Cerebrospinal Fluid Biomarkers Predict Clinical Evolution in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment.

BACKGROUND: Determination of Alzheimer's disease (AD) by cerebrospinal fluid (CSF) biomarkers - 42-amino-acid amyloid-ß (Aß42), total tau and phosphorylated tau (p-tau) - has demonstrated high validity for detecting AD neuropathological changes. However, their prognostic utility to predict the onset of dementia in predementia subjects is still questioned. We aimed to study the prospective clinical evolution of a group of subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) and to determine the prognostic capacity of AD CSF biomarkers. METHODS: 149 subjects with MCI or SCD, not meeting dementia criteria, underwent a prospective clinical, neuropsychological and CSF biomarker study. Patients were initially classified as SCD or MCI following internationally accepted criteria. CSF sampling was obtained and analysed following consensus protocols. Neuropsychological and clinical evaluations were conducted at the follow-up. Statistical analysis considering the final clinical diagnosis, regression analysis to define risk factors and survival curves for progression were made. RESULTS: 72.4% of subjects (83% MCI and 27% SCD) with a pathological CSF ratio (Aß42/p-tau) met criteria for dementia during the 5-year follow-up versus 18.7% of subjects from the group with a normal ratio. The pathological CSF ratio was a powerful marker of risk for AD dementia (OR 27.1; 95% CI 10.3-71.2). Kaplan-Meier survival curves showed that only 15% of subjects with a pathological CSF ratio remained free of AD dementia at 5 years of follow-up. All subjects who reverted to normal cognition presented a normal CSF profile at baseline. CONCLUSION: An abnormal AD CSF biomarker profile in predementia subjects is a powerful predictor of cognitive and/or functional decline in the medium term.

Cognitive impairment induced by benzodiazepine use disorder and its reversibility: a case report. / Deterioro cognitivo secundario a trastorno por uso de benzodiacepinas y su reversibilidad: a propósito de un caso.

Letter to the editor.

El consumo crónico de benzodiacepinas es un hecho cada vez más frecuente en nuestro país a pesar de que la eficacia a largo plazo es escasa y los efectos adversos notables. Haciendo incapié en los efectos sobre la cognición, tema todavía en debate, presentamos un caso de deterioro cognitivo asociado a consumo crónico de hipno-sedantes benzodiacepínicos y la mejoría clínica y de las pruebas neuropsicológicas tras su retirada. Creemos así mismo necesaria la concienciación del personal sanitario para el empleo adecuado de dichos fármacos y así disminuir las consecuencias a largo plazo de los mismos y con ello mejorar la calidad de vida y funcionalidad de nuestros pacientes.

Diagnostic Performance and Clinical Applicability of Blood-Based Biomarkers in a Prospective Memory Clinic Cohort.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort. METHODS: All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 [p-tau181], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included. RESULTS: Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value. DISCUSSION: Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.

Applying the new research diagnostic criteria: MRI findings and neuropsychological correlations of prodromal AD.

OBJECTIVE: We describe the neuroimaging characteristics of prodromal AD (PrdAD) patients diagnosed using the new research criteria in a clinical setting. In order to further characterize these patients, we also study the relationship between neuropsychology, CSF biomarkers and magnetic resonance imaging (MRI) findings. METHODS/PATIENTS: 76 participants--24 controls (CTR), 20 amnesic patients, and 32 Alzheimer's disease (AD) patients--were included in the study. PrdAD was defined on the basis of an objective episodic memory deficit and an AD CSF profile. Structural MRI was performed in all participants. RESULTS: After FWE correction, voxel-based morphometry (VBM) analysis of PrdAD patients versus CTR showed significant clusters of decreased gray matter (GM) volume in the left hemisphere regions including the parahippocampal gyrus, uncus, precuneus, and middle frontal gyrus. We did not find differences in brain atrophy between PrdAD and mild AD patients. Some significant associations were found between CSF levels and episodic and semantic fluency tests in the PrdAD group. Correlations in the PrdAD group revealed that patients with higher scores on delayed free recall had significantly greater GM volume in the left superior temporal gyrus (t = 6.64, p < 0.0001). CONCLUSIONS: PrdAD patients presented mainly medial temporal GM atrophy, which was related with significant episodic memory impairment. The cognitive deficit observed in PrdAD patients was also associated with CSF biomarker levels.

Consumption of peanut products improves memory and stress response in healthy adults from the ARISTOTLE study: A 6-month randomized controlled trial.

