Teresa Poole

Serum neurofilament light in familial Alzheimer disease: A marker of early neurodegeneration

Objectives: To investigate whether serum neurofilament light (NfL) concentration is increased in familial Alzheimer disease (FAD), both pre and post symptom onset, and whether it is associated with markers of disease stage and severity. Methods: We recruited 48 individuals from families with PSEN1 or APP mutations to a cross-sectional study: 18 had symptomatic Alzheimer disease (AD) and 30 were asymptomatic but at 50% risk of carrying a mutation. Serum NfL was measured using an ultrasensitive immunoassay on the single molecule array (Simoa) platform. Cognitive testing and MRI were performed; 33 participants had serial MRI, allowing calculation of atrophy rates. Genetic testing established mutation status. A generalized least squares regression model was used to compare serum NfL among symptomatic mutation carriers, presymptomatic carriers, and noncarriers, adjusting for age and sex. Spearman coefficients assessed associations between serum NfL and (1) estimated years to/from symptom onset (EYO), (2) cognitive measures, and (3) MRI measures of atrophy. Results: Nineteen of the asymptomatic participants were mutation carriers (mean EYO −9.6); 11 were noncarriers. Compared with noncarriers, serum NfL concentration was higher in both symptomatic (p < 0.0001) and presymptomatic mutation carriers (p = 0.007). Across all mutation carriers, serum NfL correlated with EYO (ρ = 0.81, p < 0.0001) and multiple cognitive and imaging measures, including Mini-Mental State Examination (ρ = −0.62, p = 0.0001), Clinical Dementia Rating Scale sum of boxes (ρ = 0.79, p < 0.0001), baseline brain volume (ρ = −0.62, p = 0.0002), and whole-brain atrophy rate (ρ = 0.53, p = 0.01). Conclusions: Serum NfL concentration is increased in FAD prior to symptom onset and correlates with measures of disease stage and severity. Serum NfL may thus be a feasible biomarker of early AD-related neurodegeneration.

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study

Identifying at what point atrophy rates first change in Alzheimers disease is important for informing design of presymptomatic trials.

Cerebrospinal fluid in the differential diagnosis of Alzheimer’s disease: clinical utility of an extended panel of biomarkers in a specialist cognitive clinic

BackgroundCerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer’s disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias.MethodsWe used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1–42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (nu2009=u2009156), DLB (nu2009=u200920), behavioural variant frontotemporal dementia (bvFTD; nu2009=u200945), progressive non-fluent aphasia (PNFA; nu2009=u200917), and semantic dementia (SD; nu2009=u20097); approximately 10% were pathology/genetically confirmed (nu2009=u200926). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (nu2009=u2009104), DLB (nu2009=u20095), bvFTD (nu2009=u200912), PNFA (nu2009=u20093), SD (nu2009=u20099), and controls (nu2009=u200910).ResultsThere were significant global differences in Aβ1–42, T-tau, T-tau/Aβ1–42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1–42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1–42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity >u200950%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort.ConclusionsCSF AβX-42/X-40 and T-tau/Aβ1–42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study.

Identifying at what point atrophy rates first change in Alzheimers disease is important for informing design of presymptomatic trials.

CSF Neurogranin or Tau distinguish typical and atypical Alzheimer Disease

To assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimers disease.

Navigational cue effects in Alzheimer's disease and posterior cortical atrophy

Deficits in spatial navigation are characteristic and disabling features of typical Alzheimers disease (tAD) and posterior cortical atrophy (PCA). Visual cues have been proposed to mitigate such deficits; however, there is currently little empirical evidence for their use.

LONGITUDINAL MEASUREMENT OF SERUM NEUROFILAMENT LIGHT CONCENTRATION IN FAMILIAL ALZHEIMER’S DISEASE

tau181 begin to decline significantly. Furthermore, this decline is strongly associated with the increased atrophy seen with disease progression. This suggests that measures of CSF tau do not reflect a passive release with neuronal death, but likely represent a more complex process related to the progression of AD pathology. Further, as CSF tau peptides declined with symptom onset and atrophy progression, it is possible that this might reflect the sequestration of soluble tau by the trans-synaptic spreading of insoluble tau tangles.

