The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms ...alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.
This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 range = 44-96 years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 range = 44-94 years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.
In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.
Within-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined.
We included 467 subjects from the BIOMARKAPD study with at least two serial CSF ...samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years.
CSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period.
All four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.
•In this large longitudinal multicenter cerebrospinal fluid (CSF) study each year of increase at baseline age was significantly associated with 2% higher mean CSF t-tau and p-tau levels in controls. Within the Alzheimer's disease group, each year of increase at baseline age was significantly associated with 1% lower mean CSF t-tau levels, and p-tau levels did not change with age.•Each year of increase at baseline age was significantly associated with 2% higher mean CSF neurofilament light (NfL) and YKL-40 levels in controls without differences among groups.•Longitudinally, after adjusting for baseline age, only NfL and YKL-40 levels significantly increased during the study period in all groups.•The pattern of change of CSF tau, NfL, and YKL-40 is different in Alzheimer's disease.
Abstract Introduction Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory ...clinic populations. Methods We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain. Results A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect. Discussions The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimer's disease, levels of increased CSF tau protein and ...decreased levels of β‐amyloid 1–42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α‐synuclein (α‐syn) represent a pathological hallmark of Parkinson's disease (PD). In most – but not all – studies published to date total CSF α‐syn concentrations have been found to be decreased in disorders related to α‐syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice.
To investigate potential biological (i.e., non‐technical) confounders of reported CSF levels for α‐syn, Aβ42, and tau in PD and related disorders, we carried out a methodical review of known factors that underlie signal variability and speculate on those that have not yet been tested. We discuss several biological factors, such as neuropathology, demographics, clinical phenotype, progression and duration of disease, concomitant illnesses and, last but not least, pharmacotherapy, which in isolation or combination can substantially alter values for CSF proteins of interest. Enhanced implementation of standardized clinical protocols, streamlined operating procedures, and further progress in the development of validated assays for CSF proteins have the potential to (i) inform us as to the pathogenesis of disease, (ii) support the laboratory‐based diagnosis for symptomatic subjects in the future, and (iii) facilitate breakthrough therapies to alter the course of neurodegenerative disorders, such as PD and Alzheimer's disease.
Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α‐synuclein (α‐Syn), amyloid‐β 1‐42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested.
This article is part of a special issue on Parkinson disease.
Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. To investigate potential biological confounders of reported CSF levels for α‐synuclein (α‐Syn), amyloid‐β 1‐42(Aβ42) and tau protein in Parkinson's disease and related disorders, we reviewed the current literature for known factors that underlie signal variability and speculate on those that have not yet been tested.
This article is part of a special issue on Parkinson disease.
Diagnosis of Parkinson’s disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more ...precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer’s disease (AD) biomarkers, low CSF Aβ42 levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.
Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be ...reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness.
•In Parkinson's disease patients, resting-state delta and alpha electroencephalographic source activities were abnormal.•Those abnormalities were differently related to cognitive, motor, and perceptual deficits.•Those source activities may reflect the effect of Parkinson's disease on cognitive, motor, and perceptual systems.
Purpose
To compare the incremental diagnostic value of amyloid-PET and CSF (Aβ42, tau, and phospho-tau) in AD diagnosis in patients with mild cognitive impairment (MCI) or mild dementia, in order to ...improve the definition of diagnostic algorithm.
Methods
Two independent dementia experts provided etiological diagnosis and relative diagnostic confidence in 71 patients on 3 rounds, based on (1) clinical, neuropsychological, and structural MRI information alone; (2) adding one biomarker (CSF amyloid and tau levels or amyloid-PET with a balanced randomized design); and (3) adding the other biomarker.
Results
Among patients with a pre-biomarker diagnosis of AD, negative PET induced significantly more diagnostic changes than amyloid-negative CSF at both rounds 2 (CSF 67%, PET 100%,
P
= 0.028) and 3 (CSF 0%; PET 78%,
P
< 0.001); PET induced a diagnostic confidence increase significantly higher than CSF on both rounds 2 and 3.
Conclusions
Amyloid-PET should be prioritized over CSF biomarkers in the diagnostic workup of patients investigated for suspected AD, as it provides greater changes in diagnosis and diagnostic confidence.
Trial registration
EudraCT no.: 2014-005389-31
Alzheimer's disease (AD) pathology begins decades before the onset of clinical symptoms. It is recognized as a clinicobiological entity, being detectable in vivo independently of the clinical stage ...by means of pathophysiological biomarkers. Accordingly, neuropathological studies that were carried out on healthy elderly subjects, with or without subjective experience of cognitive decline, reported evidence of AD pathology in a high proportion of cases. At present, mild cognitive impairment (MCI) represents the only clinically diagnosed pre-dementia stage. Several attempts have been carried out to detect AD as early as possible, when subtle cognitive alterations, still not fulfilling MCI criteria, appear. Importantly, pre-MCI individuals showing the positivity of pathophysiological AD biomarkers show a risk of progression similar to MCI patients. In view of successful treatment with disease modifying agents, in a clinical setting, a timely diagnosis is mandatory. In clinical routine, biomarkers assessment should be taken into consideration whenever a subject with subtle cognitive deficits (pre-MCI), who is aware of his/her decline, requests to know the cause of such disturbances. In this review, we report the available neuropsychological and biomarkers data that characterize the pre-MCI patients, thus proposing pre-MCI as the first clinical manifestation of AD.
Despite the fact that epilepsy has been associated with cognitive decline, neuropsychological, neurobiological, and neurophysiological features in patients with late-onset epilepsy of unknown ...etiology (LOEU) are still unknown. This cross-sectional study aims to investigate the neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), and resting-state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU-MCI) and with normal cognition (LOEU-CN), compared to non-epileptic MCI (NE-MCI) and cognitively normal (CN) controls.
Consecutive patients in two clinical Units diagnosed with LOEU-CN (19), LOEU-MCI (27), and NE-MCI (21) were enrolled, and compared to age and sex-matched cognitively normal subjects CN (11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho-tau and total tau, classified through A/T/(N) system). Recordings of resting-state eyes-closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (<4 Hz) to gamma (>30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed.
Most LOEU patients had an MCI status at seizure onset (59%). Patients with LOEU-MCI performed significantly worse on measures of global cognition, visuo-spatial abilities, and executive functions compared to NE-MCI patients (
< 0.05). Regarding MCI subtypes, multiple-domain MCI was 3-fold more frequent in LOEU-MCI than in NE-MCI patients (OR 3.14, 95%CI 0.93-10.58,
= 0.06). CSF Aβ42 levels were lower in the LOEU-MCI compared with the LOEU-CN group. Finally, parietal and occipital sources of alpha (8-12 Hz) rhythms were less active in the LOEU-MCI than in the NE-MCI and CN groups, while the opposite was true for frontal and temporal cortical delta sources.
MCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU-MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross-validate our findings and test the predictive value of CSF and EEG variables.
The discovery of biomarkers for the onset of Alzheimer's disease (AD) is essential for disease modification strategies. To date, AD biomarker studies have focused on brain imaging and cerebrospinal ...fluid (CSF) changes in amyloid- β (Aβ) peptide and tau proteins. While reliable to an extent, this panel could be improved by the inclusion of novel biomarkers that optimize sensitivity and specificity. In this study, we determined whether CSF levels of the nerve growth factor (NGF) precursor protein, proNGF, increased during the progression of AD, mirroring its up regulation in postmortem brain samples of people who died with a clinical diagnosis of mild cognitive impairment (MCI) or AD. Immunoblot analysis was performed on ventricular CSF harvested from participants in the Rush Religious Orders Study with an antemortem clinical diagnosis of no cognitive impairment (NCI), amnestic MCI (aMCI, a putative prodromal AD stage), or mild/moderate AD. ProNGF levels were increased 55% in aMCI and 70% in AD compared to NCI. Increasing CSF proNGF levels correlated with impairment on cognitive test scores. In a complementary study, we found that proNGF was significantly increased by 30% in lumbar CSF samples derived from patients with a clinical dementia rating (CDR) of 0.5 or 1 compared to those with a CDR = 0. Notably, proNGF/Aβ1-42 levels were 50% higher in CDR 0.5 and CDR 1 compared to CDR 0 controls. By contrast, ELISA measurements of CSF brain-derived neurotrophic factor (BDNF) did not distinguish aMCI from NCI. Taken together, these results suggest that proNGF protein levels may augment the diagnostic accuracy of currently used CSF biomarker panels.
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