Summary Background Parkinson's disease is associated with an increased incidence of cognitive impairment and dementia. Predicting who is at risk of cognitive decline early in the disease course has ...implications for clinical prognosis and for stratification of participants in clinical trials. We assessed the use of clinical information and biomarkers as predictive factors for cognitive decline in patients with newly diagnosed Parkinson's disease. Methods The Parkinson's Progression Markers Initiative (PPMI) study is a cohort study in patients with newly diagnosed Parkinson's disease. We evaluated cognitive performance (Montreal Cognitive Assessment MoCA scores), demographic and clinical data, APOE status, and biomarkers (CSF and dopamine transporter DAT imaging results). Using change in MoCA scores over 2 years, MoCA scores at 2 years' follow-up, and a diagnosis of cognitive impairment (combined mild cognitive impairment or dementia) at 2 years as outcome measures, we assessed the predictive values of baseline clinical variables and separate or combined additions of APOE status, DAT imaging, and CSF biomarkers. We did univariate and multivariate linear analyses with MoCA change scores between baseline and 2 years, and with MoCA scores at 2 years as dependent variables, using backwards linear regression analysis. Additionally, we constructed a prediction model for diagnosis of cognitive impairment using logistic regression analysis. Findings 390 patients with Parkinson's disease recruited between July 1, 2010, and May 31, 2013, and for whom data on MoCA scores at baseline and 2 years were available. In multivariate analyses, baseline age, University of Pennsylvania Smell Inventory Test (UPSIT) scores, CSF amyloid — (Aβ42 ) to t-tau ratio, and APOE status were associated with change in MoCA scores over time. Baseline age, MoCA and UPSIT scores, and CSF Aβ42 to t-tau ratio were associated with MoCA score at 2 years (using a backwards p-removal threshold of 0·1). Accuracy of prediction of cognitive impairment using age alone (area under the curve 0·68, 95% CI 0·60–0·76) significantly improved by addition of clinical scores (UPSIT, Rapid Eye Movement Sleep Behaviour Disorder Screening Questionnaire RBDSQ, Geriatric Depression Scale, and Movement Disorder Society Unified Parkinson's Disease Rating Scale motor scores; 0·76, 0·68–0·83), CSF variables (0·74, 0·68–0·81), or DAT imaging results (0·76, 0·68–0·83). In combination, the five variables showing the most significant associations with cognitive impairment (age, UPSIT, RBDSQ, CSF Aβ42 , and caudate uptake on DAT imaging) allowed prediction of cognitive impairment at 2 years (0·80, 0·74–0·87; p=0·0003 compared to age alone). Interpretation In newly diagnosed Parkinson's disease, the occurrence of cognitive impairment at 2 year follow-up can be predicted with good accuracy using a model combining information on age, non-motor assessments, DAT imaging, and CSF biomarkers. Funding None.
Hexanucleotide repeat expansions in C9orf72 are a major cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Understanding the disease mechanisms and a method ...for clinical diagnostic genotyping have been hindered because of the difficulty in estimating the expansion size. We found 96 repeat-primed PCR expansions: 85/2,974 in six neurodegenerative diseases cohorts (FTLD, ALS, Alzheimer disease, sporadic Creutzfeldt-Jakob disease, Huntington disease-like syndrome, and other nonspecific neurodegenerative disease syndromes) and 11/7,579 (0.15%) in UK 1958 birth cohort (58BC) controls. With the use of a modified Southern blot method, the estimated expansion range (smear maxima) in cases was 800–4,400. Similarly, large expansions were detected in the population controls. Differences in expansion size and morphology were detected between DNA samples from tissue and cell lines. Of those in whom repeat-primed PCR detected expansions, 68/69 were confirmed by blotting, which was specific for greater than 275 repeats. We found that morphology in the expansion smear varied among different individuals and among different brain regions in the same individual. Expansion size correlated with age at clinical onset but did not differ between diagnostic groups. Evidence of instability of repeat size in control families, as well as neighboring SNP and microsatellite analyses, support multiple expansion events on the same haplotype background. Our method of estimating the size of large expansions has potential clinical utility. C9orf72-related disease might mimic several neurodegenerative disorders and, with potentially 90,000 carriers in the United Kingdom, is more common than previously realized.
OBJECTIVE:To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease.
METHODS:Serum ...samples were collected from 74 participants (34 with behavioral variant FTD bvFTD, 3 with FTD and motor neuron disease and 37 with primary progressive aphasia PPA) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4). Serum NfL concentrations were determined with the NF-Light kit transferred onto the single-molecule array platform and compared between FTD and healthy controls and between the FTD clinical and genetic subtypes. We also assessed the relationship between NfL concentrations and measures of cognition and brain volume.
RESULTS:Serum NfL concentrations were higher in patients with FTD overall (mean 77.9 pg/mL SD 51.3 pg/mL) than controls (19.6 pg/mL SD 8.2 pg/mL; p < 0.001). Concentrations were also significantly higher in bvFTD (57.8 pg/mL SD 33.1 pg/mL) and both the semantic and nonfluent variants of PPA (95.9 and 82.5 pg/mL SD 33.0 and 33.8 pg/mL, respectively) compared with controls and in semantic variant PPA compared with logopenic variant PPA. Concentrations were significantly higher than controls in both the C9orf72 and MAPT subgroups (79.2 and 40.5 pg/mL SD 48.2 and 20.9 pg/mL, respectively) with a trend to a higher level in the GRN subgroup (138.5 pg/mL SD 103.3 pg/mL). However, there was variability within all groups. Serum concentrations correlated particularly with frontal lobe atrophy rate (r = 0.53, p = 0.003).
CONCLUSIONS:Increased serum NfL concentrations are seen in FTD but show wide variability within each clinical and genetic group. Higher concentrations may reflect the intensity of the disease in FTD and are associated with more rapid atrophy of the frontal lobes.
Alzheimer's disease (AD) is a progressive neurodegenerative disease and the single commonest cause of dementia. Many other diseases can, however, cause dementia, and differential diagnosis can be ...challenging, especially in early disease stages. For most neurodegenerative dementias, accumulation of brain pathologies starts many years before clinical onset; the ability to detect these pathologies paves the way for targeted disease‐modifying prevention trials. AD is associated with β‐amyloid and tau pathologies, which can be quantified using cerebrospinal fluid and imaging biomarkers and, more recently, using highly sensitive blood tests. While for the most part, specific biomarkers of non‐AD neurodegenerative dementias are lacking, non‐specific biomarkers of neurodegeneration are available. This review summarizes recent advances in the neurodegenerative dementia blood biomarker research and discusses the next steps required for clinical implementation.
Midlife hypertension confers increased risk for cognitive impairment in late life. The sensitive period for risk exposure and extent that risk is mediated through amyloid or vascular-related ...mechanisms are poorly understood. We aimed to identify if, and when, blood pressure or change in blood pressure during adulthood were associated with late-life brain structure, pathology, and cognition.
Participants were from Insight 46, a neuroscience substudy of the ongoing longitudinal Medical Research Council National Survey of Health and Development, a birth cohort that initially comprised 5362 individuals born throughout mainland Britain in one week in 1946. Participants aged 69–71 years received T1 and FLAIR volumetric MRI, florbetapir amyloid-PET imaging, and cognitive assessment at University College London (London, UK); all participants were dementia-free. Blood pressure measurements had been collected at ages 36, 43, 53, 60–64, and 69 years. We also calculated blood pressure change variables between ages. Primary outcome measures were white matter hyperintensity volume (WMHV) quantified from multimodal MRI using an automated method, amyloid-β positivity or negativity using a standardised uptake value ratio approach, whole-brain and hippocampal volumes quantified from 3D-T1 MRI, and a composite cognitive score—the Preclinical Alzheimer Cognitive Composite (PACC). We investigated associations between blood pressure and blood pressure changes at and between 36, 43, 53, 60–64, and 69 years of age with WMHV using generalised linear models with a gamma distribution and log link function, amyloid-β status using logistic regression, whole-brain volume and hippocampal volumes using linear regression, and PACC score using linear regression, with adjustment for potential confounders.
Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. 465 participants (238 51% men; mean age 70·7 years SD 0·7; 83 18% amyloid-β-positive) were included in imaging analyses. Higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) at age 53 years and greater increases in SBP and DBP between 43 and 53 years were positively associated with WMHV at 69–71 years of age (increase in mean WMHV per 10 mm Hg greater SBP 7%, 95% CI 1–14, p=0·024; increase in mean WMHV per 10 mm Hg greater DBP 15%, 4–27, p=0·0057; increase in mean WMHV per one SD change in SBP 15%, 3–29, p=0·012; increase in mean WMHV per 1 SD change in DBP 15%, 3–30, p=0·017). Higher DBP at 43 years of age was associated with smaller whole-brain volume at 69–71 years of age (−6·9 mL per 10 mm Hg greater DBP, −11·9 to −1·9, p=0·0068), as were greater increases in DBP between 36 and 43 years of age (−6·5 mL per 1 SD change, −11·1 to −1·9, p=0·0054). Greater increases in SBP between 36 and 43 years of age were associated with smaller hippocampal volumes at 69–71 years of age (−0·03 mL per 1 SD change, −0·06 to −0·001, p=0·043). Neither absolute blood pressure nor change in blood pressure predicted amyloid-β status or PACC score at 69–71 years of age.
High and increasing blood pressure from early adulthood into midlife seems to be associated with increased WMHV and smaller brain volumes at 69–71 years of age. We found no evidence that blood pressure affected cognition or cerebral amyloid-β load at this age. Blood pressure monitoring and interventions might need to start around 40 years of age to maximise late-life brain health.
Alzheimer's Research UK, Medical Research Council, Dementias Platform UK, Wellcome Trust, Brain Research UK, Wolfson Foundation, Weston Brain Institute, Avid Radiopharmaceuticals.
In the last 2 years, there have been 3 successful trials of antiamyloid antibodies in Alzheimer disease (AD): aducanemab, now controversially US Food and Drug Administration-approved under the ...accelerated approval pathway
; lecanemab, now FDA-approved
; and donanemab, now going through the approval process.
All 3 share a common broad mechanism, that is, antibody-mediated removal of β-amyloid (Aβ) from the brain, and this is almost certainly the basis of their therapeutic action.
When used in the earliest symptomatic stages of AD, all have modest clinical effects, all clear Aβ from the brain, and all show evidence for some changes in molecular markers believed to be downstream of Aβ accumulation in keeping with disease modification.
However, all these drugs-and several other antiamyloid immunotherapies that failed to show positive effects in clinical trials (e.g. bapineuzemab and gantenerumab)
-have the troubling adverse event of antibody-related imaging abnormalities (ARIA). ARIA can take the form of vasogenic edema or sulcal effusion (ARIA-E) or haemosiderin deposition due to hemorrhage (ARIA-H).
ARIA is detected using MRI: ARIA-E is visible on fluid attenuation inversion recovery sequences; ARIA-H is best seen on iron-sensitive (T2* or susceptibility-weighted imaging) as microbleeds and/or superficial hemosiderin deposition. The pathophysiology of ARIA has yet to be fully determined but may result from antibody-mediated breakdown of amyloid plaques releasing Aβ which is deposited in vessels leading to increased cerebral amyloid angiopathy or alterations in perivascular clearance or inflammation, possibly through complement activation.
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Accurately distinguishing between different degenerative dementias during life is challenging but increasingly important with the prospect of disease-modifying therapies. Molecular biomarkers of ...dementia pathology are becoming available, but are not widely used in clinical practice. Conversely, structural neuroimaging is recommended in the evaluation of cognitive impairment. Visual assessment remains the primary method of scan interpretation, but in the absence of a structured approach, diagnostically relevant information may be under-utilized. This definitive, multi-centre study uses post-mortem confirmed cases as the gold standard to: (i) assess the reliability of six visual rating scales; (ii) determine their associated pattern of atrophy; (iii) compare their diagnostic value with expert scan assessment; and (iv) assess the accuracy of a machine learning approach based on multiple rating scales to predict underlying pathology. The study includes T1-weighted images acquired in three European centres from 184 individuals with histopathologically confirmed dementia (101 patients with Alzheimer's disease, 28 patients with dementia with Lewy bodies, 55 patients with frontotemporal lobar degeneration), and scans from 73 healthy controls. Six visual rating scales (medial temporal, posterior, anterior temporal, orbito-frontal, anterior cingulate and fronto-insula) were applied to 257 scans (two raters), and to a subset of 80 scans (three raters). Six experts also provided a diagnosis based on unstructured assessment of the 80-scan subset. The reliability and time taken to apply each scale was evaluated. Voxel-based morphometry was used to explore the relationship between each rating scale and the pattern of grey matter volume loss. Additionally, the performance of each scale to predict dementia pathology both individually and in combination was evaluated using a support vector classifier, which was compared with expert scan assessment to estimate clinical value. Reliability of scan assessment was generally good (intraclass correlation coefficient > 0.7), and average time to apply all six scales was <3 min. There was a very close association between the pattern of grey matter loss and the regions of interest each scale was designed to assess. Using automated classification based on all six rating scales, the accuracy (estimated using the area under the receiver-operator curves) for distinguishing each pathological group from controls ranged from 0.86-0.97; and from one another, 0.75-0.92. These results were substantially better than the accuracy of any single scale, at least as good as expert reads, and comparable to previous studies using molecular biomarkers. Visual rating scores from magnetic resonance images routinely acquired as part of the investigation of dementias, offer a practical, inexpensive means of improving diagnostic accuracy.
On 7 June, the FDA approved aducanumab, the first new drug for Alzheimer’s disease in almost 20 years—and notably, the first drug with a putative disease‐modifying mechanism for the treatment of this ...devastating disorder, namely the removal of β‐amyloid (or Aβ) plaques from the brain.
G. Lalli, J. Schott, J. Hardy, and B De Strooper comment on the FDA approval of aducanumab and provide some interesting points to consider.
The neurodegenerative disorder Alzheimer's disease is characterised by the formation of β-amyloid plaques and neurofibrillary tangles in the brain parenchyma, which cause synapse and neuronal loss. ...This leads to clinical symptoms, such as progressive memory deficits. Clinically, these pathological changes can be detected in the cerebrospinal fluid and with brain imaging, although reliable blood tests for plaque and tangle pathologies remain to be developed. Plaques and tangles often co-exist with other brain pathologies, including aggregates of transactive response DNA-binding protein 43 and Lewy bodies, but the extent to which these contribute to the severity of Alzheimer's disease is currently unknown. In this 'At a glance' article and poster, we summarise the molecular biomarkers that are being developed to detect Alzheimer's disease and its related pathologies. We also highlight the biomarkers that are currently in clinical use and include a critical appraisal of the challenges associated with applying these biomarkers for diagnostic and prognostic purposes of Alzheimer's disease and related neurodegenerative disorders, also in their prodromal clinical phases.
Attenuation correction is an essential requirement for quantification of positron emission tomography (PET) data. In PET/CT acquisition systems, attenuation maps are derived from computed tomography ...(CT) images. However, in hybrid PET/MR scanners, magnetic resonance imaging (MRI) images do not directly provide a patient-specific attenuation map. The aim of the proposed work is to improve attenuation correction for PET/MR scanners by generating synthetic CTs and attenuation maps. The synthetic images are generated through a multi-atlas information propagation scheme, locally matching the MRI-derived patient's morphology to a database of MRI/CT pairs, using a local image similarity measure. Results show significant improvements in CT synthesis and PET reconstruction accuracy when compared to a segmentation method using an ultrashort-echo-time MRI sequence and to a simplified atlas-based method.