Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease.

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients.

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Strategic white matter hyperintensity locations for cognitive impairment: A multicenter lesion-symptom mapping study in 3525 memory clinic patients.

INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.

A Multiplexed Urinary Biomarker Panel Has Potential for Alzheimer's Disease Diagnosis Using Targeted Proteomics and Machine Learning.

As disease-modifying therapies are now available for Alzheimer's disease (AD), accessible, accurate and affordable biomarkers to support diagnosis are urgently needed. We sought to develop a mass spectrometry-based urine test as a high-throughput screening tool for diagnosing AD. We collected urine from a discovery cohort (n = 11) of well-characterised individuals with AD (n = 6) and their asymptomatic, CSF biomarker-negative study partners (n = 5) and used untargeted proteomics for biomarker discovery. Protein biomarkers identified were taken forward to develop a high-throughput, multiplexed and targeted proteomic assay which was tested on an independent cohort (n = 21). The panel of proteins identified are known to be involved in AD pathogenesis. In comparing AD and controls, a panel of proteins including MIEN1, TNFB, VCAM1, REG1B and ABCA7 had a classification accuracy of 86%. These proteins have been previously implicated in AD pathogenesis. This suggests that urine-targeted mass spectrometry has potential utility as a diagnostic screening tool in AD.

Amyloid processing in COVID-19-associated neurological syndromes.

SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]-6, IL-1ß, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-ɑ (p = 0.004) and sAPPß (p = 0.03) as well as amyloid ß (Aß) 40 (p = 5.2 × 10-8 ), Aß42 (p = 3.5 × 10-7 ), and Aß42/Aß40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPß. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPß. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPß. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.

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

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.

CSF biomarkers for dementia.

Although cerebrospinal fluid (CSF) biomarker testing is incorporated into some current guidelines for the diagnosis of dementia (such as England's National Institute for Health and Care Excellence (NICE)), it is not widely accessible for most patients for whom biomarkers could potentially change management. Here we share our experience of running a clinical cognitive CSF service and discuss recent developments in laboratory testing including the use of the CSF amyloid-ß 42/40 ratio and automated assay platforms. We highlight the importance of collaborative working between clinicians and laboratory staff, of preanalytical sample handling, and discuss the various factors influencing interpretation of the results in appropriate clinical contexts. We advocate for broadening access to CSF biomarkers by sharing clinical expertise, protocols and interpretation with colleagues working in psychiatry and elderly care, especially when access to CSF may be part of a pathway to disease-modifying treatments for Alzheimer's disease and other forms of dementia.

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

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/Aß, 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.

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

Familial Alzheimer's disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-ß (Aß) 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 Aß 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 Aß42:40 ratio relative to controls, yet displayed varied signatures for Aß43, Aß38, and short Aß fragments. We propose four qualitatively distinct mechanisms behind raised Aß42:40. (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 Aß mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD.

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

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 (κs 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.

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

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.

Dementia wellbeing and COVID-19: Review and expert consensus on current research and knowledge gaps.

OBJECTIVES: In response to a commissioned research update on dementia during the COVID-19 pandemic, a UK-based working group, comprising dementia researchers from a range of fields and disciplines, aimed to describe the impact of the pandemic on dementia wellbeing and identify priorities for future research. METHODS: We supplemented a rapid literature search (including unpublished, non-peer reviewed and ongoing studies/reports) on dementia wellbeing in the context of COVID-19 with expert group members' consensus about future research needs. From this we generated potential research questions the group judged to be relevant that were not covered by the existing literature. RESULTS: Themes emerged from 141 studies within the six domains of the NHS England COVID-19 Dementia Wellbeing Pathway: Preventing Well, Diagnosing Well, Treating Well, Supporting Well, Living Well and Dying Well. We describe current research findings and knowledge gaps relating to the impact on people affected by dementia (individuals with a diagnosis, their carers and social contacts, health and social care practitioners and volunteers), services, research activities and organisations. Broad themes included the potential benefits and risks of new models of working including remote healthcare, the need for population-representative longitudinal studies to monitor longer-term impacts, and the importance of reporting dementia-related findings within broader health and care studies. CONCLUSIONS: The COVID-19 pandemic has had a disproportionately negative impact on people affected by dementia. Researchers and funding organisations have responded rapidly to try to understand the impacts. Future research should highlight and resolve outstanding questions to develop evidence-based measures to improve the quality of life of people affected by dementia.

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

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 ß-amyloid 1-42 (Aß42), 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 Aß42, 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.

Longitudinal neuroanatomical and cognitive progression of posterior cortical atrophy.

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.

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

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(181)). Patients with FTD were grouped based on their Aß42 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(181)/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.

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

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.

Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy.

The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal 'visual dementia' and most common atypical Alzheimer's disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients' (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer's disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer's disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer's disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with 'sticky fixation'. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer's disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer's disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer's disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment.

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis.

Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer's disease (n = 20, eight female, aged 53-74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients' brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer's disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases.