Publications by authors named "Ross W Paterson"

56 Publications

Mass spectrometry analysis of tau and amyloid-beta in iPSC-derived models of Alzheimer's disease and dementia.

J Neurochem 2021 Feb 4. Epub 2021 Feb 4.

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK.

Induced pluripotent stem cell (iPSC) technology enables the generation of human neurons in vitro, which contain the precise genome of the cell donor, therefore permitting the generation of disease models from individuals with a disease-associated genotype of interest. This approach has been extensively used to model inherited forms of Alzheimer's disease and frontotemporal dementia. The combination of iPSC-derived neuronal models with targeted mass spectrometry analysis has provided unprecedented insights into the regulation of specific proteins in human neuronal physiology and pathology. For example enabling investigations into tau and APP/Aβ, specifically: protein isoform expression, relative levels of cleavage fragments, aggregated species and functionally critical post-translational modifications. The use of mass spectrometry has enabled a determination of how closely iPSC-derived models recapitulate disease profiles observed in the human brain. This review will highlight the progress to date in studies using iPSCs and mass spectrometry to model Alzheimer's disease and dementia. We go on to convey our optimism, as studies in the near future will make use of this precedent, together with novel techniques such as genome editing and stable isotope labelling, to provide real progress towards an in depth understanding of early neurodegenerative processes and development of novel therapeutic agents.
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http://dx.doi.org/10.1111/jnc.15315DOI Listing
February 2021

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

Eur Radiol 2021 Jan 15. 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
January 2021

Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.

Brain 2021 03;144(2):682-693

Department of Neuromuscular Diseases, University College London, London, UK.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.
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http://dx.doi.org/10.1093/brain/awaa433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799186PMC
March 2021

A blood miRNA signature associates with sporadic Creutzfeldt-Jakob disease diagnosis.

Nat Commun 2020 08 7;11(1):3960. Epub 2020 Aug 7.

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

Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are available for diagnosis or disease monitoring. Here, we profile blood microRNA (miRNA) expression in sCJD. Sequencing of 57 sCJD patients, and healthy controls reveals differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicates in an independent cohort using quantitative PCR, with concomitant upregulation of four mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes parallels the lack of association between rate of decline in miRNA expression, and rate of disease progression in a longitudinal cohort of samples from 21 patients. Finally, the miRNA signature shows a high level of accuracy in discriminating sCJD from Alzheimer's disease. These findings highlight molecular alterations in the periphery in sCJD which provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.
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http://dx.doi.org/10.1038/s41467-020-17655-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414116PMC
August 2020

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.

Brain 2020 10;143(10):3104-3120

University College London, Queen Square Institute of Neurology, London, UK.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.
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http://dx.doi.org/10.1093/brain/awaa240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454352PMC
October 2020

Relevance of biomarkers across different neurodegenerative diseases.

Alzheimers Res Ther 2020 05 13;12(1):56. Epub 2020 May 13.

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

Background: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field.

Purpose Of Review: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.
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http://dx.doi.org/10.1186/s13195-020-00601-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222479PMC
May 2020

Cerebrospinal Fluid YKL-40 and Chitotriosidase Levels in Frontotemporal Dementia Vary by Clinical, Genetic and Pathological Subtype.

Dement Geriatr Cogn Disord 2020 28;49(1):56-76. Epub 2020 Apr 28.

Dementia Research Centre, Department of Neurodegenerative Disease, Queen Square UCL Institute of Neurology, London, United Kingdom,

Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer's disease (AD) but have not been explored in detail across the spectrum of FTD.

Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers). Eighteen healthy controls and 64 people with FTD (behavioural variant FTD, n = 20; primary progressive aphasia [PPA], n = 44: nfvPPA, n = 16, svPPA, n = 11, lvPPA, n = 14, PPA-NOS, n = 3) were included. 10/64 had familial FTD, with mutations in GRN(n = 3), MAPT(n = 4), or C9orf72 (n = 3). 15/64 had neurodegenerative biomarkers consistent with AD pathology. Levels were measured by immunoassay and compared using multiple linear regressions. We also examined relationships of YKL-40 and chitotriosidase with CSF total tau (T-tau), phosphorylated tau 181 (P-tau) and β-amyloid 1-42 (Aβ42), with each other, and with age and disease du-ration.

Results: CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls. GRN mutation carriers had higher levels of both proteins than controls and C9orf72 expansion carriers, and YKL-40 was higher in MAPT mutation carriers than controls. Individuals with underlying AD pathology had higher YKL-40 and chitotriosidase levels than both controls and those with likely FTLD pathology. CSF YKL-40 and chitotriosidase levels were variably associated with levels of T-tau, P-tau and Aβ42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not chitotriosidase was associated with age, but not disease duration.

Conclusion: CSF YKL-40 and chitotriosidase levels are increased in individuals with clinical FTD syndromes, particularly due to AD pathology. In a preliminary analysis of genetic groups, levels of both proteins are found to be highly elevated in FTD due to GRN mutations, while YKL-40 is increased in individuals with MAPT mutations. As glia-derived protein levels generally correlate with T-tau and P-tau levels, they may reflect the glial response to neurodegeneration in FTLD.
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http://dx.doi.org/10.1159/000506282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513620PMC
January 2021

Imaging biomarkers in neurodegeneration: current and future practices.

Alzheimers Res Ther 2020 04 27;12(1):49. Epub 2020 Apr 27.

Wallenberg Centre for Molecular and Translational Medicine and the Department of Psychiatry and Neurochemistry, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.

There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.
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http://dx.doi.org/10.1186/s13195-020-00612-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187531PMC
April 2020

Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy.

J Alzheimers Dis 2020 ;74(4):1189-1201

Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK.

Background: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA).

Objective: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA.

Methods: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer's disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service.

Results: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38, Aβ40, Aβ42, and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aβ42, and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an "AD-like" profile.

Conclusion: CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed.
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http://dx.doi.org/10.3233/JAD-191254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242825PMC
January 2020

Perspectives in fluid biomarkers in neurodegeneration from the 2019 biomarkers in neurodegenerative diseases course-a joint PhD student course at University College London and University of Gothenburg.

Alzheimers Res Ther 2020 02 28;12(1):20. Epub 2020 Feb 28.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Until relatively recently, a diagnosis of probable Alzheimer's disease (AD) and other neurodegenerative disorders was principally based on clinical presentation, with post-mortem examination remaining a gold standard for disease confirmation. This is in sharp contrast to other areas of medicine, where fluid biomarkers, such as troponin levels in myocardial infarction, form an integral part of the diagnostic and treatment criteria. There is a pressing need for such quantifiable and easily accessible tools in neurodegenerative diseases.In this paper, based on lectures given at the 2019 Biomarkers in Neurodegenerative Diseases Course, we provide an overview of a range of cerebrospinal fluid (CSF) and blood biomarkers in neurodegenerative disorders, including the 'core' AD biomarkers amyloid β (Aβ) and tau, as well as other disease-specific and general markers of neuroaxonal injury. We then highlight the main challenges in the field, and how those could be overcome with the aid of new methodological advances, such as assay automation, mass spectrometry and ultrasensitive immunoassays.As we hopefully move towards an era of disease-modifying treatments, reliable biomarkers will be essential to increase diagnostic accuracy, allow for earlier diagnosis, better participant selection and disease activity and treatment effect monitoring.
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http://dx.doi.org/10.1186/s13195-020-00586-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049194PMC
February 2020

University College London/University of Gothenburg PhD course "Biomarkers in neurodegenerative diseases" 2019-course organisation.

Alzheimers Res Ther 2020 02 4;12(1):18. Epub 2020 Feb 4.

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

Biomarkers are increasingly employed for effective research into neurodegenerative diseases. They have become essential for reaching an accurate clinical diagnosis, monitoring disease, and refining entry criteria for participation in clinical treatment trials, and will be key in measuring target engagement and treatment outcome in disease-modifying therapies. Emerging techniques and research combining different biomarker modalities continue to strengthen our understanding of the underlying pathology and the sequence of pathogenic events. Given recent advances, we are now at a pivotal stage in biomarker research. PhD students working in the field of neurodegenerative disease require a working knowledge of a range of biomarkers available and their limitations, to correctly interpret scientific literature and to design and conduct successful research studies themselves. Here, we outline the University College London/University of Gothenburg "Biomarkers in neurodegenerative diseases course", the first initiative of its kind aimed to bring together both experts and PhD students from all areas within the field of neurodegeneration, to provide comprehensive knowledge of biomarker research for the next generation of scientists.
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http://dx.doi.org/10.1186/s13195-020-0583-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001332PMC
February 2020

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer's disease: A proof-of-principle behavioural study.

eNeurologicalSci 2019 Dec 4;17:100212. Epub 2019 Nov 4.

