Objectives
We have described cerebrospinal fluid (CSF) myeloid microvesicles (MVs) as a marker of microglia activation during neuroinflammation in Alzheimer disease (AD), and characterized their ...ability to produce toxic amyloid β1–42 (Aβ1–42) oligomers from aggregated or soluble substrate. The aim of this study is to investigate the association of CSF myeloid MVs with neuroimaging, clinical, and paraclinical data in AD and mild cognitive impairment (MCI).
Methods
We collected CSF from 106 AD patients, 51 MCI patients, and 29 neurologically healthy controls. We examined CSF myeloid MV content and AD markers. A subgroup of 34 AD and 21 MCI patients underwent structural and diffusion tensor MRI.
Results
Higher levels of myeloid MVs were found in the CSF of AD patients and MCI patients converting within 3 years relative to controls, but also, at a lower level, in MCI patients not converting to AD. CSF myeloid MVs were associated with Tau but not with Aβ1–42 CSF levels. CSF MVs levels correlated with white matter (WM) tract damage in MCI, and with hippocampal atrophy in AD.
Interpretation
Microglial MVs are neurotoxic and myelinotoxic in the presence of Aβ1–42. CSF myeloid MVs, mirroring microglia activation and MV release, are associated with WM damage in MCI and hippocampal atrophy in AD. This suggests that hippocampal microglia activation, in the presence of Aβ1–42 in excess, produces neurotoxic and oligodendrotoxic oligomers that, through WM tract damage, spread disease to neighboring and connected areas, causing local microglia activation and propagation of disease through the same sequence of events. Ann Neurol 2014;76:813–825
Primary progressive aphasia (PPA) is a clinical syndrome due to different neurodegenerative conditions in which an accurate early diagnosis needs to be supported by a reliable diagnostic tool at the ...individual level. In this study, we investigated in PPA the FDG-PET brain metabolic patterns at the single-subject level, in order to assess the case-to-case variability and its relationship with clinical-neuropsychological findings.
55 patients (i.e., 11 semantic variant/sv-PPA, 19 non fluent variant/nfv-PPA, 17 logopenic variant/lv-PPA, 3 slowly progressive anarthria/SPA, and 5 mixed PPA/m-PPA) were included. Clinical-neuropsychological information and FDG-PET data were acquired at baseline. A follow-up of 27.4±12.55 months evaluated the clinical progression. Brain metabolism was analyzed using an optimized and validated voxel-based SPM method at the single-subject level.
FDG-PET voxel-wise metabolic assessment revealed specific metabolic signatures characterizing each PPA variant at the individual level, reflecting the underlying neurodegeneration in language networks. Notably, additional dysfunctional patterns predicted clinical progression to specific dementia conditions. In the case of nfv-PPA, a metabolic pattern characterized by involvement of parietal, subcortical and brainstem structures predicted progression to a corticobasal degeneration syndrome or to progressive supranuclear palsy. lv-PPA and sv-PPA cases who progressed to Alzheimer's disease and frontotemporal dementia at the follow-up presented with extended bilateral patterns at baseline.
Our results indicate that FDG-PET voxel-wise imaging is a valid biomarker for the early differential diagnosis of PPAs and for the prediction of progression to specific dementia condition. This study supports the use of FDG-PET imaging quantitative assessment in clinical settings for a better characterization of PPA individuals and prognostic definition of possible endo-phenotypes.
Cognitive reserve may delay disease onset and mitigate symptoms presentation in neurodegenerative dementias. Although high occupation levels can be associated with higher cognitive reserve in the ...behavioural variant of frontotemporal dementia (bvFTD), it was never addressed how specific occupation profiles involving social interaction, executive and attention abilities can modulate neural reserve in bvFTD.
We retrospectively included thirty-seven bvFTD patients with clinical-neuropsychological and FDG-PET brain metabolic data. We considered occupation levels according to 1) a 5-point scale and 2) the specific cognitive dimensions from the O*Net network database. We used the Principal Component Analysis (PCA) with the O*Net variables most representative of “worker” and “occupation” socio-cognitive skills to merge the best components describing such occupation profiles. We then performed regression analyses with brain metabolism using either 5-level occupation scale or the PCA specific profiles as independent variables, controlling for education and disease severity.
According to the brain reserve hypothesis, higher occupation levels were associated with a more severe hypometabolism in the dorsolateral prefrontal cortex. In addition, among the identified PCA profiles, social skills were associated with severe hypometabolism in medial and dorsolateral prefrontal regions, and cognitive control in the left fronto-insular cortex.
This study contributes to define the role of specific occupation profiles as proxy of cognitive reserve in bvFTD, providing the first evidence for social interaction and cognitive control skills in life-occupation activities as influencing factors of neural reserve against neurodegeneration in bvFTD. Jobs placing high demand on such abilities seem to act as protective factors in bvFTD.
