This study assesses whether C-terminal fragments (CTF) of the amyloid precursor protein (APP) are present in cerebrospinal fluid (CSF) and their potential as biomarkers for Alzheimer's disease (AD). ...Immunoprecipitation and simultaneous assay by Western blotting using multiplex fluorescence imaging with specific antibodies against particular domains served to characterize CTFs of APP in human CSF. We demonstrate that APP-CTFs are detectable in human CSF, being the most abundant a 25-kDa fragment, probably resulting from proteolytic processing by η-secretase. The level of the 25-kDa APP-CTF was evaluated in three independent CSF sample sets of patients and controls. The CSF level of this 25-kDa CTF is higher in subjects with autosomal dominant AD linked to PSEN1 mutations, in demented Down syndrome individuals and in sporadic AD subjects compared to age-matched controls. Our data suggest that APP-CTF could be a potential diagnostic biomarker for AD.
We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would ...improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.
Virtual reality is a trending, widely accessible, and contemporary technology of increasing utility to biomedical and health applications. However, most implementations of virtual reality ...environments are tailored to specific applications. We describe the complete development of a novel, open-source virtual reality environment that is suitable for multipurpose biomedical and healthcare applications. This environment can be interfaced with different hardware and data sources, ranging from gyroscopes to fMRI scanners. The developed environment simulates an immersive (first-person perspective) run in the countryside, in a virtual landscape with various salient features. The utility of the developed VR environment has been validated via two test applications: an application in the context of motor rehabilitation following injury of the lower limbs and an application in the context of real-time functional magnetic resonance imaging neurofeedback, to regulate brain function in specific brain regions of interest. Both applications were tested by pilot subjects that unanimously provided very positive feedback, suggesting that appropriately designed VR environments can indeed be robustly and efficiently used for multiple biomedical purposes. We attribute the versatility of our approach on three principles implicit in the design: selectivity, immersiveness, and adaptability. The software, including both applications, is publicly available free of charge, via a GitHub repository, in support of the Open Science Initiative. Although using this software requires specialized hardware and engineering know-how, we anticipate our contribution to catalyze further progress, interdisciplinary collaborations and replicability, with regards to the usage of virtual reality in biomedical and health applications.
One of the strengths of the IWG criteria was to reconceptualize the diagnosis of AD, from a clinical-pathologic diagnosis to a clinical-biologic one, which can be performed in vivo. The diagnosis ...should, therefore, be implemented in the clinical stage of the disease, relying on the essence of the new IWG diagnostic criteria in the recognition of this dual aspect of AD: a specific clinical presentation that is related to a well-defined underlying pathology. Biomarkers measured by PET or CSF correlate with high sensitivity and specificity with AD pathologic features; episodic memory properly measured also presents high specificity to detect patients who develop AD dementia, and clinical studies have demonstrated that these criteria applied in a clinical setting present good specificity, making feasible a diagnosis in the prodromal stage of the disease. From an ethical perspective, the governing principle for early prodromal diagnosis should be autonomy, because the decision of wishing to know or not to know should be performed individually by a competent individual. Furthermore, the potential benefit of an early diagnosis may be mediated through an autonomous decision.
