ABSTRACT
Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with ß-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.
Subject(s)
Alzheimer Disease , Frontal Lobe , Microglia , Neurons , Humans , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid , Amyloid beta-Peptides/metabolism , Microglia/pathology , Neurons/pathology , Pyramidal Cells , Biopsy , Frontal Lobe/pathology , Single-Cell Gene Expression Analysis , Cell Nucleus/metabolism , Cell Nucleus/pathologyABSTRACT
Mutations in mitochondrial DNA encoded subunit of ATP synthase, MT-ATP6, are frequent causes of neurological mitochondrial diseases with a range of phenotypes from Leigh syndrome and NARP to ataxias and neuropathies. Here we investigated the functional consequences of an unusual heteroplasmic truncating mutation m.9154C>T in MT-ATP6, which caused peripheral neuropathy, ataxia and IgA nephropathy. ATP synthase not only generates cellular ATP, but its dimerization is required for mitochondrial cristae formation. Accordingly, the MT-ATP6 truncating mutation impaired the assembly of ATP synthase and disrupted cristae morphology, supporting our molecular dynamics simulations that predicted destabilized a/c subunit subcomplex. Next, we modeled the effects of the truncating mutation using patient-specific induced pluripotent stem cells. Unexpectedly, depending on mutation heteroplasmy level, the truncation showed multiple threshold effects in cellular reprogramming, neurogenesis and in metabolism of mature motor neurons (MN). Interestingly, MN differentiation beyond progenitor stage was impaired by Notch hyperactivation in the MT-ATP6 mutant, but not by rotenone-induced inhibition of mitochondrial respiration, suggesting that altered mitochondrial morphology contributed to Notch hyperactivation. Finally, we also identified a lower mutation threshold for a metabolic shift in mature MN, affecting lactate utilization, which may be relevant for understanding the mechanisms of mitochondrial involvement in peripheral motor neuropathies. These results establish a critical and disease-relevant role for ATP synthase in human cell fate decisions and neuronal metabolism.
Subject(s)
Heteroplasmy , Mitochondrial Proton-Translocating ATPases , Adenosine Triphosphate , Ataxia/genetics , DNA, Mitochondrial/genetics , Humans , Mitochondrial Proton-Translocating ATPases/genetics , Mitochondrial Proton-Translocating ATPases/metabolism , Motor Neurons/metabolism , MutationABSTRACT
Charcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers' growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.
Subject(s)
Charcot-Marie-Tooth Disease , Hereditary Sensory and Motor Neuropathy , Adult , Humans , Growth Differentiation Factor 15/genetics , Intermediate Filaments , Myelin Proteins/genetics , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/diagnosis , BiomarkersABSTRACT
The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aß) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPß (sAPPß) and Aß42 were significantly decreased on average 9-26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aß, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPß levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFß and Aß42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.
Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Humans , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/metabolism , Heterozygote , Brain/metabolismABSTRACT
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.
