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INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-ß1-42 (Aß42)-positive status. METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume. RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001). DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter. HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aß42 status in 11 memory clinic cohorts. Aß42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.
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Arterioloesclerosis , Demencia , Sustancia Blanca , Humanos , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Masculino , Sustancia Blanca/patología , Arterioloesclerosis/patología , Péptidos beta-Amiloides/metabolismo , Demencia/patología , Imagen por Resonancia MagnéticaRESUMEN
INTRODUCTION: Impact of white matter hyperintensities (WMH) on cognition likely depends on lesion location, but a comprehensive map of strategic locations is lacking. We aimed to identify these locations in a large multicenter study. METHODS: Individual patient data (n = 3525) from 11 memory clinic cohorts were harmonized. We determined the association of WMH location with attention and executive functioning, information processing speed, language, and verbal memory performance using voxel-based and region of interest tract-based analyses. RESULTS: WMH in the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus were significantly related to domain-specific impairment, independent of total WMH volume and atrophy. A strategic WMH score based on these tracts inversely correlated with performance in all domains. DISCUSSION: The data show that the impact of WMH on cognition is location-dependent, primarily involving four strategic white matter tracts. Evaluation of WMH location may support diagnosing vascular cognitive impairment. HIGHLIGHTS: We analyzed white matter hyperintensities (WMH) in 3525 memory clinic patients from 11 cohorts The impact of WMH on cognition depends on location We identified four strategic white matter tracts A single strategic WMH score was derived from these four strategic tracts The strategic WMH score was an independent determinant of four cognitive domains.
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Disfunción Cognitiva , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Imagen por Resonancia Magnética , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Cognición , Función Ejecutiva , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. METHODS: DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. RESULTS: 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39-64 vs. median 64 years, range 36-92, p = 0.018 and median 63 years, range 54-71 vs. median 74 years, range 45-92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). CONCLUSIONS: C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia.
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Esclerosis Amiotrófica Lateral , Demencia Frontotemporal , Humanos , Expansión de las Repeticiones de ADN/genética , Proteína C9orf72/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Proteínas/genética , Fenotipo , Esclerosis Amiotrófica Lateral/genéticaRESUMEN
BACKGROUND AND PURPOSE: Little is known about the character and underlying lesions of ischaemic amnesia. Episodic memory functions and brain lesions were therefore studied in 84 patients with acute ischaemic infarcts in the supply territory of the posterior cerebral artery. The aim was also to learn how the neural memory systems are organized. METHODS: Standard neuropsychological tests were used to assess verbal and figural memory. Patients were split into memory-impaired and memory-intact groups. Lesions were demarcated, normalized and anatomically labelled, using standard mapping procedures. RESULTS: Of the 84 patients more than 80% had an amnestic syndrome, mostly with combined memory impairment, less often with figural or verbal memory impairment. Amnesia in subjects with left hemispheric lesions was more frequent and more severe, with significantly lower scores on the verbal memory test. Normal performance or figural amnesia were prevalent after right hemispheric lesions. However, no amnesia subtype was strictly tied to left- or right-sided brain damage. Hippocampal and thalamic lesions were common, but 30% of lesions were extrahippocampal located in the ventral occipito-temporal cortex and long occipital white matter tracts. Most amnestic patients lacked awareness for their memory impairment. CONCLUSIONS: Memory impairment is a key clinical manifestation of acute posterior cerebral artery stroke. Amnesia is more frequent and more severe after left stroke, suggesting a left hemisphere dominance of the two memory systems. Domain specific memory appears not to be strictly lateralized, since deficits in verbal and figural memory were found after lesions of both sides. Extrahippocampal lesions may also cause memory impairment.
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Infarto de la Arteria Cerebral Posterior , Amnesia/etiología , Amnesia/patología , Humanos , Infarto de la Arteria Cerebral Posterior/complicaciones , Imagen por Resonancia Magnética , Memoria , Pruebas Neuropsicológicas , Lóbulo Temporal/patologíaRESUMEN
BACKGROUND: Primary progressive aphasia (PPA) may present with three distinct clinical sybtypes: semantic variant PPA (svPPA), nonfluent/agrammatic variant PPA (nfvPPA), and logopenic variant PPA (lvPPA). OBJECTIVE: The aim was to examine the utility of the German version of the Repeat and Point (R&P) Test for subtyping patients with PPA. METHOD: During the R&P Test, the examiner reads out aloud a noun and the participants are asked to repeat the word and subsequently point to the corresponding picture. Data from 204 patients (68 svPPA, 85 nfvPPA, and 51 lvPPA) and 33 healthy controls were analyzed. RESULTS: Controls completed both tasks with >90% accuracy. Patients with svPPA had high scores in repetition (mean=9.2±1.32) but low scores in pointing (mean=6±2.52). In contrast, patients with nfvPPA and lvPPA performed comparably in both tasks with lower scores in repetition (mean=7.4±2.7 for nfvPPA and 8.2±2.34 for lvPPA) but higher scores in pointing (mean=8.9±1.41 for nfvPPA and 8.6±1.62 for lvPPA). The R&P Test had high accuracy discriminating svPPA from nfvPPA (83% accuracy) and lvPPA (79% accuracy). However, there was low accuracy discriminating nfvPPA from lvPPA (<60%). CONCLUSION: The R&P Test helps to differentiate svPPA from 2 nonsemantic variants (nfvPPA and lvPPA). However, additional tests are required for the differentiation of nfvPPA and lvPPA.
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Afasia Progresiva Primaria , Afasia Progresiva Primaria no Fluente , Afasia Progresiva Primaria/diagnóstico , Humanos , LenguajeRESUMEN
Background and Objectives: The neurofilament light chain (NfL) is a biomarker for neuro-axonal injury in various acute and chronic neurological disorders, including Alzheimer's disease (AD). We here investigated the cross-sectional and longitudinal associations between baseline serum NfL (sNfL) levels and cognitive, behavioural as well as MR volumetric findings in the Prospective Dementia Registry Austria (PRODEM-Austria). Materials and Methods: All participants were clinically diagnosed with AD according to NINCDS-ADRDA criteria and underwent a detailed clinical assessment, cognitive testing (including the Mini Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD)), the neuropsychiatric inventory (NPI) and laboratory evaluation. A total of 237 patients were included in the study. Follow-up examinations were done at 6 months, 1 year and 2 years with 93.3% of patients undergoing at least one follow-up. We quantified sNfL by a single molecule array (Simoa). In a subgroup of 125 subjects, brain imaging data (1.5 or 3T MRI, with 1 mm isotropic resolution) were available. Brain volumetry was assessed using the FreeSurfer image analysis suite (v6.0). Results: Higher sNfL concentrations were associated with worse performance in cognitive tests at baseline, including CERAD (B = −10.084, SE = 2.999, p < 0.001) and MMSE (B = −3.014, SE = 1.293, p = 0.021). The sNfL levels also correlated with the presence of neuropsychiatric symptoms (NPI total score: r = 0.138, p = 0.041) and with smaller volumes of the temporal lobe (B = −0.012, SE = 0.003, p = 0.001), the hippocampus (B = −0.001, SE = 0.000201, p = 0.013), the entorhinal (B = −0.000308, SE = 0.000124, p = 0.014), and the parahippocampal cortex (B = −0.000316, SE = 0.000113, p = 0.006). The sNfL values predicted more pronounced cognitive decline over the mean follow-up period of 22 months, but there were no significant associations with respect to change in neuropsychiatric symptoms and brain volumetric measures. Conclusions: the sNfL levels relate to cognitive, behavioural, and imaging hallmarks of AD and predicts short term cognitive decline.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/diagnóstico por imagen , Austria/epidemiología , Estudios Transversales , Humanos , Estudios Prospectivos , Sistema de RegistrosRESUMEN
INTRODUCTION: Previous studies have shown an association between a high health numeracy and good cognitive functioning. OBJECTIVE: To investigate the moderation effect of education on this relationship and which brain structures support health numeracy. METHODS: We examined 70 healthy older persons (66% females; mean ± SD: age, 75.73 ± 4.52 years; education, 12.21 ± 2.94 years). The participants underwent a T1-weighted 3-T MRI and a neuropsychological assessment including a health numeracy task. Statistical parametric mapping was applied to identify focal changes in cortical thickness throughout the entire brain and to correlate image parameters with behavioral measures. RESULTS: Executive functions and mental calculation emerged as predictors of health numeracy (B = 0.22, p < 0.05, and B = 0.38, p < 0.01). An interaction was found between education and executive functions (B = -0.16, p = 0.01) and between education and mental calculation (B = -0.11, p < 0.05). Executive functions and mental calculation had an impact on health numeracy in participants with a low to intermediate edu-cation (≤12 years) but not in those with a higher education (>12 years). Health numeracy scores were associated with cortical thickness in the right dorsomedial prefrontal cortex and the right superior temporal gyrus (p = 0.01). CONCLUSIONS: Older people with a higher education perform better in health numeracy tasks than those with a lower education. They have access to previously acquired knowledge about ratio concepts and do not need to rely on executive functions and computational skills. This is highly relevant when decisions about health care have to be made.
