RESUMO
BACKGROUND AND PURPOSE: Human neuropathological studies indicate that the pontine nucleus Locus Coeruleus (LC) undergoes significant and early degeneration in Alzheimer's disease. This line of evidence alongside experimental data suggests that the LC functional/structural decay may represent a critical factor for Alzheimer's disease pathophysiological and clinical progression. In the present prospective study, we used Magnetic Resonance Imaging (MRI) with LC-sensitive sequence (LC-MRI) to investigate in vivo the LC involvement in Alzheimer's disease progression, and whether specific LC-MRI features at baseline are associated with prognosis and cognitive performance in amnestic Mild Cognitive Impairment. METHODS: LC-MRI parameters were measured at baseline by a template-based method on 3.0-T magnetic resonance images in 34 patients with Alzheimer's disease dementia, 73 patients with amnestic Mild Cognitive Impairment, and 53 cognitively intact individuals. A thorough neurological and neuropsychological assessment was performed at baseline and 2.5-year follow-up. RESULTS: In subjects with Mild Cognitive Impairment who converted to dementia (n = 32), the LC intensity and number of LC-related voxels were significantly lower than in cognitively intact individuals, resembling those observed in demented patients. Such a reduction was not detected in Mild Cognitive Impairment individuals, who remained stable at follow-up. In Mild Cognitive Impairment subjects converting to dementia, LC-MRI parameter reduction was maximal in the rostral part of the left nucleus. Structural equation modeling analysis showed that LC-MRI parameters positively correlate with cognitive performance. CONCLUSIONS: Our findings highlight a potential role of LC-MRI for predicting clinical progression in Mild Cognitive Impairment and support the key role of LC degeneration in the Alzheimer clinical continuum.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/patologia , Locus Cerúleo/diagnóstico por imagem , Estudos Prospectivos , Progressão da Doença , Disfunção Cognitiva/patologia , Testes Neuropsicológicos , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Chimeric Antigen Receptor (CAR) T cell therapies are innovative treatments against hematological malignancies, with increasing therapeutic indications. Despite their great efficacy, these therapies are hampered by high rates of neurotoxicity (immune effector cell-associated neurotoxicity (ICANS)). In the past few years, several risk factors have been associated with ICANS and grouped together in the attempt to build validated models able to predict neurologic complications. However, little is known about pre-existing neurologic conditions possibly related to the development of neurotoxicity. METHODS AND RESULTS: In our case series, including sixteen consecutive patients treated with CAR T cells, we observed that (i) neurotoxicity only occurred in the two patients who presented subtle clinical signs of frontal lobe impairment at baseline and (ii) neurologic manifestations of ICANS consisted of language disturbances and cortical frontal myoclonus, which were both manifestations of a frontal predominant dysfunction. DISCUSSION: Based on our experience, we suggest that a pre-existing frontal lobe impairment, even if at a subclinical level, may eventually drive to ICANS, which in turn shows symptoms compatible with a frontal encephalopathy. It is remarkable that this focal neurotoxicity involved the same CNS regions that were responsible of subtle neurological signs at baseline. Future studies on larger numbers of patients are needed to confirm the possible role of baseline frontal lobe dysfunction as a predictor of ICANS, in order to enhance efforts to safely deliver CAR T cell therapy.
Assuntos
Imunoterapia Adotiva , Síndromes Neurotóxicas , Humanos , Imunoterapia Adotiva/efeitos adversos , Síndromes Neurotóxicas/etiologia , Pesquisa , Lobo FrontalRESUMO
Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood-based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine-learning and a cross-validation-based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein-E (APOE) genotype (the major genetic risk factor for late-onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD-like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE-related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1ß was the variable most significantly associated with MCI-to-dementia conversion over a 2.5 year-clinical follow-up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker-guided pathway-based therapeutic approaches, within the precision medicine development framework.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/complicações , Citocinas , Progressão da Doença , Humanos , Interleucina-10 , Interleucina-12RESUMO
The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.
Assuntos
Envelhecimento/fisiologia , Doença de Alzheimer/epidemiologia , Pesquisa Biomédica , Progressão da Doença , Sintomas Prodrômicos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Austrália/epidemiologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/tratamento farmacológico , Humanos , Estilo de Vida , Tomografia por Emissão de PósitronsRESUMO
Methylation levels of the mitochondrial displacement loop (D-loop) region have been reported to be altered in the brain and blood of Alzheimer's disease (AD) patients. Moreover, a dynamic D-loop methylation pattern was observed in the brain of transgenic AD mice along with disease progression. However, investigations on the blood cells of AD patients in the prodromal phases of the disease have not been performed so far. The aim of this study was to analyze D-loop methylation levels by means of the MS-HRM technique in the peripheral blood cells of 14 mild cognitive impairment (MCI) patients, 18 early stage AD patients, 70 advanced stage AD patients, and 105 healthy control subjects. We found higher D-loop methylation levels in MCI patients than in control subjects and AD patients. Moreover, higher D-loop methylation levels were observed in control subjects than in AD patients in advanced stages of the disease, but not in those at early stages. The present pilot study shows that peripheral D-loop methylation levels differ in patients at different stages of AD pathology, suggesting that further studies deserve to be performed in order to validate the usefulness of D-loop methylation analysis as a peripheral biomarker for the early detection of AD.
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Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico , Animais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/genética , Metilação de DNA , Humanos , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Projetos PilotoRESUMO
Introduction: Tau protein misfolding and accumulation in toxic species is a critical pathophysiological process of Alzheimer's disease (AD) and other neurodegenerative disorders (NDDs). Tau biomarkers, namely cerebrospinal fluid (CSF) total-tau (t-tau), 181-phosphorylated tau (p-tau), and tau-PET tracers, have been recently embedded in the diagnostic criteria for AD. Nevertheless, the role of tau as a diagnostic and prognostic biomarker for other NDDs remains controversial.Areas covered: We performed a systematical PubMed-based review of the most recent advances in tau-related biomarkers for NDDs. We focused on papers published from 2015 to 2020 assessing the diagnostic or prognostic value of each biomarker.Expert opinion: The assessment of tau biomarkers in alternative easily accessible matrices, through the development of ultrasensitive techniques, represents the most significant perspective for AD-biomarker research. In NDDs, novel tau isoforms (e.g. p-tau217) or proteolytic fragments (e.g. N-terminal fragments) may represent candidate diagnostic and prognostic biomarkers and may help monitoring disease progression. Protein misfolding amplification assays, allowing the identification of different tau strains (e.g. 3 R- vs. 4 R-tau) in CSF, may constitute a breakthrough for the in vivo stratification of NDDs. Tau-PET may help tracking the spatial-temporal evolution of tau pathophysiology in AD but its application outside the AD-spectrum deserves further studies.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Proteínas tau/análise , Biomarcadores/análise , HumanosRESUMO
INTRODUCTION: The quest for reliable fluid biomarkers tracking synaptic disruption is supported by the evidence of a tight association between synaptic density and cognitive performance in neurodegenerative diseases (NDD), especially Alzheimer's disease (AD). AREAS COVERED: Neurogranin (Ng) is a post-synaptic protein largely expressed in neurons involved in the memory networks. Currently, Ng measured in CSF is the most promising synaptic biomarker. Several studies show Ng elevated in AD dementia with a hippocampal phenotype as well as in MCI individuals who progress to AD. Ng concentrations are also increased in Creutzfeldt Jacob Disease where widespread and massive synaptic disintegration takes place. Ng does not discriminate Parkinson's disease from atypical parkinsonisms, nor is it altered in Huntington disease. CSF synaptosomal-associated protein 25 (SNAP-25) and synaptotagmin-1 (SYT-1) are emerging candidates. EXPERT OPINION: CSF Ng revealed a role as a diagnostic and prognostic biomarker in NDD. Ng increase seems to be very specific for typical AD phenotype, probably for a prevalent hippocampal involvement. Synaptic biomarkers may serve different context-of-use in AD and other NDD including prognosis, diagnosis, and tracking synaptic damage - a critical pathophysiological mechanism in NDD - thus representing reliable tools for a precision medicine-oriented approach to NDD.