Subject(s)
Brain Injuries, Traumatic , Craniocerebral Trauma , Parkinson Disease , Humans , Incidence , Parkinson Disease/complications , Parkinson Disease/epidemiology , Craniocerebral Trauma/complications , Craniocerebral Trauma/epidemiology , Brain Injuries, Traumatic/epidemiology , ComorbidityABSTRACT
Plasma neurofilament light chain (NF-L) levels were assessed as a diagnostic biomarker for traumatic brain injury (TBI) and as a prognostic biomarker for somatomotor recovery, cognitive decline, and epileptogenesis. Rats with severe TBI induced by lateral fluid-percussion injury (n = 26, 13 with and 13 without epilepsy) or sham-operation (n = 8) were studied. During a 6-month follow-up, rats underwent magnetic resonance imaging (MRI) (day (D) 2, D7, and D21), composite neuroscore (D2, D6, and D14), Morris-water maze (D35−D39), and a 1-month-long video-electroencephalogram to detect unprovoked seizures during the 6th month. Plasma NF-L levels were assessed using a single-molecule assay at baseline (i.e., naïve animals) and on D2, D9, and D178 after TBI or a sham operation. Plasma NF-L levels were 483-fold higher on D2 (5072.0 ± 2007.0 pg/mL), 89-fold higher on D9 (930.3 ± 306.4 pg/mL), and 3-fold higher on D176 32.2 ± 8.9 pg/mL after TBI compared with baseline (10.5 ± 2.6 pg/mL; all p < 0.001). Plasma NF-L levels distinguished TBI rats from naïve animals at all time-points examined (area under the curve [AUC] 1.0, p < 0.001), and from sham-operated controls on D2 (AUC 1.0, p < 0.001). Plasma NF-L increases on D2 were associated with somatomotor impairment severity (ρ = −0.480, p < 0.05) and the cortical lesion extent in MRI (ρ = 0.401, p < 0.05). Plasma NF-L increases on D2 or D9 were associated with the cortical lesion extent in histologic sections at 6 months post-injury (ρ = 0.437 for D2; ρ = 0.393 for D9, p < 0.05). Plasma NF-L levels, however, did not predict somatomotor recovery, cognitive decline, or epileptogenesis (p > 0.05). Plasma NF-L levels represent a promising noninvasive translational diagnostic biomarker for acute TBI and a prognostic biomarker for post-injury somatomotor impairment and long-term structural brain damage.
Subject(s)
Brain Injuries, Traumatic , Brain Injuries , Cognitive Dysfunction , Animals , Rats , Rats, Sprague-Dawley , Prognosis , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/diagnostic imaging , Brain Injuries, Traumatic/pathology , Seizures/complications , Brain Injuries/pathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/complications , Disease Models, AnimalABSTRACT
BACKGROUND: 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. METHODS: 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 C9orf72 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. RESULTS: 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 C9orf72 repeat expansion was detected. CONCLUSIONS: 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.
Subject(s)
Brain/diagnostic imaging , Frontotemporal Dementia/diagnosis , Glial Fibrillary Acidic Protein/blood , Aged , Atrophy/blood , Atrophy/diagnostic imaging , Biomarkers/blood , Disease Progression , Female , Frontotemporal Dementia/blood , Frontotemporal Dementia/diagnostic imaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Prognosis , Sensitivity and Specificity , Survival RateABSTRACT
PURPOSE: Automated analysis of neuroimaging data is commonly based on magnetic resonance imaging (MRI), but sometimes the availability is limited or a patient might have contradictions to MRI. Therefore, automated analyses of computed tomography (CT) images would be beneficial. METHODS: We developed an automated method to evaluate medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), and the severity of white matter lesions (WMLs) from a CT scan and compared the results to those obtained from MRI in a cohort of 214 subjects gathered from Kuopio and Helsinki University Hospital registers from 2005 - 2016. RESULTS: The correlation coefficients of computational measures between CT and MRI were 0.9 (MTA), 0.82 (GCA), and 0.86 (Fazekas). CT-based measures were identical to MRI-based measures in 60% (MTA), 62% (GCA) and 60% (Fazekas) of cases when the measures were rounded to the nearest full grade variable. However, the difference in measures was 1 or less in 97-98% of cases. Similar results were obtained for cortical atrophy ratings, especially in the frontal and temporal lobes, when assessing the brain lobes separately. Bland-Altman plots and weighted kappa values demonstrated high agreement regarding measures based on CT and MRI. CONCLUSIONS: MTA, GCA, and Fazekas grades can also be assessed reliably from a CT scan with our method. Even though the measures obtained with the different imaging modalities were not identical in a relatively extensive cohort, the differences were minor. This expands the possibility of using this automated analysis method when MRI is inaccessible or contraindicated.
