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1.
Alzheimers Dement ; 20(3): 1515-1526, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38018380

ABSTRACT

INTRODUCTION: Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential. METHODS: We examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored. RESULTS: Gal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3. DISCUSSION: Our findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers.


Subject(s)
Frontotemporal Dementia , Humans , Frontotemporal Dementia/genetics , Frontotemporal Dementia/diagnosis , Galectin 3/genetics , Galectin 3/metabolism , tau Proteins/cerebrospinal fluid , Brain/pathology , Biomarkers/cerebrospinal fluid , C9orf72 Protein/genetics , Mutation/genetics
2.
Alzheimers Dement ; 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39051173

ABSTRACT

INTRODUCTION: Early-onset Alzheimer's disease (EOAD) shows a higher burden of neuropsychiatric symptoms than late-onset Alzheimer's disease (LOAD). We aim to determine the differences in the severity of neuropsychiatric symptoms and locus coeruleus (LC) integrity between EOAD and LOAD accounting for disease stage. METHODS: One hundred four subjects with AD diagnosis and 32 healthy controls were included. Participants underwent magnetic resonance imaging (MRI) to measure LC integrity, measures of noradrenaline levels in cerebrospinal fluid (CSF) and Neuropsychiatric Inventory (NPI). We analyzed LC-noradrenaline measurements and clinical and Alzheimer's disease (AD) biomarker associations. RESULTS: EOAD showed higher NPI scores, lower LC integrity, and similar levels of CSF noradrenaline compared to LOAD. Notably, EOAD exhibited lower LC integrity independently of disease stage. LC integrity negatively correlated with neuropsychiatric symptoms. Noradrenaline levels were increased in AD correlating with AD biomarkers. DISCUSSION: Decreased LC integrity negatively contributes to neuropsychiatric symptoms. The higher LC degeneration in EOAD compared to LOAD could explain the more severe neuropsychiatric symptoms in EOAD. HIGHLIGHTS: LC degeneration is greater in early-onset AD (EOAD) compared to late-onset AD. Tau-derived LC degeneration drives a higher severity of neuropsychiatric symptoms. EOAD harbors a more profound selective vulnerability of the LC system. LC degeneration is associated with an increase of cerebrospinal fluid noradrenaline levels in AD.

3.
Int J Mol Sci ; 25(10)2024 May 16.
Article in English | MEDLINE | ID: mdl-38791483

ABSTRACT

Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer's disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue.


Subject(s)
Alzheimer Disease , DNA Methylation , Epigenesis, Genetic , Humans , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Female , Male , Middle Aged , Brain/metabolism , Brain/pathology , Genome-Wide Association Study , Aged , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Frontotemporal Dementia/metabolism , CpG Islands/genetics , Cell Line , Lymphocytes/metabolism
4.
Hum Brain Mapp ; 44(6): 2234-2244, 2023 04 15.
Article in English | MEDLINE | ID: mdl-36661219

ABSTRACT

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are common causes of dementia with partly overlapping, symptoms and brain signatures. There is a need to establish an accurate diagnosis and to obtain markers for disease tracking. We combined unsupervised and supervised machine learning to discriminate between AD and FTD using brain magnetic resonance imaging (MRI). We included baseline 3T-T1 MRI data from 339 subjects: 99 healthy controls (CTR), 153 AD and 87 FTD patients; and 2-year follow-up data from 114 subjects. We obtained subcortical gray matter volumes and cortical thickness measures using FreeSurfer. We used dimensionality reduction to obtain a single feature that was later used in a support vector machine for classification. Discrimination patterns were obtained with the contribution of each region to the single feature. Our algorithm differentiated CTR versus AD and CTR versus FTD at the cross-sectional level with 83.3% and 82.1% of accuracy. These increased up to 90.0% and 88.0% with longitudinal data. When we studied the classification between AD versus FTD we obtained an accuracy of 63.3% at the cross-sectional level and 75.0% for longitudinal data. The AD versus FTD versus CTR classification has reached an accuracy of 60.7%, and 71.3% for cross-sectional and longitudinal data respectively. Disease discrimination brain maps are in concordance with previous results obtained with classical approaches. By using a single feature, we were capable to classify CTR, AD, and FTD with good accuracy, considering the inherent overlap between diseases. Importantly, the algorithm can be used with cross-sectional and longitudinal data.


