Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.

Hepatitis E Virus Seroprevalence is Associated with Neurodegenerative Disorders in Older People with Dementia: A Case-Control Study.

In this case-control study, we evaluated the association between serum antibodies against hepatitis E virus (HEV) and central nervous system (CNS) neurodegenerative disorders (NDs) in older people with dementia. The presence of anti-HEV antibodies was related to a higher adjusted odds ratio (aOR) of having CNS NDs by neuropathological diagnosis (aOR, 2.13; P = .007) and clinical/neuropathological diagnosis (1.84; P = .02). Besides, serum anti-HEV antibodies were directly related to neuropathological injury (higher vascular pathology [aOR, 1.97; P = .006]) and higher probability of Alzheimer-type pathology (1.84; P = .02). In conclusion, the presence of anti-HEV antibodies was related to higher odds of CNS NDs and neuropathological injury in older people.

A novel histological staging of hippocampal sclerosis that is evident in gray matter loss in vivo.

INTRODUCTION: Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. METHODS: We studied 159 brain donations from the multimodal Vallecas Alzheimer's Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and magnetic resonance imaging (MRI) data. RESULTS: Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anterior-posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging. DISCUSSION: The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS. HIGHLIGHTS: The definition of hippocampal sclerosis of aging (HS) is currently limited to an end-stage pathological fingerprint. We characterize early HS histological features to define a complete staging system. The proposed staging displays a parallel but not identical progression to limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). The proposed staging also reflects the expected demographic and cognitive differences associated with HS. In vivo magnetic resonance imaging (MRI) showed focal hippocampal gray matter loss as a function of HS staging.

Residence, Clinical Features, and Genetic Risk Factors Associated with Symptoms of COVID-19 in a Cohort of Older People in Madrid.

BACKGROUND: The older population has been especially affected by the severe acute respiratory syndrome coronavirus 2 pandemic (COVID-19). OBJECTIVE: The aim of the study was to explore the incidence, severity, mortality rate, clinical features, and risk factors of symptoms of COVID-19 in home-dwelling older people, and its association with type of residence, cognitive deterioration, and neurodegenerative diseases. METHODS: Data about symptoms of COVID-19 were collected through a telephone survey in the cohort of 913 older volunteers of the Vallecas Project, aged 75-90 years, most of them (902) home-dwelling, in Madrid, Spain. The association of demographic and anthropometric measures, genetic polymorphisms, comorbidities, life habits, type of residence, and frailty surrogates were explored as potential risk factors for the incidence, severity, and mortality of COVID-19 in the older population. FINDINGS: Sixty-two cases reported symptoms compatible with COVID-19; 6 of them had died, 4 in their home and 2 in the nursing home. Moderate/severe cases were significantly older and more frequently males. The APOE ε4 allele was associated with the presence of symptoms of COVID-19. Higher systolic blood pressure, more intense smoking habit, more alcohol intake, lower consumption of coffee and tea, and cognitive impairment were associated with disease severity. CONCLUSIONS: The estimated incidence of symptomatic COVID-19 in this older cohort of Madrid was 6.8%, with an overall mortality rate of 0.7% (18.2% in those living in a nursing home) and a fatality rate of 9.9%. Our exploratory study indicates that life habits, other clinical conditions and, the ε4 variant of the APOE gene are associated with the presence and clinical severity of coronavirus infection.

Combined Alzheimer's disease and cerebrovascular staging explains advanced dementia cognition.

INTRODUCTION: The absence of a consensus system for full neuropathological evaluation limits clinicopathological studies and comparability between laboratories. Combined staging for Alzheimer's type and cerebral vascular pathology may allow a better classification of cases for clinical and cognitive correlation. METHODS: Cognitive and postmortem neuropathological data were obtained from 70 brains donated to the Tissue Bank of the Centro de Investigación de Enfermedades Neurológicas (CIEN) Foundation according to recently developed staging schemes for Alzheimer's type and vascular pathology. Subjects belonged to a cohort of institutionalized patients with moderate or severe dementia and a mean follow-up period of 7 years. RESULTS: Cases were classified into three groups: Alzheimer's predominant (64.1%), vascular predominant (6.3%) and mixed pathology (29.6%). Significant differences were observed in Severe Mini-Mental State Examination and verbal fluency between the vascular predominant and the other groups of patients. DISCUSSION: The combination of scales measuring cerebral vascular and Alzheimer's type pathology allowed a classification of patients that reveals differences between groups in premortem cognitive features.

