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The glymphatic system (GS) is a whole-brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non-invasive methods based on magnetic resonance imaging (MRI) along with aquaporin-4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi-shell diffusion-weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF-AQP4. CSF-AQP4 levels and MRI measures-including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW-WM) and mean kurtosis (MK-WM), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) (mean, left and right)-were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF-AQP4 (exp(b) = 2.05, p = .005) and FW-WM FW-WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF-AQP4 and FW-WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK-WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF-AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage.
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Doença de Alzheimer , Aquaporina 4 , Imagem de Difusão por Ressonância Magnética , Sistema Glinfático , Humanos , Aquaporina 4/líquido cefalorraquidiano , Feminino , Sistema Glinfático/diagnóstico por imagem , Masculino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Idoso , Pessoa de Meia-Idade , Imagem de Difusão por Ressonância Magnética/métodos , Idoso de 80 Anos ou mais , Demência/diagnóstico por imagem , Demência/líquido cefalorraquidiano , Demência/patologia , Imagem de Tensor de Difusão/métodos , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
BACKGROUND: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI). METHODS: Mesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)]. RESULTS: The following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1ß, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found. Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001). Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged. CONCLUSION: We showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease.
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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.
Assuntos
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
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
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
The monoaminergic neurotransmitters dopamine, noradrenaline, and serotonin are pivotal actors of the interplay between the nervous and the immune system due to their ability of binding to cell-receptors of both systems, crucially regulating their function within the central nervous system and the periphery. As monoamines are dysfunctional in many neurological and psychiatric diseases, they have been successfully used as pharmacological targets. Multiple sclerosis (MS) is one of the best examples of neurological disease caused by an altered interaction between the nervous and immune system and emerging evidence supports a dysregulation of monoaminergic systems in the pathogenesis of MS, secondary to both inflammation-induced reduction of monoamines' synthesis and structural damage to monoaminergic pathways within the brain. Here we review the evidence for monoamines being key mediators of neuroimmune interaction, affecting MS pathogenesis and course. Moreover, we discuss how the reduction/dysfunction of monoamines in MS may contribute to some clinical features typical of the disease, particularly fatigue and depression. Finally, we summarize different drugs targeting monoamines that are currently under evaluation for their potential efficacy to treat MS, as well as to alleviate fatigue and depression in MS.
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Esclerose Múltipla , Dopamina , Humanos , Neurotransmissores , Norepinefrina , SerotoninaRESUMO
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has dramatically stressed the health care system and has provoked changes in population use of digital technologies. Digital divide is any uneven distribution in Information and Communications Technologies between people. AIMS: The purpose of this work was to describe the digital divide of a population of patients with dementia contacted by telemedicine during Italian lockdown for COVID-19 pandemic. METHOD: One hundred eight patients with cognitive impairment were contacted by video call to perform a telemedicine neurological evaluation. Information on patients and caregivers attending the televisit were recorded. RESULTS: Seventy-four patients connected with neurologist (successful televisit, 68.5%) and 34 patients were not able to perform televisit and were contacted by phone (failed televisit, 31.5%). No significant differences were observed among the two groups concerning age, gender, and education, but the prevalence of successful televisit was higher in the presence of younger caregivers: televisits performed in the presence of subjects of younger generation (sons and grandsons) had a successful rate higher (86% successful, 14% failed) than the group without younger generation caregiver (49% successful, 51% failed). This difference is mainly due to the ability of technological use among younger people. DISCUSSION: The most impacting factors on digital divide in our population are the social support networks and the experience with the technology: the presence of a digital native caregiver. The COVID-19 pandemic is unmasking an emerging form of technology-related social inequalities: political and community interventions are needed to support the most socially vulnerable population and prevent social health inequalities.
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COVID-19 , Cuidadores/estatística & dados numéricos , Demência/terapia , Exclusão Digital , Pandemias , Telemedicina/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cuidadores/psicologia , Escolaridade , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neurologistas , Prevalência , Quarentena , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: Neurodegenerative processes are present since the early stages of multiple sclerosis (MS), constituting the primary substrate of disability. As part of the CNS, retinal damage could be considered a reliable prognostic biomarker of neurodegeneration in MS. OBJECTIVES: To characterize longitudinal changes in the retinal layers' thickness and to investigate correlations between retinal atrophy and other prognostic biomarkers, i.e., cerebrospinal fluid (CSF) ß-amyloid1-42 (Aß) levels. METHODS: Forty-two eyes without a history of optic neuritis of 23 MS patients were recruited. All patients underwent spectral-domain-OCT scans (SD-OCT), brain magnetic resonance imaging (MRI), and lumbar puncture at baseline. SD-OCT and brain MRI were repeated after 12 months. Ten controls underwent the same OCT procedure. RESULTS: At baseline, macular ganglion cell/inner plexiform layer (mGCIPL) thickness was reduced in patients compared to controls (p = 0.008), without retinal nerve fiber layer (RNFL) thinning, that was revealed only at follow-up (p = 0.005). Patients with lower CSF Aß levels displayed reduced RNFL thickness values, both at baseline and follow-up. CONCLUSIONS: At very early clinical stages, mGCIPL thickness values were reduced without a concomitant peripapillary RNFL thinning. The longitudinal assessment demonstrated a RNFL loss in patients compared to HC, together with a plateau of mGCIPL thinning. Aßlow subgroup of patients showed a reduction of retinal nerve fiber layer thickness.
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Esclerose Múltipla , Neurite Óptica , Humanos , Estudos Longitudinais , Esclerose Múltipla/diagnóstico por imagem , Neurite Óptica/diagnóstico por imagem , Retina/diagnóstico por imagem , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with ß-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) ß-amyloid1-42 (Aß) levels, amyloid tracer uptake, and brain volumes. METHODS: Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and 18F-florbetapir PET. Aß levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted. RESULTS: We found a lower SUV in DWM compared to NAWM (p < 0.001) in all patients. Decreased NAWM-SUV was observed in the active compared to non-active group (p < 0.05). Considering only active patients, NAWM volume correlated with NAWM-SUV (p = 0.01). Interestingly, CSF Aß concentration was a predictor of both NAWM-SUV (r = 0.79; p = 0.01) and NAWM volume (r = 0.81, p = 0.01). CONCLUSIONS: The correlation between CSF Aß levels and NAWM-SUV suggests that the predictive role of ß-amyloid may be linked to early myelin damage and may reflect disease activity and clinical progression.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Tomografia por Emissão de Pósitrons , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Tomografia por Emissão de Pósitrons/normas , Valores de Referência , Substância Branca/metabolismo , Adulto JovemRESUMO
BACKGROUND: The importance of neurodegeneration in multiple sclerosis (MS) is increasingly well recognized. OBJECTIVES: To evaluate retinal pathology using optical coherence tomography (OCT) and to investigate possible associations between retinal layers' thickness and specific patterns of gray matter volume in patients with a new diagnosis of MS. METHODS: A total of 31 patients underwent OCT scans and brain magnetic resonance imaging. In total, 30 controls underwent the same OCT procedure. The association between focal cortical volume and OCT measurements was investigated with voxel-based morphometry (VBM). RESULTS: Compared to controls, patients' macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), and macular ganglion cell-inner plexiform layer (mGCIPL) thickness were significantly reduced ( p = 0.0009, p = 0.0003, p = 0.0049, and p = 0.0007, respectively). Peripapillary RNFL (pRNFL) and temporal sector pRNFL (T-pRNFL) did not show any significant changes, although there was a trend toward T-pRNFL thinning ( p = 0.0254). VBM analysis showed that mGCIPL and pRNFL were significantly correlated with the volume reduction of occipital-parietal cortex ( p < 0.005). CONCLUSION: mRNFL, mGCL, and mIPL are significantly reduced in MS patients without concomitant pRNFL thinning. These retinal changes show a significant association with cortical regions that are known to be important for visuospatial performance.
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Progressão da Doença , Lobo Occipital/patologia , Lobo Parietal/patologia , Células Ganglionares da Retina/patologia , Adulto , Atrofia/diagnóstico por imagem , Atrofia/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Lobo Occipital/diagnóstico por imagem , Lobo Parietal/diagnóstico por imagem , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. OBJECTIVES: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta1-42 (Aß) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. METHODS: Sixty patients were recruited and followed up for 3-5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aß levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. RESULTS: Lower CSF Aß levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = -0.65, p < 0.001). The multiple regression analysis confirmed CSF Aß concentration as a predictor of patients' EDSS increase (r = -0.59, p < 0.0001). Generating a receiver operating characteristic curve, a cut-off value of 813 pg/mL was determined as the threshold able to identify patients with worse prognosis (95% confidence interval (CI): 0.690-0.933, p = 0.0001). No differences in CSF tau and neurofilament light chain (NfL) levels were observed (p > 0.05). CONCLUSION: Low CSF Aß levels may represent a predictive biomarker of disease progression in MS.
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Peptídeos beta-Amiloides/líquido cefalorraquidiano , Progressão da Doença , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico por imagem , Fragmentos de Peptídeos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Adulto , Biomarcadores/líquido cefalorraquidiano , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
OBJECTIVE: To assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls. METHODS: Eighty-five participants were recruited: 65 with newly diagnosed Alzheimer's disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. ß-amyloid1-42 (Aß) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aß levels (Aß(+)), while 23 had normal CSF Aß levels (Aß(-)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses. RESULTS: We found an increased WM-LL in Aß(+) compared with both, healthy controls (p=0.003) and Aß(-) patients (p=0.02). Interestingly, CSF Aß concentration was the best predictor of patients' WM-LL (r=-0.30, p<0.05) when using age as a covariate. Lesion apparent diffusion coefficient value was higher in all patients than in controls (p=0.0001) and correlated with WM-LL (r=0.41, p=0.001). In Aß(+), WM-LL correlated with WM microstructural damage in the left peritrigonal WM (p<0.0001). CONCLUSIONS: WM damage is crucial in AD pathogenesis. The correlation between CSF Aß levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.
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Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Substância Branca/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
The role of myeloid cells in the pathogenesis of MS is determined by the polarization they acquire after activation, and mediated by release of extracellular vesicles (MVs). We assessed the effects of treatments for MS on activation and polarization of myeloid cells. MVs levels and markers of polarization of myeloid cells have been assessed at baseline and up to 6 months after the start of a MS treatment. Patients had higher levels of MVs than controls, and these increased significantly over 6 months under natalizumab. Interferon ß-1a significantly decreased M1 pro-inflammatory marker IL1ß and upregulated Trem2, a receptor important for debris clearance; both interferon ß-1a and fingolimod decreased pro-inflammatory marker IL6. Current treatments for MS significantly modulate myeloid cells activity.
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Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Células Mieloides/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Polaridade Celular/efeitos dos fármacos , Estudos de Coortes , Vesículas Extracelulares , Feminino , Cloridrato de Fingolimode/uso terapêutico , Humanos , Interferon beta-1a/uso terapêutico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Células Mieloides/patologia , Natalizumab/uso terapêutico , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de TempoAssuntos
Doenças Desmielinizantes , Hipofosfatemia , Leucoencefalopatias , Doenças Desmielinizantes/diagnóstico por imagem , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/genética , Humanos , Hipofosfatemia/etiologia , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/etiologia , SíndromeAssuntos
Alemtuzumab/efeitos adversos , Infecções por Coronavirus/imunologia , Imunossupressores/efeitos adversos , Linfopenia/induzido quimicamente , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Neutropenia/induzido quimicamente , Pneumonia Viral/imunologia , Adulto , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Feminino , Humanos , Leucopenia/induzido quimicamente , Leucopenia/imunologia , Linfopenia/imunologia , Esclerose Múltipla Recidivante-Remitente/complicações , Neutropenia/imunologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Differential diagnosis among subjects with Primary Progressive Aphasia (PPA) can be challenging. Structural MRI can support the clinical profile. Visual rating scales are a simple and reliable tool to assess brain atrophy in the clinical setting. The aims of the study were to establish to what extent the visual rating scales could be useful in the differential diagnosis of PPA, to compare the clinical diagnostic impressions derived from routine MRI interpretations with those obtained using the visual rating scale and to correlate results of the scales in a voxel-based morphometry (VBM) analysis. METHOD: Patients diagnosed with primary progressive aphasia (PPA) according to current criteria from two centers-Ospedale Maggiore Policlinico of Milan and Hospital Clínic de Barcelona-were included in the study. Two blinded clinicians evaluated the subjects MRIs for cortical atrophy and white matter hyperintensities using two protocols: routine readings and the visual rating scale. The diagnostic accuracy between patients and controls and within PPA subgroups were compared between the two protocols. RESULTS: One hundred fifty Subjects were studied. All the scales showed a good to excellent intra and inter-rater agreement. The left anterior temporal scale could differentiate between semantic PPA and all other variants. The rater impression after the protocol can increase the accuracy just for the logopenic PPA. In the VBM analysis, the scores of visual rating scales correlate with the corresponding area of brain atrophy. CONCLUSION: The Left anterior temporal rating scale can distinguish semantic PPA from other variants. The rater impression after structured view improved the diagnostic accuracy of logopenic PPA compared to normal readings. The unstructured view of the MRI was reliable for identifying semantic PPA and controls. Neither the structured nor the unstructured view could identify the nonfluent and undetermined variants.
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Afasia Primária Progressiva , Encéfalo , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Afasia Primária Progressiva/diagnóstico por imagem , Afasia Primária Progressiva/patologia , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons , Atrofia/patologiaRESUMO
Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and Progranulin (GRN) genes are not well understood. Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI). Methods: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72, MAPT, and GRN, including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC). Results: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression. Conclusions: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs' relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications.
Assuntos
Proteína C9orf72 , Demência Frontotemporal , Progranulinas , RNA Longo não Codificante , Proteínas tau , Humanos , Demência Frontotemporal/genética , RNA Longo não Codificante/genética , Feminino , Masculino , Pessoa de Meia-Idade , Proteína C9orf72/genética , Progranulinas/genética , Proteínas tau/genética , Idoso , Mutação , Biomarcadores/sangueRESUMO
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.
Assuntos
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
BACKGROUND: The longevity gene Klotho (KL) was recently associated with neurodegenerative diseases including Alzheimer's disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E É4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far. OBJECTIVE: To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene. METHODS: A population consisting of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software. RESULTS: KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation - 4.286 and - 6.561 versus controls in AD and FTD, respectively, pâ=â0.0037). CONCLUSION: This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration.