RESUMEN
OBJECTIVE: To report clinical and laboratory characteristics, treatment, and clinical outcomes of patients admitted for neurologic diseases with and without coronavirus disease 2019 (COVID-19). METHODS: In this retrospective, single-center cohort study, we included all adult inpatients with confirmed COVID-19 admitted to a neuro-COVID unit beginning February 21, 2020, who had been discharged or died by April 5, 2020. Demographic, clinical, treatment, and laboratory data were extracted from medical records and compared (false discovery rate corrected) to those of neurologic patients without COVID-19 admitted in the same period. RESULTS: One hundred seventy-three patients were included in this study, of whom 56 were positive and 117 were negative for COVID-19. Patients with COVID-19 were older (77.0 years, interquartile range [IQR] 67.0-83.8 years vs 70.1 years, IQR 52.9-78.6 years, p = 0.006), had a different distribution regarding admission diagnoses, including cerebrovascular disorders (n = 43, 76.8% vs n = 68, 58.1%), and had a higher quick Sequential Organ Failure Assessment (qSOFA) score on admission (0.9, IQR 0.7-1.1 vs 0.5, IQR 0.4-0.6, p = 0.006). In-hospital mortality rates (n = 21, 37.5% vs n = 5, 4.3%, p < 0.001) and incident delirium (n = 15, 26.8% vs n = 9, 7.7%, p = 0.003) were significantly higher in the COVID-19 group. Patients with COVID-19 and without COVID with stroke had similar baseline characteristics, but patients with COVID-19 had higher modified Rankin Scale scores at discharge (5.0, IQR 2.0-6.0 vs 2.0, IQR 1.0-3.0, p < 0.001), with a significantly lower number of patients with a good outcome (n = 11, 25.6% vs n = 48, 70.6%, p < 0.001). In patients with COVID-19, multivariable regressions showed increasing odds of in-hospital death associated with higher qSOFA scores (odds ratio [OR] 4.47, 95% confidence interval [CI] 1.21-16.5, p = 0.025), lower platelet count (OR 0.98, 95% CI 0.97-0.99, p = 0.005), and higher lactate dehydrogenase (OR 1.01, 95% CI 1.00-1.03, p = 0.009) on admission. CONCLUSIONS: Patients with COVID-19 admitted with neurologic disease, including stroke, have a significantly higher in-hospital mortality and incident delirium and higher disability than patients without COVID-19.
Asunto(s)
Infecciones por Coronavirus/epidemiología , Pacientes Internos/estadística & datos numéricos , Enfermedades del Sistema Nervioso/epidemiología , Neumonía Viral/epidemiología , Anciano , Anciano de 80 o más Años , Betacoronavirus/aislamiento & purificación , COVID-19 , Estudios de Casos y Controles , Comorbilidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/mortalidad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
Huntington's disease is an inherited disorder caused by expanded stretch of consecutive trinucleotides (cytosine-adenosine-guanine, CAG) within the first exon of the huntingtin (HTT) gene on chromosome 4 (p16.3). The mutated huntingtin (mHTT) gains toxic function, probably through mechanisms that involve aberrant interactions in several pathways, causing cytotoxicity. Pathophysiology of disease involves several tissues; indeed it has been shown that there is a broad toxic effect of mHTT in the peripheral tissue of patients with HD, not only in the central nervous system. In this study we compared gene expression profiles (GEP) of HD fibroblasts and matched controls using microarray technology. We used RT-PCR to test the consistency of the microarray data and we found four genes up-regulated in HD patients with respect to control individuals. The genes appear to be involved in different pathways that have been shown to be perturbed even in HD models and patients. Although our study is preliminary and has to be extended to a larger cohort of HD patients and controls, nevertheless it shows that gene expression profiles seem to be altered in the fibroblasts of HD patients. Validation of the differential expressions at the protein level is required to ascertain if this cell type can be considered a suitable model for the identification of HD biomarkers.