Rating scales and questionnaires for assessment of sleep disorders in Parkinson's disease: what they inform about?

Sleep disorders are very prevalent in Parkinson's disease (PD) and include a diversity of disturbances. Rating scales and questionnaires are widely used to assess the presence and severity of the sleep disorders. The objective is to review rating scales and questionnaires used for assessment of sleep disorders in PD. To this purpose, a description and update of the sleep scales reviewed by the ad hoc Movement Disorder Society task force (MDS-TF) and other sleep disorder assessments was performed. Two specific (Parkinson's Disease Sleep Scale and Scales for Outcomes in PD Sleep) and two generic scales (Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale) were "Recommended" by the MDS-TF as they were used in PD patients, by researchers others than their developers and properly validated. Two other generic scales (Inappropriate Sleep Composite Score and Stanford Sleepiness Scale), "Suggested" due to incomplete validation, are also reviewed. Other instruments included in this review are three comprehensive PD-specific instruments for assessing multiple domains in addition to sleep problems (e.g., Non-Motor Symptoms Questionnaire, Non-Motor Symptoms Scale, MDS-UPDRS), and three generic instruments focused on particular disturbances (e.g., International Restless Legs Syndrome Study Group Rating Scale, REM behavioral disorders questionnaires), although these latter lack formal validation in PD populations. The "Recommended" instruments cover satisfactorily the needs for screening and evaluation of the nocturnal sleep disorders and daytime sleepiness in PD patients. It would be convenient to validate or complete the validation in PD populations of those instruments that cannot be recommended due to the lack of information on their clinimetric attributes.

Role of Citicoline in Patients With Mild Cognitive Impairment.

The term mild cognitive impairment (MCI) defines an intermediate state between normal aging and dementia. Vascular cognitive impairment refers to a decline in cognitive function that is caused by or associated with vascular disease and comprises all the spectrum of cognitive impairments, from MCI of vascular origin to vascular dementia. One of the available treatments for cognitive impairment is cytidine diphosphate-choline (CDP-Choline), or citicoline. The objective of the present manuscript is to provide complete evidence about the efficacy of citicoline for MCI, especially of vascular origin, but also due to other neurodegenerative disorders. Citicoline is a pharmaceutical product constituted by the combination of 2 natural molecules (cytidine and choline) and is marketed as a food supplement. It has been proposed to provide neuroprotective effects through diverse mechanisms of action. Taking into account the available literature, citicoline has shown a consistent improvement in cognitive function in patients with MCI, especially of vascular origin. Moreover, it provides beneficial effects on vascular, Alzheimer, and mixed dementias, stroke sequelae, intracerebral hemorrhages, traumatic brain injuries, and neurodegenerative diseases. Long-term treatment with citicoline has also been demonstrated to be well-tolerated and has not been associated with severe adverse events. Citicoline is a safe, well-tolerated, and promising agent with evidenced neuroprotective properties.

[Discriminant validity and inter-rater concordance of two scoring systems for the clock test]. / Validez discriminante y concordancia interobservador de 2 métodos de puntuación del test del reloj.

OBJECTIVE: To compare the discriminant validity and inter-rater reliability of the two scoring systems for the Clock test that are most used in Spain. METHODOLOGY: Two collections of clock drawings obtained in a clinical context (116 cases; 56.8% women, mean age 73.1±7.7 years) and in a cohort of volunteers (2039 drawings of 579 subjects; 59.5% women, mean age 78.3±3.8 years) have been assessed. All subjects were classified as cognitively normal (CN) or cognitively impaired (CI) after extensive clinical and neuropsychological evaluation. Expert raters have evaluated these drawings independently and without knowledge of the diagnosis using the Sunderland and Solomon systems standardized in Spanish by Cacho (range 0 to 10) and del Ser (range 0 to 7) respectively. The discriminant validity of each method was calculated in the two samples using the area under the ROC curve (aROC), and the inter-rater reliability was calculated in the clinical sample, that was assessed by the two evaluators, using the intraclass correlation coefficient (ICC) and the kappa coefficient. RESULTS: There are no significant differences in the discriminant validity of the Sunderland and Solomon systems in any of the samples (clinical: aROC 0.73 [CI95%: 0.64-0.81] and 0.77 [CI95%: 0.69-0.85] respectively, P=.19; volunteers: aROC 0.69 [CI95%: 0.67-0.71] and 0.72 [CI95%: 0.69-0.73] respectively, P=.08). The cut-off points ≤8 and ≤5 correctly classify 71% and 73% of the clinical sample and 82% and 84% of the volunteer sample, respectively. Both systems have good agreement in the clinical sample (Sunderland: ICC 0.90 [CI95%: 0.81-0.93], kappa 0.76 [CI95%: 0.70-0.83]; Solomon: 0.92 [CI95%: 0.88-0.95] and 0.77 [CI95%: 0.71-0.83] respectively), somewhat higher in the second, although the differences are not significant. CONCLUSIONS: The discriminant validity and inter-observer reliability of these two Clock Test correction systems are similar. Solomon's method, shorter and simpler, may be more advisable in pragmatic terms.

Proteins and microRNAs are differentially expressed in tear fluid from patients with Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a progressive loss of neurons and cognitive functions. Therefore, early diagnosis of AD is critical. The development of practical and non-invasive diagnostic tests for AD remains, however, an unmet need. In the present proof-of-concept study we investigated tear fluid as a novel source of disease-specific protein and microRNA-based biomarkers for AD development using samples from patients with mild cognitive impairment (MCI) and AD. Tear protein content was evaluated via liquid chromatography-mass spectrometry and microRNA content was profiled using a genome-wide high-throughput PCR-based platform. These complementary approaches identified enrichment of specific proteins and microRNAs in tear fluid of AD patients. In particular, we identified elongation initiation factor 4E (eIF4E) as a unique protein present only in AD samples. Total microRNA abundance was found to be higher in tears from AD patients. Among individual microRNAs, microRNA-200b-5p was identified as a potential biomarker for AD with elevated levels present in AD tear fluid samples compared to controls. Our study suggests that tears may be a useful novel source of biomarkers for AD and that the identification and verification of biomarkers within tears may allow for the development of a non-invasive and cost-effective diagnostic test for AD.

The Vallecas Project: A Cohort to Identify Early Markers and Mechanisms of Alzheimer's Disease.

INTRODUCTION: Alzheimer's disease (AD) is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late-onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers) may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects. METHODS: We launched the Vallecas Project (VP), a cohort study of non-demented people aged 70-85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods. RESULTS: A total of 1169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9), 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one ε4 allele of the apolipoprotein E gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI) 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI). Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for 4 years after the baseline. CONCLUSION: We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention.

[Effect of anticholinergic drugs on cognitive impairment in the elderly]. / Efecto de los fármacos anticolinérgicos en el rendimiento cognitivo de las personas mayores.

The use of anticholinergic drugs is common in the elderly, even in people with cognitive impairment. A systematic search was conducted in PubMed (anticholinergic effects, anticholinergic and dementia) to define the effects of anticholinergic drugs in the elderly. We emphasized the search in patterns of use, the combined use with AChEIs, the measurement of the Serum Anticholinergic Activity, and the short-term and long-term cognitive effects. The conclusions are that the use of anticholinergic drugs is common in the elderly, even more so than the medical prescription of AChEIs in Alzheimer's disease. The use of anticholinergic drugs may result in cognitive impairment. In long-term use it may generate a worsening of cognitive functions. It can lead to a wrong diagnosis of mild cognitive impairment or dementia, and they can also initiate signs of dementia. Greater cognitive effects appear when there is a previous deficit, but cognitive effects from anticholinergic drugs disappear in severe dementia. The presence of ApoEɛ4 increases the vulnerability for cognitive impairment when these drugs are employed.