Detection of cerebrospinal fluid biomarkers changes of Alzheimer's disease using a cognitive stress test in persons with subjective cognitive decline and mild cognitive impairment.

Introduction: Timely and accurate diagnosis of the earliest manifestations of Alzheimer's disease (AD) is critically important. Cognitive challenge tests such as the Loewenstein Acevedo Scales for Semantic Interference and Learning (LASSI-L) have shown favorable diagnostic properties in a number of previous investigations using amyloid or FDG PET. However, no studies have examined LASSI-L performance against cerebrospinal fluid biomarkers of AD, which can be affected before the distribution of fibrillar amyloid and other changes that can be observed in brain neuroimaging. Therefore, we aimed to evaluate the relationship between LASSI-L scores and CSF biomarkers and the capacity of the cognitive challenge test to detect the presence of amyloid and tau deposition in patients with subjective cognitive decline and amnestic mild cognitive impairment (MCI). Methods: One hundred and seventy-nine patients consulting for memory loss without functional impairment were enrolled. Patients were examined using comprehensive neuropsychological assessment, the LASSI-L, and cerebrospinal fluid (CSF) biomarkers (Aß1-42/Aß1-40 and ptau181). Means comparisons, correlations, effect sizes, and ROC curves were calculated. Results: LASSI-L scores were significantly associated with CSF biomarkers Aß1-42/Aß1-40 in patients diagnosed with MCI and subjective cognitive decline, especially those scores evaluating the capacity to recover from proactive semantic interference effects and delayed recall. A logistic regression model for the entire sample including LASSI-L and age showed an accuracy of 0.749 and an area under the curve of 0.785 to detect abnormal amyloid deposition. Conclusion: Our study supports the biological validity of the LASSI-L and its semantic interference paradigm in the context of the early stages of AD. These findings emphasize the utility and the convenience of including sensitive cognitive challenge tests in the assessment of patients with suspicion of early stages of AD.

In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use.

TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.

Cognitive dysfunction characteristics of multiple sclerosis with aging.

BACKGROUND: We aimed to investigate the characteristics of cognitive impairment in older people with multiple sclerosis (MS). METHODS: Cross-sectional study that included participants that were examined with a common and comprehensive neuropsychological protocol. The subjects were matched by sociodemographic variables and the following groups were generated for comparisons: young MS versus healthy controls (HC) (n = 246), old MS versus HC (n = 198), young MS vs old MS (n = 226), MS vs Alzheimer's disease (AD)(n = 70), and MS vs Parkinson's disease (PD) (n = 62). The ICCoDiMS criteria were used to define cognitive impairment in MS. RESULTS: Cognitive impairment was more frequent in young than old patients (70.8 % vs 52.2 %). Attention and speed processing is the most frequent cognitive domain impaired in MS (54.9 % of young MS vs 32.7 % of old MS). The frequency of impairment in attention/processing speed (54.9 % vs 32.7 %) and episodic memory (27.9 % vs 14.3) was higher in the young group than in the old group. There were no statistically significant differences in the distribution of impairment in executive function (46.0 % vs 35.3 %), visuospatial (17.9 % vs 9.5 %), and language (12.4 % vs 17.7 %). In those patients meeting the criteria for cognitive impairment, young MS patients showed lower performance in attention/processing speed tests. Conversely, old MS patients showed lower performance in episodic memory, verbal fluency, and planning. There were no differences in the correlations between SDMT and other neuropsychological tests in young and old patients, which suggests similar cognitive processes underlying SDMT performance in both groups. There were differences between old MS and prodromal AD, especially in episodic memory, while the cognitive profile of old MS was largely shared with PD. CONCLUSIONS: Our study found that the cognitive profile of MS is defined by a characteristic impairment in attention and processing speed, which is present during the lifespan. The impairment in processing speed is less prominent in old age, whereas the impairment of other cognitive functions becomes more relevant. These findings suggest potential differences in the pathophysiological processes associated with cognitive impairment between young and old ages that warrant further investigation.

Cognitive profile in multiple sclerosis and post-COVID condition: a comparative study using a unified taxonomy.

Post-COVID condition (PCC) and multiple sclerosis (MS) share some clinical and demographic features, including cognitive symptoms and fatigue. Some pathophysiological mechanisms well-known in MS, such as autoimmunity, neuroinflammation and myelin damage, have also been implicated in PCC. In this study, we aimed to compare the cognitive phenotypes of two large cohorts of patients with PCC and MS, and to evaluate the relationship between fatigue and cognitive performance. Cross-sectional study including 218 patients with PCC and 218 with MS matched by age, sex, and years of education. Patients were evaluated with a comprehensive neuropsychological protocol and were categorized according to the International Classification of Cognitive Disorders system. Fatigue and depression were also assessed. Cognitive profiles of PCC and MS largely overlapped, with a greater impairment in episodic memory in MS, but with small effect sizes. The most salient deficits in both disorders were in attention and processing speed. The severity of fatigue was greater in patients with PCC. Still, the correlations between fatigue severity and neuropsychological tests were more prominent in the case of MS. There were no differences in the severity of depression among groups. Our study found similar cognitive profiles in PCC and MS. Fatigue was more severe in PCC, but was more associated with cognitive performance in MS. Further comparative studies addressing the mechanisms related to cognitive dysfunction and fatigue may be of interest to advance the knowledge of these disorders and develop new therapies.

Translating NIA-AA criteria into usual practice: Report from the ReDeMa Project.

INTRODUCTION: Biomarker-informed criteria were proposed for the diagnosis of Alzheimer's disease (AD) by the National Institute on Aging and the Alzheimer's Association (NIA-AA) in 2011; however, the adequacy of this criteria has not been sufficiently evaluated. METHODS: ReDeMa (Red de Demencias de Madrid) is a regional cohort of patients attending memory and neurology clinics. Core cerebrospinal fluid biomarkers were obtained, NIA-AA diagnostic criteria were considered, and changes in diagnosis and management were evaluated. RESULTS: A total of 233 patients were analyzed (mean age 70 years, 50% women, 73% AD). The diagnostic language was modified significantly, with a majority assumption of NIA-AA definitions (69%). Confidence in diagnosis increased from 70% to 92% (p < 0.0005) and management was changed in 71% of patient/caregivers. The influence of neurologist's age or expertise on study results was minimal. DISCUSSION: The NIA-AA criteria are adequate and utile for usual practice in memory and neurology clinics, improving diagnostic confidence and significantly modifying patient management. HIGHLIGHTS: Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers increase diagnostic certainty regardless of the neurologist.AD CSF biomarkers lead to changes in disease management .Biomarker-enriched, 2011 NIA-AA diagnostic criteria are adequate for usual practice.

Leptin haploinsufficiency exerts sex-dependent partial protection in SOD1G93A mice by reducing inflammatory pathways in the adipose tissue.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant metabolic disruptions, including weight loss and hypermetabolism in both patients and animal models. Leptin, an adipose-derived hormone, displays altered levels in ALS. Genetically reducing leptin levels (Lepob/+) to maintain body weight improved motor performance and extended survival in female SOD1G93A mice, although the exact molecular mechanisms behind these effects remain elusive. Here, we corroborated the sexual dimorphism in circulating leptin levels in ALS patients and in SOD1G93A mice. We reproduced a previous strategy to generate a genetically deficient leptin SOD1G93A mice (SOD1G93ALepob/+) and studied the transcriptomic profile in the subcutaneous adipose tissue and the spinal cord. We found that leptin deficiency reduced the inflammation pathways activated by the SOD1G93A mutation in the adipose tissue, but not in the spinal cord. These findings emphasize the importance of considering sex-specific approaches in metabolic therapies and highlight the role of leptin in the systemic modulation of ALS by regulating immune responses outside the central nervous system.

A data-driven approach to complement the A/T/(N) classification system using CSF biomarkers.

AIMS: The AT(N) classification system not only improved the biological characterization of Alzheimer's disease (AD) but also raised challenges for its clinical application. Unbiased, data-driven techniques such as clustering may help optimize it, rendering informative categories on biomarkers' values. METHODS: We compared the diagnostic and prognostic abilities of CSF biomarkers clustering results against their AT(N) classification. We studied clinical (patients from our center) and research (Alzheimer's Disease Neuroimaging Initiative) cohorts. The studied CSF biomarkers included Aß(1-42), Aß(1-42)/Aß(1-40) ratio, tTau, and pTau. RESULTS: The optimal solution yielded three clusters in both cohorts, significantly different in diagnosis, AT(N) classification, values distribution, and survival. We defined these three CSF groups as (i) non-defined or unrelated to AD, (ii) early stages and/or more delayed risk of conversion to dementia, and (iii) more severe cognitive impairment subjects with faster progression to dementia. CONCLUSION: We propose this data-driven three-group classification as a meaningful and straightforward approach to evaluating the risk of conversion to dementia, complementary to the AT(N) system classification.

Normative Data in Cross-Cultural Neuropsychological Instruments in Spaniards and Colombians Living in Spain.

BACKGROUND: Cross-Cultural Dementia Screening (CCD), Rowland Universal Dementia Assessment Scale (RUDAS), and European Cross-cultural Neuropsychological Test Battery (CNTB) are three novel neuropsychological instruments developed from a cross-cultural perspective to reduce the impact of culture in cognitive assessment and improve the assessment in diverse populations. OBJECTIVE: We aimed to collect and present normative data on these tests in a majority population sample (Spaniards living in Spain) and in a minority population sample (Colombians living in Spain). METHODS: CCD, RUDAS, and CNTB were administered to a group of 300 cognitively healthy participants (150 Spaniards and 150 Colombians). Linear regression modeling strategy was used to provide adjusted norms for demographic factors and to explore the influence of these factors on test performance. RESULTS: Most of the CCD and CNTB scores were predicted by age and years of education, with some tests only predicted by age or showing a ceiling effect. The comparison of normative data between the two samples confirmed the favorable cross-cultural properties of these instruments, with only some differences in processing speed and executive functioning scores. CONCLUSIONS: Our study finds a comparable influence of demographic factors in both populations on the performance of CCD, RUDAS, and CNTB, confirming their adequate cross-cultural properties. We provide normative data for these tests in Spaniards and Colombians living in Spain.

FDG-PET-based neural correlates of Addenbrooke's cognitive examination III scores in Alzheimer's disease and frontotemporal degeneration.

Introduction: The Addenbrooke's Cognitive Examination III (ACE-III) is a brief test useful for neuropsychological assessment. Several studies have validated the test for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, we aimed to examine the metabolic correlates associated with the performance of ACE-III in AD and behavioral variant FTD. Methods: We enrolled 300 participants in a cross-sectional study, including 180 patients with AD, 60 with behavioral FTD (bvFTD), and 60 controls. An 18F-Fluorodeoxyglucose positron emission tomography study was performed in all cases. Correlation between the ACE-III and its domains (attention, memory, fluency, language, and visuospatial) with the brain metabolism was estimated. Results: The ACE-III showed distinct neural correlates in bvFTD and AD, effectively capturing the most relevant regions involved in these disorders. Neural correlates differed for each domain, especially in the case of bvFTD. Lower ACE-III scores were associated with more advanced stages in both disorders. The ACE-III exhibited high discrimination between bvFTD vs. HC, and between AD vs. HC. Additionally, it was sensitive to detect hypometabolism in brain regions associated with bvFTD and AD. Conclusion: Our study contributes to the knowledge of the brain regions associated with ACE-III, thereby facilitating its interpretation, and highlighting its suitability for screening and monitoring. This study provides further validation of ACE-III in the context of AD and FTD.