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

Sleep disruption is a key clinical issue in the dementias but the sleep phenotypes of these diseases remain poorly characterised. Here we addressed this issue in a proof-of-principle study of 67 patients representing major syndromes of frontotemporal dementia (FTD) and Alzheimer's disease (AD), in relation to 25 healthy older individuals. We collected reports on clinically-relevant sleep characteristics - time spent overnight in bed, sleep quality, excessive daytime somnolence and disruptive sleep events. Difficulty falling or staying asleep at night and excessive daytime somnolence were significantly more frequently reported for patients with both FTD and AD than healthy controls. On average, patients with FTD and AD retired earlier and patients with AD spent significantly longer in bed overnight than did healthy controls. Excessive daytime somnolence was significantly more frequent in the FTD group than the AD group; AD syndromic subgroups showed similar sleep symptom profiles while FTD subgroups showed more variable profiles. Sleep disturbance is a significant clinical issue in major FTD and AD variant syndromes and may be even more salient in FTD than AD. These preliminary findings warrant further systematic investigation with electrophysiological and neuroanatomical correlation in major proteinopathies.
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http://dx.doi.org/10.1016/j.ensci.2019.100212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889070PMC
December 2019

Prion disease diagnosis using subject-specific imaging biomarkers within a multi-kernel Gaussian process.

Neuroimage Clin 2019 25;24:102051. Epub 2019 Oct 25.

Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; School of Biomedical Engineering & Imaging Sciences, King's College London, King's Health Partners, St Thomas' Hospital, London, SE1 7EH, United Kingdom.

Prion diseases are a group of rare neurodegenerative conditions characterised by a high rate of progression and highly heterogeneous phenotypes. Whilst the most common form of prion disease occurs sporadically (sporadic Creutzfeldt-Jakob disease, sCJD), other forms are caused by prion protein gene mutations, or exposure to prions in the diet or by medical procedures, such us surgeries. To date, there are no accurate quantitative imaging biomarkers that can be used to predict the future clinical diagnosis of a healthy subject, or to quantify the progression of symptoms over time. Besides, CJD is commonly mistaken for other forms of dementia. Due to the heterogeneity of phenotypes and the lack of a consistent geometrical pattern of disease progression, the approaches used to study other types of neurodegenerative diseases are not satisfactory to capture the progression of human form of prion disease. In this paper, using a tailored framework, we aim to classify and stratify patients with prion disease, according to the severity of their illness. The framework is initialised with the extraction of subject-specific imaging biomarkers. The extracted biomakers are then combined with genetic and demographic information within a Gaussian Process classifier, used to calculate the probability of a subject to be diagnosed with prion disease in the next year. We evaluate the effectiveness of the proposed method in a cohort of patients with inherited and sporadic forms of prion disease. The model has shown to be effective in the prediction of both inherited CJD (92% of accuracy) and sporadic CJD (95% of accuracy). However the model has shown to be less effective when used to stratify the different stages of the disease, in which the average accuracy is 85%, whilst the recall is 59%. Finally, our framework was extended as a differential diagnosis tool to identify both forms of CJD among another neurodegenerative disease. In summary we have developed a novel method for prion disease diagnosis and prediction of clinical onset using multiple sources of features, which may have use in other disorders with heterogeneous imaging features.
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http://dx.doi.org/10.1016/j.nicl.2019.102051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978211PMC
September 2020

Retinal thickness as potential biomarker in posterior cortical atrophy and typical Alzheimer's disease.

Alzheimers Res Ther 2019 07 18;11(1):62. Epub 2019 Jul 18.

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

Background: Retinal thickness can be measured non-invasively with optical coherence tomography (OCT) and may offer compelling potential as a biomarker for Alzheimer's disease (AD). Retinal thinning is hypothesized to be a result of retrograde atrophy and/or parallel neurodegenerative processes. Changes in the visual pathway are of particular interest in posterior cortical atrophy (PCA), the most common atypical AD phenotype predominantly affecting the parietal-occipital cortices. We therefore evaluated retinal thickness as non-invasive biomarker of neurodegeneration in well-characterized participants with posterior cortical atrophy (PCA) and typical Alzheimer's disease (tAD).

Methods: Retinal thickness measures were acquired from 48 patient participants (N = 25 PCA; N = 23 tAD) fulfilling consensus diagnostic criteria and 70 age-matched controls. Participants were recruited between 2014 and 2016. All participants underwent optical coherence tomography (OCT) imaging, including measurement of peripapillary retinal nerve fiber layer (pRNFL) thickness and total macular thickness (mRT). Participants did not show evidence of any significant ophthalmological conditions. Subgroup analyses were performed in participants with available MRI and CSF measures, providing evidence of neurodegeneration and underlying AD pathology respectively.

Results: There was no evidence of overall between-group differences in pRNFL thickness (mean PCA 98.7 ± 12.2; tAD 99.9 ± 8.7; controls 99.6 ± 10.0 μm, one-way analysis of variance (ANOVA) p = 0.92) or total mRT (mean PCA 266.9 ± 16.3; tAD 267.8 ± 13.6; controls 269.3 ± 13.6 μm, one-way ANOVA p = 0.75). Similarly, subgroup analysis with MRI biomarkers (PCA = 18, tAD = 17, controls = 31) showing neurodegeneration, and CSF biomarkers (PCA = 18, tAD = 14, controls = 13) supporting underlying AD pathology did not provide evidence of overall between-group differences in pRNFL or mRT measures (all p > 0.3).

Conclusions: Retinal thickness did not discriminate tAD and PCA from controls or from one another despite unequivocal differences on standard clinical, neuro-imaging and CSF measures. Findings from this well-characterized sample, including cases with PCA, do not support the hypothesis that retinal neurodegeneration, measured using conventional OCT, is a useful biomarker for AD or PCA.
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http://dx.doi.org/10.1186/s13195-019-0516-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639972PMC
July 2019

SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases.

Nat Rev Neurol 2019 07 20;15(7):419-427. Epub 2019 Jun 20.

Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.

Alzheimer disease (AD) is one of several neurodegenerative diseases characterized by dysregulation, misfolding and accumulation of specific proteins in the CNS. The stable isotope labelling kinetics (SILK) technique is based on generating amino acids labelled with naturally occurring stable (that is, nonradioactive) isotopes of carbon and/or nitrogen. These labelled amino acids can then be incorporated into proteins, enabling rates of protein production and clearance to be determined in vivo and in vitro without the use of radioactive or chemical labels. Over the past decade, SILK studies have been used to determine the turnover of key pathogenic proteins amyloid-β (Aβ), tau and superoxide dismutase 1 (SOD1) in the cerebrospinal fluid of healthy individuals, patients with AD and those with other neurodegenerative diseases. These studies led to the identification of several factors that alter the production and/or clearance of these proteins, including age, sleep and disease-causing genetic mutations. SILK studies have also been used to measure Aβ turnover in blood and within brain tissue. SILK studies offer the potential to elucidate the mechanisms underlying various neurodegenerative disease mechanisms, including neuroinflammation and synaptic dysfunction, and to demonstrate target engagement of novel disease-modifying therapies.
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http://dx.doi.org/10.1038/s41582-019-0222-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876864PMC
July 2019

Longitudinal neuroanatomical and cognitive progression of posterior cortical atrophy.

Brain 2019 07;142(7):2082-2095

Dementia Research Centre, Institute of Neurology, University College London, 8-11 Queen Square, London, UK.

Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy of posterior brain regions. With the majority of cases attributable to Alzheimer's disease and recent evidence for genetic risk factors specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer's disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer's disease were recruited from three centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical Alzheimer's disease using differential equation models. We compared and contrasted the order in which regional brain volumes become abnormal within posterior cortical atrophy and typical Alzheimer's disease using event-based models. We also examined trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models. Temporally aligned trajectories for eight regions of interest revealed distinct (P < 0.002) patterns of progression in posterior cortical atrophy and typical Alzheimer's disease. Patients with posterior cortical atrophy showed early occipital and parietal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent of posterior cortical involvement. Patients with typical Alzheimer's disease showed early hippocampal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction declined earlier in posterior cortical atrophy than typical Alzheimer's disease whilst tests sensitive to working memory impairment declined earlier in typical Alzheimer's disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy and typical Alzheimer's disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy.
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http://dx.doi.org/10.1093/brain/awz136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598737PMC
July 2019

Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis.

JAMA Neurol 2019 Jun 17. Epub 2019 Jun 17.

UCL Institute of Neurology, Queen Square, London, United Kingdom.

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.

Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.

Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.

Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.

Data Extraction And Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.

Main Outcome And Measure: The cNfL levels adjusted for age and sex across diagnoses.

Results: Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.

Conclusions And Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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http://dx.doi.org/10.1001/jamaneurol.2019.1534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580449PMC
June 2019

Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest.

J Neurol Neurosurg Psychiatry 2019 07 13;90(7):740-746. Epub 2019 Apr 13.

Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

Background: Frontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer's disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.

Methods: 86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau). Patients with FTD were grouped based on their Aβ level into those likely to have underlying Alzheimer's disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.

Results: Significantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.

Conclusions: Despite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.
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http://dx.doi.org/10.1136/jnnp-2018-319266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585261PMC
July 2019

Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta.

Mol Psychiatry 2020 11 12;25(11):2919-2931. Epub 2019 Apr 12.

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

Familial Alzheimer's disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD.
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http://dx.doi.org/10.1038/s41380-019-0410-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577860PMC
November 2020

The functional neuroanatomy of musical memory in Alzheimer's disease.

Cortex 2019 06 15;115:357-370. Epub 2019 Feb 15.

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

Background: Memory for music has attracted much recent interest in Alzheimer's disease but the underlying brain mechanisms have not been defined in patients directly. Here we addressed this issue in an Alzheimer's disease cohort using activation fMRI of two core musical memory systems.

Methods: We studied 34 patients with younger onset Alzheimer's disease led either by episodic memory decline (typical Alzheimer's disease) or by visuospatial impairment (posterior cortical atrophy) in relation to 19 age-matched healthy individuals. We designed a novel fMRI paradigm based on passive listening to melodies that were either previously familiar or unfamiliar (musical semantic memory) and either presented singly or repeated (incidental musical episodic memory).

Results: Both syndromic groups showed significant functional neuroanatomical alterations relative to the healthy control group. For musical semantic memory, disease-associated activation group differences were localised to right inferior frontal cortex (reduced activation in the group with memory-led Alzheimer's disease); while for incidental musical episodic memory, disease-associated activation group differences were localised to precuneus and posterior cingulate cortex (abnormally enhanced activation in the syndromic groups). In post-scan behavioural testing, both patient groups had a deficit of musical episodic memory relative to healthy controls whereas musical semantic memory was unimpaired.

Conclusions: Our findings define functional neuroanatomical substrates for the differential involvement of musical semantic and incidental episodic memory in major phenotypes of Alzheimer's disease. The complex dynamic profile of brain activation group differences observed suggests that musical memory may be an informative probe of neural network function in Alzheimer's disease. These findings may guide the development of future musical interventions in dementia.
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http://dx.doi.org/10.1016/j.cortex.2019.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525150PMC
June 2019

Differences in hippocampal subfield volume are seen in phenotypic variants of early onset Alzheimer's disease.

Neuroimage Clin 2019 11;21:101632. Epub 2018 Dec 11.

Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London, UK.