Asunto(s)
Fibroblastos/fisiología , Enfermedad de Huntington/patología , Transcriptoma/fisiología , Regulación hacia Arriba/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Adulto , Anciano , Femenino , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Fosfolipasa C beta/genética , Fosfolipasa C beta/metabolismo , Reproducibilidad de los Resultados , Expansión de Repetición de Trinucleótido/genética , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Regulación hacia Arriba/fisiología , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismoRESUMEN
Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative syndrome characterized by supranuclear palsy, postural instability, and mild dementia. Neuropathologically, PSP is a four-repeat tauopathy, defined by the accumulation of neurofibrillary tangles and tufted astrocytes. Etiology remains elusive, but genetic background has a key-role in the disease pathogenesis. Recent studies have reported high familial aggregation in PSP patients, and it has been widely demonstrated that Microtuble Associated Protein Tau (MAPT) gene mutations are causative of monogenic autosomal dominant PSP. In sporadic cases, genetic advances have further confirmed the role of MAPT in increasing disease risk, and the H1 MAPT haplotype has been consistently associated with PSP, while the H2 haplotype seems protective. Conversely, no major environmental risk factors have been reported so far. A proper evaluation of known susceptibility factors related to PSP pathogenesis may help in defining neuroprotective therapeutic approaches.
Asunto(s)
Parálisis Supranuclear Progresiva/genética , Proteínas tau/genética , Adulto , Anciano , Femenino , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Ovillos Neurofibrilares/patología , Tauopatías/genéticaRESUMEN
BACKGROUND: Corticobasal syndrome (CBS) has a heterogeneous neuropathological spectrum, ranging from the classical corticobasal degeneration to Alzheimer's disease (AD). The neuropathology of CBS is still unpredictable. CSF tau/abeta ratio is a reliable marker of AD. OBJECTIVE: To evaluate the presence of a distinct clinical and neuroimaging CBS phenotype according to CSF pattern. METHODS: 30 patients fulfilling current clinical criteria for CBS entered the study. Each patient underwent a clinical and standardised neuropsychological assessment, and CSF analysis (total tau and abeta42 dosages). CSF AD-like pattern and CSF non-AD like pattern (nAD-like) were identified. In 23 CBS cases, (99m)Tc-ECD single photon emission computed tomography (SPECT) scan was performed and analysed by statistical parametric mapping. RESULTS: CSF AD-like pattern was reported in six cases (20%). The two subgroups did not differ in demographic characteristics or global cognitive impairment. The AD-like group showed greater impairment of memory performances, language and psychomotor speed while the nAD-like group had more severe extrapyramidal syndrome with comparable apraxia scores. Voxel by voxel analysis on SPECT images demonstrated that CBS AD-like patients had greater hypoperfusion in the brain areas typically affected by AD-namely, precuneus, posterior cingulate and hippocampus, bilaterally-compared with nAD-like patients (p<0.001). No clusters above the pre-established threshold were detected when nAD-like were compared with AD-like patients. CONCLUSIONS: CSF AD-like profile in CBS is associated with earlier memory impairment and brain abnormalities typically found in classical AD. These findings argue for the usefulness of CSF testing to identify AD in CBS, and might suggest a different pharmacological approach on the basis of biological data.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Ganglios Basales/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/psicología , Pruebas Neuropsicológicas , Valor Predictivo de las Pruebas , Síndrome , Exametazima de Tecnecio Tc 99m , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Early-onset Alzheimer's disease (EOAD) is a rare genetic disorder mainly attributable to a mutation in the presenilin 1 (PSEN1) gene. Clinical profile and instrumental findings share common features with adult neuronal ceroid lipofuscinosis. We documented the clinical course in EOAD patients bearing mutations in PSEN1. Genetic screening for dementia, EEG acquisition and determination of granular osmiophilic elements (GRODs) from skin biopsy were performed in a patient suffering from a severe cognitive decline and visual hallucinations. The pathogenic M146I mutation in PSEN1, and instrumental findings common to adult neuronal ceroid lipofuscinosis were found in the same patient. Posterior low pseudoperiodic sequences at EEG and GRODS elements at skin biopsy might constitute a signature in EOAD.
