Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome.

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-ß 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-ß 42/amyloid-ß 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.

Diagnostic performance of plasma pTau 217, pTau 181, Aß 1-42 and Aß 1-40 in the LUMIPULSE automated platform for the detection of Alzheimer disease.

BACKGROUND: Recently developed blood markers for Alzheimer's disease (AD) detection have high accuracy but usually require ultra-sensitive analytic tools not commonly available in clinical laboratories, and their performance in clinical practice is unknown. METHODS: We analyzed plasma samples from 290 consecutive participants that underwent lumbar puncture in routine clinical practice in a specialized memory clinic (66 cognitively unimpaired, 130 participants with mild cognitive impairment, and 94 with dementia). Participants were classified as amyloid positive (A+) or negative (A-) according to CSF Aß1-42/Aß1-40 ratio. Plasma pTau217, pTau181, Aß1-42 and Aß1-40 were measured in the fully-automated LUMIPULSE platform. We used linear regression to compare plasma biomarkers concentrations between A + and A- groups, evaluated Spearman's correlation between plasma and CSF and performed ROC analyses to assess their diagnostic accuracy to detect brain amyloidosis as determined by CSF Aß1-42/Aß1-40 ratio. We analyzed the potential of pTau217 to predict amyloidosis in CSF. RESULTS: Plasma pTau217 and pTau181 concentration were higher in A + than A- while the plasma Aß1-42/Aß1-40 ratio was lower in A + compared to A-. pTau181 and the Aß1-42/Aß1-40 ratio showed moderate correlation between plasma and CSF (Rho = 0.66 and 0.69, respectively). The areas under the ROC curve to discriminate A + from A- participants were 0.94 (95% CI 0.92-0.97) for pTau217, and 0.88 (95% CI 0.84-0.92) for both pTau181 and Aß1-42/Aß1-40. Chronic kidney disease (CKD) was related to increased plasma biomarker concentrations, but ratios were less affected. Plasma pTau217 had the highest fold change (x4.2) and showed high predictive capability in discriminating A + from A-, having 4-7% misclassification rate. The global accuracy of plasma pTau217 using a two-threshold approach was robust in symptomatic groups, exceeding 90%. CONCLUSION: The evaluation of blood biomarkers on an automated platform exhibited high diagnostic accuracy for AD pathophysiology, and pTau217 showed excellent diagnostic accuracy to identify participants with AD in a consecutive sample representing the routine clinical practice in a specialized memory unit.

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

Plasma Tau and Neurofilament Light in Frontotemporal Lobar Degeneration and Alzheimer Disease.

OBJECTIVE: To test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically diagnosed Alzheimer disease syndromes (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses. METHODS: We measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression, and survival, and cortical thickness. RESULTS: Plasma NfL, but not plasma t-tau, discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology-confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone. CONCLUSION: Plasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance vs plasma t-tau in FTLD and AD.

Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study.

BACKGROUND: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. METHODS: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1-42 and 1-40 and their ratio (Aß1-42/1-40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. FINDINGS: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1-42/1-40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life. INTERPRETATION: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. FUNDING: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.

Downregulation of miR-335-5P in Amyotrophic Lateral Sclerosis Can Contribute to Neuronal Mitochondrial Dysfunction and Apoptosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease for which the pathophysiological mechanisms of motor neuron loss are not precisely clarified. Environmental and epigenetic mechanisms such as microRNAs (miRNAs) could have a role in disease progression. We studied the expression pattern of miRNAs in ALS serum from 60 patients and 29 healthy controls. We also analyzed how deregulated miRNAs found in serum affected cellular pathways such as apoptosis, autophagy and mitochondrial physiology in SH-SY5Y cells. We found that miR-335-5p was downregulated in ALS serum. SH-SY5Y cells were transfected with a specific inhibitor of miR-335-5p and showed abnormal mitochondrial morphology, with an increment of reactive species of oxygen and superoxide dismutase activity. Pro-apoptotic caspases-3 and 7 also showed an increased activity in transfected cells. The downregulation of miR-335-5p, which has an effect on mitophagy, autophagy and apoptosis in SH-SY5Y neuronal cells could have a role in the motor neuron loss observed in ALS.

APP-derived peptides reflect neurodegeneration in frontotemporal dementia.

OBJECTIVE: We aimed to investigate the relationship between cerebrospinal fluid levels (CSF) of amyloid precursor protein (APP)-derived peptides related to the amyloidogenic pathway, cortical thickness, neuropsychological performance, and cortical gene expression profiles in frontotemporal lobar degeneration (FTLD)-related syndromes, Alzheimer's disease (AD), and healthy controls. METHODS: We included 214 participants with CSF available recruited at two centers: 93 with FTLD-related syndromes, 57 patients with AD, and 64 healthy controls. CSF levels of amyloid ß (Aß)1-42, Aß1-40, Aß1-38, and soluble ß fragment of APP (sAPPß) were centrally analyzed. We compared CSF levels of APP-derived peptides between groups and, we studied the correlation between CSF biomarkers, cortical thickness, and domain-specific cognitive composites in each group. Then, we explored the relationship between cortical thickness, CSF levels of APP-derived peptides, and regional gene expression profile using a brain-wide regional gene expression data in combination with gene set enrichment analysis. RESULTS: The CSF levels of Aß1-40, Aß1-38, and sAPPß were lower in the FTLD-related syndromes group than in the AD and healthy controls group. CSF levels of all APP-derived peptides showed a positive correlation with cortical thickness and the executive cognitive composite in the FTLD-related syndromes group but not in the healthy control or AD groups. In the cortical regions where we observed a significant association between cortical thickness and CSF levels of APP-derived peptides, we found a reduced expression of genes related to synaptic function. INTERPRETATION: APP-derived peptides in CSF may reflect FTLD-related neurodegeneration. This observation has important implications as Aß1-42 levels are considered an indirect biomarker of cerebral amyloidosis.

Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. RESULTS: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. CONCLUSION: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.

Nonconvulsive status epilepticus secondary to paclitaxel administration.

Nonconvulsive status epilepticus (NCSE) can be triggered by metabolic disturbances and drugs in adults without previous epilepsy. We present the case of a 51-year-old woman without previous history of epilepsy and recently diagnosed with infiltrating lobular breast carcinoma. Following the administration of paclitaxel-cremophor, she presented a striking disinhibited behavior with episodic spatial disorientation, emotional indifference, and irritability. Urgent EEG was consistent with NCSE. Clinical improvement and resolution of EEG abnormalities were observed following the administration of intravenous levetiracetam and lacosamide. Other causes of NCSE were ruled out, and antiepileptic drugs were slowly tapered off without new episodes of abnormal behavior after three months of follow-up. We have reported the first case of NCSE secondary to paclitaxel-cremophor. Neurologists and oncologists should consider NCSE as an unusual complication of treatment with paclitaxel-cremophor in patients without a history of epilepsy.