The most common presentation of early onset Alzheimer's disease (EOAD - defined as symptom onset <65 years) is with progressive episodic memory impairment - amnestic or typical Alzheimer's disease (tAD). However, EOAD is notable for its phenotypic heterogeneity, with posterior cortical atrophy (PCA) - characterised by prominent higher-order visual processing deficits and relative sparing of episodic memory - the second most common canonical phenotype. The hippocampus, which comprises a number of interconnected anatomically and functionally distinct subfields, is centrally involved in Alzheimer's disease and is a crucial mediator of episodic memory. The extent to which volumes of individual hippocampal subfields differ between different phenotypes in EOAD is unclear. The aim of this analysis was to investigate the hypothesis that patients with a PCA phenotype will exhibit differences in specific hippocampal subfield volumes compared to tAD. We studied 63 participants with volumetric T1-weighted MRI performed on the same 3T scanner: 39 EOAD patients [27 with tAD and 12 with PCA] and 24 age-matched controls. Volumetric estimates of the following hippocampal subfields for each participant were obtained using Freesurfer version 6.0: CA1, CA2/3, CA4, presubiculum, subiculum, hippocampal tail, parasubiculum, the molecular and granule cell layers of the dentate gryus (GCMLDG), the molecular layer, and the hippocampal amygdala transition area (HATA). Linear regression analyses comparing mean hippocampal subfield volumes between groups, adjusting for age, sex and head size, were performed. Using a Bonferonni-corrected p-value of p < 0.0025, compared to controls, tAD was associated with atrophy in all hippocampal regions, except the parasubiculum. In PCA patients compared to controls, the strongest evidence for volume loss was in the left presubiclum, right subiculum, right GCMLDG, right molecular layer and the right HATA. Compared to PCA, patients with tAD had strong evidence for smaller volumes in left CA1 and left hippocampal tail. In conclusion, these data provide evidence that hippocampal subfield volumes differ in different phenotypes of EOAD.
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http://dx.doi.org/10.1016/j.nicl.2018.101632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411912PMC
December 2019

Cerebrospinal fluid soluble TREM2 levels in frontotemporal dementia differ by genetic and pathological subgroup.

Alzheimers Res Ther 2018 08 16;10(1):79. Epub 2018 Aug 16.

Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Background: Reliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer's disease (AD), but they have not been fully explored in FTD.

Methods: We investigated whether cerebrospinal fluid (CSF) sTREM2 levels differ between FTD and controls, across different clinical and genetic subtypes of FTD, or between individuals with FTD due to AD versus non-AD pathology (based on CSF neurodegenerative biomarkers). We also assessed relationships between CSF sTREM2 and other CSF biomarkers (total tau [T-tau], tau phosphorylated at position threonine-181 [P-tau] and β-amyloid 1-42 [Aβ42]) and age and disease duration. Biomarker levels were measured using immunoassays in 17 healthy controls and 64 patients with FTD (behavioural variant FTD, n = 20; primary progressive aphasia, n = 44). Ten of 64 had familial FTD, with mutations in GRN (n = 3), MAPT (n = 4), or C9orf72 (n = 3). Fifteen of 64 had neurodegenerative biomarkers consistent with AD pathology (11 of whom had logopenic variant PPA). Levels were compared using multivariable linear regressions.

Results: CSF sTREM2 levels did not differ between FTD and controls or between clinical subgroups. However, GRN mutation carriers had higher levels than controls (mean ([SD] = 9.7 [2.9] vs. 6.8 [1.6] ng/ml; P = 0.028) and MAPT (3.9 [1.5] ng/ml; P = 0.003] or C9orf72 [4.6 [1.8] ng/ml; P = 0.006) mutation carriers. Individuals with AD-like CSF had higher sTREM2 levels than those with non-AD-like CSF (9.0 [3.6] vs. 6.9 [3.0] ng/ml; P = 0.029). CSF sTREM2 levels were associated with T-tau levels in control and FTD groups and also with P-tau in those with FTD and AD-like CSF. CSF sTREM2 levels were influenced by both age and disease duration in FTD.

Conclusions: Although CSF sTREM2 levels are not raised in FTD overall or in a particular clinical subtype of FTD, levels are raised in familial FTD associated with GRN mutations and in FTD syndromes due to AD pathology. Because CSF sTREM2 levels correlate with a marker of neuronal injury (T-tau), sTREM2 should be explored as a biomarker of disease intensity in future longitudinal studies of FTD.
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http://dx.doi.org/10.1186/s13195-018-0405-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094471PMC
August 2018

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

Ann Clin Transl Neurol 2018 Jun 20;5(6):697-709. Epub 2018 Apr 20.