Assuntos
Doenças Neurodegenerativas/genética , Neurogranina/genética , Proteína 25 Associada a Sinaptossoma/genética , Sinaptotagmina I/genética , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Biomarcadores/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Humanos , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/diagnóstico , Neurogranina/líquido cefalorraquidiano , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Sinaptotagmina I/líquido cefalorraquidianoRESUMO
Introduction: Neuroinflammation is a common pathophysiological mechanism in neurodegenerative diseases (ND). Cerebrospinal fluid (CSF) YKL-40 has recently been candidated as a neuroinflammatory biomarker of ND. Areas covered: We provide an update on the role of CSF YKL-40 as a pathophysiological biomarker of ND. YKL-40 may discriminate Alzheimer's disease (AD) from controls and may predict the progression from the early preclinical to the late dementia stage. In genetic AD, YKL-40 increases decades before the clinical onset. It does not seem a specific biomarker of a certain ND although sporadic Creutzfeldt-Jacob disease shows the highest YKL-40 concentrations. YKL-40 may discriminate between amyotrophic lateral sclerosis (ALS) and ALS-mimics. YKL-40 is potentially associated with the rate of ALS progression. YKL-40 correlates with biomarkers of neuronal injury, large axonal damage and synaptic disruption in various ND. It is not associated with the presence of the APOE-ε4 allele whereas possibly linked to aging, female sex, Hispanic ethnicity and some genetic variants of the chitinase-3-like 1 locus. Expert opinion: There is growing evidence expanding the relevance of CSF YKL-40 as a pathophysiological biomarker for ND. Patients showing high YKL-40 levels might benefit from targeted clinical trials that use compounds acting against neuroinflammatory mechanisms, independently of the initial clinical diagnosis of ND.
Assuntos
Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Humanos , Doenças Neurodegenerativas/fisiopatologia , Medicina de Precisão/métodosRESUMO
The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective disease-modifying pathway-based targeted therapies. PP is based on an exploratory and integrative strategy to complex diseases such as brain proteinopathies including AD, aimed at identifying simultaneous aberrant molecular pathways and predicting their temporal impact on the systems levels. The depiction of pathway-based molecular signatures of complex diseases contributes to the accurate and mechanistic stratification of distinct subcohorts of individuals at the earliest compensatory stage when treatment intervention may reverse, stop, or delay the disease. In addition, individualized drug selection may optimize treatment safety by decreasing risk and amplitude of side effects and adverse reactions. From a methodological point of view, comprehensive "omics"-based biomarkers will guide the exploration of spatio-temporal systems-wide morpho-functional shifts along the continuum of AD pathophysiology, from adaptation to irreversible failure. The Alzheimer Precision Medicine Initiative (APMI) and the APMI cohort program (APMI-CP) have commenced to facilitate a paradigm shift towards effective drug discovery and development in AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Medicina de Precisão , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Biomarcadores/sangue , Descoberta de Drogas , Humanos , Proteínas tau/antagonistas & inibidoresRESUMO
INTRODUCTION: Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls. METHODS: The pathophysiological role of CSF α-syn in asymptomatic subjects at risk of AD has not been explored. We performed a large-scale cross-sectional observational monocentric study of preclinical individuals at risk for AD (INSIGHT-preAD). RESULTS: We found a positive association between CSF α-syn concentrations and brain ß-amyloid deposition measures as mean cortical standard uptake value ratios. We demonstrate positive correlations between CSF α-syn and both CSF t-tau and p-tau181 concentrations. DISCUSSION: Animal models presented evidence, indicating that α-syn may synergistically and directly induce fibrillization of both tau and ß-amyloid. Our data indicate an association of CSF α-syn with AD-related pathophysiological mechanisms, during the preclinical phase of the disease.