Gender and age effect on brain morphology have been extensively investigated. However, the great variety in methods applied to morphology partly explain the conflicting results of linear patterns of ...tissue changes and lateral asymmetry in men and women. The aim of the present study was to assess the effect of age, gender and laterality on the volumes of gray matter (GM) and white matter (WM) in a large group of healthy adults by means of voxel-based morphometry. This technique, based on observer-independent algorithms, automatically segments the 3 types of tissue and computes the amount of tissue in each single voxel.
Subjects were 229 healthy subjects of 40 years of age or older, who underwent magnetic resonance (MR) for reasons other than cognitive impairment. MR images were reoriented following the AC-PC line and, after removing the voxels below the cerebellum, were processed by Statistical Parametric Mapping (SPM99). GM and WM volumes were normalized for intracranial volume.
Women had more fractional GM and WM volumes than men. Age was negatively correlated with both fractional GM and WM, and a gender x age interaction effect was found for WM, men having greater WM loss with advancing age. Pairwise differences between left and right GM were negative (greater GM in right hemisphere) in men, and positive (greater GM in left hemisphere) in women (-0.56+/-4.2 vs 0.99+/-4.8; p=0.019).
These results support side-specific accelerated WM loss in men, and may help our better understanding of changes in regional brain structures associated with pathological aging.
In this work, Vapor Annealing Sintering (VAS) process was introduced for low-cost pressureless producing dense Zinc Oxide (ZnO) thin films deposited from nanoparticles at near-room temperature ...(50 °C). Spontaneous densification evolution from nanoparticulate to a dense film via a dissolution-diffusion-reprecipitation mechanism was observed exposing ZnO layers to the vapor of an acetic acid aqueous solution at isothermal condition. The influence of the annealing on the optical properties of the treated films was investigated in order to study the structural changes. The proposed method can allow new opportunities for simple and low-cost ceramics thin film manufacturing also involving pressure and temperature-sensitive materials.
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Background
The amnestic presentation of mild cognitive impairment (aMCI) represents the most common prodromal stage of Alzheimer's disease (AD) dementia. There is, however, some evidence of aMCI with ...typical amnestic syndrome but showing long‐term clinical stability. The ability to predict stability or progression to dementia in the aMCI condition is important, particularly for the selection of candidates in clinical trials. We aimed to establish the role of in vivo biomarkers, as assessed by cerebrospinal fluid (CSF) measures and 18Ffluorodeoxyglucose (FDG)‐positron emission tomography (PET) imaging, in predicting prognosis in a large aMCI cohort.
Methods
We conducted a retrospective study, including 142 aMCI subjects who had a long follow‐up (4–19 years), baseline CSF data and 18FFDG‐PET scans individually assessed by validated voxel‐based procedures, classifying subjects into either limbic‐predominant or AD‐like hypometabolism patterns.
Results
The two aMCI cohorts were clinically comparable at baseline. At follow‐up, the aMCI group with a limbic‐predominant 18FFDG‐PET pattern showed clinical stability over a very long follow‐up (8.20 ± 3.30 years), no decline in Mini‐Mental State Examination score, and only 7% conversion to dementia. Conversely, the aMCI group with an AD‐like 18FFDG‐PET pattern had a high rate of dementia progression (86%) over a shorter follow‐up (6.47 ± 2.07 years). Individual 18FFDG‐PET hypometabolism patterns predicted stability or conversion with high accuracy (area under the curve = 0.89), sensitivity (0.90) and specificity (0.89). In the limbic‐predominant aMCI cohort, CSF biomarkers showed large variability and no prognostic value.
Conclusions
In a large series of clinically comparable subjects with aMCI at baseline, the specific 18FFDG‐PET limbic‐predominant hypometabolism pattern was associated with clinical stability, making progression to AD very unlikely. The identification of a biomarker‐based benign course in aMCI subjects has important implications for prognosis and in planning clinical trials.
This biomarker‐based study assessed the clinical outcome with a long follow‐up in a large population of amnestic mild cognitive impairment with baseline CSF and 18FFDG‐PET evaluations. The single‐subject 18FFDG‐PET analysis classified subjects either in the limbic‐predominant or in the Alzheimer’s disease hypometabolism patterns. At follow‐up, the group with limbic‐predominant hypometabolism showed clinical stability and only 7% conversion to dementia, while the group with Alzheimer’s disease hypometabolism pattern presented with a high rate of dementia progression (86%). CSF measures did not predict stability in the limbic‐predominant group. Thus the specific 18FFDG‐PET limbic‐predominant hypometabolism pattern predicts clinical stability in aMCI subjects, representing a biomarker of benign course with important implications for prognosis and planning clinical trials.
Objective
The hexanucleotide repeat expansion in C9orf72 is an associated genetic cause in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the “ALS/FTD” spectrum prevails ...clinical heterogeneity and an in vivo knowledge of the underling brain dysfunction in patients carrying C9orf72 mutation remain limited and only described at group level. The study aimed to assess the brain metabolic alterations characterizing patients with C9orf72 mutation using FDG-PET in single individuals.
Methods
We applied a validated statistical parametric mapping (SPM) voxel-based procedure for FDG-PET data to obtain maps of brain relative hypometabolism and hypermetabolism at single-subject level in six FTD/ALS patients carrying the C9orf72 mutation.
