between the CAA and AD groups in CSF nickel and cobalt (unadjusted analyses).

Conclusions: In this exploratory study, we provide preliminary evidence for a distinct CSF metallomic profile in patients with CAA. Replication and validation of these results in larger cohorts is needed.
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http://dx.doi.org/10.1007/s00415-021-10711-6DOI Listing
July 2021

Suspecting dementia: canaries, chameleons and zebras.

Pract Neurol 2021 Jul 2. Epub 2021 Jul 2.

Dementia Research Centre, UCL, London, UK

The early and accurate diagnosis of dementia is more important than ever before but remains challenging. Dementia is increasingly the business of neurologists and, with ageing populations worldwide, will become even more so in future. Here we outline a practical, symptom-led, bedside approach to suspecting dementia and its likely diagnosis, inspired by clinical experience and based on recognition of characteristic syndromic patterns. We show how clinical intuition reflects underlying signature profiles of brain involvement by the diseases that cause dementia and suggest next steps that can be taken to define the diagnosis. We propose 'canaries' that provide an early warning signal of emerging dementia and highlight the 'chameleons' that disguise or mimic this, as well as the 'zebras' that herald a rare (and sometimes curable) diagnostic opportunity.
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http://dx.doi.org/10.1136/practneurol-2021-003019DOI Listing
July 2021

Subjective cognitive complaints at age 70: associations with amyloid and mental health.

J Neurol Neurosurg Psychiatry 2021 May 25. Epub 2021 May 25.

Dementia Research Centre, Queen Square Institute of Neurology, University College London, London, UK

Objective: 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 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.
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http://dx.doi.org/10.1136/jnnp-2020-325620DOI Listing
May 2021

Investigating the relationship between BMI across adulthood and late life brain pathologies.

Alzheimers Res Ther 2021 04 30;13(1):91. Epub 2021 Apr 30.

Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, Box 16, Queen Square, London, WC1N 3BG, UK.

Background: In view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69-71 years.

Methods: Four hundred sixty-five dementia-free participants from Insight 46, a sub-study of the British 1946 birth cohort, who had cross-sectional T1/FLAIR volumetric MRI, and florbetapir amyloid-PET imaging at age 69-71 years, were included in analyses. We quantified white matter hyperintensity volume (WMHV) using T1 and FLAIR 3D-MRI; β-amyloid (Aβ) positivity/negativity using a SUVR approach; and whole brain (WBV) and hippocampal volumes (HV) using 3D T1-MRI. We investigated the influence of BMI, and BMI changes at and between 36, 43, 53, 60-64, 69 and 71 years, on late-life WMHV, Aβ-status, WBV and mean HV. Analyses were repeated using overweight and obese status.

Results: At no time-point was BMI, change in BMI or overweight/obese status associated with WMHV or WBV at age 69-71 years. Decreasing BMI in the 1-2 years before imaging was associated with an increased odds of being β-amyloid positive (OR 1.45, 95% confidence interval 1.09, 1.92). There were associations between being overweight and larger mean HV at ages 60-64 (β = 0.073 ml, 95% CI 0.009, 0.137), 69 (β = 0.076 ml, 95% CI 0.012, 0.140) and 71 years (β = 0.101 ml, 95% CI 0.037, 0.165). A similar, albeit weaker, trend was seen with obese status.

Conclusions: Using WMHV, β-amyloid status and brain volumes as indicators of brain health, we do not find evidence to explain reported associations between midlife obesity and late-life dementia risk. Declining BMI in later life may reflect preclinical Alzheimer's disease.
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http://dx.doi.org/10.1186/s13195-021-00830-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091727PMC
April 2021

Beyond the average patient: how neuroimaging models can address heterogeneity in dementia.

Brain 2021 Apr 23. Epub 2021 Apr 23.

Centre for Medical Image Computing, Medical Physics and Biomedical Engineering, University College London, London, UK.