Assuntos
Amiloide/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Transtornos da Memória/diagnóstico , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/diagnóstico , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Cognição , Estudos de Coortes , Estudos Transversais , Autoavaliação Diagnóstica , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Sintomas ProdrômicosRESUMO
INTRODUCTION: The diagnostic and classificatory performances of all combinations of three core (amyloid ß peptide [i.e., Aß1-42], total tau [t-tau], and phosphorylated tau) and three novel (neurofilament light chain protein, neurogranin, and YKL-40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimer's disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10-fold cross-validation. METHODS: The combinations ranking in the top 10 according to diagnostic accuracy in differentiating between distinct diagnostic categories were identified. RESULTS: The single biomarkers or biomarker combinations generating the best area under the receiver operating characteristics (AUROCs) were the following: the combination [amyloid ß peptide + phosphorylated tau + neurofilament light chain] for distinguishing between ADD patients and HC (AUROC = 0.86), t-tau for distinguishing between ADD and FTD patients (AUROC = 0.82), and t-tau for distinguishing between FTD patients and HC (AUROC = 0.78). CONCLUSIONS: Novel and established cerebrospinal fluid markers perform with at least fair accuracy in the discrimination between ADD and FTD. The classification of mild cognitive impairment individuals was poor.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/classificação , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Área Sob a Curva , Biomarcadores/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/classificação , Estudos Transversais , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/líquido cefalorraquidiano , Demência Frontotemporal/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas Nucleares/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas de Ligação a RNA , Curva ROC , Estudos Retrospectivos , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Neuroinflammation is a crucial mechanism in the pathophysiology of neurodegenerative diseases pathophysiology. Cerebrospinal fluid (CSF) YKL-40 - an indicator of microglial activation - has recently been identified by proteomic studies as a candidate biomarker for Alzheimer's disease (AD). Areas covered: We review the impact of CSF YKL-40 as a pathophysiological biomarker for AD and other neurodegenerative diseases. CSF YKL-40 concentrations have been shown to predict progression from prodromal mild cognitive impairment to AD dementia. Moreover, a positive association between CSF YKL-40 and other biomarkers of neurodegeneration - particularly total tau protein - has been reported during the asymptomatic preclinical stage of AD and other neurodegenerative diseases. Albeit preliminary, current data do not support an association between APOE-ε4 status and CSF YKL-40 concentrations. When interpreting the diagnostic/prognostic significance of CSF YKL-40 concentrations in neurodegenerative diseases, potential confounders - including age, metabolic and cardiovascular risk factors, diagnostic criteria for selecting cases/controls - need to be considered. Expert opinion/commentary: CSF YKL-40 represents a pathophysiological biomarker reflecting immune/inflammatory mechanisms in neurodegenerative diseases, associated with tau protein pathology. Besides being associated with tau pathology, CSF YKL-40 adds to the growing array of biomarkers reflecting distinct molecular brain mechanisms potentially useful for stratifying individuals for biomarker-guided, targeted anti-inflammatory therapies emerging from precision medicine.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Doenças Neurodegenerativas/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/fisiopatologia , Biomarcadores/líquido cefalorraquidiano , Humanos , Inflamação/líquido cefalorraquidiano , Inflamação/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Proteômica , Fatores de RiscoRESUMO
Abnormal levels of beta amyloid (Aß42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aß42 and tau) in order to better discriminate between AD and FTD; we identified Aß42/p-Tau181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Demência Frontotemporal/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Biomarcadores , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fosforilação , Curva ROCRESUMO
INTRODUCTION: We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) YKL-40 in discriminating (1) clinical Alzheimer's disease (AD) from cognitively healthy controls (HCs) and frontotemporal dementia (FTD) (level I) and (2) patients stratified by different pathophysiological profiles from HCs and FTD following a novel unbiased/descriptive categorization based on CSF biomarkers, independent of cognitive impairment severity (level II). METHODS: YKL-40 was compared among HCs (n = 21), mild cognitive impairment (n = 41), AD (n = 35), and FTD (n = 9) (level I) and among HCs (n = 21), AD pathophysiology (tau and amyloid ß) negative (n = 15), tau positive (n = 15), amyloid ß positive (n = 13), AD pathophysiology positive (n = 33), and FTD (n = 9) (level II). RESULTS: Level I: YKL-40 discriminated AD from HC and FTD (area under the receiver operating characteristic curves [AUROCs] = 0.69, 0.71). Level II: YKL-40 discriminated tau-positive individuals and AD pathophysiology-positive individuals from HC, AD pathophysiology-positive patients from FTD (AUROCs = 0.76, 0.72, 0.73). DISCUSSION: YKL-40 demonstrates fair performance in distinguishing tau-positive patients from HCs, suggesting it may aid clinical diagnosis and support a biomarker-guided pathophysiological stratification.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Idoso , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Feminino , Demência Frontotemporal/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos RetrospectivosRESUMO
Migraine clinical presentation and life-time course can be highly heterogeneous, with a subgroup of patients developing chronic migraine; moreover, migraine clinical spectrum is expanded by the association with different coexisting conditions and interictal dysfunctions. The aim of this study was to systematically evaluate migraine clinical features, daily functioning parameters, sleep pattern, presence of depressive-anxiety symptoms and body mass index (BMI) in a sample of 75 episodic and 75 chronic migraine without aura patients. Migraine-related disability, fatigue, daily sleepiness, subjective sleep quality, anxiety and depressive symptoms were, respectively, evaluated using the following questionnaires: Fatigue Severity Scale (FSS), Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder 7-item Scale (GAD-7), Patient Health Questionnaire 9-item Scale (PHQ-9). Mean FSS score (p < 0.001), PSQI score (p = 0.015), GAD-7 score (p = 0.019), PHQ-9 score (p < 0.001) and BMI score (p = 0.012) were significantly higher in chronic compared to episodic migraineurs. Additionally, a correlation analysis carried out in the total sample of 150 migraine patients documented a statistically significant, positive correlation between monthly frequency of migraine attacks and FSS score (p < 0.001), PSQI score (p = 0.006), GAD-7 score (p = 0.019), PHQ-9 score (p < 0.001) and BMI score (p = 0.049). Data from the present report seem to expand the concept of migraine as a continuum or spectrum, with greater occurrence of fatigue, poor sleep quality, anxiety-depressive symptoms and higher BMI score in chronic compared to episodic migraine patients; further investigation is certainly necessary to better define the biological basis and mechanisms associated with migraine transformation from episodic to chronic pattern.