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Envejecimiento/psicología , Cognición , Escolaridad , Función Ejecutiva , Matemática , Anciano , Anciano de 80 o más Años , Toma de Decisiones , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas/estadística & datos numéricosRESUMEN
Recent evidence has suggested that the hippocampus supports learning and retrieval of arithmetic facts during childhood and adolescence. Whether the hippocampus is also involved in retrieving overlearned arithmetic facts (such as 3â¯×â¯5â¯=â¯15) during adult age is open for investigation. In this study, we assessed whether patients with hippocampal atrophy due to Alzheimer's disease (AD) are still able to retrieve overlearned arithmetic facts from memory. Sixteen patients (nâ¯=â¯13 with AD, nâ¯=â¯3 with Mild Cognitive Impairment - MCI) were evaluated using standard radiological, neurological, and neuropsychological test procedures. We adopted a multiple single-case analysis in order to acknowledge possible dissociations between hippocampal degeneration and intact arithmetic fact retrieval. All patients performed a neuropsychological screening battery assessing episodic memory as well as arithmetic processing, and underwent a 3-Tesla MRI procedure. A morphometric analysis comprising estimation of both cortical thickness and hippocampal volume, which also included a subfield analysis, was conducted. All patients had marked hippocampal atrophy (bilateral nâ¯=â¯15, unilateral nâ¯=â¯1) in comparison to healthy matched controls and showed deficits in episodic memory (delayed recall). However, 13 out of 16 patients performed in the average range of standardised norms during retrieval of overlearned arithmetic facts (i.e. multiplication tables). Our results suggest that intact retrieval of consolidated arithmetic facts from memory does not depend on the integrity of the hippocampus. This is in line with the view that the hippocampus plays a dynamic and time-limited role in arithmetic processing. While the hippocampus seems to be necessary for learning and consolidating new arithmetic facts in memory, it might not be critically involved in retrieving arithmetic facts when these are well consolidated in memory.
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Enfermedad de Alzheimer/patología , Hipocampo/patología , Memoria Episódica , Lóbulo Temporal/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/patología , Disfunción Cognitiva/psicología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Recuerdo Mental , Pruebas NeuropsicológicasRESUMEN
Clinical diagnosis of Creutzfeldt-Jakob disease (CJD) can be supported by the analysis of Tau and 14-3-3 in the cerebrospinal fluid (CSF). In this short report, we report about a retrospective analysis performed on 2,296 routinely collected CSF samples, and 44 samples with a ratio of phosphoTau181/Tau <0.075 were selected. Analysis was performed with a novel 14-3-3 gamma CircuLex Elisa. We show that control levels were around 6,000 AU/mL and samples from Alzheimer patients were not different from those collected from healthy controls. Four cases of verified CJD had 14-3-3 CSF levels of >100,000 AU/mL, while 10 out of 12 suspected CJD samples with 14-3-3 CSF levels between 50,000-100,000 AU/mL were CJD positive. All samples with 14-3-3 levels between 15,000 and 50,000 AU/mL were not CJD cases but disorders with complex neuropathology. In conclusion, our data suggests that in CSF samples with a phospho-Tau-181/Tau ratio <0.075 CSF levels of 14-3-3 should be analyzed. Our data suggests a very high risk for CJD with 14-3-3 levels above 100,000 AU/mL and a probable diagnosis of CJD based on laboratory parameters above 50,000 AU/mL.