SAMPLE SIZE ESTIMATES FOR SECONDARY PREVENTION STUDIES USING REGIONAL ATROPHY RATES

Background:Metacognition refers to one’s self-awareness and selfmonitoring of their cognitive process. Brain areas that support metacognition are not well understood. We examined the relationship of brain atrophy with metacognition to better understand the neural mechanisms underlying this process. Methods: 45 cognitively normal, 53 mild cognitive impairment, and 10 probable AD dementia participants from the ImaGene study underwent metacognitive and cognitive testing, and magnetic resonance imaging (MRI). A performance-prediction paradigm was used to evaluate metacognitive abilities in which subjects were asked to predict their future performance for each cognitive task (selfawareness) and to make postdictions about how well they performed the task (self-monitoring). Prediction and postdiction scores were derived as follows: %predicted-%performed and % postdicted-%performed. MRI data were registered to the FreeSurfer Template (Fischl et al. 1999). Cortical thickness maps were derived using FreeSurfer 6.0.0. We ran vertex-wise multivariate linear regression with metacognitive as predictor variables while controlling for age, gender, education, and intracranial volume in SurfStat. We applied random field theory (RFT) cluster-level-corrected p<0.01. Results: Table 1 shows the demographic comparisons between the groups. Figure 1 shows our statistical results. Overall, the observed associations showed an AD-like neurodegenerative pattern with involvement of the medial, inferior and lateral temporal, and parietal lobes, as well as the anterior and posterior cingulate, and precuneus with the expected lateralization (left-sided for verbal memory tasks and right-sided for visuospatial/visual memory tasks). Subjects with thinner cortex tended to overestimate their future performance on delayed recall of verbal and visual information (CVLT-II DR and VR-II DR prediction), and their past performance on verbal learning and delayed recall (CVLT-II 1-5 and CVLT-II DR postdiction). They also tended to overestimate their future performance on copying simple figures (VR-I copy prediction), but underestimated their actual performance on copying a complex figure (Rey-O copy postdiction). Conclusions: Our data show that poor self-awareness and impaired self-monitoring of verbal memory is associated with cortical atrophy across the cognitive spectrum. As one might predict, poor self-awareness of verbal memory showed left greater than right associations while the opposite was true for visuospatial tasks. Future investigations into longitudinal changes in metacognition is warranted. IC-P-048 SAMPLE SIZE ESTIMATES FOR SECONDARY PREVENTION STUDIES USING REGIONAL ATROPHY RATES David M. Cash, Thomas Veale, Teresa Poole, Marc Modat, Erika Molteni, M. Jorge Cardoso, Tammie L. S. Benzinger, Clifford R. Jack, Jr.,, Eric McDade, Randall J. Bateman, John C. Morris, Martin N. Rossor, Sebastien Ourselin, Christopher Frost, Nick C. Fox, and the Dominantly Inherited Alzheimer Network, Dementia Research Centre, University College London, Institute of Neurology, London, United Kingdom; University College London, Centre for Medical Image Computing, London, United Kingdom; University College London, Institute of Neurology, London, United Kingdom; London School of Hygiene and Tropical Medicine, London, United Kingdom; Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; Translational Imaging Group, University College London, Centre for Medical Image Computing, London, United Kingdom; Dementia Research Centre and Department of Neurodegenerative Disease, University College London, Institute of Neurology, University College London, London, United Kingdom; Washington University School of Medicine, St. Louis, MO, USA; Mayo Clinic, Rochester, MN, USA; Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA; Washington University, St. Louis, MO, USA; Translational Imaging Group, Centre for Medical Image Computing, University College London, London, United Kingdom; London School of Hygiene and Tropical Medicine, University of London, London, United Kingdom. Contact e-mail: d.cash@ucl.ac.uk

SERUM NEUROFILAMENT LIGHT CONCENTRATION IN FAMILIAL ALZHEIMER’S DISEASE AND ASSOCIATION WITH MARKERS OF DISEASE STAGE AND SEVERITY

O4-02-04 SERUM NEUROFILAMENT LIGHT CONCENTRATION IN FAMILIAL ALZHEIMER’S DISEASE AND ASSOCIATION WITH MARKERS OF DISEASE STAGE AND SEVERITY Philip S. J. Weston, Teresa Poole, Natalie S. Ryan, Akshay Nair, Yuying Liang, Kirsty Macpherson, Ronald Druyeh, Ian B. Malone, R. Laila Ahsan, Hugh Pemberton, Jana Klimova, Simon Mead, Kaj Blennow, Martin N. Rossor, Jonathan M. Schott, Henrik Zetterberg, Nick C. Fox, UCL Institute of Neurology, London, United Kingdom; London School of Hygiene and Tropical Medicine, London, United Kingdom; Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom; University College London, Institute of Neurology, London, United Kingdom; Institute of Neurology, University College London, London, United Kingdom; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M€olndal, Sweden. Contact e-mail: philip.weston.11@ucl.ac.uk

[Accepted Manuscript] Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial MRI study.

Identifying at what point atrophy rates first change in Alzheimers disease is important for informing design of presymptomatic trials.