Unraveling brain fog in post-COVID syndrome: Relationship between subjective cognitive complaints and cognitive function, fatigue, and neuropsychiatric symptoms.

BACKGROUND AND PURPOSE: "Brain fog" is a frequent and disabling symptom that can occur after SARS-CoV-2 infection. However, its clinical characteristics and the relationships among brain fog and objective cognitive function, fatigue, and neuropsychiatric symptoms (depression, anxiety) are still unclear. In this study, we aimed to examine the characteristics of brain fog and to understand how fatigue, cognitive performance, and neuropsychiatric symptoms and the mutual relationships among these variables influence subjective cognitive complaints. METHODS: A total of 170 patients with cognitive complaints in the context of post-COVID syndrome were evaluated using a comprehensive neuropsychological protocol. The FLEI scale was used to characterize subjective cognitive complaints. Correlation analysis, regression machine-learning algorithms, and mediation analysis were calculated. RESULTS: Cognitive complaints were mainly attention and episodic memory symptoms, while executive functions (planning) issues were less often reported. The FLEI scale, a mental ability questionnaire, showed high correlations with a fatigue scale and moderate correlations with the Stroop test, and anxiety and depressive symptoms. Random forest algorithms showed an R2 value of 0.409 for the prediction of FLEI score, with several cognitive tests, fatigue and depression being the best variables used in the prediction. Mediation analysis showed that fatigue was the main mediator between objective and subjective cognition, while the effect of depression was indirect and mediated through fatigue. CONCLUSIONS: Brain fog associated with COVID-19 is mainly characterized by attention and episodic memory, and fatigue, which is the main mediator between objective and subjective cognition. Our findings contribute to understanding the pathophysiology of brain fog and emphasize the need to unravel the main mechanisms underlying brain fog, considering several aspects.

Hippocampal subfield abnormalities and biomarkers of pathologic brain changes: from SARS-CoV-2 acute infection to post-COVID syndrome.

BACKGROUND: Cognitive deficits are among the main disabling symptoms in COVID-19 patients and post-COVID syndrome (PCS). Within brain regions, the hippocampus, a key region for cognition, has shown vulnerability to SARS-CoV-2 infection. Therefore, in vivo detailed evaluation of hippocampal changes in PCS patients, validated on post-mortem samples of COVID-19 patients at the acute phase, would shed light into the relationship between COVID-19 and cognition. METHODS: Hippocampal subfields volume, microstructure, and perfusion were evaluated in 84 PCS patients and compared to 33 controls. Associations with blood biomarkers, including glial fibrillary acidic protein (GFAP), myelin oligodendrocyte glycoprotein (MOG), eotaxin-1 (CCL11) and neurofilament light chain (NfL) were evaluated. Besides, biomarker immunodetection in seven hippocampal necropsies of patients at the acute phase were contrasted against eight controls. FINDINGS: In vivo analyses revealed that hippocampal grey matter atrophy is accompanied by altered microstructural integrity, hypoperfusion, and functional connectivity changes in PCS patients. Hippocampal structural and functional alterations were related to cognitive dysfunction, particularly attention and memory. GFAP, MOG, CCL11 and NfL biomarkers revealed alterations in PCS, and showed associations with hippocampal volume changes, in selective hippocampal subfields. Moreover, post mortem histology showed the presence of increased GFAP and CCL11 and reduced MOG concentrations in the hippocampus in post-mortem samples at the acute phase. INTERPRETATION: The current results evidenced that PCS patients with cognitive sequalae present brain alterations related to cognitive dysfunction, accompanied by a cascade of pathological alterations in blood biomarkers, indicating axonal damage, astrocyte alterations, neuronal injury, and myelin changes that are already present from the acute phase. FUNDING: Nominative Grant FIBHCSC 2020 COVID-19. Department of Health, Community of Madrid. Instituto de Salud Carlos III through the project INT20/00079, co-funded by European Regional Development Fund "A way to make Europe" (JAMG). Instituto de Salud Carlos III (ISCIII) through Sara Borrell postdoctoral fellowship Grant No. CD22/00043) and co-funded by the European Union (MDC). Instituto de Salud Carlos III through a predoctoral contract (FI20/000145) (co-funded by European Regional Development Fund "A way to make Europe") (MVS). Fundación para el Conocimiento Madri+d through the project G63-HEALTHSTARPLUS-HSP4 (JAMG, SOM).