Dementia is a highly heterogeneous condition, with pronounced individual differences in onset age, clinical presentation, progression rates and neuropathological hallmarks, even within a specific diagnostic group. However, the most common statistical designs used in dementia research studies and clinical trials overlook this heterogeneity, instead relying on the comparison of group average differences (e.g., patient versus control, treatment versus placebo), implicitly assuming within-group homogeneity. This one-size-fits-all approach potentially limits our understanding of dementia aetiology, hindering the identification of effective treatments. Neuroimaging has enabled characterisation of the average neuroanatomical substrates of dementias; however, the increasing availability of large open neuroimaging datasets provides the opportunity to examine patterns of neuroanatomical variability in individual patients. In this Update review we outline the causes and consequences of heterogeneity in dementia and discuss recent research which aims to directly tackle heterogeneity, rather than assume that dementia affects everyone in the same way. We introduce spatial normative modelling as an emerging data-driven technique which can be applied to dementia data to model neuroanatomical variation, capturing individualised neurobiological "fingerprints". Such methods have the potential to detect clinically relevant subtypes, track an individual's disease progression or evaluate treatment responses, with the goal of moving towards precision medicine for dementia.
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http://dx.doi.org/10.1093/brain/awab165DOI Listing
April 2021

When dementia is misdiagnosed.

Int J Geriatr Psychiatry 2021 06 20;36(6):799-801. Epub 2021 Apr 20.

UCL Dementia Research Centre, Institute of Neurology, London, UK.

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http://dx.doi.org/10.1002/gps.5538DOI Listing
June 2021

A population-based study of head injury, cognitive function and pathological markers.

Ann Clin Transl Neurol 2021 04 11;8(4):842-856. Epub 2021 Mar 11.

Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.

Objective: To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later-life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia-free individuals.

Methods: Participants (n = 502, age = 69-71) from the 1946 British Birth Cohort underwent cognitive testing (subtests of Preclinical Alzheimer Cognitive Composite), F-florbetapir Aβ-PET and MR imaging. Measures include Aβ-PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) microstructure, Alzheimer's disease (AD)-related cortical thickness, and serum neurofilament light chain (NFL). LOC HI metrics include HI occurring: (i) >15 years prior to the scan (ii) anytime up to age 71.

Results: Compared to those with no evidence of an LOC HI, only those reporting an LOC HI>15 years prior (16%, n = 80) performed worse on cognitive tests at age 69-71, taking into account premorbid cognition, particularly on the digit-symbol substitution test (DSST). Smaller brain volume (BV) and adverse NAWM microstructural integrity explained 30% and 16% of the relationship between HI and DSST, respectively. We found no evidence that LOC HI was associated with Aβ load, hippocampal volume, WMH volume, AD-related cortical thickness or NFL (all p > 0.01).

Interpretation: Having a LOC HI aged 50's and younger was linked with lower later-life cognitive function at age ~70 than expected. This may reflect a damaging but small impact of HI; explained in part by smaller BV and different microstructure pathways but not via pathology related to AD (amyloid, hippocampal volume, AD cortical thickness) or ongoing neurodegeneration (serum NFL).
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http://dx.doi.org/10.1002/acn3.51331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045921PMC
April 2021

Evaluation of plasma tau and neurofilament light chain biomarkers in a 12-year clinical cohort of human prion diseases.

Mol Psychiatry 2021 Mar 5. Epub 2021 Mar 5.

MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK.

Prion diseases are fatal neurodegenerative conditions with highly accurate CSF and imaging diagnostic tests, but major unmet needs for blood biomarkers. Using ultrasensitive immuno-assays, we measured tau and neurofilament light chain (NfL) protein concentrations in 709 plasma samples taken from 377 individuals with prion disease during a 12 year prospective clinical study, alongside healthy and neurological control groups. This provides an unprecedented opportunity to evaluate their potential as biomarkers. Plasma tau and NfL were increased across all prion disease types. For distinguishing sCJD from control groups including clinically-relevant "CJD mimics", both show considerable diagnostic value. In sCJD, NfL was substantially elevated in every sample tested, including during early disease with minimal functional impairment and in all follow-up samples. Plasma tau was independently associated with rate of clinical progression in sCJD, while plasma NfL showed independent association with severity of functional impairment. In asymptomatic PRNP mutation carriers, plasma NfL was higher on average in samples taken within 2 years of symptom onset than in samples taken earlier. We present biomarker trajectories for nine mutation carriers healthy at enrolment who developed symptoms during follow-up. NfL started to rise as early as 2 years before onset in those with mutations typically associated with more slowly progressive clinical disease. This shows potential for plasma NfL as a "proximity marker", but further work is needed to establish predictive value on an individual basis, and how this varies across different PRNP mutations. We conclude that plasma tau and NfL have potential to fill key unmet needs for biomarkers in prion disease: as a secondary outcome for clinical trials (NfL and tau); for predicting onset in at-risk individuals (NfL); and as an accessible test for earlier identification of patients that may have CJD and require more definitive tests (NfL). Further studies should evaluate their performance directly in these specific roles.
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http://dx.doi.org/10.1038/s41380-021-01045-wDOI Listing
March 2021

Investigating the Relationship Between IGF-I, IGF-II, and IGFBP-3 Concentrations and Later-Life Cognition and Brain Volume.

J Clin Endocrinol Metab 2021 05;106(6):1617-1629

MRC Unit for Lifelong Health and Ageing at UCL, University College London, London, UK.

Background: The insulin/insulin-like signaling (IIS) pathways, including insulin-like growth factors (IGFs), vary with age. However, their association with late-life cognition and neuroimaging parameters is not well characterized.

Methods: Using data from the British 1946 birth cohort, we investigated associations of IGF-I, IGF-II and IGF binding protein 3 (IGFBP-3; measured at 53 and 60-64 years of age) with cognitive performance [word-learning test (WLT) and visual letter search (VLS) at 60-64 years and 69 years of age] and cognitive state [Addenbrooke's Cognitive Exam III (ACE-III) at 69-71 years of age], and in a proportion, quantified neuroimaging measures [whole brain volume (WBV), white matter hyperintensity volume (WMHV), hippocampal volume (HV)]. Regression models included adjustments for demographic, lifestyle, and health factors.

Results: Higher IGF-I and IGF-II at 53 years of age was associated with higher ACE-III scores [ß 0.07 95% confidence interval (CI) (0.02, 0.12); scoreACE-III 89.48 (88.86, 90.1), respectively). IGF-II at 53 years of age was additionally associated with higher WLT scores [scoreWLT 20 (19.35, 20.65)]. IGFBP-3 at 60 to 64 years of age was associated with favorable VLS score at 60 to 64 and 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.02, 0.12), respectively], higher memory and cognitive state at 69 years of age [ß 0.07 (0.01, 0.12); ß 0.07 (0.01, 0.13), respectively], and reduced WMHV [ß -0.1 (-0.21, -0.00)]. IGF-I/IGFBP-3 at 60 to 64 years of was associated with lower VLS scores at 69 years of age [ß -0.08 (-0.15, -0.02)].

Conclusions: Increased measure in IIS parameters (IGF-I, IGF-II, and IGFBP-3) relate to better cognitive state in later life. There were apparent associations with specific cognitive domains (IGF-II relating to memory; IGFBP-3 relating to memory, processing speed, and WMHV; and IGF-I/IGFBP-3 molar ratio related to slower processing speed). IGFs and IGFBP-3 are associated with favorable cognitive function outcomes.
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http://dx.doi.org/10.1210/clinem/dgab121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118585PMC
May 2021

Visuomotor integration deficits are common to familial and sporadic preclinical Alzheimer's disease.

Brain Commun 2021 25;3(1):fcab003. Epub 2021 Jan 25.

Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.

We investigated whether subtle visuomotor deficits were detectable in familial and sporadic preclinical Alzheimer's disease. A circle-tracing task-with direct and indirect visual feedback, and dual-task subtraction-was completed by 31 individuals at 50% risk of familial Alzheimer's disease (19 presymptomatic mutation carriers; 12 non-carriers) and 390 cognitively normal older adults (members of the British 1946 Birth Cohort, all born during the same week; age range at assessment = 69-71 years), who also underwent β-amyloid-PET/MRI to derive amyloid status (positive/negative), whole-brain volume and white matter hyperintensity volume. We compared preclinical Alzheimer's groups against controls cross-sectionally (mutation carriers versus non-carriers; amyloid-positive versus amyloid-negative) on speed and accuracy of circle-tracing and subtraction. Mutation carriers (mean 7 years before expected onset) and amyloid-positive older adults traced disproportionately less accurately than controls when visual feedback was indirect, and were slower at dual-task subtraction. In the older adults, the same pattern of associations was found when considering amyloid burden as a continuous variable (Standardized Uptake Value Ratio). The effect of amyloid was independent of white matter hyperintensity and brain volumes, which themselves were associated with different aspects of performance: greater white matter hyperintensity volume was also associated with disproportionately poorer tracing accuracy when visual feedback was indirect, whereas larger brain volume was associated with faster tracing and faster subtraction. Mutation carriers also showed evidence of poorer tracing accuracy when visual feedback was direct. This study provides the first evidence of visuomotor integration deficits common to familial and sporadic preclinical Alzheimer's disease, which may precede the onset of clinical symptoms by several years.
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http://dx.doi.org/10.1093/braincomms/fcab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882207PMC
January 2021

KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers.

Neurobiol Aging 2021 05 23;101:123-129. Epub 2021 Jan 23.

Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.

KLOTHO∗VS heterozygosity (KL∗VS) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE∗4 carriers. Additional studies suggest that KL∗VS protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-analysis across 5 independent studies, comprising 3581 pre-clinical participants ages 60-80, to investigate whether KL∗VS reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE∗4 status. KL∗VS reduced the risk of amyloid positivity in APOE∗4 carriers (odds ratio = 0.67 [0.52-0.88]; p = 3.5 × 10), but not in APOE∗4 non-carriers (odds ratio = 0.94 [0.73-1.21]; p = 0.63). The combination of APOE∗4 and KL∗VS genotypes should help enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD. KL-related pathways may help elucidate protective mechanisms against amyloid accumulation and merit exploration for novel AD drug targets. Future investigation of the biological mechanisms by which KL interacts with APOE∗4 and AD are warranted.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122023PMC
May 2021

New insights into atypical Alzheimer's disease in the era of biomarkers.

Lancet Neurol 2021 03;20(3):222-234

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Most patients with Alzheimer's disease present with amnestic problems; however, a substantial proportion, over-represented in young-onset cases, have atypical phenotypes including predominant visual, language, executive, behavioural, or motor dysfunction. In the past, these individuals often received a late diagnosis; however, availability of CSF and PET biomarkers of Alzheimer's disease pathologies and incorporation of atypical forms of Alzheimer's disease into new diagnostic criteria increasingly allows them to be more confidently diagnosed early in their illness. This early diagnosis in turn allows patients to be offered tailored information, appropriate care and support, and individualised treatment plans. These advances will provide improved access to clinical trials, which often exclude atypical phenotypes. Research into atypical Alzheimer's disease has revealed previously unrecognised neuropathological heterogeneity across the Alzheimer's disease spectrum. Neuroimaging, genetic, biomarker, and basic science studies are providing key insights into the factors that might drive selective vulnerability of differing brain networks, with potential mechanistic implications for understanding typical late-onset Alzheimer's disease.
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http://dx.doi.org/10.1016/S1474-4422(20)30440-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056394PMC
March 2021

Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays.

Alzheimers Dement (Amst) 2021 6;13(1):e12131. Epub 2021 Feb 6.

Dementia Research Centre UCL Queen Square Institute of Neurology, University College London London UK.

Introduction: We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET).

Methods: In 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays and inter-platform Pearson correlations derived. Lumipulse Aβ42 measures were adjusted to incorporate standardization to certified reference materials. Logistic regressions and receiver operating characteristics analysis generated CSF cut-points optimizing concordance with F-florbetapir amyloid PET status (n = 63).

Results: Measurements of CSF Aβ, p-tau181, and their ratios correlated well across platforms (r 0.84 to 0.94, < .0001); those of t-tau and t-tau/Aβ42 correlated moderately (r 0.57 to 0.79, < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.075 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40 and 17.3 for Lumipulse Aβ42/p-tau181.

Discussion: The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology.
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http://dx.doi.org/10.1002/dad2.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867115PMC
February 2021

Population-based blood screening for preclinical Alzheimer's disease in a British birth cohort at age 70.

Brain 2021 03;144(2):434-449

Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.