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Enfermedad de Alzheimer/diagnóstico , Gránulos Citoplasmáticos/ultraestructura , Adulto , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Electroencefalografía , Femenino , Humanos , Cuerpos de Inclusión/ultraestructura , Microscopía Electrónica de Transmisión , Presenilina-1/genética , Piel/patologíaRESUMEN
Though neuroimaging, pathology and pathophysiology suggest a subcortical and deep cortical involvement in Frontotemporal Lobar Degeneration (FTLD), no studies have comprehensively assessed the associated gray matter (GM) volume changes. We measured caudate, putamen, thalamus, and amygdala GM volume using probabilistic a-priori regions of interest (ROIs) in 53 early FTLD patients (38 behavioral variant FTD [bvFTD], 9 Semantic Dementia [SD], 6 Progressive Non-Fluent Aphasia [PNFA]), and 25 age-matched healthy controls (HC). ANOVA showed significant (P<0.001) main effect of diagnosis, and significant interactions for diagnosis and region, and diagnosis and hemisphere. Post-hoc comparisons with HC showed bilateral GM atrophy in the caudate, putamen and thalamus, in bvFTD; a left-confined GM reduction in the amygdala in SD; and bilateral GM atrophy in the caudate and thalamus, and left-sided GM reduction in the putamen and amygdala in PNFA. Correlation analyses suggested an association between GM volumes and language, psychomotor speed and behavioral disturbances. This study showed a widespread involvement of subcortical and deep cortical GM in early FTLD with patterns specific for clinical entity.
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Corteza Cerebral/patología , Degeneración Lobar Frontotemporal/patología , Anciano , Amígdala del Cerebelo/patología , Afasia/patología , Atrofia/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Putamen/patologíaRESUMEN
Progranulin (PGRN) mutations have been recognized to be monogenic causes of frontotemporal lobar degeneration (FTLD). PGRN Thr272fs mutation in the Italian population has been previously identified. In the present study, we evaluated the occurrence of a founder effect studying 8 polymorphic microsatellite markers flanking the PGRN gene in 14 apparently unrelated families. We identified a common haplotype associated with PGRN Thr272fs carriers, assuming common ancestry. The inferred age analysis (range between 260 [95% credible set: 227-374] and 295 [95% credible set: 205-397] generations) places the introduction of the mutation back to the Neolithic era when the Celts, the population of that period, settled in Northern Italy. PGRN Thr272fs mutation appears to be as either behavioral frontotemporal dementia (80%) or primary progressive aphasia (20%), it was equally distributed between male and female, and the mean age at onset was 59.6 ± 5.9 (range 53-68). In 14 families, autosomal dominant pattern of inheritance was present in 64.2% of cases. No clinical predictors of disease onset were demonstrated. The identification of a large cohort of frontotemporal lobar degeneration (FTLD) patients with homogeneous genetic background well may be used in the search of disease modulators to elucidate genotype-phenotype correlations of progranulopathies.
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Degeneración Lobar Frontotemporal/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Linaje , Fenilalanina/genética , Treonina/genética , Edad de Inicio , Anciano , Encéfalo/irrigación sanguínea , Encéfalo/patología , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Degeneración Lobar Frontotemporal/epidemiología , Degeneración Lobar Frontotemporal/patología , Frecuencia de los Genes , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Italia/epidemiología , Imagen por Resonancia Magnética , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Oxígeno/sangre , ProgranulinasRESUMEN
The FOXP2 gene is mutated in a severe monogenic form of speech and language deficits, but no study on the influence of genetic variations within FOXP2 in neurological disorders characterized by language impairment is available yet. In the present study, we investigated the impact of common FOXP2 polymorphisms with regard to frontotemporal lobar degeneration (FTLD). Two-hundred ten FTLD patients underwent clinical and a wide standardized neuropsychological examination as well as brain imaging. In all patients, and in 200 age-matched healthy controls, four FOXP2 polymorphisms were evaluated, namely rs2396753, rs1456031, rs17137124 and rs1852469. SPECT images were analyzed by Statistical Parametric Mapping (SPM5). No significant differences of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls were observed. A significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores was reported. The two polymorphisms showed an addictive effect. When the analysis was computed on the number of observations over time, and 391 assessments considered, comparable results were obtained. FTLD patients carrying at-risk polymorphisms showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers (p < 0.005). Genetic variations within FOXP2 do not represent a genetic risk to FTLD per se, but modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language-associated brain areas.
Asunto(s)
Factores de Transcripción Forkhead/fisiología , Degeneración Lobar Frontotemporal/genética , Trastornos del Lenguaje/genética , Fenotipo , Habla/fisiología , Anciano , Femenino , Estudios de Seguimiento , Factores de Transcripción Forkhead/genética , Degeneración Lobar Frontotemporal/complicaciones , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Humanos , Lenguaje , Trastornos del Lenguaje/diagnóstico por imagen , Trastornos del Lenguaje/etiología , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
Cerebrospinal fluid (CSF) tau ratio decrease (33kDa/55kDa forms) and mid-saggital midbrain-to-pons (MP) atrophy have been suggested as diagnostic markers for progressive supranuclear palsy (PSP). The usefulness of their combined evaluation has never been tested. We evaluated the CSF tau ratio and the MP atrophy as a combined marker for early identification of PSP. A total of 87 subjects, namely 18 PSP, 25 controls (CON), 16 corticobasal syndrome (CBS), and 28 frontotemporal dementia (FTD), were included. Each subject underwent a lumbar puncture and a conventional MRI scan to assess CSF tau 33 kDa/55 kDa ratio and mid-saggital MP measure, respectively. CSF tau ratio and MP ratio were significantly reduced in PSP patients when compared to CON, CBS, and FTD (p< 0.001). Data-based "optimal" combination of CSF tau ratio and MP measure was defined, and the combined marker TrMp= sqrt[3]{CSF Tau ratio}} × {MP ratio} was considered. Considering the combined marker, the difference between the area under the curve (dAUC) of the receiver operating characteristic analysis in PSP versus the various subgroups was higher by about 10% than that obtained by each marker individually. In PSP versus others, a proposed "best" cut-off of TrMP = 0.182 resulted in 94.2% sensitivity and 84.0% specificity. When patients with onset of symptoms ≤ 2 years were included, TrMP resulted significantly decreased in PSP compared to CBS (p< 0.001) and FTD (p< 0.001). The combined marker increases the discriminative power in identifying PSP and suggests that the interplay of different markers should be considered in future trials to enhance diagnostic accuracy from the early stages.
Asunto(s)
Mesencéfalo/patología , Puente/patología , Parálisis Supranuclear Progresiva/líquido cefalorraquídeo , Parálisis Supranuclear Progresiva/patología , Proteínas tau/líquido cefalorraquídeo , Anciano , Atrofia , Enfermedades de los Ganglios Basales/líquido cefalorraquídeo , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/patología , Biomarcadores/líquido cefalorraquídeo , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Demencia Frontotemporal/líquido cefalorraquídeo , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/patología , Humanos , Masculino , Mesencéfalo/metabolismo , Persona de Mediana Edad , Pruebas Neuropsicológicas , Puente/metabolismo , Parálisis Supranuclear Progresiva/diagnósticoRESUMEN
Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are in the spectrum of tauopathies and recognized to have a strong genetic background. It has been widely reported that MAPT tau haplotype H1 is a genetic risk factor in both conditions, but no other genetic determinants have so far been proposed. Recently, vascular endothelial growth factor (VEGF) haplotypes were reported to confer risk to frontotemporal dementia (FTD). The aim of this study was to evaluate the role of VEGF genetic determinants in PSP and CBS susceptibility. We evaluated a cohort of 687 unrelated Italian subjects, including 117 PSP, 108 CBS, 199 FTD, and 263 healthy controls. Genotype and allele frequencies of three well-known polymorphisms located within the VEGF promoter (-2578C/A, -1190G/A, and -1154G/A) were carried out. Genetic analysis revealed the presence of significant changes in terms of genotype and allele distributions in patients compared to healthy controls. A-G-G haplotype (-2578C/A, 1190G/A, -1154G/A) was overrepresented in both PSP (OR=6.64, 95% CI=2.3-19.6, P=0.0003, CGG=reference) and CBS (OR=5.20, 95% CI=1.70-15.9, P=0.003, CGG=reference) compared to healthy subjects. No differences between PSP and CBS and FTD were found, and the A-G-G haplotype was also overrepresented in FTD. Overall, these data suggest that VEGF gene variability represents a susceptibility factor for PSP and CBS. These data argue that additional genes may confer disease risk to PSP and CBS, and to FTD as well, beyond the MAPT tau haplotype. Further studies are warranted.