Dementia Research Centre Department of Neurodegeneration UCL Institute of Neurology University College London London United Kingdom.

Objective: Deficits in spatial navigation are characteristic and disabling features of typical Alzheimer's 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.

Methods: The effect of visual cues on visually guided navigation was assessed within a simplified real-world setting in individuals with tAD ( = 10), PCA ( = 8), and healthy controls ( = 12). In a repeated-measures design comprising 36 trials, participants walked to a visible target destination (an open door within a built environment), with or without the presence of an obstacle. Contrast and motion-based cues were evaluated; both aimed to facilitate performance by applying perceptual changes to target destinations without carrying explicit information. The primary outcome was completion time; secondary outcomes were measures of fixation position and walking path directness during consecutive task phases, determined using mobile eyetracking and motion capture methods.

Results: Results illustrate marked deficits in patients' navigational ability, with patient groups taking an estimated two to three times longer to reach target destinations than controls and exhibiting tortuous walking paths. There were no significant differences between tAD and PCA task performance. Overall, patients took less time to reach target destinations under cue conditions (contrast-cue: 11.8%; 95% CI: [2.5, 20.3]) and were more likely initially to fixate on targets.

Interpretation: The study evaluated navigation to destinations within a real-world environment. There is evidence that introducing perceptual changes to the environment may improve patients' navigational ability.
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http://dx.doi.org/10.1002/acn3.566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989777PMC
June 2018

Amyloid β peptides are differentially vulnerable to preanalytical surface exposure, an effect incompletely mitigated by the use of ratios.

Alzheimers Dement (Amst) 2018 22;10:311-321. Epub 2018 Mar 22.

Department of Molecular Neuroscience, University College London, London, UK.

Introduction: We tested the hypothesis that the amyloid β (Aβ) peptide ratios are more stable than Aβ alone when biofluids are exposed to two preanalytical conditions known to modify measurable Aβ concentration.

Methods: Human cerebrospinal fluid (CSF) and culture media (CM) from human cortical neurons were exposed to a series of volumes and polypropylene surfaces. Aβ, Aβ, and Aβ peptide concentrations were measured using a multiplexed electrochemiluminescence immunoassay. Data were analyzed using mixed models in R.

Results: Decrease of measurable Aβ peptide concentrations was exaggerated in longer peptides, affecting the Aβ:Aβ and Aβ:Aβ ratios. However, the effect size of surface treatment was reduced in Aβ peptide ratios versus Aβ alone. For Aβ:Aβ, the effect was reduced by approximately 50% (volume) and 75% (transfer) as compared to Aβ alone.

Discussion: Use of Aβ ratios, in conjunction with concentrations, may mitigate confounding factors and assist the clinical diagnostic process for Alzheimer's disease.
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http://dx.doi.org/10.1016/j.dadm.2018.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956932PMC
March 2018

Cortical microstructure in young onset Alzheimer's disease using neurite orientation dispersion and density imaging.

Hum Brain Mapp 2018 07 25;39(7):3005-3017. Epub 2018 Mar 25.

Department of Neurodegenerative Disease, Institute of Neurology, UCL, London, United Kingdom.

Alzheimer's disease (AD) is associated with extensive alterations in grey matter microstructure, but our ability to quantify this in vivo is limited. Neurite orientation dispersion and density imaging (NODDI) is a multi-shell diffusion MRI technique that estimates neuritic microstructure in the form of orientation dispersion and neurite density indices (ODI/NDI). Mean values for cortical thickness, ODI, and NDI were extracted from predefined regions of interest in the cortical grey matter of 38 patients with young onset AD and 22 healthy controls. Five cortical regions associated with early atrophy in AD (entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, fusiform gyrus, and precuneus) and one region relatively spared from atrophy in AD (precentral gyrus) were investigated. ODI, NDI, and cortical thickness values were compared between controls and patients for each region, and their associations with MMSE score were assessed. NDI values of all regions were significantly lower in patients. Cortical thickness measurements were significantly lower in patients in regions associated with early atrophy in AD, but not in the precentral gyrus. Decreased ODI was evident in patients in the inferior and middle temporal gyri, fusiform gyrus, and precuneus. The majority of AD-related decreases in cortical ODI and NDI persisted following adjustment for cortical thickness, as well as each other. There was evidence in the patient group that cortical NDI was associated with MMSE performance. These data suggest distinct differences in cortical NDI and ODI occur in AD and these metrics provide pathologically relevant information beyond that of cortical thinning.
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http://dx.doi.org/10.1002/hbm.24056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055830PMC
July 2018

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

Alzheimers Res Ther 2018 03 20;10(1):32. Epub 2018 Mar 20.