Alzheimer's disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for screening. We compared three different blood-based techniques-liquid chromatography-mass spectrometry measures of plasma amyloid-β, and single molecule array (Simoa) measures of plasma amyloid-β and phospho-tau181-to detect cortical 18F-florbetapir amyloid PET positivity (defined as a standardized uptake value ratio of >0.61 between a predefined cortical region of interest and eroded subcortical white matter) in dementia-free members of Insight 46, a substudy of the population-based British 1946 birth cohort. We used logistic regression models with blood biomarkers as predictors of amyloid PET status, with or without age, sex and APOE ε4 carrier status as covariates. We generated receiver operating characteristics curves and quantified areas under the curves to compare the concordance of the different blood tests with amyloid PET. We determined blood test cut-off points using Youden's index, then estimated numbers needed to screen to obtain 100 amyloid PET-positive individuals. Of the 502 individuals assessed, 441 dementia-free individuals with complete data were included; 82 (18.6%) were amyloid PET-positive. The area under the 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 two best-performing Simoa plasma biomarkers were amyloid-β42/40 (0.620; 0.548-0.691) and phospho-tau181 (0.707; 0.646-0.768), but neither outperformed the base model. Mass spectrometry plasma measures performed significantly better than any other measure (amyloid-β1-42/1-40: 0.817; 0.770-0.864 and amyloid-β composite: 0.820; 0.775-0.866). At a cut-off point of 0.095, mass spectrometry measures of amyloid-β1-42/1-40 detected amyloid PET positivity with 86.6% sensitivity and 71.9% specificity. Without screening, to obtain 100 PET-positive individuals from a population with similar amyloid PET positivity prevalence to Insight 46, 543 PET scans would need to be performed. Screening using age, sex and APOE ε4 status would require 940 individuals, of whom 266 would proceed to scan. Using mass spectrometry amyloid-β1-42/1-40 alone would reduce these numbers to 623 individuals and 243 individuals, respectively. Across a theoretical range of amyloid PET positivity prevalence of 10-50%, mass spectrometry measures of amyloid-β1-42/1-40 would consistently reduce the numbers proceeding to scans, with greater cost savings demonstrated at lower prevalence.
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http://dx.doi.org/10.1093/brain/awaa403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940173PMC
March 2021

Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia: a multi-rater, clinical accuracy study.

Eur Radiol 2021 Jul 15;31(7):5312-5323. Epub 2021 Jan 15.

Centre for Medical Image Computing (CMIC), Department of Medical Physics and Bioengineering, University College London, London, UK.

Objectives: We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone.

Methods: Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'.

Results: The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's κ) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (κ 0.41➔0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'.

Conclusion: Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses.

Key Points: • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists' assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.
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http://dx.doi.org/10.1007/s00330-020-07455-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213665PMC
July 2021

Mild cognitive impairment: the Manchester consensus.

Age Ageing 2021 01;50(1):72-80

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.
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http://dx.doi.org/10.1093/ageing/afaa228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793599PMC
January 2021

Genetic testing in dementia - utility and clinical strategies.

Nat Rev Neurol 2021 Jan 9;17(1):23-36. Epub 2020 Nov 9.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, UK.

Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information.
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http://dx.doi.org/10.1038/s41582-020-00416-1DOI Listing
January 2021

A Clinicopathologic Study of Movement Disorders in Frontotemporal Lobar Degeneration.

Mov Disord 2021 03 6;36(3):632-641. Epub 2020 Nov 6.

Department of Clinical and Movement Neurosciences, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, United Kingdom.

Background: Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking.

Objective: The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD.

Methods: In this cohort study, movement disorder clinical data were retrospectively collected from medical records of consecutive patients with a postmortem diagnosis of FTLD from the Queen Square Brain Bank between January 2010 and December 2018. At postmortem, neurodegenerative pathologies were systematically evaluated following consensus criteria. Degeneration of the substantia nigra was assessed as a marker of presynaptic dopaminergic parkinsonism using semiquantitative methods.

Results: A total of 55 patients (35 men [64%]) were included with median (interquartile range) age at diagnosis of 58.8 (52.6-63.9) years and a disease duration of 9.6 (6.2-12.9) years. Movement disorders were present in 19 (35%) patients without differences among disease subtypes. The most common syndromes were parkinsonism (9 patients [16%]), usually as an additional late feature, and corticobasal syndrome (CBS, 7 patients [13%]), commonly as a presenting feature. Substantia nigra degeneration was present in 37 (67%) patients although it did not show a good clinical correlation with movement disorders. Those with Pick's disease showed milder substantia nigra degeneration and better response to levodopa.

Conclusions: Movement disorders can present in all FTLD subtypes, more commonly as a late additional feature (parkinsonism) or as a presenting symptom (CBS). The underlying pathophysiology is complex and likely to involve structures outside the presynaptic striatonigral system. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28356DOI Listing
March 2021

Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury.

Brain 2020 12;143(12):3685-3698

Department of Brain Sciences, Division of Medicine, Imperial College London, London, UK.

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials.
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http://dx.doi.org/10.1093/brain/awaa316DOI Listing
December 2020

Concordance of CSF measures of Alzheimer's pathology with amyloid PET status in a preclinical cohort: A comparison of Lumipulse and established immunoassays.

Alzheimers Dement (Amst) 2020 13;12(1):e12097. Epub 2020 Sep 13.

Dementia Research Centre UCL Queen Square Institute of Neurology University College London London UK.

Introduction: We assessed the concordance of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau measured on the fully automated Lumipulse platform with pre-symptomatic Alzheimer's disease (AD) pathology on amyloid positron emission tomography (PET).

Methods: In 72 individuals from the Insight 46 study, CSF Aβ40, Aβ42, total tau (t-tau), and phosphorylated tau at site 181 (p-tau181) were measured using Lumipulse, INNOTEST, and Meso Scale Discovery (MSD) assays, and inter-platform Pearson correlations were derived. Logistic regressions and receiver-operating characteristic analysis generated CSF cut-points optimizing concordance with F-florbetapir amyloid PET status (n = 63).

Results: Measurements of CSF Aβ, p-tau181, and their ratios correlated well across platforms (r 0.84-.94, < .0001); those of t-tau and t-tau/Aβ42 correlated moderately (r 0.57-0.79, < .0001). The best concordance with amyloid PET (100% sensitivity and 94% specificity) was afforded by cut-points of 0.110 for Lumipulse Aβ42/Aβ40, 0.087 for MSD Aβ42/Aβ40, and 25.3 for Lumipulse Aβ42/p-tau181.

Discussion: The Lumipulse platform provides comparable sensitivity and specificity to established CSF immunoassays in identifying pre-symptomatic AD pathology.
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http://dx.doi.org/10.1002/dad2.12097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503103PMC
September 2020

Measuring cortical mean diffusivity to assess early microstructural cortical change in presymptomatic familial Alzheimer's disease.

Alzheimers Res Ther 2020 09 17;12(1):112. Epub 2020 Sep 17.

Dementia Research Centre, UCL Institute of Neurology, Queen Square, Box 16, London, WC1N 3BG, UK.

Background: There is increasing interest in improving understanding of the timing and nature of early neurodegeneration in Alzheimer's disease (AD) and developing methods to measure this in vivo. Autosomal dominant familial Alzheimer's disease (FAD) provides the opportunity for investigation of presymptomatic change. We assessed early microstructural breakdown of cortical grey matter in FAD with diffusion-weighted MRI.

Methods: Diffusion-weighted and T1-weighed MRI were acquired in 38 FAD mutation carriers (17 symptomatic, 21 presymptomatic) and 39 controls. Mean diffusivity (MD) was calculated for six cortical regions previously identified as being particularly vulnerable to FAD-related neurodegeneration. Linear regression compared MD between symptomatic and presymptomatic carriers and controls, adjusting for age and sex. Spearman coefficients assessed associations between cortical MD and cortical thickness. Spearman coefficients also assessed associations between cortical MD and estimated years to/from onset (EYO). Across mutation carriers, linear regression assessed associations between MD and EYO, adjusting for cortical thickness.