Subject(s)
Alzheimer Disease , Frontotemporal Dementia , Humans , Alzheimer Disease/pathology , Frontotemporal Dementia/diagnostic imaging , Frontotemporal Dementia/pathology , Cross-Sectional Studies , Magnetic Resonance Imaging/methods , Machine Learning
5.
Eur J Neurol ; 30(3): 597-605, 2023 03.
Article in English | MEDLINE | ID: mdl-36463489

ABSTRACT

BACKGROUND AND PURPOSE: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. METHOD: Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. RESULTS: Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. CONCLUSIONS: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.


Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Apolipoprotein E4/genetics , Magnetic Resonance Imaging/methods , Age of Onset , Brain/pathology , Atrophy/pathology , Biomarkers
6.
Article in English | MEDLINE | ID: mdl-37898567

ABSTRACT

Core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers have shown incomplete agreement with amyloid-positron emission tomography (PET). Our goal was to analyze the agreement between AD CSF biomarkers and amyloid-PET in a multicenter study. Retrospective multicenter study (5 centers). Participants who underwent both CSF biomarkers and amyloid-PET scan within 18 months were included. Clinical diagnoses were made according to latest diagnostic criteria by the attending clinicians. CSF Amyloid Beta1-42 (Aß1-42, A), phosphorliated tau 181 (pTau181, T) and total tau (tTau, N) biomarkers were considered normal (-) or abnormal ( +) according to cutoffs of each center. Amyloid-PET was visually classified as positive/negative. Agreement between CSF biomarkers and amyloid-PET was analyzed by overall percent agreement (OPA). 236 participants were included (mean age 67.9 years (SD 9.1), MMSE score 24.5 (SD 4.1)). Diagnoses were mild cognitive impairment or dementia due to AD (49%), Lewy body dementia (22%), frontotemporal dementia (10%) and others (19%). Mean time between tests was 5.1 months (SD 4.1). OPA between single CSF biomarkers and amyloid-PET was 74% for Aß1-42, 75% for pTau181, 73% for tTau. The use of biomarker ratios improved OPA: 87% for Aß1-42/Aß1-40 (n = 155), 88% for pTau181/Aß1-42 (n = 94) and 82% for tTau/Aß1-42 (n = 160). A + T + N + cases showed the highest agreement between CSF biomarkers and amyloid-PET (96%), followed by A-T-N- cases (89%). Aß1-42/Aß1-40 was a better marker of cerebral amyloid deposition, as identified by amyloid tracers, than Aß1-42 alone. Combined biomarkers in CSF predicted amyloid-PET result better than single biomarkers.

7.
Neuropathol Appl Neurobiol ; 48(3): e12781, 2022 04.
Article in English | MEDLINE | ID: mdl-34825396

ABSTRACT

We report the neuropathological examination of a patient with Alzheimer's disease (AD) treated for 38 months with low doses of the BACE-1 inhibitor verubecestat. Brain examination showed small plaque size, reduced dystrophic neurites around plaques and reduced synaptic-associated Aß compared with a group of age-matched untreated sporadic AD (SAD) cases. Our findings suggest that BACE-1 inhibition has an impact on synaptic soluble Aß accumulation and neuritic derangement in AD.


Subject(s)
Alzheimer Disease , Thiadiazines , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Brain/pathology , Cyclic S-Oxides/therapeutic use , Humans , Plaque, Amyloid/drug therapy , Plaque, Amyloid/pathology , Thiadiazines/therapeutic use
8.
Acta Neuropathol ; 144(5): 843-859, 2022 11.
Article in English | MEDLINE | ID: mdl-35895141

ABSTRACT

Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer's disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aß plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n = 119) compared to control individuals (n = 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-ß. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-ß positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/-) (A + T + N+/-) groups compared to the A + T-N- group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.


Subject(s)
Alzheimer Disease , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Animals , Biomarkers/cerebrospinal fluid , Brain/pathology , Chitinase-3-Like Protein 1/metabolism , GAP-43 Protein/metabolism , Galectin 3 , Humans , Mice , Neurogranin , Plaque, Amyloid/pathology , beta-Galactosidase/metabolism , tau Proteins/metabolism
9.
Eur J Neurol ; 29(12): 3623-3632, 2022 12.
Article in English | MEDLINE | ID: mdl-36005384

ABSTRACT

BACKGROUND AND PURPOSE: Sex is believed to drive heterogeneity in Alzheimer's disease (AD), although evidence in early-onset AD (EOAD; <65 years) is scarce. METHODS: We included 62 EOAD patients and 44 healthy controls (HCs) with core AD cerebrospinal fluid (CSF) biomarkers, neurofilament light chain levels, neuropsychological assessment, and 3-T magnetic resonance imaging. We measured cortical thickness (CTh) and hippocampal subfield volumes (HpS) using FreeSurfer. Adjusted linear models were used to analyze sex-differences and the relationship between atrophy and cognition. RESULTS: Compared to same-sex HCs, female EOAD subjects showed greater cognitive impairment and broader atrophy burden than male EOAD subjects. In a direct female-EOAD versus male-EOAD comparison, there were slight differences in temporal CTh, with no differences in cognition or HpS. CSF tau levels were higher in female EOAD than in male EOAD subjects. Greater atrophy was associated with worse cognition in female EOAD subjects. CONCLUSIONS: At diagnosis, there are sex differences in the pattern of cognitive impairment, atrophy burden, and CSF tau in EOAD, suggesting there is an influence of sex on pathology spreading and susceptibility to the disease in EOAD.


Subject(s)
Alzheimer Disease , Female , Humans , Male , Alzheimer Disease/pathology , Sex Characteristics , Atrophy , Magnetic Resonance Imaging/methods , Cognition , Biomarkers/cerebrospinal fluid
10.
Hum Brain Mapp ; 41(8): 2004-2013, 2020 06 01.
Article in English | MEDLINE | ID: mdl-31944489

ABSTRACT

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early-onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid-long form of the amyloid-beta protein [Aß42], total-tau protein [T-tau], neurofilament light chain [NfL], neurogranin [Ng], and 14-3-3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSF-biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aß and 14-3-3; whereas NfL and 14-3-3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.


Subject(s)
14-3-3 Proteins/cerebrospinal fluid , Alzheimer Disease , Amyloid beta-Peptides/cerebrospinal fluid , Cerebral Cortex/pathology , Frontotemporal Dementia , Neurofilament Proteins/cerebrospinal fluid , Neurogranin/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Age of Onset , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/pathology , Biomarkers/cerebrospinal fluid , Cerebral Cortex/diagnostic imaging , Diffusion Tensor Imaging , Female , Frontotemporal Dementia/cerebrospinal fluid , Frontotemporal Dementia/diagnostic imaging , Frontotemporal Dementia/pathology , Hippocampus/diagnostic imaging , Hippocampus/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neuroimaging
11.
Alzheimers Dement ; 16(2): 262-272, 2020 02.
Article in English | MEDLINE | ID: mdl-31668967

ABSTRACT

INTRODUCTION: Synaptic damage, axonal neurodegeneration, and neuroinflammation are common features in Alzheimer's disease (AD), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD). METHODS: Unicentric cohort of 353 participants included healthy control (HC) subjects, AD continuum stages, genetic AD and FTD, and FTD and CJD. We measured cerebrospinal fluid neurofilament light (NF-L), neurogranin (Ng), 14-3-3, and YKL-40 proteins. RESULTS: Biomarkers showed differences in HC subjects versus AD, FTD, and CJD. Disease groups differed between them except AD versus FTD for YKL-40. Only NF-L differed between all stages within the AD continuum. AD and FTD symptomatic mutation carriers presented differences with respect to HC subjects. Applying the AT(N) system, 96% subjects were positive for neurodegeneration if 14-3-3 was used, 94% if NF-L was used, 62% if Ng was used, and 53% if YKL-40 was used. DISCUSSION: Biomarkers of synapse and neurodegeneration differentiate HC subjects from neurodegenerative dementias and between AD, FTD, and CJD. NF-L and 14-3-3 performed similar to total tau when AT(N) system was applied.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Axons/pathology , Biomarkers/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Frontotemporal Dementia/cerebrospinal fluid , Inflammation , Aged , Case-Control Studies , Chitinase-3-Like Protein 1/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Mutation , Neurofilament Proteins/cerebrospinal fluid , Neurogranin/cerebrospinal fluid
12.
Dement Geriatr Cogn Disord ; 44(3-4): 213-221, 2017.
Article in English | MEDLINE | ID: mdl-28934750

ABSTRACT

BACKGROUND/AIMS: We identified and studied 13 patients carrying the P301L mutation in the MAPT gene from the same area (Baix Llobregat County) in Barcelona, Spain. METHODS: The demographic and clinical features were reviewed retrospectively. Detailed neuropathological characterization was obtained in 9 subjects. To investigate the origin of the P301L mutation in these families, 20 single nucleotide polymorphisms (SNPs) in the MAPT gene were analyzed. RESULTS: The mean age at disease onset was 51 years and the mean disease duration was 7 years. The most common initial symptoms were behavioral changes (54%), followed by language disturbances (31%) and memory loss (15%). 46% developed parkinsonism. Neuropathology showed an extensive neuronal and glial 4-repeat (4R) tauopathy with "mini-Pick"-like bodies in the dentate gyrus as the characteristic underlying pathology in all cases. In 1 subject, additional 4R globular glial inclusions were observed. All the mutation carriers showed the same haplotype for the SNPs analyzed, suggesting a common ancestor. CONCLUSION: These findings suggest a relative homogeneous clinicopathological phenotype in P301L MAPT mutation carriers in our series. This phenotype might help in the differential diagnosis from other tauopathies and be a morphological hint for genetic testing. The haplotype analysis results suggest a founder effect of the P301L mutation in this area.


Subject(s)
Alleles , DNA Mutational Analysis , Frontotemporal Dementia/genetics , tau Proteins/genetics , Adult , Aged , Female , Founder Effect , Frontal Lobe/pathology , Frontotemporal Dementia/diagnosis , Frontotemporal Dementia/pathology , Genetic Carrier Screening , Haplotypes , Humans , Male , Middle Aged , Phenotype , Polymorphism, Single Nucleotide/genetics , Retrospective Studies , Spain , Temporal Lobe/pathology
13.
Alzheimers Dement ; 13(11): 1251-1260, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28463681

ABSTRACT

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid ß (Aß) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aß040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aß40 levels are not a useful biomarker for CAA in AD.


Subject(s)
Alzheimer Disease/complications , Cerebral Amyloid Angiopathy/etiology , Down Syndrome/complications , Adult , Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoprotein E4/genetics , Cerebral Amyloid Angiopathy/cerebrospinal fluid , Cerebral Amyloid Angiopathy/diagnostic imaging , Cerebral Amyloid Angiopathy/genetics , Down Syndrome/cerebrospinal fluid , Down Syndrome/diagnostic imaging , Down Syndrome/genetics , Female , Gene Frequency , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Peptide Fragments/cerebrospinal fluid
14.
Alzheimers Dement ; 13(9): 1013-1023, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28263741

ABSTRACT

INTRODUCTION: Hippocampal volume is a core biomarker of Alzheimer's disease (AD). However, its contribution over the standard diagnostic workup is unclear. METHODS: Three hundred fifty-six patients, under clinical evaluation for cognitive impairment, with suspected AD and Mini-Mental State Examination ≥20, were recruited across 17 European memory clinics. After the traditional diagnostic workup, diagnostic confidence of AD pathology (DCAD) was estimated by the physicians in charge. The latter were provided with the results of automated hippocampal volumetry in standardized format and DCAD was reassessed. RESULTS: An increment of one interquartile range in hippocampal volume was associated with a mean change of DCAD of -8.0% (95% credible interval: [-11.5, -5.0]). Automated hippocampal volumetry showed a statistically significant impact on DCAD beyond the contributions of neuropsychology, 18F-fluorodeoxyglucose positron emission tomography/single-photon emission computed tomography, and cerebrospinal fluid markers (-8.5, CrI: [-11.5, -5.6]; -14.1, CrI: [-19.3, -8.8]; -10.6, CrI: [-14.6, -6.1], respectively). DISCUSSION: There is a measurable effect of hippocampal volume on DCAD even when used on top of the traditional diagnostic workup.


Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/pathology , Cognition Disorders/etiology , Diagnosis, Computer-Assisted , Hippocampus/pathology , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/complications , Amyloid beta-Peptides/cerebrospinal fluid , Cognition Disorders/diagnostic imaging , Diagnosis, Differential , Disease Progression , Europe , Female , Fluorodeoxyglucose F18/metabolism , Humans , Male , Neuropsychological Tests , Peptide Fragments/cerebrospinal fluid , Positron-Emission Tomography , Tomography, Emission-Computed, Single-Photon , tau Proteins/cerebrospinal fluid
15.
Neurodegener Dis ; 16(1-2): 69-76, 2016.
Article in English | MEDLINE | ID: mdl-26560503

ABSTRACT

BACKGROUND: Determination of Alzheimer's disease (AD) by cerebrospinal fluid (CSF) biomarkers - 42-amino-acid amyloid-ß (Aß42), total tau and phosphorylated tau (p-tau) - has demonstrated high validity for detecting AD neuropathological changes. However, their prognostic utility to predict the onset of dementia in predementia subjects is still questioned. We aimed to study the prospective clinical evolution of a group of subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) and to determine the prognostic capacity of AD CSF biomarkers. METHODS: 149 subjects with MCI or SCD, not meeting dementia criteria, underwent a prospective clinical, neuropsychological and CSF biomarker study. Patients were initially classified as SCD or MCI following internationally accepted criteria. CSF sampling was obtained and analysed following consensus protocols. Neuropsychological and clinical evaluations were conducted at the follow-up. Statistical analysis considering the final clinical diagnosis, regression analysis to define risk factors and survival curves for progression were made. RESULTS: 72.4% of subjects (83% MCI and 27% SCD) with a pathological CSF ratio (Aß42/p-tau) met criteria for dementia during the 5-year follow-up versus 18.7% of subjects from the group with a normal ratio. The pathological CSF ratio was a powerful marker of risk for AD dementia (OR 27.1; 95% CI 10.3-71.2). Kaplan-Meier survival curves showed that only 15% of subjects with a pathological CSF ratio remained free of AD dementia at 5 years of follow-up. All subjects who reverted to normal cognition presented a normal CSF profile at baseline. CONCLUSION: An abnormal AD CSF biomarker profile in predementia subjects is a powerful predictor of cognitive and/or functional decline in the medium term.


Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Cognition Disorders/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged , Apolipoproteins E/genetics , Biomarkers/cerebrospinal fluid , Cognition Disorders/genetics , Disease Progression , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Neuropsychological Tests , Prognosis , Prospective Studies , Regression Analysis , Risk Factors
16.
Alzheimers Dement ; 12(2): 154-163, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26368321

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.


Subject(s)
Ambulatory Care Facilities , Memory/physiology , Spinal Puncture/adverse effects , Aged , Cognition Disorders/cerebrospinal fluid , Dementia/cerebrospinal fluid , Feasibility Studies , Female , Humans , Incidence , Male , Middle Aged , Post-Dural Puncture Headache/epidemiology , Post-Dural Puncture Headache/etiology , Prospective Studies , Risk Factors , Spinal Puncture/methods
17.
Neuropathol Appl Neurobiol ; 41(7): 882-92, 2015 Dec.
Article in English | MEDLINE | ID: mdl-25381753

ABSTRACT

AIMS: The aims of this study were to assess the sensitivity of the International Behavioural Variant FTD Criteria Consortium (FTDC) revised criteria of behavioural variant frontotemporal dementia (bvFTD) in a pathological cohort and to determine their predictive values in a clinical context suggestive of bvFTD. In addition, the study aimed to assess the influence of the age at onset and underlying pathology in the clinicopathological correlations. METHODS: Retrospective, blinded review of the clinical and neuropathological data from the Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS, Barcelona (Spain) was conducted, assessing the fulfilment of the diagnostic criteria on a case-by-case basis. Two separate nonexclusive cohorts were selected: Cohort 1 (n = 58) subjects with pathological diagnosis of frontotemporal lobar degeneration (FTLD) and Cohort 2 (n = 66) subjects with the premortem diagnosis of bvFTD. RESULTS: The FTDC criteria reached a sensitivity of 93% for possible and 80% for probable bvFTD. Early-onset cases displayed significantly more disinhibition, loss of empathy and compulsive behaviour with respect to late-onset bvFTD, leading to a slightly higher sensitivity of the diagnostic criteria (97% vs. 91%). There were no differences in the diagnostic performance between tau-positive and tau-negative cases. In subjects clinically diagnosed as bvFTD, a 'possible bvFTD' diagnosis reached a positive predictive value for FTLD pathology of 90%, irrespective of underlying proteinopathy. False-positive clinical diagnoses were mainly Alzheimer's disease. These cases were significantly older, had less family history of dementia and had a predominantly apathetic clinical picture. CONCLUSIONS: The revised bvFTD criteria present good sensitivity and positive predictive value in both early- and late-onset cases and regardless of the underlying FTLD pathology.


Subject(s)
Brain/pathology , Frontotemporal Dementia/diagnosis , Frontotemporal Lobar Degeneration/diagnosis , Adult , Age of Onset , Aged , Aged, 80 and over , Biological Specimen Banks , Female , Frontotemporal Dementia/pathology , Frontotemporal Lobar Degeneration/pathology , Humans , Male , Middle Aged , Neuropsychological Tests , Retrospective Studies
18.
Neurogenetics ; 15(2): 145-9, 2014 May.
Article in English | MEDLINE | ID: mdl-24691562

ABSTRACT

We report a 54-year-old man who was admitted to the hospital because of acute neurological symptoms due to a cerebral haemorrhage. Postmortem brain examination revealed a lobar haemorrhage and advanced AD neuropathologic changes associated with severe cerebral amyloid angiopathy. Genetic study evidenced the presence of a large APP locus duplication (APPdup) in the patient and a PSEN1 p.E318G polymorphism in him and his older asymptomatic sibling. The APPdup spanned 14.5 Mb and blocks of segmental duplications were detected in the breakpoints. We propose the replication-based mechanism of Fork Stalling Template Switching (FoSTeS) to explain this APPdup rearrangement.


Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Cerebral Amyloid Angiopathy/genetics , Cerebral Hemorrhage/complications , Presenilin-1/genetics , Brain/pathology , Gene Duplication , Genetic Loci , Humans , Male , Middle Aged
19.
J Speech Lang Hear Res ; 67(10): 3762-3777, 2024 Oct 08.
Article in English | MEDLINE | ID: mdl-39302879

ABSTRACT

PURPOSE: Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by worsening of speech and/or language. Script training intervention promotes automatized speech production via repeated practice of scripted content. This study evaluated the acceptability, feasibility, and effects of a modified version of Video-Implemented Script Training for Aphasia (VISTA) in the three PPA variants and compared outcomes by intervention modality (teletherapy vs. in person). METHOD: Thirteen bilingual (Spanish-Catalan) participants were included (semantic variant, n = 5; logopenic variant, n = 5; nonfluent/agrammatic variant, n = 3; teletherapy, n = 7). Using a nonrandomized design, intervention was administered in participants' dominant language. Participants were trained on an individualized script twice per week, over 8 weeks. Performance on measures related to script accuracy, content, and subjective ratings of production quality was evaluated at baseline, immediately post, and at 3 and 6 months post-intervention. RESULTS: No significant differences were observed on the basis of intervention modality. Participants demonstrated significant improvements from pre- to post-intervention in script production, synonym production, keywords, and global quality on the trained script. Maintenance was observed when comparing performance at post-intervention relative to 3- and 6-month follow-up for script and synonym production. Significant improvement in production quality of the untrained topic was observed following intervention. Different patterns of benefit were observed by PPA variant. CONCLUSIONS: Modified VISTA was acceptable and effective across the three PPA variants, as evidenced by improvements on a broader array of outcome measures than those previously reported. Findings also provide further support for provision for teletherapy in individuals with PPA. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.26999326.


Subject(s)
Aphasia, Primary Progressive , Humans , Female , Male , Aged , Middle Aged , Speech Therapy/methods , Treatment Outcome , Feasibility Studies , Video Recording , Language Therapy/methods
20.
J Alzheimers Dis ; 97(3): 1091-1096, 2024.
Article in English | MEDLINE | ID: mdl-38250774

ABSTRACT

We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer's disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein (α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB pathology in ADAD.


Subject(s)
Alzheimer Disease , Lewy Body Disease , Humans , alpha-Synuclein/cerebrospinal fluid , Alzheimer Disease/diagnosis , Lewy Bodies/pathology , Lewy Body Disease/pathology , tau Proteins/cerebrospinal fluid
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