Alzheimer's disease (AD) pathology begins several years before the clinical onset. The long preclinical phase is composed of three stages according to the 2011National Institute on Aging and ...Alzheimer's Association (NIA-AA) criteria, followed by mild cognitive impairment (MCI), a featured clinical entity defined as "due to AD", or "prodromal AD", when pathophysiological biomarkers (i.e., cerebrospinal fluid or positron emission tomography with amyloid tracer) are positive. In the clinical setting, there is a clear need to detect the earliest symptoms not yet fulfilling MCI criteria, in order to proceed to biomarker assessment for diagnostic definition, thus offering treatment with disease-modifying drugs to patients as early as possible. According to the available evidence, we thus estimated the prevalence and risk of progression at each preclinical AD stage, with special interest in Stage 3.
Cross-sectional and longitudinal studies published from April 2008 to May 2018 were obtained through MEDLINE-PubMed, screened, and systematically reviewed by four independent reviewers. Data from included studies were meta-analyzed using random-effects models. Heterogeneity was assessed by I
statistics.
Estimated overall prevalence of preclinical AD was 22% (95% CI = 18-26%). Rate of biomarker positivity overlapped in cognitively normal individuals and people with subjective cognitive decline. The risk of progression increases across preclinical AD stages, with individuals classified as NIA-AA Stage 3 showing the highest risk (73%, 95% CI = 40-92%) compared to those in Stage 2 (38%, 95% CI = 21-59%) and Stage 1 (20%, 95% CI = 10-34%).
Available data consistently show that risk of progression increases across the preclinical AD stages, where Stage 3 shows a risk of progression comparable to MCI due to AD. Accordingly, an effort should be made to also operationalize the diagnostic work-up in subjects with subtle cognitive deficits not yet fulfilling MCI criteria. The possibility to define, in the clinical routine, a patient as "pre-MCI due to AD" could offer these subjects the opportunity to use disease-modifying drugs at best.
CSF-to-plasma transition will open new avenues for molecular phenotyping of Alzheimer's disease (AD). Here we evaluated a panel of AD biomarkers in matched CSF and plasma samples across the AD ...continuum, from preclinical AD to dementia. The aims were to: 1) compare diagnostic performance of the two biofluids, 2) evaluate trajectories of the biomarkers along AD progression. We analyzed CSF and plasma Aβ42/40, p-tau181, p-tau231, t-tau, NF-L, GFAP, UCHL-1 and CSF SNAP-25 in a cohort (n = 173) of preclinical AD, MCI-AD, AD dementia, frontotemporal dementia patients, and controls. We found a significant correlation between CSF and plasma levels of Aβ42/40, p-tau181, p-tau231, NF-L, and GFAP, while no CSF-plasma correlation was observed for t-tau and UCHL-1. Next to the core CSF biomarkers (Aβ42/40, p-tau181, t-tau), those providing the best discrimination between controls and preclinical AD were CSF p-tau231 and SNAP-25 and plasma Aβ42/40, p-tau231, and GFAP. Among plasma biomarkers, we found Aβ42/Aβ40, GFAP, and p-tau231 to show the largest rate of change at the CSF biomarker-defined cut-offs for amyloidosis and tauopathy. Finally, we identified GFAP, NF-L, and p-tau181 as the biomarkers most significantly associated with disease progression in both CSF and plasma. We suggest that a well-standardized and validated panel of selected plasma markers can facilitate early AD diagnosis, even at the asymptomatic disease stage. We propose that both CSF and plasma measurement of NF-L, p-tau181, and GFAP may play a significant role in disease staging and monitoring.