Results: Compared with controls, cortical MD was higher in symptomatic mutation carriers (mean ± SD CDR = 0.88 ± 0.39) for all six regions (p < 0.001). In late presymptomatic carriers (within 8.1 years of predicted symptom onset), MD was higher in the precuneus (p = 0.04) and inferior parietal cortex (p = 0.003) compared with controls. Across all presymptomatic carriers, MD in the precuneus correlated with EYO (p = 0.04). Across all mutation carriers, there was strong evidence (p < 0.001) of association between MD and cortical thickness in all regions except entorhinal cortex. After adjusting for cortical thickness, there remained an association (p < 0.05) in mutation carriers between MD and EYO in all regions except entorhinal cortex.

Conclusions: Cortical MD measurement detects microstructural breakdown in presymptomatic FAD and correlates with proximity to symptom onset independently of cortical thickness. Cortical MD may thus be a feasible biomarker of early AD-related neurodegeneration, offering additional/complementary information to conventional MRI measures.
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http://dx.doi.org/10.1186/s13195-020-00679-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499910PMC
September 2020

Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt-Jakob disease.

Acta Neuropathol 2020 12 12;140(6):863-879. Epub 2020 Sep 12.

MRC Prion Unit at UCL, UCL Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London, W1W 7FF, UK.

Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). Our case-control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10). Nine of these sites were taken forward in a replication study, performed in an independent case-control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case-control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer's disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.
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http://dx.doi.org/10.1007/s00401-020-02224-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666287PMC
December 2020

Study Protocol - Insight 46 Cardiovascular: A Sub-study of the MRC National Survey of Health and Development.

Artery Res 2020 Sep 24;26(3):170-179. Epub 2020 Apr 24.

MRC Unit for Lifelong Health and Ageing at UCL, Department of Population Science & Experimental Medicine, UCL Institute of Cardiovascular Science, University College London, London, UK.

The commonest causes of dementia are Alzheimer's disease and vascular cognitive impairment. Although these conditions have been viewed as distinct entities, there is increasing evidence that neurodegenerative and vascular pathologies interact or overlap to cause cognitive decline, and that at least in some cases individuals at risk of cognitive decline exhibit abnormal cardiovascular physiology long before emergence of disease. However, the mechanisms linking haemodynamic disturbances with cognitive impairment and the various pathologies that cause dementia are poorly understood. A sub-sample of 502 participants from the Medical Research Council National Survey of Health and Development (NSHD) have participated in the first visit of a neuroscience sub-study referred to as Insight 46, where clinical, cognitive, imaging, and lifestyle data have been collected for the purpose of elucidating the pathological changes preceding dementia. This paper outlines the cardiovascular phenotyping performed in the follow-up visit of Insight 46, with the study participants now aged 74. In addition to standard cardiovascular assessments such as blood pressure measurements, echocardiography, and electrocardiography (ECG), functional Near Infrared Spectroscopy (fNIRS) has been included to provide an assessment of cerebrovascular function. A detailed description of the fNIRS protocol along with preliminary results from pilot data is presented. The combination of lifestyle data, brain structure/function, cognitive performance, and cardiovascular health obtained not only from Insight 46, but also from the whole NSHD provides an exciting opportunity to advance our understanding of the cardiovascular mechanisms underlying dementia and cognitive decline, and identify novel targets for intervention.
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http://dx.doi.org/10.2991/artres.k.200417.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116008PMC
September 2020

Precision prevention of Alzheimer's and other dementias: Anticipating future needs in the control of risk factors and implementation of disease-modifying therapies.

Alzheimers Dement 2020 10 20;16(10):1457-1468. Epub 2020 Aug 20.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Empirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular health). While the effect on individuals may be modest, it might have a large societal impact by decreasing overall dementia incidence by up to 35%. Secondary prevention will target cognitively normal persons at high risk of dementia due to Alzheimer's disease pathology with future anti-amyloid, anti-tau, or other drugs. This approach is likely to have major benefits to both individuals and society. Memory clinics will need structural and functional changes to adapt to novel technologies and increased patients' demands, and brand-new services may need to be developed with specific skills on risk profiling, risk communication, and personalized risk reduction plans.
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http://dx.doi.org/10.1002/alz.12132DOI Listing
October 2020

Functional cognitive disorder: dementia's blind spot.

Brain 2020 10;143(10):2895-2903

Centre for Clinical Brain Sciences, The University of Edinburgh, EH16 4SB, UK.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.
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http://dx.doi.org/10.1093/brain/awaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586080PMC
October 2020
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