Validation of the European Cross-Cultural Neuropsychological Test Battery (CNTB) for the assessment of mild cognitive impairment due to Alzheimer's disease and Parkinson's disease.

Background: The Cross-Cultural Neuropsychological Test Battery (CNTB) is a novel test battery specifically designed to reduce the impact of multiculturality in cognitive assessment. Objective: We aimed to validate the CNTB in Spaniards in patients with Alzheimer's disease (AD), including patients at mild cognitive impairment (MCI) and mild dementia stages, and Parkinson's disease with MCI (PD-MCI). Methods: Thirty patients with AD-MCI, 30 with AD-dementia (AD-D), and 30 with PD-MCI were recruited. Each clinical group was compared against a healthy control group (HC) with no differences in sex, age, or years of education. Intergroup comparisons, ROC analysis, and cut-off scores were calculated. Results: AD-MCI scored lower than HC in those subtests associated with episodic memory and verbal fluency. AD-D also showed lower scores in executive functions and visuospatial tests. Effect sizes for all the subtests were large. PD-MCI showed lower performance than HC in memory and executive functions, particularly on error scores, with large effect sizes. Comparing AD-MCI and PD-MCI, AD-MCI had lower memory scores, while PD-MCI showed the worst performance in executive functions. CNTB showed appropriate convergent validity with standardized neuropsychological tests measuring the same cognitive domains. We obtained similar cut-off scores to previous studies performed in other populations. Conclusions: The CNTB showed appropriate diagnostic properties in AD and PD, including those stages with mild cognitive impairment. This supports the utility of the CNTB for the early detection of cognitive impairment in AD and PD.

Transcranial direct current stimulation for post-COVID fatigue: a randomized, double-blind, controlled pilot study.

Fatigue is one of the most frequent and disabling symptoms of the post-COVID syndrome. In this study, we aimed to assess the effects of transcranial direct current stimulation on fatigue severity in a group of patients with post-COVID syndrome and chronic fatigue. We conducted a double-blind, parallel-group, sham-controlled study to evaluate the short-term effects of anodal transcranial direct current stimulation (2 mA, 20 min/day) on the left dorsolateral prefrontal cortex. The modified fatigue impact scale score was used as the primary endpoint. Secondary endpoints included cognition (Stroop test), depressive symptoms (Beck depression inventory) and quality of life (EuroQol-5D). Patients received eight sessions of transcranial direct current stimulation and were evaluated at baseline, immediately after the last session, and one month later. Forty-seven patients were enrolled (23 in the active treatment group and 24 in the sham treatment group); the mean age was 45.66 ± 9.49 years, and 37 (78.72%) were women. The mean progression time since the acute infection was 20.68 ± 6.34 months. Active transcranial direct current stimulation was associated with a statistically significant improvement in physical fatigue at the end of treatment and 1 month as compared with sham stimulation. No significant effect was detected for cognitive fatigue. In terms of secondary outcomes, active transcranial direct current stimulation was associated with an improvement in depressive symptoms at the end of treatment. The treatment had no effects on the quality of life. All the adverse events reported were mild and transient, with no differences between the active stimulation and sham stimulation groups. In conclusion, our results suggest that transcranial direct current stimulation on the dorsolateral prefrontal cortex may improve physical fatigue. Further studies are needed to confirm these findings and optimize stimulation protocols.

Multi-Disease Validation of the RUDAS for Cognitive Screening in Alzheimer's Disease, Parkinson's Disease, and Multiple Sclerosis.