Neuropsychological evidence of memory impairment represents the main feature of the clinical onset of typical Alzheimer's disease (AD). Rey's Auditory Verbal Learning Test (RAVLT) and Logical Memory ...(LM) are two tests both assessing verbal episodic memory, widely used in clinical practice. Our aim was to investigate the added value of their combined use in predicting cerebrospinal fluid (CSF) AD biomarkers positivity in a retrospective consecutive series of patients with mild cognitive impairment (MCI). 169 MCI patients were included. For all of them neuropsychological assessment and CSF analysis were available. According to CSF A/T/(N) profile, 109 were defined as MCI due to AD (A+T+), and 60 were non-AD MCI (A-T-). Logistic regression model and receiver-operating characteristic (ROC) curves were analyzed to evaluate the discriminatory power of single and combined sub-measures between AD and non-AD patients. The combination of RAVLT-del with LM could acceptably discriminate the two groups (AUC: 0.69, CI 95% 0.617-0.761, sens: 0.75, spec. 0.58, p < 0.001), while the single tests did not show sufficient discriminative performance. Our study shows that the combination of RAVLT delayed recall with LM better predicts the biological AD diagnosis (A+T+), showing a good discriminative power between MCI-AD from non-AD MCI. Since RAVLT and LM assess different components of verbal episodic memory, they should be considered as complementary, rather than interchangeable, tests.
Accurate and reproducible automated segmentation of human hippocampal subfields is of interest to study their roles in cognitive functions and disease processes. Multispectral structural MRI methods ...have been proposed to improve automated hippocampal subfield segmentation accuracy, but the reproducibility in a multicentric setting is, to date, not well characterized. Here, we assessed test–retest reproducibility of FreeSurfer 6.0 hippocampal subfield segmentations using multispectral MRI analysis pipelines (22 healthy subjects scanned twice, a week apart, at four 3T MRI sites). The harmonized MRI protocol included two 3D-T1, a 3D-FLAIR, and a high-resolution 2D-T2. After within-session T1 averaging, subfield volumes were segmented using three pipelines with different multispectral data: two longitudinal (“long_T1s” and “long_T1s_FLAIR”) and one cross-sectional (“long_T1s_FLAIR_crossT2”). Volume reproducibility was quantified in magnitude (reproducibility error—RE) and space (DICE coefficient). RE was lower in all hippocampal subfields, except for hippocampal fissure, using the longitudinal pipelines compared to long_T1s_FLAIR_crossT2 (average RE reduction of 0.4–3.6%). Similarly, the longitudinal pipelines showed a higher spatial reproducibility (1.1–7.8% of DICE improvement) in all hippocampal structures compared to long_T1s_FLAIR_crossT2. Moreover, long_T1s_FLAIR provided a small but significant RE improvement in comparison to long_T1s (
p
= 0.015), whereas no significant DICE differences were found. In addition, structures with volumes larger than 200 mm
3
had better RE (1–2%) and DICE (0.7–0.95) than smaller structures. In summary, our study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and 3D-FLAIR. Adapting a longitudinal pipeline to include high-resolution 2D-T2 may lead to further improvements.
Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders ...including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer's disease, fronto-temporal dementia, Parkinson's disease, Huntington's disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.
Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do ...play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.
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.
Alzheimer's disease (AD) cerebrospinal fluid (CSF) core biomarkers (Aβ42/40 ratio, p-tau, and t-tau) provide high diagnostic accuracy, even at the earliest stage of disease. However, these markers do ...not fully reflect the complex AD pathophysiology. Recent large scale CSF proteomic studies revealed several new AD candidate biomarkers related to metabolic pathways. In this study we measured the CSF levels of four metabolism-related proteins not directly linked to amyloid- and tau-pathways (i.e., pyruvate kinase, PKM; aldolase, ALDO; ubiquitin C-terminal hydrolase L1, UCHL1, and fatty acid-binding protein 3, FABP3) across the AD continuum. We aimed at validating the potential value of these proteins as new CSF biomarkers for AD and their possible involvement in AD pathogenesis, with specific interest on the preclinical phase of the disease.