BACKGROUND: Peanuts are rich in bioactive compounds that may have a positive impact on memory and stress response. OBJECTIVE: To evaluate the effect of regular consumption of peanut products on cognitive functions and stress response in healthy young adults. DESIGN: A three-arm parallel-group randomized controlled trial was conducted in 63 healthy young adults that consumed 25 g/day of skin roasted peanuts (SRP, n = 21), 32 g/d of peanut butter (PB, n = 23) or 32 g/d of a control butter made from peanut oil (free of phenolic compounds and fiber) (CB, n = 19) for six months. Polyphenol intake, cognitive functions, and anxiety and depression scores were evaluated using validated tests. Fecal short-chain fatty acids (SCFAs) and plasma and fecal fatty acids were assessed by chromatographic methods. Urinary cortisol was quantified by an enzymatic method. RESULTS: Comparing the two interventions with the control, a significant reduction in anxiety scores was observed in the SRP compared to the CB group. After the intervention, consumers of SRP and PB had an improved immediate memory (p = 0.046 and p = 0.011). Lower anxiety scores were associated with SRP and PB (p < 0.001 and p = 0.002, respectively) and lower depression scores with SRP, PB and CB (p = 0.007, p = 0.003 and p = 0.032, respectively). Memory functions and stress response were significantly correlated with polyphenol intake, fecal SCFAs, plasma and fecal very long chain saturated fatty acids (VLCSFAs). CONCLUSIONS: Regular peanut and peanut butter consumption may enhance memory function and stress response in a healthy young population. These effects seem to be associated with the intake of peanut polyphenols, increased levels of fecal SCFAs, and unexpectedly, VLCSFAs, which were also present in the control product.

The hippocampal longitudinal axis-relevance for underlying tau and TDP-43 pathology.

Recent studies suggest that hippocampus has different cortical connectivity and functionality along its longitudinal axis. We sought to elucidate the possible different pattern of atrophy in longitudinal axis of hippocampus between Amyloid/Tau pathology and TDP-43-pathies. Seventy-three presenile subjects were included: Amyloid/Tau group (33 Alzheimer's disease with confirmed cerebrospinal fluid [CSF] biomarkers), probable TDP-43 group (7 semantic variant progressive primary aphasia, 5 GRN and 2 C9orf72 mutation carriers) and 26 healthy controls. We conducted a region-of-interest voxel-based morphometry analysis on the hippocampal longitudinal axis, by contrasting the groups, covarying with CSF biomarkers (Aß42, total tau, p-tau) and covarying with episodic memory scores. Amyloid/Tau pathology affected mainly posterior hippocampus while anterior left hippocampus was more atrophied in probable TDP-43-pathies. We also observed a significant correlation of posterior hippocampal atrophy with Alzheimer's disease CSF biomarkers and visual memory scores. Taken together, these data suggest that there is a potential differentiation along the hippocampal longitudinal axis based on the underlying pathology, which could be used as a potential biomarker to identify the underlying pathology in different neurodegenerative diseases.

A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease.

BACKGROUND: Autosomal dominant early-onset Alzheimer disease is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. OBJECTIVE: To describe a novel mutation in the PSEN2 gene associated with early-onset autosomal dominant Alzheimer disease. PATIENTS AND METHODS: The proband was a 49-year-old individual who displayed progressive dementia beginning at age 45 years. One of the parents and one of the grandparents had developed dementia at ages 64 years and 60 years, respectively, and 1 sibling had mild cognitive impairment. Some family members also had Tourette syndrome. Mutation analysis of the APP, PSEN1, PSEN2, and tau (TAU) genes was performed. Apolipoprotein E (APOE) was also genotyped. RESULTS: We found a missense mutation at codon 430 of the PSEN2 gene that predicts a threonine-to-methionine substitution. This mutation was detected in the affected individuals and in 1 cognitively healthy sibling. The mutation was absent in 260 control chromosomes. The normal amino acid was conserved in the human and mouse PSEN1 and mouse PSEN2 homologues. No influence of the APOE genotype was observed. CONCLUSIONS: We have found a novel mutation in the PSEN2 gene in a family with early-onset Alzheimer disease. The variation in the age at onset confirms that PSEN2 mutations are associated with variable clinical expression.

Uncommon polymorphism in the presenilin genes in human familial Alzheimer's disease: not to be mistaken with a pathogenic mutation.

In this article, we studied the frequency of mutations in the presenilin (PSEN) 1, PSEN2 and amyloid precursor protein genes in a group of patients with late-onset Alzheimer's disease (AD). No pathogenic mutations were found, but a rare non-conservative single-nucleotide polymorphism was detected in the PSEN2 gene (P334R) in a large kindred with familial late-onset AD. No cosegregation was observed in this family. Uncommon polymorphisms can be easily mistaken as a pathogenic mutation when segregation is not analyzed. Family segregation study represents an essential point in considering the pathogenicity of these mutations. These uncommon single-nucleotide polymorphisms should be always taken into account in the genetic testing of AD. They may well have important implications for genetic counselling in AD.

[Clinical characteristics of a family with early-onset Alzheimer's disease associated with a presenilin 1 mutation (M139T)]. / Características clínicas de una familia con enfermedad de Alzheimer de inicio temprano asociada a una mutación (M139T) en el gen de la presenilina 1.

BACKGROUND: The objective of this study was to describe the clinical features and the genetic analysis of a family with autosomal-dominant familial Alzheimer's disease. PATIENTS AND METHOD: In addition to the clinical findings of different family members, we performed a genetic analysis to detect mutations in the amyloid precursor protein genes, presenilin 1 and presenilin 2 genes, by means of single-strand conformation polymorphism and subsequent sequencing. The APOE genotype was also determined. RESULTS: The proband was a 52-year-old patient whose Alzheimer's disease started at age 49 years. Family history revealed that several members had developed an early onset dementia. The clinical picture in all them was characterized by cognitive and behavioral abnormalities that started at age 40 to 50 years. An important variability in the age of onset was observed among family members (range 39-51 years). The proband's genetic study identified a mutation in the presenilin 1 gene which predicted a methionine-to-treonine substitution at codon 139 (M139T). APOE genotype was *3/*3. CONCLUSIONS: The clinical picture of this family carrying the M139T mutation was similar to that of the sporadic variant of Alzheimer's disease. The observed variability in the age of onset suggests that, yet being genetically determined, other genetic or environmental factors modify the clinical expression of the disease.

Usefulness of biomarkers in the diagnosis and prognosis of early-onset cognitive impairment.

Early-onset cognitive impairment diagnosis is often challenging due to the overlapping symptoms between the different degenerative and non-degenerative conditions. We aimed to evaluate the usefulness of cerebrospinal fluid (CSF) biomarkers in early-onset cognitive impairment differential diagnosis, to assess their contribution to the diagnosis of Alzheimer's disease (AD) based on the new National Institute of Aging-Alzheimer's Association (NIA-AA) workgroup's recommendations and their capacity to predict subsequent decline in early-onset mild cognitive impairment (MCI). 37 controls and 120 patients (clinical onset <65 years) with diagnosis based on criteria available in 2009 (51 MCI, 42 AD, 10 frontotemporal dementia (FTD), 3 posterior cortical atrophy, and 14 primary progressive aphasia (PPA)) were included. In addition, all subjects were also reclassified according to the revised criteria for MCI, AD, FTD, and PPA, excluding CSF data. We assessed the impact of adding the CSF data to the subject categorization according to the NIA-AA criteria. After inclusion of CSF results, 90% of amnestic and 82% of the non-amnestic AD presentation could be categorized as "high probability", while 3% of AD patients fit into the category "dementia probably not due to AD". All the 24 MCI patients who progressed to AD dementia and only 1/27 stable MCI presented pathological CSF at baseline. Only 4% of the FTD clinical diagnosis had pathological CSF levels. CSF biomarkers provide high diagnostic accuracy in a clinical context in differentiating AD, frontotemporal lobar degeneration, and controls in presenile subjects and can be used equally in amnestic and non-amnestic AD. Abnormal CSF-AD biomarker levels predict subsequent progression to AD dementia in subjects with early-onset MCI.

The Subjective Cognitive Decline Questionnaire (SCD-Q): a validation study.

BACKGROUND: Subjective cognitive decline (SCD) is gaining importance as a focus of investigation, but adequate tools are needed for its quantification. OBJECTIVE: To develop and validate a questionnaire to quantify SCD, termed the Subjective Cognitive Decline Questionnaire (SCD-Q). METHODS: 124 controls (CTR), 144 individuals with SCD, 83 mild cognitive impairment subjects, 46 Alzheimer's disease patients, and 397 informants were included. The SCD-Q contains: part I, named MyCog, which is answered by the subject; and part II, TheirCog, which includes the same questions and is answered by the informant or caregiver. The 24 SCD-Q items assess the perceived subjective decline in memory, language, and executive functions in the last two years. RESULTS: The MyCog scores of controls differed significantly from those of the other groups (p < 0.05) and there were significant differences in TheirCog scores between all groups. The optimal TheirCog cut-off score for discriminating between individuals with and without cognitive impairment was 7/24 (sensitivity 85%, specificity 80%). MyCog scores correlated significantly with anxiety and depression (r = 0.29, r = 0.43, p < 0.005), but no correlations were found with neuropsychological tests. TheirCog scores correlated significantly with most of the neuropsychological tests (p < 0.05). Informants' depression and anxiety influenced TheirCog scores in controls and SCD groups. CONCLUSION: Self-perceived cognitive decline, measured by the SCD-Q part I (MyCog), discriminated SCD from CTR. Part II (TheirCog) was strongly related to subjects' objective cognitive performance, and discriminated between subjects with or without cognitive impairment. The SCD-Q is a useful tool to measure self-perceived cognitive decline incorporating the decliner and the informant perspective.

Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis.

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo-inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo-osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by (1)H-magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline-containing compounds, creatine/phosphocreatine, and N-acetyl-aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients.