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Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.
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BACKGROUND: There is a need for biomarkers of disease progression and therapeutic response in multiple sclerosis (MS). This study aimed to identify cerebrospinal fluid (CSF) lipids that differentiate MS from other neuroinflammatory conditions and correlate with Expanded Disability Status Scale (EDSS) scores, gadolinium-enhancing lesions or inflammatory mediators. METHODS: Lipids and inflammatory cytokines/chemokines were quantified with liquid chromatography-tandem mass spectrometry and multiplex ELISA, respectively, in CSF from people with untreated MS, neuromyelitis optica spectrum disorder (NMOSD), other inflammatory neurological diseases and non-inflammatory neurological diseases (NIND). Analytes were compared between groups using analysis of variance, and correlations were assessed with Pearson's analysis. RESULTS: Twenty-five sphingolipids and four lysophosphatidylcholines were significantly higher in NMOSD compared with MS and NIND cases, whereas no lipids differed significantly between MS and NIND. A combination of three sphingolipids differentiated NMOSD from MS with the area under the curve of 0.92 in random forest models. Ninety-four lipids, including those that differentiated NMOSD from MS, were positively correlated with macrophage migration inhibitory factor (MIF) and 37 lipids were positively correlated with CSF protein in two independent MS cohorts. EDSS was inversely correlated with cholesterol ester CE(16:0) in both MS cohorts. In contrast, MIF and soluble triggering receptor expressed on myeloid cells 2 were positively associated with EDSS. CONCLUSIONS: CSF sphingolipids are positively correlated with markers of neuroinflammation and differentiate NMOSD from MS. The inverse correlation between EDSS and CE(16:0) levels may reflect poor clearance of cholesterol released during myelin break-down and warrants further investigation as a biomarker of therapeutic response.
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BACKGROUND: Predominant right temporal atrophy is a radiological sign usually associated with frontotemporal dementia but this sign can also be present in Alzheimer's disease. Given the overlap of clinical symptoms between the two conditions, it is important to know which characteristics allow them to be differentiated. OBJECTIVES: To compare clinical, neuropsychological and structural magnetic resonance imaging (MRI) data of subjects with prominent right anterior temporal atrophy, depending on the status of amyloid biomarkers. METHODS: Among patients followed in the dementia center of Ospedale Maggiore Policlinico, subjects with right anterior temporal atrophy, defined as grade 3 or 4 on the corresponding visual rating scale, were identified. Only subjects with both an MRI scan and amyloid status available were considered. For selected subjects, data were extracted from clinical and neuropsychological records at initial presentation and at last available follow-up. Two raters applied a protocol of eight visual rating scales to compare brain atrophy and white matter hyperintensities. RESULTS: Of 497 subjects, 17 fulfilled the inclusion criteria: 7 amyloid-positive and 10 amyloid-negative. At initial presentation, executive dysfunction and topographical disorientation were more common in amyloid-positive patients. At follow-up, behavioral symptoms, such as social awkwardness and compulsive attitude, were more frequent in the amyloid-negative patients. Amyloid-positive patients presented an overall worse neuropsychological performance, especially in the language and visuospatial domain, and had higher scores on the right anterior cingulate visual rating scale. CONCLUSION: Patients with predominant right temporal atrophy showed clinical, neuropsychological and radiological differences, depending on the status of amyloid biomarkers.
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Doença de Alzheimer , Demência Frontotemporal , Humanos , Doença de Alzheimer/complicações , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Atrofia/patologia , BiomarcadoresRESUMO
Background: Perivascular spaces (PVS) are fluid-filled compartments that dilate in response to many different conditions. A high burden of enlarged PVS (EPVS) in the centrum semiovale (CSO) has been linked to neurodegeneration. Moreover, an increase in cerebrospinal fluid (CSF) levels of aquaporin-4 (AQP4), a water channel expressed on PVS-bounding astrocytes, has been described in patients with neurodegenerative dementia. Our aim was to investigate the relationship between neurodegenerative diseases and two putative glymphatic system biomarkers: AQP4 and EPVS. Methods: We included 70 individuals, 54 patients with neurodegenerative diseases and 16 subjects with non-degenerative conditions. EPVS were visually quantified on MRI-scans applying Paradise's scale. All subjects underwent lumbar puncture for the measurement of AQP4 levels in the cerebrospinal fluid (CSF). CSF levels of amyloid-ß-1-42, phosphorylated and total tau (tTau) were also measured. Linear regression analyses were adjusted for age, sex, education and disease duration, after excluding outliers. Results: Cerebrospinal fluid (CSF)-AQP4 levels were independent predictors of total (ß = 0.28, standard error [SE] = 0.08, p = 0.001), basal ganglia (ß = 0.20, SE = 0.08, p = 0.009) and centrum semiovale EPVS (ß = 0.37, SE = 0.12, p = 0.003). tTau levels predicted CSO-EPVS (ß = 0.30, SE = 0.15, p = 0.046). Moreover, increased levels of AQP4 were strongly associated with higher levels of tTau in the CSF (ß = 0.35, SE = 0.13, p = 0.008). Conclusion: We provide evidence that CSO-EPVS and CSF-AQP4 might be clinically meaningful biomarkers of glymphatic dysfunction and associated neurodegeneration.
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OBJECTIVE: This study aimed to evaluate the experience with telemedicine in patients with cognitive impairments and their caregivers. METHODS: We conducted a survey-based study of patients who completed neurological consultation via video link between January and April 2022. RESULTS: A total of 62 eligible neurological video consultations were conducted for the following categories of patients: Alzheimer's disease (33.87%), amnesic mild cognitive impairment (24.19%), frontotemporal dementia (17.74%), Lewy body dementia (4.84%), mixed dementia (3.23%), subjective memory disorders (12.90%), non-amnesic mild cognitive impairment (1.61%), and multiple system atrophy (1.61%). The survey was successfully completed by 87.10% of the caregivers and directly by the patients in 12.90% of cases. Our data showed positive feedback regarding the telemedicine experience; both caregivers and patients reported that they found neurological video consultation useful (caregivers: 87.04%, 'very useful'; patients: 87.50%, 'very useful') and were satisfied overall (caregivers: 90.74%, 'very satisfied'; patients: 100%, 'very satisfied'). Finally, all caregivers (100%) agreed that neurological video consultation was a useful tool to reduce their burden (Visual Analogue Scale mean ± SD: 8.56 ± 0.69). CONCLUSIONS: Telemedicine is well received by patients and their caregivers. However, successful delivery incorporates support from staff and care partners to navigate technologies. The exclusion of older adults with cognitive impairment in developing telemedicine systems may further exacerbate access to care in this population. Adapting technologies to the needs of patients and their caregivers is critical for the advancement of accessible dementia care through telemedicine.
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Doença de Alzheimer , Disfunção Cognitiva , Telemedicina , Humanos , Idoso , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/terapia , Disfunção Cognitiva/epidemiologia , Doença de Alzheimer/psicologia , Cuidadores/psicologia , Encaminhamento e Consulta , TelefoneRESUMO
BACKGROUND: Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer's disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM). OBJECTIVE: Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions. METHODS: Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (nâ=â19) and non-AD (nâ=â15) groups according to their clinical profile, CSF (Aß42/40) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted. RESULTS: QSM in left BANKSSTS was significantly different among groups (pâ=â0.003, Hâ=â11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aß42 (rho -0.55, pâ=â0.005), Aß42/40 (rho -0.66, pâ<â0.001), pTau (rho 0.63, pâ<â0.001), tTau (rho 0.56, pâ=â0.005), tTau/Aß42 (rho 0.68, pâ<â0.001) and pTau/Aß42 (rho 0.71, pâ<â0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUCâ=â0.80, CI95 % [0.66-0.93]). Higher QSM values were independent predictors of Aß42 (Bâ=â0.63, pâ=â0.032), Aß42/40 (Bâ=â0.81, pâ=â0.028), pTau (Bâ=â0.96, pâ=â0.046), tTau (Bâ=â0.55, pâ=â0.027), and tTau/Aß42 (Bâ=â1.13, pâ=â0.042) positivity. CONCLUSION: Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Proteínas tau , Lobo Temporal/diagnóstico por imagem , Ferro , Biomarcadores , Fragmentos de PeptídeosRESUMO
OBJECTIVES: To investigate the normal-appearing white matter (NAWM) susceptibility in a cohort of newly diagnosed multiple sclerosis (MS) patients and to evaluate possible correlations between NAWM susceptibility and disability progression. METHODS: Fifty-nine patients with a diagnosis of MS (n = 53) or clinically isolated syndrome (CIS) (n = 6) were recruited and followed up. All participants underwent neurological examination, blood sampling for serum neurofilament light chain (sNfL) level assessment, lumbar puncture for the quantification of cerebrospinal fluid (CSF) ß-amyloid1-42 (Aß) levels, and brain MRI. T2-weighted scans were used to quantify white matter (WM) lesion loads. For each scan, we derived the NAWM volume fraction and the WM lesion volume fraction. Quantitative susceptibility mapping (QSM) of the NAWM was calculated using the susceptibility tensor imaging (STI) suite. Susceptibility maps were computed with the STAR algorithm. RESULTS: Primary progressive patients (n = 9) showed a higher mean susceptibility value in the NAWM than relapsing-remitting (n = 44) and CIS (n = 6) (p = 0.01 and p = 0.02). Patients with a higher susceptibility in the NAWM showed increased sNfL concentration (ρ = 0.38, p = 0.004) and lower CSF Aß levels (ρ = -0.34, p = 0.009). Mean NAWM susceptibility turned out to be a predictor of the expanded disability status scale (EDSS) worsening at follow-up (ß = 0.41, t = 2.66, p = 0.01) and of the MS severity scale (MSSS) (ß = 0.38, t = 2.43, p = 0.019). CONCLUSIONS: QSM in the NAWM seems to predict the EDSS increment over time. This finding might provide evidence on the role of QSM in identifying patients with an increased risk of early disability progression. KEY POINTS: ⢠NAWM-QSM is higher in PPMS patients than in RRMS. ⢠NAWM-QSM seems to be a predictor of EDSS worsening over time. ⢠Patients with higher NAWM-QSM show increased sNfL concentration and lower CSF Aß levels.
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Doenças Desmielinizantes , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Substância Branca , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Imageamento por Ressonância Magnética/métodos , Neuroimagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Esclerose Múltipla Recidivante-Remitente/patologiaRESUMO
Aquaporin-4 (AQP4) is a channel protein that plays a fundamental role in glymphatic system, a newly described pathway for fluid exchange in the central nervous system, as well as a central figure in a fascinating new theory for the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, cerebrospinal fluid (CSF) concentration of AQP4, amyloid-ß, total tau and P-tau were determined in 103 CSF samples from patients affected by neurodegenerative dementias (AD and FTD) or psychiatric diseases and 21 controls. Significantly higher levels of AQP4 were found in AD and FTD patients compared to subjects not affected by neurodegenerative diseases, and a significant, positive correlation between AQP4 and total tau levels was found. This evidence may pave the way for future studies focused on the role of this channel protein in the clinical assessment of the glymphatic function and degree of neurodegeneration.
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Doença de Alzheimer , Aquaporina 4 , Demência Frontotemporal , Sistema Glinfático , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo , Aquaporina 4/líquido cefalorraquidiano , Aquaporina 4/metabolismo , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/metabolismo , Sistema Glinfático/metabolismo , Humanos , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/metabolismo , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismoRESUMO
BACKGROUND: Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion's metrics and clinical outcomes in relapse-onset MS has not been widely investigated. OBJECTIVES: To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients. METHODS: 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP). RESULTS: Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI -0.005 to -0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed-effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95%CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006). CONCLUSIONS: SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity and MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS.
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Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Feminino , Humanos , Masculino , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos Transversais , Imageamento por Ressonância Magnética , Esclerose Múltipla/patologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , RecidivaRESUMO
BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is an autoimmune disease confined in the CNS, and its course is frequently subtle and variable. Therefore, predictive biomarkers are needed. In this scenario, we conducted a systematic review and meta-analysis to evaluate the reliability of chitinase 3-like 1 as a biomarker of MS. METHODS: Research through the main scientific databases (PubMed, Scopus, Web of Science, and Cochrane Library) published from January 2010 to December 2020 was performed using the following keywords: "chitinase 3-like 1 and multiple sclerosis" and "YKL40 and multiple sclerosis." Articles were selected according to the 2020 updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines by 2 authors independently, and data were extracted; 20 of the 90 studies screened were included in the meta-analysis. The main efficacy measure was represented by the standardized mean difference of CSF and blood CHI3L1 levels; Review Manager version 5.4 and R software applications were used for analysis. RESULTS: Higher levels of CHI3L1 were found in CSF of 673 patients with MS compared with 336 healthy controls (size-weighted mean difference [SMD] 50.88; 95% CI = 44.98-56.79; p < 0.00001) and in 461 patients with MS than 283 patients with clinically isolated syndrome (CIS) (SMD 28.18; 95% CI = 23.59-32.76; p < 0.00001). Mean CSF CHI3L1 levels were significantly higher in 561 converting than 445 nonconverting CIS (SMD 30.6; 95% CI = 28.31-32.93; p < 0.00001). CSF CHI3L1 levels were significantly higher in patients with primary progressive MS (PPMS) than in patients with relapsing-remitting MS (RRMS) (SMD 43.15; 95% CI = 24.41-61.90; p < 0.00001) and in patients with secondary progressive MS (SMD 41.86 with 95% CI = 32.39-51.33; p < 0.00001). CSF CHI3L1 levels in 407 patients with MS during remission phase of disease were significantly higher than those in 395 patients with MS with acute relapse (SMD 10.48; 95% CI = 08.51-12.44; p < 0.00001). The performances of CHI3L1 in blood for differentiating patients with MS from healthy controls were not significant (SMD 0.48; 95% CI = -1.18 to 2.14; p: 0.57). DISCUSSION: CSF levels of CHI3L1 have a strong correlation with the MS pathologic course, in particular with the mechanism of progression of the disease; it helps to distinguish the PPMS from the RRMS. The potential role of CHI3L1 in serum needs to be further studied in the future.
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Quitinases , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Biomarcadores , Proteína 1 Semelhante à Quitinase-3 , Humanos , Esclerose Múltipla/diagnóstico , Reprodutibilidade dos TestesRESUMO
Cognitive deficits strongly affect the quality of life of patients with multiple sclerosis (MS). However, no cognitive MS biomarkers are currently available. Extracellular vesicles (EVs) contain markers of parental cells and are able to pass from the brain into blood, representing a source of disease biomarkers. The aim of this study was to investigate whether small non-coding microRNAs (miRNAs) targeting synaptic genes and packaged in plasma EVs may reflect cognitive deficits in MS patients. Total EVs were precipitated by Exoquick from the plasma of twenty-six cognitively preserved (CP) and twenty-three cognitively impaired (CI) MS patients belonging to two independent cohorts. Myeloid EVs were extracted by affinity capture from total EVs using Isolectin B4 (IB4). Fourteen miRNAs targeting synaptic genes were selected and measured by RT-PCR in both total and myeloid EVs. Myeloid EVs from CI patients expressed higher levels of miR-150-5p and lower levels of let-7b-5p compared to CP patients. Stratification for progressive MS (PMS) and relapsing-remitting MS (RRMS) and correlation with clinical parameters suggested that these alterations might be attributable to cognitive deficits rather than disease progression. This study identifies miR-150-5p and let-7b-5p packaged in blood myeloid EVs as possible biomarkers for cognitive deficits in MS.
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Vesículas Extracelulares , MicroRNAs , Esclerose Múltipla , Biomarcadores , Cognição , Vesículas Extracelulares/genética , Humanos , MicroRNAs/genética , Esclerose Múltipla/genética , Qualidade de VidaRESUMO
PURPOSE: Positron emission tomography (PET) with amyloid tracers (amy-PET) allows the quantification of pathological amyloid deposition in the brain tissues, including the white matter (WM). Here, we evaluate amy-PET uptake in WM lesions (WML) and in the normal-appearing WM (NAWM) of patients with Alzheimer's disease (AD) and non-AD type of dementia. METHODS: Thirty-three cognitively impaired subjects underwent brain magnetic resonance imaging (MRI), Aß1-42 (Aß) determination in the cerebrospinal fluid (CSF) and amy-PET. Twenty-three patients exhibiting concordant results in both CSF analysis and amy-PET for cortical amyloid deposition were recruited and divided into two groups, amyloid positive (A+) and negative (A-). WML quantification and brain volumes' segmentation were performed. Standardized uptake values ratios (SUVR) were calculated in the grey matter (GM), NAWM and WML on amy-PET coregistered to MRI images. RESULTS: A+ compared to A- showed a higher WML load (p = 0.049) alongside higher SUVR in all brain tissues (p < 0.01). No correlations between CSF Aß levels and WML and NAWM SUVR were found in A+, while, in A-, CSF Aß levels were directly correlated to NAWM SUVR (p = 0.04). CSF Aß concentration was the only predictor of NAWM SUVR (adj R2 = 0.91; p = 0.04) in A-. In A+ but not in A- direct correlations were identified between WM and GM SUVR (p < 0.01). CONCLUSIONS: Our data provide evidence on the role of amy-PET in the assessment of microstructural WM injury in non-AD dementia, whereas amy-PET seems less suitable to assess WM damage in AD patients due to a plausible amyloid accrual therein.
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Doença de Alzheimer , Substância Branca , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons/métodos , Substância Branca/diagnóstico por imagemRESUMO
BACKGROUND: Superficial white matter (SWM) alterations correlated with cognitive decline have been described in Alzheimer's disease (AD). OBJECTIVE: The study aims to extend the investigation of the SWM alterations to AD and non-AD neurodegenerative dementia (ND) and explore the relationship with cerebrospinal fluid (CSF) biomarkers and clinical data. METHODS: From a database of 323 suspected dementia cases, we retrospectively recruited 55 ND with abnormal amyloid-ß42 (AD) and 38 ND with normal amyloid-ß42 (non-AD) and collected clinical data, CSF biomarkers, and magnetic resonance images. Ten healthy controls (HC) were recruited for imaging and Mini-Mental State Examination (MMSE). Diffusion tensor imaging (DTI) measurements were performed in the lobar SWM regions and Kruskal Wallis tests were used for among-group comparison. Spearman's correlation tests were performed between DTI measures, CSF biomarkers, and clinical data. RESULTS: AD and non-AD showed significant differences in the DTI measures across the SWM compared to HC. Significant differences between AD and non-AD were detected in the left parietal lobe. DTI measures correlated with amyloid-ß42 and MMSE diffusely in the SWM, less extensively with total-tau and phosphorylated tau, and with disease duration in the parietal lobe bilaterally. CONCLUSION: Widespread SWM alterations occur in both AD and non-AD ND and AD shows appreciably more severe alterations in the parietal SWM. Notably, the alterations in the SWM are strongly linked not only to the cognitive decline but also to the diagnostic CSF biomarkers. Further studies are encouraged to evaluate the DTI measures in the SWM as in vivo non-invasive biomarkers in the preclinical phase.
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Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/patologia , Imagem de Tensor de Difusão , Substância Branca/patologia , Idoso , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Estudos Retrospectivos , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: Association between cerebrospinal fluid (CSF)-amyloid-ß (Aß)42 and amyloid-PET measures is inconstant across the Alzheimer's disease (AD) spectrum. However, they are considered interchangeable, along with Aß42/40 ratio, for defining 'Alzheimer's Disease pathologic change' (A+). OBJECTIVE: Herein, we further characterized the association between amyloid-PET and CSF biomarkers and tested their agreement in a cohort of AD spectrum patients. METHODS: We included 23 patients who underwent amyloid-PET, MRI, and CSF analysis showing reduced levels of Aß42 within a 365-days interval. Thresholds used for dichotomization were: Aß42â<â640âpg/mL (Aß42+); pTauâ>â61âpg/mL (pTau+); and Aß42/40â<â0.069 (ADratio+). Amyloid-PET scans were visually assessed and processed by four pipelines (SPMCL, SPMAAL, FSGM, FSWC). RESULTS: Different pipelines gave highly inter-correlated standardized uptake value ratios (SUVRs) (rhoâ=â0.93-0.99). The most significant findings were: pTau positive correlation with SPMCL SUVR (rhoâ=â0.56, pâ=â0.0063) and Aß42/40 negative correlation with SPMCL and SPMAAL SUVRs (rhoâ=â-0.56, pâ=â0.0058; rhoâ=â-0.52, pâ=â0.0117 respectively). No correlations between CSF-Aß42 and global SUVRs were observed. In subregion analysis, both pTau and Aß42/40 values significantly correlated with cingulate SUVRs from any pipeline (R2â=â0.55-0.59, pâ<â0.0083), with the strongest associations observed for the posterior/isthmus cingulate areas. However, only associations observed for Aß42/40 ratio were still significant in linear regression models. Moreover, combining pTau with Aß42 or using Aß42/40, instead of Aß42 alone, increased concordance with amyloid-PET status from 74% to 91% based on visual reads and from 78% to 96% based on Centiloids. CONCLUSION: We confirmed that, in the AD spectrum, amyloid-PET measures show a stronger association and a better agreement with CSF-Aß42/40 and secondarily pTau rather than Aß42 levels.