Dementia Research Centre, UCL Institute of Neurology, 8-11 Queen Square, London, WC1N 3BG, UK.

Background: Cerebrospinal 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.

Methods: We 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 (n = 156), DLB (n = 20), behavioural variant frontotemporal dementia (bvFTD; n = 45), progressive non-fluent aphasia (PNFA; n = 17), and semantic dementia (SD; n = 7); approximately 10% were pathology/genetically confirmed (n = 26). 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 (n = 104), DLB (n = 5), bvFTD (n = 12), PNFA (n = 3), SD (n = 9), and controls (n = 10).

Results: There 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 > 50%. 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.

Conclusions: CSF 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.
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http://dx.doi.org/10.1186/s13195-018-0361-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861624PMC
March 2018

CSF neurogranin or tau distinguish typical and atypical Alzheimer disease.

Ann Clin Transl Neurol 2018 02 11;5(2):162-171. Epub 2018 Jan 11.

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

Objective: To assess whether high levels of cerebrospinal fluid neurogranin are found in atypical as well as typical Alzheimer's disease.

Methods: Immunoassays were used to measure cerebrospinal fluid neurogranin in 114 participants including healthy controls ( = 27), biomarker-proven amnestic Alzheimer's disease ( = 68), and the atypical visual variant of Alzheimer's ( = 19) according to international criteria. CSF total-tau, Aβ42, and neurofilament light concentrations were investigated using commercially available assays. All affected individuals had T1-weighted volumetric MR images available for analysis of whole and regional brain volumes. Associations between neurogranin, brain volumes, total-tau, Aβ42, and neurofilament light were assessed.

Results: Median cerebrospinal fluid neurogranin concentrations were higher in typical and atypical Alzheimer's compared to controls ( < 0.001 and  = 0.005). Both neurogranin and total-tau concentrations, but not neurofilament light and Aβ42, were higher in typical Alzheimer's compared to atypical patients ( = 0.004 and  = 0.03). There were significant differences in the left hippocampus and right and left superior parietal lobules in atypical patients, which were larger ( = 0.03) and smaller ( = 0.001 and  < 0.001), respectively, compared to typical patients. We found no evidence of associations between neurogranin and brain volumes but a strong association with total-tau ( < 0.001) and a weaker association with neurofilament light ( = 0.005).

Interpretation: These results show significant differences in neurogranin and total-tau between typical and atypical patients, which may relate to factors other than disease topography. The differential relationships between neurogranin, total-tau and neurofilament light in the Alzheimer's variants, provide evidence for mechanistically distinct and coupled markers of neurodegeneration.
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http://dx.doi.org/10.1002/acn3.518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817822PMC
February 2018

Inhibiting the Ca Influx Induced by Human CSF.

Cell Rep 2017 Dec;21(11):3310-3316

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; UK Dementia Research Institute, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address:

One potential therapeutic strategy for Alzheimer's disease (AD) is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the measurement of aggregate-induced toxicity at low concentrations. We have developed highly sensitive single vesicle and single-cell-based assays that detect the Ca influx caused by the CSF of individuals affected with AD and healthy controls, and we have found comparable effects for both types of samples. We also show that an extracellular chaperone clusterin; a nanobody specific to the amyloid-β peptide (Aβ); and bapineuzumab, a humanized monoclonal antibody raised against Aβ, could all reduce the Ca influx caused by synthetic Aβ oligomers but are less effective in CSF. These assays could be used to characterize potential therapeutic agents in CSF before clinical trials.
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http://dx.doi.org/10.1016/j.celrep.2017.11.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745229PMC
December 2017