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Ansiedade/etiologia , Índice de Massa Corporal , Depressão/etiologia , Fadiga/etiologia , Transtornos de Enxaqueca/complicações , Transtornos do Sono-Vigília/etiologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/classificação , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Índice de Gravidade de Doença , Inquéritos e QuestionáriosAssuntos
Betacoronavirus/patogenicidade , Cognição/fisiologia , Infecções por Coronavirus/complicações , Doença de Parkinson/fisiopatologia , Pneumonia Viral/complicações , Idoso , COVID-19 , Infecções por Coronavirus/virologia , Demência/fisiopatologia , Feminino , Humanos , Masculino , Pandemias , Doença de Parkinson/complicações , Pneumonia Viral/virologia , SARS-CoV-2RESUMO
BACKGROUND: Migraine is a complex multifactorial, neurobiological disorder, whose pathogenesis is not fully understood, nor are the mechanisms associated with migraine transformation from episodic to chronic pattern. A possible role of impaired oxidative mitochondrial metabolism in migraine pathogenesis has been hypothesized, and increased levels of peripheral markers of oxidative stress have been reported in migraine patients, although the literature data are limited and heterogeneous. OBJECTIVES: The aim of this cross-sectional study was to determine plasmatic levels of advanced oxidation protein products, ferric-reducing antioxidant power and total plasmatic thiol groups, all plasmatic markers related to oxidative stress, in a sample of chronic migraine patients and medication-overuse headache, compared to a control group of healthy subjects. METHODS: Thirty-three patients with a diagnosis of both chronic migraine and medication-overuse headache (International Classification of Headache Disorders,3rd edition, beta version) and 33 healthy, headache-free subjects were enrolled. Patients with comorbid/coexisting conditions were excluded, as well as patients in treatment with migraine preventive drugs. Plasmatic levels of advanced oxidation protein products, ferric-reducing antioxidant power, and total thiol groups were determined in migraine patients and controls; moreover, oxidative stress biomarkers were compared in migraine patients with triptan compared to non-steroidal anti-inflammatory drug overuse. RESULTS: The statistical analysis showed significantly lower levels of ferric-reducing antioxidant power and total plasmatic thiol groups, both expression of antioxidant power, in patients with chronic migraine and medication-overuse headache compared to controls (respectively, ferric antioxidant power median [interquartile range] 0.53 [0.22] vs 0.82 [0.11] mmol/L, P < .001; total thiol groups 0.25 [0.08] vs 0.51 [0.11] µmol/L, P < .001). Moreover, no statistically significant differences in oxidative stress biomarkers were detected between patients with triptan and nonsteroidal anti-inflammatory drug overuse. CONCLUSIONS: The data from the present study suggest that antioxidant capacity is lower in chronic migraine patients and medication-overuse headache compared to healthy headache-free subjects, with no differences between patients with triptan or nonsteroidal anti-inflammatory drug overuse. Further investigation is certainly necessary in order to define the causal or consequential role of an imbalance between pro-oxidants and antioxidant defenses in migraine pathogenesis and "chronification" and the possible therapeutic implications in clinical practice.