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Enfermedades de los Ganglios Basales/etiología , Enfermedades de los Ganglios Basales/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Parálisis Supranuclear Progresiva/genética , Factor A de Crecimiento Endotelial Vascular/genética , Anciano , Distribución de Chi-Cuadrado , Femenino , Demencia Frontotemporal/sangre , Demencia Frontotemporal/etiología , Demencia Frontotemporal/genética , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo/métodos , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Estadísticas no Paramétricas , Parálisis Supranuclear Progresiva/sangre , Parálisis Supranuclear Progresiva/etiología , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
BACKGROUND: Frontotemporal lobar degeneration (FTLD) encompasses different clinical subtypes but with overlapping features. Establishing whether FTLD represents a continuum or recognizes distinct subgroups may be crucial for diagnostic purposes and therapeutic approaches. OBJECTIVE: To investigate whether cognitive profiles in a large sample of FTLD patients reflect qualitatively distinct subtypes, variants along a single continuum of severity, or severity differences within subtypes. METHOD: Latent class analysis (LCA), exploratory factor analysis (FA), and mixture factor analysis (MFA) modeling were applied to a wide neuropsychological assessment data. LCA corresponds to qualitatively distinct subtypes, FA corresponds to quantitatively severity differences, and MFA allows for both subtypes and severity differences within subtypes. RESULTS: The authors consecutively enrolled 314 FTLD patients. A comparison of the different models shows that MFA models provided a superior fit to the data than any of the LCA or exploratory FA models. The "best" MFA model was defined by two continuous variables evaluating the disease severity within two groups of patients ("good" and "bad" performers). These two populations have been called "benign" and "malignant" FTLD. CONCLUSIONS: FTLD recognizes distinct subgroups beyond the disease severity, namely a benign form and a more malignant form. This observation needs to be taken into account in future clinical trials and for therapeutic approaches.
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Demencia/diagnóstico , Degeneración Lobar Frontotemporal , Índice de Severidad de la Enfermedad , Anciano , Investigación Conductal/instrumentación , Investigación Conductal/métodos , Investigación Conductal/normas , Cognición , Demencia/patología , Análisis Factorial , Estudios de Factibilidad , Femenino , Lóbulo Frontal/patología , Degeneración Lobar Frontotemporal/diagnóstico , Degeneración Lobar Frontotemporal/epidemiología , Degeneración Lobar Frontotemporal/patología , Humanos , Italia , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas/normas , Pruebas Neuropsicológicas/estadística & datos numéricos , Lóbulo Temporal/patologíaRESUMEN
BACKGROUND: Establishing the short-term prognosis in Frontotemporal Lobar Degeneration (FTLD) is a clinical challenge for defining disease outcomes and monitoring therapeutic interventions. No reliable neuropsychological assessment balancing all FTLD aspects is available yet, thus no clear-cut follow-up study has been performed. OBJECTIVE: To evaluate the rate of progression and the predictors of worsening in FTLD patients. METHODS: One-hundred twenty-seven FTLD patients entered the study and were re-evaluated at 1-year follow-up. A statistical driven approach on wide neuropsychological, behavioral, and functional data was applied to identify homogeneous groups both at baseline and at follow-up within FTLD. Three set of predictors on disease progression were considered: (i) the demographic characteristics, (ii) the genetic background, i.e. Apolipoprotein E (APOE) genotype, Tau haplotype, and functional polymorphisms affecting serotonin and dopamine pathways, and (iii) the clinical phenotype. RESULTS: Among FTLD, two groups of patients were recognized on the basis of the overall assessment, thus termed for different disease severity as "good performers" and "bad performers". At 1-year follow-up, almost 30% of FTLD patients progressed from "good" to "bad" performances, whilst 70% maintained stable "good" performances. APOE varepsilon4 allele, Tau H2 haplotype and behavioral variant FTD phenotype were associated with worse prognosis over time. CONCLUSIONS: This preliminary study proposed genetic and clinical predictors in FTLD progression. The identification of disease-modifying predictors of prognosis opens a new avenue in studying FTLD, and may contribute to define outcomes and to monitor pharmacological targets.