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Proteínas 14-3-3/líquido cefalorraquídeo , Líquido Cefalorraquídeo/metabolismo , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Diagnóstico Diferencial , Humanos , Persona de Mediana Edad , Fosforilación/fisiología , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeoRESUMEN
We analyzed the relation of several synchrony markers in the electroencephalogram (EEG) and Alzheimer's disease (AD) severity as measured by Mini-Mental State Examination (MMSE) scores. The study sample consisted of 79 subjects diagnosed with probable AD. All subjects were participants in the PRODEM-Austria study. Following a homogeneous protocol, the EEG was recorded both in resting state and during a cognitive task. We employed quadratic least squares regression to describe the relation between MMSE and the EEG markers. Factor analysis was used for estimating a potentially lower number of unobserved synchrony factors. These common factors were then related to MMSE scores as well. Most markers displayed an initial increase of EEG synchrony with MMSE scores from 26 to 21 or 20, and a decrease below. This effect was most prominent during the cognitive task and may be owed to cerebral compensatory mechanisms. Factor analysis provided interesting insights in the synchrony structures and the first common factors were related to MMSE scores with coefficients of determination up to 0.433. We conclude that several of the proposed EEG markers are related to AD severity for the overall sample with a wide dispersion for individual subjects. Part of these fluctuations may be owed to fluctuations and day-to-day variability associated with MMSE measurements. Our study provides a systematic analysis of EEG synchrony based on a large and homogeneous sample. The results indicate that the individual markers capture different aspects of EEG synchrony and may reflect cerebral compensatory mechanisms in the early stages of AD.
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Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Sincronización Cortical/fisiología , Anciano , Anciano de 80 o más Años , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Procesamiento de Señales Asistido por ComputadorRESUMEN
BACKGROUND: Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated. METHODS: Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12â months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject. RESULTS: CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p<0.001), glutamate (r=0.45, p<0.001), pyruvate (r=0.26, p<0.001), and the lactate-pyruvate ratio (r=0.26, p<0.001), and were higher in episodes of hypoxic (PbtO2<20â mmâ Hg) brain extracellular lactate elevation (>4â mmol/L) (p<0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12â months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1â year after aSAH (p<0.01). CONCLUSIONS: These results suggest that CMD-total tau may be an important biomarker for predicting long-term outcome in patients with severe aSAH. The value of axonal injury needs further confirmation in a larger patient cohort, preferably combined with advanced imaging techniques.
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Encéfalo/metabolismo , Trastornos del Conocimiento/metabolismo , Aneurisma Intracraneal/metabolismo , Aneurisma Intracraneal/psicología , Hemorragia Subaracnoidea/metabolismo , Hemorragia Subaracnoidea/psicología , Proteínas tau/metabolismo , Anciano , Biomarcadores/metabolismo , Encéfalo/patología , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/patología , Femenino , Estudios de Seguimiento , Ácido Glutámico , Humanos , Aneurisma Intracraneal/complicaciones , Ácido Láctico/metabolismo , Masculino , Microdiálisis , Persona de Mediana Edad , Pruebas Neuropsicológicas , Evaluación de Resultado en la Atención de Salud , Oxígeno/metabolismo , Ácido Pirúvico/metabolismo , Hemorragia Subaracnoidea/complicacionesRESUMEN
Consensus diagnostic criteria for multiple system atrophy consider dementia as a nonsupporting feature, despite emerging evidence demonstrating that cognitive impairments are an integral part of the disease. Cognitive disturbances in multiple system atrophy occur across a wide spectrum from mild single domain deficits to impairments in multiple domains and even to frank dementia in some cases. Frontal-executive dysfunction is the most common presentation, while memory and visuospatial functions also may be impaired. Imaging and neuropathological findings support the concept that cognitive impairments in MSA originate from striatofrontal deafferentation, with additional contributions from intrinsic cortical degeneration and cerebellar pathology. Based on a comprehensive evidence-based review, the authors propose future avenues of research that ultimately may lead to diagnostic criteria for cognitive impairment and dementia associated with multiple system atrophy.
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Trastornos del Conocimiento/diagnóstico , Cognición/fisiología , Demencia/diagnóstico , Memoria/fisiología , Atrofia de Múltiples Sistemas/diagnóstico , Animales , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Demencia/etiología , Humanos , Atrofia de Múltiples Sistemas/complicaciones , Atrofia de Múltiples Sistemas/terapia , Pruebas NeuropsicológicasRESUMEN
Friedreich ataxia (FRDA) is the most frequent inherited ataxia. Neuropsychological studies suggest that FRDA may be associated with specific cognitive impairment. Very little is known about the relation between cognitive performance, demographics and disease-related parameters, such as GAA repeat size, age of onset and disease duration. The present investigation aimed at assessing cognitive functions in a representative sample of FRDA patients and at identifying the most relevant disease-related parameters. Twenty-nine adult FRDA patients underwent neuropsychological tests assessing executive functions, attention, memory and visual perception. Performance was compared with 28 age- and education-matched controls as well as with standardized norms. The relation between neuropsychological outcome, demographical variables and disease-related parameters was assessed. Cognitive impairment affected only a subgroup of patients and mostly concerned attentional and executive functions. Good cognitive performance was associated with a later disease onset, shorter GAA repeat length and lower burden of disease. Age at disease onset has been found to be a good predictor when a cut-off of 14 years was chosen. No correlation was found between cognitive performance and education, age or disease duration. The present study extends earlier findings in FRDA showing that performance in attentional and executive function tasks is best predicted by the age at disease onset. Moreover, executive functions show a clear relationship to disease severity and repeat size of the shorter GAA allele. These findings therefore have important implications for patient counselling regarding education and career choices.