Subject(s)
Alzheimer Disease , White Matter , Alzheimer Disease/pathology , Atrophy/diagnostic imaging , Atrophy/pathology , Brain/diagnostic imaging , Brain/pathology , Humans , Magnetic Resonance Imaging , Tomography, X-Ray Computed , White Matter/diagnostic imaging , White Matter/pathologyABSTRACT
INTRODUCTION: The potential of neurofilament light (NfL) as a blood-based biomarker is currently being investigated in autosomal dominant neurodegenerative disease. This study explores the clinical utility of serum-NfL in frontotemporal dementia due to CHMP2B mutation (FTD-3). METHODS: This cross-sectional study included serum and CSF data from 38 members of the Danish FTD-3 family: 12 affected CHMP2B mutation carriers, 10 presymptomatic carriers, and 16 noncarriers. Serum-NfL levels measured by single-molecule array (Simoa) technology were tested for associations with the clinical groups and clinical parameters. Serum and CSF data were compared, and CSF/serum-albumin ratio was included as a measure of blood-brain barrier (BBB) function. RESULTS: Serum-NfL concentrations were significantly increased in symptomatic CHMP2B mutation carriers compared to presymptomatic carriers and in both groups compared to healthy family controls. Serum-NfL levels appear to increase progressively with age in presymptomatic carriers, and this is perhaps followed by a change in trajectory when patients become symptomatic. Measurements of NfL in serum and CSF were highly correlated and fold-changes in serum and CSF between clinical groups were similar. Increase in serum-NFL levels was correlated with reduced ACE-score. Higher CSF/serum-albumin ratios were demonstrated in FTD-3 patients, but this did not affect the significant associations between serum-NfL and clinical groups. CONCLUSION: Serum-NfL could be utilized as an accurate surrogate marker of CSF levels to segregate symptomatic CHMP2B carriers, presymptomatic carriers, and non-carriers. The observed indication of BBB dysfunction in FTD-3 patients did not confound this use of serum-NfL. The results support the occurrence of mutation-related differences in NfL dynamics in familial FTD.
Subject(s)
Endosomal Sorting Complexes Required for Transport/genetics , Frontotemporal Dementia/blood , Frontotemporal Dementia/genetics , Mutation , Neurofilament Proteins/blood , Adult , Aged , Biomarkers/blood , Cross-Sectional Studies , Female , Humans , Intermediate Filaments , Male , Middle AgedABSTRACT
OBJECTIVE: To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer's disease-related amyloid ß (Aß) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. METHODS: The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson's disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer's disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPß), Aß species (Aß38, Aß40 and Aß42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1). RESULTS: Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aß40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aß40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers. CONCLUSIONS: The combination of the CSF biomarkers T-tau, Aß40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.
Subject(s)
Alzheimer Disease/diagnosis , Dementia, Vascular/diagnosis , Diagnosis, Differential , Frontotemporal Lobar Degeneration/diagnosis , Hydrocephalus, Normal Pressure/diagnosis , Multiple System Atrophy/diagnosis , Parkinson Disease/diagnosis , Supranuclear Palsy, Progressive/diagnosis , Aged , Aged, 80 and over , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Amyloid beta-Protein Precursor/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Case-Control Studies , Chemokine CCL2/cerebrospinal fluid , Dementia, Vascular/cerebrospinal fluid , Female , Frontotemporal Lobar Degeneration/cerebrospinal fluid , Humans , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Male , Middle Aged , Multiple System Atrophy/cerebrospinal fluid , Neurofilament Proteins/cerebrospinal fluid , Parkinson Disease/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Phosphoproteins/cerebrospinal fluid , Sensitivity and Specificity , Supranuclear Palsy, Progressive/cerebrospinal fluid , tau Proteins/cerebrospinal fluidABSTRACT