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Degeneración Lobar Frontotemporal/diagnóstico , Degeneración Lobar Frontotemporal/genética , Anciano , Apolipoproteína E4/genética , Catecol O-Metiltransferasa/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Degeneración Lobar Frontotemporal/terapia , Predisposición Genética a la Enfermedad , Humanos , Masculino , Pruebas Neuropsicológicas , Fenotipo , Pronóstico , Factores de Riesgo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Factores de Tiempo , Proteínas tau/genéticaRESUMEN
A correct clinical diagnosis in the early stage of Alzheimer Disease (AD) is mandatory given the current available treatment with acetylcholine esterase inhibitors. Moreover, a early to preclinical diagnosis would allow to identify patients eligible for future disease-modifying therapies. In the last ten years, we have focused our attention on peripheral markers, evaluating the role of platelet Amyloid Precursor Protein (APP) forms as a reliable tool for AD diagnosis since preclinical stages. APP is the key player in AD pathogenesis, and platelets contain all the enzymatic machinery to its processing, thus being the ideal candidate where to study AD pathogenetic mechanisms. In this review, we summarise the published data regarding the usefulness of platelet APP form ratio in the diagnosis of early AD. Approaches combining APP form ratio along with neuroimaging markers show the promise to accurately identify AD, even in the pre-symptomatic stage.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Biomarcadores/metabolismo , Plaquetas/metabolismo , Anciano , Diagnóstico Precoz , HumanosRESUMEN
BACKGROUND: A careful characterization of behavioral abnormalities in corticobasal degeneration syndrome (CBDS) and progressive supranuclear palsy (PSP) by reliable tools is still lacking. Literature data provided evidence of the usefulness of the Frontal Behavioral Inventory (FBI) to operationalize such disturbances, particularly in the frontotemporal lobar degeneration spectrum. The study aimed to evaluate the frequency and pattern of presentation of behavioral disturbances in a large sample of CBDS and PSP patients by FBI. METHODS: Sixty-eight CBDS and 57 PSP patients entered the study and underwent a standardized clinical and neuropsychological battery, and a structural brain imaging study. Behavioral disturbances were carefully analyzed by FBI. RESULTS: FBI scores were relatively low in both groups, being 6.7 +/- 8.2 and 5.6 +/- 6.1 in CBDS and PSP, respectively. Comparison of the behavioral profile between CBDS and PSP patients showed significant differences in apathy were more frequent in the latter (57.9% vs. 33.8%, P = 0.007), and the presence of alien hand/apraxia more frequent in the former group 39.7% vs. 10.5%, P = 0.001). Apathy correlated neither with age nor with motor disturbances as measured by UPDRS-III. Overall, the most frequent behavioral abnormalities present in both groups (>25%) were aspontaneity and logopenia. Aphasia (27.9%) and irritability (35.3%) were more frequent in CBDS compared to PSP, even if not statistically different. DISCUSSION: The present study has provided measures of behavioral disturbances in a population of PSP and CBDS patients, and further confirms the usefulness of the FBI scale.