BACKGROUND: The Rowland Universal Dementia Assessment Scale (RUDAS) is a cognitive test with favorable diagnostic properties for detecting dementia and a low influence of education and cultural biases. OBJECTIVE: We aimed to validate the RUDAS in people with Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). METHODS: We enrolled one hundred and fifty participants (60 with AD, 30 with PD, 60 with MS, and 120 healthy controls (HC)). All clinical groups completed a comprehensive neuropsychological battery, RUDAS, and standard cognitive tests of each disorder: MMSE, SCOPA-COG, and Symbol Digit Modalities Test. Intergroup comparisons between clinical groups and HC and ROC curves were estimated. Random Forest algorithms were trained and validated to detect cognitive impairment using RUDAS and rank the most relevant scores. RESULTS: The RUDAS scores were lower in patients with AD, and patients with PD and MS showed cognitive impairment compared to healthy controls. Effect sizes were generally large. The total score was the most discriminative, followed by the memory score. Correlations with standardized neuropsychological tests were moderate to high. Random Forest algorithms obtained accuracies over 80-90% using the RUDAS for diagnosing AD and cognitive impairment associated with PD and MS. CONCLUSION: Our results suggest the RUDAS is a valid test candidate for multi-disease cognitive screening tool in AD, PD, and MS.

Neuropsychological, Metabolic, and Connectivity Underpinnings of Semantic Interference Deficits Using the LASSI-L.

BACKGROUND: LASSI-L is a novel neuropsychological test specifically designed for the early diagnosis of Alzheimer's disease (AD) based on semantic interference. OBJECTIVE: To examine the cognitive and neural underpinnings of the failure to recover from proactive semantic and retroactive semantic interference. METHODS: One hundred and fifty-five patients consulting for memory loss were included. Patients underwent neuropsychological assessment, including the LASSI-L, and FDG-PET imaging. They were categorized as subjective memory complaints (SMC) (n=32), pre-mild cognitive impairment (MCI) due to AD (Pre-MCI) (n=39), MCI due to AD (MCI-AD) (n=71), and MCI without evidence of neurodegeneration (MCI-NN) (n=13). Voxel-based brain mapping and metabolic network connectivity analyses were conducted. RESULTS: A significant group effect was found for all the LASSI-L scores. LASSI-L scores measuring failure to recover from proactive semantic interference and retroactive semantic interference were predicted by other neuropsychological tests with a precision of 64.1 and 44.8%. The LASSI-L scores were associated with brain metabolism in the bilateral precuneus, superior, middle and inferior temporal gyri, fusiform, angular, superior and inferior parietal lobule, superior, middle and inferior occipital gyri, lingual gyrus, and posterior cingulate. Connectivity analysis revealed a decrease of node degree and centrality in posterior cingulate in patients showing frPSI. CONCLUSION: Episodic memory dysfunction and the involvement of the medial temporal lobe, precuneus and posterior cingulate constitute the basis of the failure to recover from proactive semantic interference and retroactive semantic interference. These findings support the role of the LASSI-L in the detection, monitoring and outcome prediction during the early stages of AD.

Fatigue and Cognitive Dysfunction Are Associated with Occupational Status in Post-COVID Syndrome.

Post-COVID syndrome (PCS) is a medical condition characterized by the persistence of a wide range of symptoms after acute infection by SARS-CoV-2. The work capacity consequences of this disorder have scarcely been studied. We aimed to analyze the factors associated with occupational status in patients with PCS. This cross-sectional study involved 77 patients with PCS on active work before SARS-CoV-2 infection. Patients were evaluated 20.71 ± 6.50 months after clinical onset. We conducted a survey on occupational activity and cognitive and clinical symptoms. The association between occupational activity and fatigue, depression, anxiety, sleep quality, and cognitive testing was analyzed. Thirty-eight (49.4%) patients were working, and thirty-nine (50.6%) patients were not. Of those not working at the moment of the assessment, 36 (92.3%) patients were on sick leave. In 63 patients (81.8% of the sample), sick leave was needed at some point due to PCS. The mean duration of sick leave was 12.07 ± 8.07 months. According to the patient's perspective, the most disabling symptoms were cognitive complaints (46.8%) and fatigue (31.2%). Not working at the moment of the assessment was associated with higher levels of fatigue and lower cognitive performance in the Stroop test. No association was found between occupational status with depression and anxiety questionnaires. Our study found an influence of PCS on work capacity. Fatigue and cognitive issues were the most frequent symptoms associated with loss of work capacity.

Lipid Metabolic Alterations in the ALS-FTD Spectrum of Disorders.

There is an increasing interest in the study of the relation between alterations in systemic lipid metabolism and neurodegenerative disorders, in particular in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). In ALS these alterations are well described and evident not only with the progression of the disease but also years before diagnosis. Still, there are some discrepancies in findings relating to the causal nature of lipid metabolic alterations, partly due to the great clinical heterogeneity in ALS. ALS presentation is within a disorder spectrum with Frontotemporal Dementia (FTD), and many patients present mixed forms of ALS and FTD, thus increasing the variability. Lipid metabolic and other systemic metabolic alterations have not been well studied in FTD, or in ALS-FTD mixed forms, as has been in pure ALS. With the recent development in lipidomics and the integration with other -omics platforms, there is now emerging data that not only facilitates the identification of biomarkers but also enables understanding of the underlying pathological mechanisms. Here, we reviewed the recent literature to compile lipid metabolic alterations in ALS, FTD, and intermediate mixed forms, with a view to appraising key commonalities or differences within the spectrum.

Validation of the cross-cultural dementia screening test in Alzheimer's disease and Parkinson's disease.

Objective: The Cross-Cultural Dementia (CCD) is a new screening tool to evaluate cognitive impairment based on a cross-cultural perspective to reduce the bias of education, and language and cultural differences. We aimed to evaluate the diagnostic properties of the CCD in Spaniards for the assessment of patients with Alzheimer's disease in mild cognitive impairment (AD-MCI) and mild dementia stages (AD-D) and patients with mild cognitive impairment associated with Parkinson's disease (PD-MCI). Methods: Sixty participants with AD (50% MCI) and thirty with PD-MCI were enrolled. Each clinical group was compared against a healthy control group (HC) with the same number of participants and no significant differences in age, education, and sex. A comprehensive neuropsychological test battery and CCD were completed. Intergroup comparisons, ROC curves, and cut-off scores were calculated for the study of diagnostic properties. Results: Intergroup differences were found in accordance with the cognitive profile of each clinical condition. Memory measures (Objects test) were especially relevant for the classification between AD and HC. Memory and executive function scores (Sun-Moon and Dots tests) were useful in the case of PD-MCI and HC. Furthermore, CCD described differences in executive functions and speed scores comparing AD-MCI and PD-MCI. Correlations between standardized neuropsychological tests and CCD measures supported the convergent validity of the test. Conclusion: CCD showed good discrimination properties and cut-off scores for dementia and extended its application to a sample of prodromal stages of AD and PD with mild cognitive impairment.

Neurólogos y demencias avanzadas, ¿estamos preparados para los mejores cuidados? / Neurologists and advanced dementia, are we prepared for the best care?