Assuntos
Produtos da Oxidação Avançada de Proteínas/sangue , Transtornos da Cefaleia Secundários/metabolismo , Transtornos de Enxaqueca/metabolismo , Estresse Oxidativo , Adulto , Produtos da Oxidação Avançada de Proteínas/metabolismo , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Doença Crônica , Estudos Transversais , Feminino , Transtornos da Cefaleia Secundários/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/tratamento farmacológico , Agonistas do Receptor de Serotonina/efeitos adversos , Agonistas do Receptor de Serotonina/uso terapêutico , Triptaminas/efeitos adversos , Triptaminas/uso terapêuticoRESUMO
Parkinson's disease (PD) is a major worldwide public health problem with a prevalence that is expected to increase dramatically in the coming decades. Because administrative data are useful for epidemiologic and health service studies, we aimed to define procedural algorithms to identify PD patients (on a regional basis) using these data. We built two a priori algorithms, respecting privacy laws, with increasing theoretical specificity for PD including: (1) a hospital discharge diagnosis of PD; (2) PD-specific exemption; (3) a minimum of two separate prescriptions of an antiparkinsonian drug. The two algorithms differed for drugs included. Sensitivities were tested on an opportunistic sample of 319 PD patients from the databases of 5 regional movement disorders clinics. The estimated prevalence of PD in the sample population from Tuscany was 0.49 % for algorithm 1 and 0.28 % for algorithm 2. Algorithm 1 correctly identified 291 PD patients (sensitivity 91.2 %), and algorithm 2 identified 242 PD patients (sensitivity 75.9 %). We developed two reproducible algorithms demonstrating increasing theoretical specificity with good sensitivity in identifying PD patients based on an evaluation of administrative data. This may represent a low-cost strategy to reliably follow up a large number of PD patients as a whole for evaluating the effects of therapies, disease progression and prevalence.
Assuntos
Bases de Dados Factuais/estatística & dados numéricos , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Antiparkinsonianos/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Prevalência , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Olfactory hypersensitivity may occur during migraine attacks and has been found to be very specific for this form of headache. Aim of this study was to investigate if migraineurs with ictal osmophobia have particular clinical features comparing to patients without ictal osmophobia. We recruited 200 consecutive migraineurs. Other primary headaches comorbidity and migraine prophylaxis were exclusion criteria. Each patient was interviewed following a structured questionnaire including general features about migraine, depression and anxiety symptoms. Migraine triggers both spontaneously and selecting from a specific list. Allodynia during the migraine attack was measured using the Allodynia symptoms check-list 12 (ASC-12). Eighty four (42 %) patients are non-osmophobic vs. 116 patients (58 %) who are osmophobic. After a logistic regression analysis, pain intensity (OR 1.391; p = 0.008) and anxiety (OR 1.099; p = 0.047) were significantly higher while aura (OR 0.421; p = 0.028) is less frequent in osmophobic migraineurs. We found significant differences in clinical features of osmophobic patients in respect to non-osmophobic ones. Ictal osmophobia seems being related to a broader sensorial hypersensitivity that could lead to a more florid clinical presentation.
Assuntos
Transtornos de Enxaqueca/epidemiologia , Transtornos do Olfato/epidemiologia , Adulto , Ansiedade/epidemiologia , Estudos Transversais , Depressão/epidemiologia , Feminino , Humanos , Hiperalgesia/epidemiologia , Entrevistas como Assunto , Modelos Logísticos , Masculino , Medição da Dor , Inquéritos e QuestionáriosRESUMO
The presence of brain atrophy and its progression in early Parkinson's disease (PD) are still a matter of debate, particularly in patients without cognitive impairment. The aim of this longitudinal study was to assess whether PD patients who remain cognitively intact develop progressive atrophic changes in the early stages of the disease. For this purpose, we employed high-resolution T1-weighted MR imaging to compare 22 drug-naïve de novo PD patients without cognitive impairment to 17 age-matched control subjects, both at baseline and at three-year follow-up. We used tensor-based morphometry to explore the presence of atrophic changes at baseline and to compute yearly atrophy rates, after which we performed voxel-wise group comparisons using threshold-free cluster enhancement. At baseline, we did not observe significant differences in regional atrophy in PD patients with respect to control subjects. In contrast, PD patients showed significantly higher yearly atrophy rates in the prefrontal cortex, anterior cingulum, caudate nucleus, and thalamus when compared to control subjects. Our results indicate that even cognitively preserved PD patients show progressive cortical and subcortical atrophic changes in regions related to cognitive functions and that these changes are already detectable in the early stages of the disease.