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Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Función Ejecutiva , Ataxia de Friedreich/genética , Ataxia de Friedreich/psicología , Expansión de Repetición de Trinucleótido , Adulto , Edad de Inicio , Atención , Escolaridad , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Curva ROC , Análisis de Regresión , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
BACKGROUND: The background of route learning (RL) abilities in Alzheimer disease (AD), mild cognitive impairment (MCI), and normal aging needs further study. We searched for neuropsychological and demographical predictors of RL impairment. METHODS: RL was investigated in a clinical study including subjects classified as early AD (n=37), MCI (n=34), and aged normal controls (n=46). An ecological assessment procedure of RL was employed and landmarks learning and navigational abilities were evaluated. The consortium to establish a registry of Alzheimer's disease test battery was used for neuropsychological assessment. RESULTS: Almost all AD patients, and most subjects with MCI misidentified landmarks and made navigational errors when following the route without assistance. Moreover, a small subgroup of normal controls also had problems with RL. Poor RL performance was best predicted by impairments in memory and executive functions. CONCLUSIONS: RL impairment is common in early AD and MCI, and is occasionally also found in normal elderly subjects. Its characteristic appearance is a combination of poor landmark recognition and defective directional guidance. Poor RL can be predicted by neuropsychological testing. In MCI and in a subset of normal aged persons, RL impairment may herald incipient dementia.
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Envejecimiento/psicología , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/psicología , Aprendizaje Espacial , Navegación Espacial , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Enfermedad de Alzheimer/fisiopatología , Disfunción Cognitiva/fisiopatología , Función Ejecutiva , Femenino , Humanos , Masculino , Memoria , Persona de Mediana EdadRESUMEN
Alzheimer's disease (AD) imposes a major burden on affected individuals, their caregivers and health-care systems alike. Though quite many risk factors for disease progression have been identified, there is a lack of prospective studies investigating the interplay and predictive value of a wide variety of patient variables associated with cognitive deterioration (defined as key feature of AD progression). Study participants were patients with probable and possible AD, that were assessed at four time points over a period of two years (T1-T4). The main results were threefold: (i) over time, significant changes were observed regarding patients' cognitive functioning, activities of daily living and caregiver load (but not depression, pain, neuropsychiatric symptoms); (ii) intercorrelations between caregiver load and patients' cognitive and functional variables were high, correlation patterns remaining rather stable across time; (iii) cognitive functioning at T4 was best predicted by patients' age, sex, atrial fibrillation and activities of daily living at T1; and (iv) across all four assessment points, cognitive functioning was best predicted by time (i.e., disease duration), age, sex, activities of daily living and depression. Overall, even in early stages of AD and during a short two-year period, functional changes were significant and tightly intertwined with caregiver load, thus stressing the need to consider caregiver load when diagnosing and treating patients with AD. A novel and clinically relevant finding is that even in early stages of AD, cognitive deterioration was best predicted by a combination of patients' demographic, somatic and functional variables.
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Actividades Cotidianas , Enfermedad de Alzheimer , Cuidadores , Progresión de la Enfermedad , Humanos , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/psicología , Masculino , Femenino , Anciano , Estudios Prospectivos , Cuidadores/psicología , Anciano de 80 o más Años , Cognición/fisiología , Sistema de Registros , Disfunción Cognitiva/fisiopatología , Pruebas Neuropsicológicas , Persona de Mediana Edad , Depresión , Factores de RiesgoRESUMEN
Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed this approach to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. Methods & results: We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity across 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. The capacity of total and regional WMH volumes and LNM scores in predicting cognitive function was compared using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention and executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater disruptive effects of WMH on regional connectivity, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Conclusion: Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network effects, particularly in attentionrelated brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.
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The objective of this study was to further explore proper name (PN) retrieval and conceptual knowledge in patients with left and right temporal lobe epilepsy (69 patients with LTLE and 62 patients with RTLE) using a refined assessment procedure. Based on the performance of a large group of age- and education-matched normals, a new test of famous faces and famous landmarks was designed. Recognition, naming, and semantic knowledge were assessed consecutively, allowing for a better characterization of deficient levels in the naming system. Impairment in PN retrieval was common in the cohort with TLE. Furthermore, side of seizure onset impaired stages of name retrieval differently: LTLE impaired the lexico-phonological processing, whereas RTLE mainly impaired the perceptual-semantic stage of object recognition. In addition to deficient PN retrieval, patients with TLE had reduced conceptual knowledge regarding famous persons and landmarks.
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Epilepsia del Lóbulo Temporal/complicaciones , Cara , Personajes , Trastornos de la Memoria/etiología , Recuerdo Mental/fisiología , Nombres , Adolescente , Adulto , Anciano , Análisis de Varianza , Electroencefalografía , Femenino , Lateralidad Funcional/fisiología , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Reconocimiento Visual de Modelos/fisiología , Estimulación Luminosa , Adulto JovenRESUMEN
Background: Functional (un-)coupling (task-related change of functional connectivity) between different sites of the brain is a mechanism of general importance for cognitive processes. In Alzheimer's disease (AD), prior research identified diminished cortical connectivity as a hallmark of the disease. However, little is known about the relation between the amount of functional (un-)coupling and cognitive performance and decline in AD. Method: Cognitive performance (based on CERAD-Plus scores) and electroencephalogram (EEG)-based functional (un-)coupling measures (connectivity changes from rest to a Face-Name-Encoding task) were assessed in 135 AD patients (age: M = 73.8 years; SD = 9.0). Of these, 68 patients (M = 73.9 years; SD = 8.9) participated in a follow-up assessment of their cognitive performance 1.5 years later. Results: The amounts of functional (un-)coupling in left anterior-posterior and homotopic interhemispheric connections in beta1-band were related to cognitive performance at baseline (ß = .340; p < .001; ß = .274; P = .001, respectively). For both markers, a higher amount of functional coupling was associated with better cognitive performance. Both markers also were significant predictors for cognitive decline. However, while patients with greater functional coupling in left anterior-posterior connections declined less in cognitive performance (ß = .329; P = .035) those with greater functional coupling in interhemispheric connections declined more (ß = -.402; P = .010). Conclusion: These findings suggest an important role of functional coupling mechanisms in left anterior-posterior and interhemispheric connections in AD. Especially the complex relationship with cognitive decline in AD patients might be an interesting aspect for future studies.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Imagen por Resonancia Magnética , Electroencefalografía/métodos , Encéfalo , Progresión de la EnfermedadRESUMEN
INTRODUCTION: The spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as "unusual", but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. METHODS: Individual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. RESULTS: WMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DISCUSSION: Aggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.
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Disfunción Cognitiva , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Neuroimagen , Disfunción Cognitiva/patología , Estudios Multicéntricos como AsuntoRESUMEN
OBJECTIVE: To investigate long-term cognitive outcome, mood, and quality of life in a family with genetically proven familial hemiplegic migraine (FHM). BACKGROUND: FHM is a rare autosomal-dominant subtype of migraine with aura, characterized by some degree of hemiparesis during the aura. In a previous study, we showed preserved and impaired cognitive functions in patients with FHM. Until now, the progression of cognitive dysfunctions has not been known. However, the ability to predict progression is important for counseling patients about education, career, and family life. METHODS: Seven years after extensive baseline neuropsychological testing, we retested 6 members of a family with FHM, including questionnaires about mood and quality of life. RESULTS: The follow-up assessment revealed no global cognitive decline. All the patients' linguistic abilities and verbal memory remained intact; however, their figural memory, attention, and some aspects of executive function were impaired. Half the patients had a slight deterioration in their visuoconstructional functions. Half had higher scores on the trait and state anxiety measures. CONCLUSIONS: Cognitive deficits in a family with FHM persisted, but without marked progression. Worsening of visuoconstructional abilities may be related to executive dysfunction, confirming a disturbance of cerebrocerebellar circuits.