Laura Videla

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease

We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early‐onset forms of Alzheimers disease (AD) (early‐onset AD [EOAD]).

Feasibility of Lumbar Puncture in the Study of Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in Subjects with Down Syndrome

BACKGROUND Alzheimers disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population. OBJECTIVE To analyze the frequency of complications after a LP in DS. METHODS We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included. RESULTS There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group. CONCLUSION LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for.

Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer’s Disease

BACKGROUND Episodic memory impairment is the core feature of typical Alzheimers disease. OBJECTIVE To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimers disease (MCI-AD) and to predict progression to Alzheimers disease dementia (AD-d). METHODS Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimers disease (CERAD-WL). Cerebrospinal fluid (CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/Aβ1-42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model. RESULTS A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9-65.3% and 59.4-62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test. CONCLUSIONS The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.

Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study

BACKGROUND Diagnosis of Alzheimers disease in Down syndrome is challenging because of the absence of validated diagnostic biomarkers. We investigated the diagnostic performance of plasma and CSF biomarkers in this population. METHODS We did a cross-sectional study of adults aged 18 years and older with Down syndrome enrolled in a population-based health plan in Catalonia, Spain. Every person with Down syndrome assessed in the health plan was eligible to enter the Down Alzheimer Barcelona Neuroimaging Initiative, and those with a plasma or CSF sample available were included in this study. Participants underwent neurological and neuropsychological examination and blood sampling, and a subset underwent a lumbar puncture. Adults with Down syndrome were classified into asymptomatic, prodromal Alzheimers disease, or Alzheimers disease dementia groups by investigators masked to biomarker data. Non-trisomic controls were a convenience sample of young (23-58 years) healthy people from the Sant Pau Initiative on Neurodegeneration. Amyloid-β (Aβ)1-40, Aβ1-42, total tau (t-tau), 181-phosphorylated tau (p-tau; only in CSF), and neurofilament light protein (NfL) concentrations were measured in plasma with a single molecule array assay and in CSF with ELISA. Plasma and CSF biomarker concentrations were compared between controls and the Down syndrome clinical groups. Diagnostic performance was assessed with receiver operating characteristic curve analyses between asymptomatic participants and those with prodromal Alzheimers disease and between asymptomatic participants and those with Alzheimers disease dementia. FINDINGS Between Feb 1, 2013, and Nov 30, 2017, we collected plasma from 282 participants with Down syndrome (194 asymptomatic, 39 prodromal Alzheimers disease, 49 Alzheimers disease dementia) and 67 controls; CSF data were available from 94 participants (54, 18, and 22, respectively) and all 67 controls. The diagnostic performance of plasma biomarkers was poor (area under the curve [AUC] between 0·53 [95% CI 0·44-0·62] and 0·74 [0·66-0·82]) except for plasma NfL concentrations, which had an AUC of 0·88 (0·82-0·93) for the differentiation of the asymptomatic group versus the prodromal Alzheimers disease group and 0·95 (0·92-0·98) for the asymptomatic group versus the Alzheimers disease dementia group. In CSF, except for Aβ1-40 concentrations (AUC 0·60, 95% CI 0·45-0·75), all biomarkers had a good performance in the asymptomatic versus prodromal Alzheimers disease comparison: AUC 0·92 (95% CI 0·85-0·99) for Aβ1-42, 0·81 (0·69-0·94) for t-tau, 0·80 (0·67-0·93) for p-tau, and 0·88 (0·79-0·96) for NfL. Performance of the CSF biomarkers was optimal in the asymptomatic versus Alzheimers disease dementia comparison (AUC ≥0·90 for all except Aβ1-40 [0·59, 0·45-0·72]). Only NfL concentrations showed a strong correlation between plasma and CSF biomarker concentrations in participants with Down syndrome (rho=0·80; p<0·0001). INTERPRETATION Plasma NfL and CSF biomarkers have good diagnostic performance to detect Alzheimers disease in adults with Down syndrome. Our findings support the utility of plasma NfL for the early detection of Alzheimers disease in Down syndrome in clinical practice and clinical trials. FUNDING Institute of Health Carlos III, Fundació La Marató de TV3, Fundació Bancaria Obra Social La Caixa, Fundació Catalana Síndrome de Down, and Fundació Víctor Grífols i Lucas.

Weight loss in the healthy elderly might be a non-cognitive sign of preclinical Alzheimer’s disease

Weight loss has been proposed as a sign of pre-clinical Alzheimer Disease (AD). To test this hypothesis, we have evaluated the association between longitudinal changes in weight trajectories, cognitive performance, AD biomarker profiles and brain structure in 363 healthy controls from the Alzheimer´s Disease Neuroimaging Initiative (mean follow-up 50.5±30.5 months). Subjects were classified according to body weight trajectory into a weight loss group (WLG; relative weight loss ≥ 5%) and a non-weight loss group (non-WLG; relative weight loss < 5%). Linear mixed effects models were used to estimate the effect of body weight changes on ADAS-Cognitive score across time. Baseline CSF tau/AΔ42 ratio and AV45 PET uptake were compared between WLG and non-WLG by analysis of covariance. Atrophy maps were compared between groups at baseline and longitudinally at a 2-year follow-up using Freesurfer. WLG showed increased baseline levels of cerebrospinal fluid tau/AΔ42 ratio, increased PET amyloid uptake and diminished cortical thickness at baseline. WLG also showed faster cognitive decline and faster longitudinal atrophy. Our data support weight loss as a non-cognitive manifestation of pre-clinical AD.

Obesity and Alzheimer’s disease, does the obesity paradox really exist? A magnetic resonance imaging study

Mid-life obesity is an established risk factor for Alzheimers disease (AD) dementia, whereas late-life obesity has been proposed as a protective state. Weight loss, which predates cognitive decline, might explain this obesity paradox on AD risk. We aimed to assess the impact of late life obesity on brain structure taking into account weight loss as a potential confounder. We included 162 elderly controls of the Alzheimers Disease Neuroimaging Initiative (ADNI) with available 3T MRI scan. Significant weight loss was defined as relative weight loss ≥5% between the baseline and last follow-up visit. To be able to capture weight loss, only subjects with a minimum clinical and anthropometrical follow-up of 12 months were included. Individuals were categorized into three groups according to body mass index (BMI) at baseline: normal-weight (BMI<25 Kg/m2), overweight (BMI 25-30 Kg/m2) and obese (BMI>30 Kg/m2). We performed both an interaction analysis between obesity and weight loss, and stratified group analyses in the weight-stable and weigh-loss groups. We found a significant interaction between BMI and weight loss affecting brain structure in widespread cortical areas. The stratified analyses showed atrophy in occipital, inferior temporal, precuneus and frontal regions in the weight stable group, but increased cortical thickness in the weight-loss group. In conclusion, our data support that weight loss negatively confounds the association between late-life obesity and brain atrophy. The obesity paradox on AD risk might be explained by reverse causation.

Monoaminergic impairment in Down syndrome with Alzheimer's disease compared to early-onset Alzheimer's disease

People with Down syndrome (DS) are at high risk for Alzheimers disease (AD). Defects in monoamine neurotransmitter systems are implicated in DS and AD but have not been comprehensively studied in DS.

STRUCTURAL CORRELATES OF ALZHEIMER’S DISEASE AND AGING IN DOWN SYNDROME: AN MRI STUDY

P3-274 STRUCTURAL CORRELATES OF ALZHEIMER’S DISEASE AND AGING IN DOWN SYNDROME: AN MRI STUDY Victor Montal, Eduard Vilaplana, Maria CarmonaIragui, Jordi Pegueroles, Sof ıa Gonz alez-Ortiz, Bessy Benejam, Daniel Alcolea, Laura Videla, Susana Fernandez, Sebasti an Videla, Rafael Blesa, Alberto Lle o, Juan Fortea, Centre of Biomedical Investigation Network for Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain; Catalan Foundation for Down Syndrome, Barcelona, Spain; Parc de Salut, Hospital del Mar, Barcelona, Spain. Contact e-mail: VMontalB@santpau.cat