Neurofilament light chain (NfL) is a novel biomarker reflecting neuroaxonal damage and associates with brain atrophy, and glial fibrillary acidic protein (GFAP) is a marker of astrocytic activation, ...associated with several neurodegenerative diseases. Since obesity is associated with increased risk for several neurodegenerative disorders, we hypothesized that circulating NfL and GFAP levels could reflect neuronal damage in obese patients. 28 morbidly obese and 18 lean subjects were studied with voxel based morphometry (VBM) MRI to assess gray and white matter densities. Serum NfL and GFAP levels were determined with single-molecule array. Obese subjects were re-studied 6 months after bariatric surgery. Morbidly obese subjects had lower absolute concentrations of circulating NfL and GFAP compared to lean individuals. Following bariatric surgery-induced weight loss, both these levels increased. Both at baseline and after weight loss, circulating NfL and GFAP values correlated inversely with eGFR. Cross-sectionally, circulating NfL levels correlated inversely with gray matter (GM) density, and this association remained significant also when accounting for age and total eGFR. GFAP values did not correlate with GM density. Our data suggest that when determining circulating NfL and GFAP levels, eGFR should also be measured since renal function can affect these measurements. Despite the potential confounding effect of renal function on NfL measurement, NfL correlated inversely with gray matter density in this group of subjects with no identified neurological disorders, suggesting that circulating NfL level may be a feasible biomarker of cerebral function even in apparently neurologically healthy subjects.
Due to the significant clinical overlap between frontotemporal lobar degeneration (FTLD) spectrum disorders and late-onset primary psychiatric disorders (PPD), diagnostic biomarkers reflecting the ...different underlying pathophysiologies are urgently needed. Thus far, elevated cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) have been reported in various neurological conditions. Furthermore, recent advancements in ultrasensitive analytical methods (e.g., single molecule array, Simoa) have enabled sensitive and less invasive NfL detection also from blood samples. In this study, we evaluated the potential of serum NfL (sNfL) as a diagnostic tool between FTLD and PPD. We analyzed sNfL levels with Simoa from 125 participants including patients from FTLD (
n
= 91) and PPD (
n
= 34) spectra. Our results show that sNfL levels are higher in the FTLD group compared to the PPD group as well as in separate clinical subtypes of FTLD compared to different psychiatric manifestations (i.e., mood or psychotic disorders). At single-subject level, discrimination between FTLD and PPD was possible with 80% sensitivity and 85% specificity (AUC = 0.850, 95% CI 0.776–0.923), and between behavioral variant frontotemporal dementia (bvFTD) and PPD with 79% sensitivity and 85% specificity (AUC = 0.830, 95% CI 0.732–0.908). These findings highlight the potential of sNfL as a discriminating biomarker for FTLD over PPD in patients with wide-ranging behavioral, psychiatric and cognitive symptoms.
Background and purpose
Fall‐related injuries are a major health concern among people with Parkinson disease (PD). We compared the incidence and postinjury mortality of head injuries and traumatic ...brain injury (TBI) among persons with and without PD.
Methods
This register‐based study was conducted on the FINPARK cohort, which includes 22,189 persons who were diagnosed with PD in Finland during 1996–2015. We excluded persons with a previous head injury, leaving 20,514 persons with PD. For each person with PD, 1–7 matching persons without PD and previous head injury were identified with respect to age, sex, and residence. The Cox proportional hazard model was used to estimate hazard ratios for head injury. A logistic regression model was used to compare mortality.
Results
Persons with PD had 2.16‐fold (95% confidence interval CI = 2.06–2.26) risk of all head injuries and 1.97‐fold (95% CI = 1.84–2.10) risk of TBI after adjustment for age, sex, and comorbidities. Persons with PD had higher 1‐year mortality after any type of head injury (adjusted odds ratio aOR = 1.44, 95% CI = 1.28–1.62), TBI (aOR = 1.33, 95% CI = 1.14–1.57), or non‐TBI head injury (aOR = 1.72, 95% CI = 1.42–2.07) than persons without PD. The higher risk of mortality was observed 6 months after TBI and 1 month after non‐TBI injury in persons with PD. Persons with PD and head injury also had higher 1‐year mortality than persons with PD and without head injury.
Conclusions
Persons with PD have a higher risk of head injury and higher postinjury mortality than persons without PD.
Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and ...National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
We investigated the association of Alzheimer's disease (AD)‐related rare variants APP A673T and ABCA7 rs200538373‐C with the levels of β‐amyloid (Aβ) and parameters of metabolic and cardiovascular ...health in a population‐based cohort of healthy middle‐aged and elderly men. Carriers of protective APP A673T variant had, on average, 28% lower levels of Aβ40 and Aβ42 in plasma as compared to the controls and the carriers of ABCA7 rs200538373‐C. This is the first report to show decreased Aβ levels in plasma in APP A673T carriers and thus provides evidence that lower Aβ levels throughout life may be protective against AD. Ann Neurol 2017;82:128–132
Frontotemporal lobar degeneration (FTLD) and primary psychiatric disorders (PPD) are characterised by overlapping clinical features but different aetiologies. Here, we assessed for the first time the ...potential of blood glial fibrillar acidic protein (GFAP), marker of astrogliosis, as a discriminative and prognostic tool in FTLD and PPD.
The levels of GFAP in serum (sGFAP) of patients with FTLD (N=107) and PPD (N=44) and GFAP in whole blood samples (bGFAP) from FTLD (N=10), PPD (N=10) and healthy controls (N=18) were measured. We evaluated whether the sGFAP levels associate with
repeat expansion, survival of FTLD and PPD patients, and brain atrophy assessed cross-sectionally and longitudinally by structural T1W MRI. We also examined the correlation between sGFAP and bGFAP levels in a subset of patients.
sGFAP and bGFAP levels were elevated in the FTLD group compared with the PPD or control groups. Receiver operating characteristic analysis indicated an excellent diagnostic performance between FTLD and PPD (the area under the curve (AUC)=0.820, 95% CI 0.745 to 0.896). sGFAP and bGFAP levels showed a strong correlation and elevated sGFAP levels significantly associated with atrophy rate in the temporal cortex and predicted shorter survival time in patients with FTLD. No association with
repeat expansion was detected.
sGFAP enabled differentiation of patients with FTLD and PPD and associated with shorter survival and more severe brain atrophy rate in patients with FTLD. These results suggest that blood-based GFAP represents a minimally invasive and useful biomarker in the differential diagnostics between patients with FTLD and PPD and in evaluating disease progression and astrogliosis in FTLD.
Abstract Introduction The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aβ1–42 ), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's ...disease (AD) dementia from other forms of dementia. Methods A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto-temporal dementia (FTD), depression, or other neurological diseases. Results CSF Aβ1–42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32–62) to 77% (for FTD, 95% CI = 62–90). Discussion CSF Aβ1–42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies.
Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become ...available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.
In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models—a demographics model, a hippocampal volume model, and a CSF biomarkers model—by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.
We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59–0·65), validated hippocampal volume model (0·67, 0·62–0·72), and updated CSF biomarkers model (0·72, 0·68–0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71–0·76).
We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.
ZonMW-Memorabel.
We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-ß1-42 (Aβ42), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis ...of Alzheimer's disease (AD).
We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442).
Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/Aβ42 ratio and 0.08 for the p-tau/Aβ42 ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/Aβ42 ratio.
A tau/Aβ42 ratio of >0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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