CSF PKM and ALDO activities were measured with specific enzyme assays while UCHL1 and FABP3 levels were measured with immunoassays in a cohort of patients composed as follows: preclinical AD (pre-AD, n = 19, cognitively unimpaired), mild cognitive impairment due to AD (MCI-AD, n = 50), dementia due to AD (ADdem, n = 45), and patients with frontotemporal dementia (FTD, n = 37). Individuals with MCI not due to AD (MCI, n = 30) and subjective cognitive decline (SCD, n = 52) with negative CSF AD-profile, were enrolled as control groups.
CSF UCHL1 and FABP3 levels, and PKM activity were significantly increased in AD patients, already at the pre-clinical stage. CSF PKM activity was also increased in FTD patients compared with control groups, being similar between AD and FTD patients. No difference was found in ALDO activity among the groups. UCHL1 showed good performance in discriminating early AD patients (pre-AD and MCI-AD) from controls (AUC ~ 0.83), as assessed by ROC analysis. Similar results were obtained for FABP3. Conversely, PKM provided the best performance when comparing FTD vs. MCI (AUC = 0.80). Combination of PKM, FABP3, and UCHL1 improved the diagnostic accuracy for the detection of patients within the AD continuum when compared with single biomarkers.
Our study confirmed the potential role of UCHL1 and FABP3 as neurodegenerative biomarkers for AD. Furthermore, our results validated the increase of PKM activity in CSF of AD patients, already at the preclinical phase of the disease. Increased PKM activity was observed also in FTD patients, possibly underlining similar alterations in energy metabolism in AD and FTD.
Neuropathological investigations report that in synucleinopathies with dementia, namely Parkinson's disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB), the histopathological ...hallmarks of Alzheimer's Disease (AD), in particular amyloid plaques, are frequently observed. In this study, we investigated the cerebrospinal fluid (CSF) AD biomarkers in different clinical phenotypes of synucleinopathies. CSF Aβ42/Aβ40 ratio, phosphorylated tau and total tau were measured as markers of amyloidosis (A), tauopathy (T) and neurodegeneration (N) respectively, in 98 PD (48 with mild cognitive impairment, PD-MCI; 50 cognitively unimpaired, PD-nMCI), 14 PDD and 15 DLB patients, and 48 neurological controls (CTRL). In our study, CSF AD biomarkers did not significantly differ between CTRL, PD-MCI and PD-nMCI patients. In PD-nMCI and PD-MCI groups, A-/T-/N- profile was the most represented. Prevalence of A+ was similar in PD-nMCI and PD-MCI (10% and 13%, respectively), being higher in PDD (64%) and in DLB (73%). DLB showed the lowest values of Aβ42/Aβ40 ratio. Higher total tau at baseline predicted a worse neuropsychological outcome after one year in PD-MCI. A+/T+, i.e., AD-like CSF profile, was most frequent in the DLB group (40% vs. 29% in PDD).
Epilepsy is classically considered a childhood disease. However, it represents the third most frequent neurological condition in the elderly, following stroke, and dementia. With the progressive ...aging of the general population, the number of patients with Late-Onset Epilepsy (LOE) is constantly growing, with important economic and social consequences, in particular for the more developed countries where the percentage of elderly people is higher. The most common causes of LOE are structural, mainly secondary to cerebrovascular or infectious diseases, brain tumors, trauma, and metabolic or toxic conditions. Moreover, there is a growing body of evidence linking LOE with neurodegenerative diseases, particularly Alzheimer's disease (AD). However, despite a thorough characterization, the causes of LOE remain unknown in a considerable portion of patients, thus termed as Late-Onset Epilepsy of Unknown origin (LOEU). In order to identify the possible causes of the disease, with an important impact in terms of treatment and prognosis, LOE patients should always undergo an exhaustive phenotypic characterization. In this work, we provide a detailed review of the main clinical and instrumental techniques for the adequate characterization of LOE patients in the clinical practice. This work aims to provide an easy and effective tool that supports routine activity of the clinicians facing LOE.
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