BACKGROUND AND PURPOSE: We studied serum neurofilaments diagnostic value in patients with acute ischemic stroke (AIS) or TIA and evaluated any correlation with symptom severity, cerebral infarction volume, aetiology, and clinical outcome. METHODS: One hundred and thirty-six patients (101 with AIS, and 35 with TIA) were included. Acute-phase serum neurofilament light chain (sNfL) was analyzed with a novel ultrasensitive single molecule array (Simoa). Cerebral infarction volume was measured from brain computed tomography in the subacute phase (>2 days). Stroke aetiology was defined by trial of ORG 10172 in acute stroke treatment classification, severity by National Institute of Health stroke scale (NIHSS) and the degree of disability by the Modified Rankin Scale (mRS) after 90 days. RESULTS: sNfL was markedly higher in patients with AIS (89.5 pg/mL [IQR: 44.7-195.3]) than with TIA (25.2 pg/mL [IQR: 14.6-48.0]), P= <.001), also after adjusting for age, NIHSS, and stroke volume (P= .003). In receiver operating characteristic analysis, sNfL concentration greater than or equal to 49 pg/mL proved to be the best cut-off value to differentiate between patients with stroke and those with TIA (sensitivity of 73% and specificity of 80%). sNfL concentration significantly correlated with cerebral infarction volume (râ¯=â¯.413, P= <.001), this association remained significant after adjusting for established predictors (P= .019). Patients with AIS due to cardioembolism or large artery atherosclerosis had the highest sNfL concentrations. NIHSS on admission (râ¯=â¯.343, Pâ¯=â¯<.001) and mRS scores after 3 months (râ¯=â¯.306, Pâ¯=â¯.004) correlated with sNfL concentration, however functional outcome 3 months after stroke was not associated with sNfL after adjusting for potential confounders. CONCLUSIONS: Cases with stroke were distinguishable from those with TIA following the determination of sNfL in the blood samples. The presence and amount of axonal damage estimated by sNfL correlated with the final cerebral infarction volume but was not predictive of degree of disability.
Subject(s)
Brain Infarction/blood , Neurofilament Proteins/blood , Biomarkers/blood , Brain/diagnostic imaging , Brain Infarction/diagnostic imaging , Brain Infarction/therapy , Disability Evaluation , Female , Finland , Humans , Magnetic Resonance Imaging , Male , Predictive Value of Tests , Prognosis , Prospective Studies , Severity of Illness Index , Time Factors , Tomography, X-Ray Computed , Up-RegulationABSTRACT
We investigated the association of Alzheimer's disease (AD)-related rare variants APP A673T and ABCA7 rs200538373-C with the levels of ß-amyloid (Aß) 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 Aß40 and Aß42 in plasma as compared to the controls and the carriers of ABCA7 rs200538373-C. This is the first report to show decreased Aß levels in plasma in APP A673T carriers and thus provides evidence that lower Aß levels throughout life may be protective against AD. Ann Neurol 2017;82:128-132.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , ATP-Binding Cassette Transporters/genetics , Alzheimer Disease/blood , Amyloid beta-Peptides/blood , Case-Control Studies , Heterozygote , Humans , Male , Middle Aged , Mutation , Peptide Fragments/blood , Protective FactorsABSTRACT
INTRODUCTION: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid ß (Aß) pathology. METHODS: We included 3451 Aß+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. RESULTS: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aß+ cognitively normal and Aß+ mild cognitive impairment (P < .05) but not in Aß+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education. DISCUSSION: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aß pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Apolipoprotein E4/genetics , Cognitive Dysfunction/metabolism , Aged , Alleles , Biomarkers/cerebrospinal fluid , Europe , Female , Humans , Male , Positron-Emission Tomography , PrevalenceABSTRACT
The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-ß42; (ii) centrally measured cerebrospinal fluid amyloid-ß42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-ß42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-ß production, by using the ratio of amyloid-ß42 to amyloid-ß40 Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer's and Parkinson's Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer's disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-ß42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-ß42 and amyloid-ß40) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer's disease, while more variable results were observed for cognitively normal and non-Alzheimer's disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference measurement procedure findings was further improved when using amyloid-ß42/40 Agreement between Pittsburgh compound B visual ratings and Centiloids was near complete. Despite improved agreement between Pittsburgh compound B and centrally analysed cerebrospinal fluid, a minority of subjects showed discordant findings. While future studies are needed, our results suggest that amyloid biomarker results may not be interchangeable in some individuals.
Subject(s)
Amyloid beta-Peptides/metabolism , Aniline Compounds , Biomarkers/metabolism , Cognitive Dysfunction/metabolism , Dementia/metabolism , Thiazoles , Aged , Amyloid beta-Peptides/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Cognitive Dysfunction/cerebrospinal fluid , Cognitive Dysfunction/diagnostic imaging , Dementia/cerebrospinal fluid , Dementia/diagnostic imaging , Enzyme-Linked Immunosorbent Assay , Europe , Female , Humans , Male , Mass Spectrometry , Middle Aged , Peptide Fragments/cerebrospinal fluid , Positron-Emission TomographyABSTRACT
This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-ß1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimer's disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost-effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnosis , Biomarkers/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Databases, Bibliographic/statistics & numerical data , Humans , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluidABSTRACT
This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-ß1-42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Cognitive Dysfunction/diagnosis , Amyloid beta-Peptides/cerebrospinal fluid , Humans , MEDLINE/statistics & numerical data , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluidABSTRACT
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.
Subject(s)
Alzheimer Disease/epidemiology , Cognitive Dysfunction/epidemiology , Adult , Aged , Aged, 80 and over , Alzheimer Disease/complications , Biomarkers/metabolism , Cognitive Dysfunction/etiology , Disease Progression , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Prevalence , Prognosis , Survival AnalysisABSTRACT
OBJECTIVES: Optimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer's disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH. METHODS: In this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients' memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure. RESULTS: Our analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC = 0.58). CONCLUSIONS: Prediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.
Subject(s)
Cerebrospinal Fluid Shunts/adverse effects , Hydrocephalus, Normal Pressure/pathology , Neurosurgical Procedures/adverse effects , Aged , Biomarkers/metabolism , Cerebrospinal Fluid Shunts/methods , Clinical Decision-Making , Female , Humans , Hydrocephalus, Normal Pressure/diagnostic imaging , Hydrocephalus, Normal Pressure/surgery , Intracranial Pressure , Magnetic Resonance Imaging , Male , Memory , Middle Aged , Neurosurgical Procedures/methods , Patient Selection , Retrospective StudiesABSTRACT
BACKGROUND: The C9ORF72 expansion is one of the most common causes of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The C9ORF72 expansion is associated with TDP-43 and p62 neuropathology, and amyloid plaques and neurofibrillary tangles are not common in patients with the C9ORF72 expansion. Therefore, we hypothesized that cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease [AD; Aß1-42, total tau (T-tau) and phospho-tau] are normal in these patients. METHODS: The CSF Aß1-42, T-tau and phospho-tau levels were measured in 40 Finnish patients with the C9ORF72 expansion (29 FTLD, 10 ALS and 1 FTLD-ALS) using ELISA. RESULTS: A decreased Aß1-42 level was found in 25% of cases, while there were only single cases with changes in the t-Tau or phospho-tau level. The patients with abnormal biomarkers fulfilled the clinical criteria of the behavioral variant frontotemporal dementia and expressed no clinical signs of AD. CONCLUSIONS: In clinical diagnostics, a decreased CSF Aß1-42 level does not exclude the C9ORF72 expansion associated with FTLD.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyotrophic Lateral Sclerosis/cerebrospinal fluid , DNA Repeat Expansion , Frontotemporal Lobar Degeneration/cerebrospinal fluid , Proteins/genetics , Age of Onset , Aged , Alzheimer Disease/genetics , Amyotrophic Lateral Sclerosis/genetics , Biomarkers/cerebrospinal fluid , Brain/pathology , C9orf72 Protein , Cohort Studies , DNA-Binding Proteins/genetics , Female , Frontotemporal Lobar Degeneration/genetics , Humans , Male , Middle Aged , tau Proteins/geneticsABSTRACT
IMPORTANCE: Cerebral amyloid-ß aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.