Results
Clinical diagnoses classified the patients as right semantic variant of frontotemporal dementia (one case, C9svFTD), behavioral variant of frontotemporal dementia (two cases, C9bvFTD), and bulbar amyotrophic lateral sclerosis (three cases, C9bALS). The FDG-PET SPM revealed a prevalent frontal hypometabolism in C9bvFTD cases, and right temporal polar and lateral involvement in C9svFTD, consistent with the clinical diagnosis. There was a quite comparable occipital and cerebellar hypermetabolism in these cases. The three C9bALS patients showed variable patterns of hypo- and hypermetabolism.
Conclusions
The present work is the first in vivo FDG-PET study showing the heterogeneous patterns of brain regional hypo- and hypermetabolism in single patients sharing C9orf72 mutation. Brain hypometabolism was consistent with the clinical phenotypes, supporting the diagnostic importance of neuroimaging functional biomarkers to capture at single-subject level specific brain dysfunction.
To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates.
The same standardized picture ...naming test was administered to a consecutive sample of patients (n = 148) who had been studied with
F FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network.
Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors.
Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.
Background and purpose
This study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters ...in a large cohort of patients with amyotrophic lateral sclerosis (ALS).
Methods
One hundred forty‐three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45 healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array.
Results
NfL correlated with disease progression rate (p < 0.001) and with the measures of upper motor neuron burden (p < 0.001). NfL was higher in the ALS patients with classic and pyramidal phenotype. GFAP was raised in ALS with cognitive–behavioral impairment compared with ALS with normal cognition. NfL displayed the best diagnostic performance in discriminating ALS from HC (area under the curve AUC = 0.990), DEG (AUC = 0.946), and ALSmd (AUC = 0.850). UCHL1 performed well in distinguishing ALS from HC (AUC = 0.761), whereas it was not helpful in differentiating ALS from DEG and ALSmd. In multivariate analysis, NfL (p < 0.001) and UCHL1 (p = 0.038) were independent prognostic factors. Survival analysis combining NfL and UCHL1 effectively stratified patients with lower NfL levels (p < 0.001).
Conclusions
NfL is a useful biomarker for the diagnosis of ALS and the strongest predictor of survival. UCHL1 is an independent prognostic factor helpful in stratifying survival in patients with low NfL levels, likely to have slowly progressive disease. GFAP reflects extramotor involvement, namely cognitive impairment or frontotemporal dementia.
Neurofilament light chain (NfL) is a useful biomarker for the diagnosis of amyotrophic lateral sclerosis and the strongest predictor of survival. Ubiquitin carboxyl‐terminal hydrolase isozyme L1 is an independent prognostic factor and may be helpful in further stratifying the prognosis of patients showing low NfL concentrations. Glial fibrillary acidic protein reflects extramotor involvement, namely, cognitive impairment or frontotemporal dementia.
Lifelong bilingualism is associated with delayed dementia onset, suggesting a protective effect on the brain. Here, we aim to study the effects of lifelong bilingualism as a dichotomous and ...continuous phenomenon, on brain metabolism and connectivity in individuals with Alzheimer's dementia. Ninety‐eight patients with Alzheimer's dementia (56 monolinguals; 42 bilinguals) from three centers entered the study. All underwent an 18F‐fluorodeoxyglucose positron emission tomography (PET) imaging session. A language background questionnaire measured the level of language use for conversation and reading. Severity of brain hypometabolism and strength of connectivity of the major neurocognitive networks was compared across monolingual and bilingual individuals, and tested against the frequency of second language life‐long usage. Age, years of education, and MMSE score were included in all above mentioned analyses as nuisance covariates. Cerebral hypometabolism was more severe in bilingual compared to monolingual patients; severity of hypometabolism positively correlated with the degree of second language use. The metabolic connectivity analyses showed increased connectivity in the executive, language, and anterior default mode networks in bilingual compared to monolingual patients. The change in neuronal connectivity was stronger in subjects with higher second language use. All effects were most pronounced in the left cerebral hemisphere. The neuroprotective effects of lifelong bilingualism act both against neurodegenerative processes and through the modulation of brain networks connectivity. These findings highlight the relevance of lifelong bilingualism in brain reserve and compensation, supporting bilingual education and social interventions aimed at usage, and maintenance of two or more languages, including dialects, especially crucial in the elderly people.
We investigated the neural mechanisms underlying the ability of bilingual senior individuals to better cope with pathology and symptoms of Alzheimer dementia, as compared to matched monolingual individuals with Alzheimer dementia. By using FDG‐PET to measure brain glucose metabolism and connectivity, we found evidence of neural reserve on brain hypometabolism and compensatory effects on brain metabolic connectivity, predominantly in the left hemisphere. In both cases, effects of lifelong bilingualism on the brain were linearly associated with the degree of second language use, that is, the higher the second language use, the higher the neural reserve/compensatory effect on brain metabolism and connectivity, respectively.
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