Asunto(s)
Síntomas Conductuales/diagnóstico , Trastornos del Conocimiento/diagnóstico , Demencia/diagnóstico , Parálisis Supranuclear Progresiva/diagnóstico , Anciano , Síntomas Conductuales/psicología , Encéfalo/patología , Trastornos del Conocimiento/psicología , Demencia/patología , Demencia/psicología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Inventario de Personalidad , Parálisis Supranuclear Progresiva/patología , Parálisis Supranuclear Progresiva/psicología , Encuestas y Cuestionarios , Síndrome , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
OBJECTIVE: To assess the prevalence and the characteristics of silent myocardial ischaemia (SMI) and ventricular arrhythmias (VA) in subjects with Alzheimer's disease (AD) and mild cognitive impairment (MCI) and their relationships with QT interval dispersion (QTD). METHODS: Thirty-three subjects with AD, 39 subjects with MCI, and 29 cognitive healthy control subjects matched for demographic characteristics, hypertensive condition, smoking habits, and laboratory parameters were enrolled. Each subject underwent clinical and cognitive examination, a structural brain imaging study, electrocardiogram (ECG), 24-h ECG recording, 24-h blood pressure monitoring, and echocardiogram. Detection and characterization of QT dispersion, SMI and VA were performed. RESULTS: The three groups were comparable regarding demographic and basal cardiovascular characteristics: notwithstanding this, SMI episodes were observed only in AD and MCI patients (19 and 14, respectively). A significantly greater prevalence of repetitive ventricular premature beats was observed in AD (mean 8.56+/-13.1) and in MCI (1.8+/-7.2) vs. control (0.7+/-1.7). The QTD, the ischaemic burden and the number of repetitive ventricular beats revealed to be significantly related. CONCLUSIONS: Increased prevalence of SMI and potentially ominous VA were found in AD and, to a lesser extent, in MCI. SMI and repetitive VA were significantly related with QTD. These findings could be related to an increased risk of sudden cardiac death in AD and MCI patients.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Arritmias Cardíacas/epidemiología , Trastornos del Conocimiento/complicaciones , Isquemia Miocárdica/epidemiología , Anciano , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/mortalidad , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/mortalidad , Monitoreo Ambulatorio de la Presión Arterial , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/mortalidad , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Ecocardiografía , Electrocardiografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/mortalidad , Escalas de Valoración Psiquiátrica , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Data on white matter changes in corticobasal degeneration syndrome (CBDS) are not yet available, whereas cortical gray matter loss is a feature of this condition. The structural abnormalities related to a key feature of CBDS (limb apraxia) are unknown. OBJECTIVES: To measure selective structural changes in early CBDS using diffusion tensor imaging and voxel-based morphometry and to evaluate the structural correlates of limb apraxia. DESIGN: Patient and control group comparison. SETTING: Referral center for dementia and movement disorders. PARTICIPANTS: Twenty patients with CBDS and 21 matched control subjects. INTERVENTIONS: Clinical and standardized neuropsychological evaluations, including assessment of limb apraxia. MAIN OUTCOME MEASURES: Gray and white matter changes in early CBDS. RESULTS: Diffusion tensor imaging revealed decreases in fractional anisotropy in the long frontoparietal connecting tracts, the intraparietal associative fibers, and the corpus callosum. Fractional anisotropy was also reduced in the sensorimotor projections of the cortical hand areas. Voxel-based morphometry showed a prevalent gray matter reduction in the left hemisphere (in the inferior frontal and premotor cortices, parietal operculum, superotemporal gyrus, and hippocampus). The pulvinar, bilaterally, and the right cerebellar cortex also showed atrophy. Limb apraxia correlated with parietal atrophy and with fractional anisotropy reductions in the parietofrontal associative fibers (P < .01). The limb-kinetic component of apraxia correlated with reduction of hand sensorimotor connecting fibers. CONCLUSIONS: The present integrative approach to in vivo structural anatomy combines hodologic imaging, describing patterns of white matter connections between cortical areas, with neuropsychological data. This provides new evidence of gray matter and fiber tract abnormalities in early-phase disease and contributes to clarifying the neural basis of apraxia in CBDS.
Asunto(s)
Apraxias/patología , Enfermedades de los Ganglios Basales/patología , Corteza Cerebral/patología , Cuerpo Calloso/patología , Enfermedades Neurodegenerativas/patología , Anciano , Apraxias/diagnóstico , Apraxias/psicología , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/psicología , Imagen de Difusión por Resonancia Magnética/métodos , Extremidades/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/psicología , SíndromeRESUMEN
Frontotemporal lobar degeneration (FTLD) recognises high familial incidence, with up to 50% of patients reported to have a family history of similar dementia. It has been reported that mutations within progranulin (PGRN) gene are a major cause of FTLD in the USA and worldwide, counting for 5-10% of FTLD and for 20-25% of familiar FTLD cases. The aim of the present study was to define the role of PGRN genetic variations in a large sample of consecutive patients with FTLD in Italy. Two-hundred forty-three FTLD patients were investigated. Each subject performed a clinical and neuropsychological evaluation, a functional and structural brain imaging, and the diagnosis was confirmed by at least 1 year follow-up. PGRN sequencing was performed in all FTLD patients and in 121 healthy age-matched controls drawn from the same geographic area. Only one PGRN pathogenetic mutation was found, consisting of a four-base pair deletion in the coding sequence of exon 8 (delCACT). This mutation was recognised in four patients, being the overall frequency of mutations in our clinical series of 1.64%. Considering only patients with a well-known family history for dementia, the frequency of this mutation was 6%. Moreover, four missense mutations within intron regions (g.100474G>A, g.100674G>A, g.101266G>A, g.102070G>A) were found. The frequency of these genetic variations did not differ in patients compared to controls, and they did not influence on clinical FTLD phenotype. In conclusion, this study supports a lower frequency of PGRN mutations amongst FTLD patients in Italy compared to literature data and further underlies the genetic heterogeneity of FTLD.
Asunto(s)
Demencia/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Mutación , Anciano , Secuencia de Bases , Estudios de Casos y Controles , Cartilla de ADN/genética , Demencia/patología , Demencia/fisiopatología , Exones , Femenino , Mutación del Sistema de Lectura , Frecuencia de los Genes , Variación Genética , Humanos , Intrones , Italia , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido Simple , Progranulinas , Eliminación de SecuenciaRESUMEN
BACKGROUND: The role of modifiable and non-modifiable variables in Frontotemporal Dementia (FTD) as compared to Alzheimer's dDisease (AD) and to Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration Syndrome (CBDS) has not been extensively evaluated. In particular, low education levels have been reported to be a risk factor for AD, but their contribution in FTD is yet not known. OBJECTIVE: To investigate the role of education, other modifiable and non-modifiable factors in FTD as compared to AD, PSP and CBDS patients. METHODS: One hundred and seventeen FTD patients, 400 AD, 55 PSP, and 55 CBDS entered the study. Demographic and clinical characteristics were carefully recorded. Age, gender, family history for dementia and Apolipoprotein E (APOE) genotype were considered as non-modifiable factors; education and comorbidities were included as modifiable variables. Regression analyses were applied in order to identify differences among groups. RESULTS: FTD differed from AD patients in terms of younger age, positive family history and gender status. In regard to APOE genotype, no differences between FTD and AD were found, but FTD showed higher prevalence of epsilon 4 allele compared to both CBDS and PSP patients (p < 0.05). When modifiable factors were considered, FTD were higher educated than AD patients (p < 0.001). Regression analysis identified younger age, positive family history, and education levels as independently associated variables to FTD diagnosis compared to AD (F = 21.27, R(2) = 24.1, p = 0.036). CONCLUSION: Our results highlight that the contribution of education and non-modifiable factors is likely different in FTD and AD. Further work is needed to completely establish the role of this modifiable variable as a potential area of intervention for dementias.