OBJETIVO: Analizar si los neurólogos identifican las demencias en fases avanzadas y si ello implica un cambio en la orientación del manejo del paciente. MÉTODO: se revisaron las historias de los pacientes diagnosticados de demencia según el CIE-9 con los siguientes términos y fallecidos en el hospital de Torrejón, entre enero y diciembre de 2016: alzheimer, demencia frontotemporal, demencia vascular, parkinson, demencia relacionada con parkinson, demencia por cuerpos de Lewy y demencia mixta. Se analizó si las historias contenían los datos suficientes para determinar la fase de la demencia de acuerdo con las escalas GDS-FAST, si las anotaciones permitían determinar si los pacientes cumplían los criterios de terminalidad para demencia de la NPHCO y si existían alusiones a planificaciones específicas en situaciones de alta complejidad, como en caso de disfagia/afagia o infecciones graves. RESULTADO: se encontraron 52 historias. Estadificación de la demencia: se pudo definir la escala FAST o GDS en 46 historias. Terminalidad: no se pudo completar en ningún caso si los pacientes cumplían criterios de terminalidad. Ingresos o eventos médicos: en los 6-12 meses previos. Se hizo mención a ingresos o incidencias médicas en 16 pacientes (31 de los 52 habían sufrido incidencias médicas). Situación nutricional: se hizo la pregunta sobre la presencia de disfagia en 30. Mención al peso: se anotó referencia al peso en 13 pacientes. Se especificó la existencia de un análisis de sangre en dos. Planteamiento en consulta sobre las fases predecibles: se escribió en la historia sobre la información acerca de fases venideras en cuatro pacientes. Instrucciones previas: hay una única historia que recoge este elemento. Verbalización sobre planificación en determinados escenarios clínicos (sonda o no, manejo paliativo en fase avanzada, etc.). Hallada en dos pacientes. CONCLUSIONES: Los neurólogos no realizamos una recogida de datos en nuestras historias dirigida a identificar situación de terminalidad y, por tanto, que abra la puerta a un manejo paliativo

OBJECTIVE: To analyze whether neurologists identify dementias in advanced stages and whether this implies a change in the orientation of patient management. METHOD: We reviewed the clinical records of patients diagnosed with dementia according to ICD-9 with the following terms and died at the Torrejón hospital between January and December 2016: Alzheimer's disease, fronto temporal dementica, vascular dementia, lewy body dementia, Parikinson's disease and mixed dementia. We analyzed whether the records contained sufficient data to determine the phase of the dementia according to the GDS-FAST scales, if the annotations made it possible to determine if the patients met NPHCO dementia's termination criteria and if there were allusions to specific schedules in situations of high complexity, such as dysphagia/aphagia or infections. RESULTS: 52 histories were found. Staging of dementia: the FAST or GDS scale could be defined in 46 stories. Terminality: in no case could it be completed if the patients fulfilled criteria of terminality. Medical income or events in the previous 6-12 months. Mention was made of income or medical incidents in 16 patients (31 out of 52 had medical incidents). Nutritional status: the question was asked about the presence of dysphagia in 30. Mention of weight: weight was recorded in 13 patients. The existence of a blood test was specified in 2. Approach on the predictable phases: Information about upcoming was written down in 4 patients. Advance directives: there is a single patient. Verbalization on planning in certain clinical scenarios (probe or not, advanced palliative management ...). Found in 2 patients. CONCLUSIONS: Neurologists do not perform a rigourous data collection aimed at identifying terminality situation and, therefore, open the door to palliative management, so palliative care can be hardly offered

A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and EGFR-Mutant Non-Small Cell Lung Cancer.

BACKGROUND: Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the co-existence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT). METHODS: We collected data on clinical and molecular characteristics and outcomes of female patients with LC and a previous or simultaneous history of primary BC treated in our hospital from 2008 to 2014. RESULTS: Data on treatment, follow-up, and EGFR mutation status were available for 356 patients. 17.7% (11/62) of patients with EGFR mutations had BC, compared to 1.02% (3/294) of EGFR-WT patients (p < 0.001). Both tumors were metachronous in 81.8%, with LC diagnosed 9 years after the diagnosis of BC. 5 of the 6 (83.3%) BC patients treated with radiotherapy developed LC in an area within the radiation field. No EGFR mutations were detected in BC tissue and no HER2 expression was detected in LC samples. CONCLUSION: SPM in the lung and breast occur more frequently among EGFR-mutant compared to EGFR-WT LC patients. Radiotherapy for BC may increase the risk of developing primary LC.