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Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides , Amiloide , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: COVID-19 pandemic worsened vulnerability of patients with dementia (PWD). This new reality associated with government restriction and isolation worsened stress burden and psychological frailties in PWD caregivers. OBJECTIVE: To give tele-psychological support to caregivers and evaluate the effect of this intervention by quantifying stress burden and quality of life during the first COVID-19 lockdown. METHODS: 50 caregivers were divided into two groups: "Caregiver-focused group" (Cg) and "Patient-focused group" (Pg). Both groups received telephone contact every 2 weeks over a 28-week period, but the content of the call was different: in Cg, caregivers answered questions about the state of the PWD but also explored their own emotional state, stress burden, and quality of life. In Pg instead, telephone contacts were focused only on the PWD, and no evaluation regarding the caregiver mood or state of stress was made. Psychometric scales were administered to evaluate COVID-19 impact, stress burden, and quality of life. RESULTS: Considering the time of intervention, from baseline (W0) to W28, Zarit Burden Interview and Quality of Life-caregiver questionnaires remained unchanged in Cg as compared with baseline (pâ>â0.05), whereas they worsened significantly in Pg (pâ<â0.01), showing increased stress over time and decreased quality of life in this group. Moreover, Impact on Event Scale values improved over the weeks in Cg (pâ=â0.015), while they remained unchanged in Pg (pâ=â0.483). CONCLUSION: Caregivers who received telephone support about their mood and stress burden did not worsen their psychological state during the time of intervention, as did instead those who did not get such support.
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Sobrecarga do Cuidador/terapia , Cuidadores/psicologia , Demência/enfermagem , Angústia Psicológica , Sistemas de Apoio Psicossocial , Telefone , Idoso , Idoso de 80 Anos ou mais , COVID-19/psicologia , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer's disease (AD). OBJECTIVE: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-ß 1-42 (Aß) deposition and to correlate genetic data with clinical phenotypes. METHODS: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aß levels or positive PET with Aß tracer and 200 non-demented geriatric subjects. RESULTS: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (pâ>â0.05). CONCLUSION: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aß deposition is higher than in the general population.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Demência , Proteína C1 de Niemann-Pick/genética , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas de Transporte Vesicular/genética , Idoso , Encéfalo/patologia , Demência/genética , Demência/psicologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Fenótipo , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: the distinct MRI features of MOG-antibody disease (MOG-AD) and AQP4-NMOSD are still poorly defined. We performed a systematic review and meta-analysis to identify specific patterns of MRI abnormalities able to discriminate between MOG-AD and AQP4-NMOSD. METHODS: fourteen case-series (1028 patients) were included. Outcomes were MRI lesion patterns in optic nerve (ON), brain and spinal cord (SC) that were selected after a systematic literature review and analysed separately as the event rate for individual MRI lesions in MOG-AD (experimental group) and AQP4-NMOSD (control group) by using a random effect model. RESULTS: MOG-AD showed a higher number of MRI lesions than AQP4-NMOSD patients in the retrobulbar ON (OR=5.67; 95%CI=2.11-15.24; p=0.0006) with ON head swelling (OR=8.20; 95%CI=4.13-16.28; p<0.00001), corpus callosum (OR=2.30; 95%CI=1.11-4.76; p=0.02), pons (OR=2.87; 95%CI=1.45-5.67; p=0.002), and lumbar/conus SC (OR=3.47; 95%CI=1.66-7.24; p=0.0009). Conversely, lesions in the canalicular (OR=0.42; 95%CI=0.18-0.98; p=0.05) and intracranial ON (OR=0.30; 95%CI=0.11=0.84; p=0.02), area postrema (OR=0.12; 95%CI=0.02-0.61; p=0.01), medulla (OR=0.40; 95%CI=0.20-0.78; p=0.007), and cervical SC (OR=0.29; 95%CI=0.09-0.92; p=0.04) were prominent in patients with AQP4-NMOSD. Participants' age was found to be a source of heterogeneity across studies. CONCLUSION: our study provides further evidence that MOG-AD and AQP4-NMOSD have distinct MRI features that may help clinicians for an early differential diagnosis.
Assuntos
Aquaporina 4 , Neuromielite Óptica , Autoanticorpos , Humanos , Imageamento por Ressonância Magnética , Glicoproteína Mielina-Oligodendrócito , Neuromielite Óptica/diagnóstico por imagemRESUMO
BACKGROUND: Diogenes syndrome is a neurobehavioural syndrome characterised by domestic squalor, hoarding and lack of insight. It is an uncommon but high-mortality condition, often associated with dementia. AIMS: To describe the clinical features and treatment of Diogenes syndrome secondary to behavioural variant frontotemporal dementia (bvFTD). METHOD: We describe a case of bvFTD in a 77-year-old man presenting with Diogenes syndrome. RESULTS: The patient's medical and psychiatric histories were unremarkable, but in recent years he had begun packing his flat with 'art pieces'. Mental state examination revealed confabulation and more structured delusions. Neuropsychological evaluation outlined an impairment in selective attention and letter verbal fluency, but no semantic impairment, in the context of an overall preserved mental functioning. Brain magnetic resonance imaging and positron emission tomography (PET) with fluorodeoxyglucose showed mild bilateral temporo-insular atrophy and hypometabolism in the left-superior temporal gyrus respectively. An amyloid PET scan and genetic analysis covering the dementia spectrum were normal. A diagnosis of bvFTD was made. CONCLUSIONS: The clinical framing of behavioural symptoms of dementia such as hoarding poses a diagnostic challenge. This case illustrates the importance of a deeper understanding of Diogenes syndrome, leading to timelier diagnosis and effective therapeutic strategies.
RESUMO
Since the end of February 2020, Italy has suffered one of the most severe outbreaks of coronavirus disease 2019 (COVID-19). However, what happened just before the Italian index case has not yet been investigated. To answer this question, we evaluated the potential impact of COVID-19 on the clinical features of a cohort of neurological inpatients admitted right before the Italian index case, as compared to the same period of the previous year. Demographic, clinical, treatment and laboratory data were extracted from medical records. The data collected included all inpatients who had been admitted to the Neurology and Stroke Units of the Ospedale Maggiore Policlinico, Milan, Italy, from December 15, 2018 to February 20, 2019 and from December 15, 2019 to February 20, 2020. Of the 248 patients, 97 subjects (39.1%) were admitted for an acute cerebrovascular event: 46 in the 2018/2019 period (mean [SD] age, 72.3 [15.6] years; 22 men [47.8%]), and 51 in the 2019/2020 interval (mean [SD] age, 72.8 [12.4] years; 24 men [47.1%]). The number of cryptogenic strokes has increased during the 2019-2020 year, as compared to the previous year (30 [58.8%] vs. 18 [39.1%], p = 0.05). These patients had a longer hospitalization (mean [SD] day, 15.7 [10.5] days vs. mean [SD] day, 11.7 [7.2] days, p = 0.03) and more frequent cerebrovascular complications (9 [30.0%] vs. 2 [11.1%]), but presented a lower incidence of cardiocerebral risk factors (18 [60.0%] vs. 14 [77.8%]). Right before the Italian index case, an increase in cryptogenic strokes has occurred, possibly due to the concomitant COVID-19.