Research into hippocampal self-regulation abilities may help determine the clinical significance of hippocampal hyperactivity throughout the pathophysiological continuum of Alzheimer's disease. In ...this study, we aimed to identify the effects of amyloid-β peptide 42 (amyloid-β42) and phosphorylated tau on the patterns of functional connectomics involved in hippocampal downregulation. We identified 48 cognitively unimpaired participants (22 with elevated CSF amyloid-β peptide 42 levels, 15 with elevated CSF phosphorylated tau levels, mean age of 62.705 ± 4.628 years), from the population-based 'Alzheimer's and Families' study, with baseline MRI, CSF biomarkers, APOE genotyping and neuropsychological evaluation. We developed a closed-loop, real-time functional MRI neurofeedback task with virtual reality and tailored it for training downregulation of hippocampal subfield cornu ammonis 1 (CA1). Neurofeedback performance score, cognitive reserve score, hippocampal volume, number of apolipoprotein ε4 alleles and sex were controlled for as confounds in all cross-sectional analyses. First, using voxel-wise multiple regression analysis and controlling for CSF biomarkers, we identified the effect of healthy ageing on eigenvector centrality, a measure of each voxel's overall influence based on iterative whole-brain connectomics, during hippocampal CA1 downregulation. Then, controlling for age, we identified the effects of abnormal CSF amyloid-β42 and phosphorylated tau levels on eigenvector centrality during hippocampal CA1 downregulation. Across subjects, our main findings during hippocampal downregulation were: (i) in the absence of abnormal biomarkers, age correlated with eigenvector centrality negatively in the insula and midcingulate cortex, and positively in the inferior temporal gyrus; (ii) abnormal CSF amyloid-β42 (<1098) correlated negatively with eigenvector centrality in the anterior cingulate cortex and primary motor cortex; and (iii) abnormal CSF phosphorylated tau levels (>19.2) correlated with eigenvector centrality positively in the ventral striatum, anterior cingulate and somatosensory cortex, and negatively in the precuneus and orbitofrontal cortex. During resting state functional MRI, similar eigenvector centrality patterns in the cingulate had previously been associated to CSF biomarkers in mild cognitive impairment and dementia patients. Using the developed closed-loop paradigm, we observed such patterns, which are characteristic of advanced disease stages, during a much earlier presymptomatic phase. In the absence of CSF biomarkers, our non-invasive, interactive, adaptive and gamified neuroimaging procedure may provide important information for clinical prognosis and monitoring of therapeutic efficacy. We have released the developed paradigm and analysis pipeline as open-source software to facilitate replication studies.
The aim of this study was to characterize the neuropsychological and neuroimaging profiles of mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients, and to study the magnitude of the ...differences by comparing both outcomes with healthy subjects in a cross-sectional manner. Five hundred and thirty-five subjects (356 cognitively normal adults (CONT), 79 MCI, and 100 AD) were assessed with the NEURONORMA neuropsychological battery. Thirty CONT, 23 MCI, and 23 AD subjects from this sample were included in the neuroimaging substudy. Patients' raw cognitive scores were converted to age and education-adjusted scaled ones (range 2-18) using co-normed reference values. Medians were plotted to examine the cognitive profile. MRIs were processed by means of FreeSurfer. Effect size indices (Cohen's d) were calculated in order to compare the standardized differences between patients and healthy subjects. Graphically, the observed cognitive profiles for MCI and AD groups produced near to parallel lines. Verbal and visual memories were the most impaired domains in both groups, followed by executive functions and linguistic/semantic ones. The largest effect size between AD and cognitively normal subjects was found for the FCSRT (d = 4.05, AD versus CONT), which doubled the value obtained by the best MRI measure, the right hippocampus (d = 1.65, AD versus CONT). Our results support the notion of a continuum in cognitive profile between MCI and AD. Neuropsychological outcomes, in particular the FCSRT, are better than neuroimaging ones at detecting differences among subjects.
The Memory Binding Test (MBT) is a novel test based on the learning of two lists of words, developed to detect early memory impairment suggestive of Alzheimer's disease (AD).
To present and provide ...reference data of the Spanish MBT in a midlife population of mainly first-degree descendants of AD patients.
472 cognitively unimpaired subjects, aged 45 to 65 and participants of the ALFA STUDY, were included. Raw scores were transformed to scaled scores on which multivariate regression analysis was applied adjusting by age, gender, and education level. A standard linear regression was employed to derive the scaled score adjusted. Sociodemographic corrections were applied and an adjustment table was constructed.
Performance was heterogeneously influenced by sociodemographic factors. Age negatively influenced free recall. Education tends to have an influence in the results showing lower performance with lower education level. Women tend to outperform men in the learning of the first list and total recall. Only a few variables were unaffected by sociodemographic factors such as those related to semantic proactive interference (SPI) and to the retention of learned material. Our results point out that some vulnerability to SPI is expectable in cognitively healthy subjects. Close to 100% of the learned material was maintained across the delay interval.
This study contributes with reference data for the MBT providing the necessary adjustments for sociodemographic characteristics. Our data may prove to be useful for detecting asymptomatic at-risk candidates for secondary prevention studies of AD.
Early diagnosis of neurodegenerative disorders such as Alzheimer's (AD) or Parkinson's disease (PD) is needed to slow down or halt the disease at the earliest stage. Cerebrospinal fluid (CSF) ...biomarkers can be a good tool for early diagnosis. However, their use in clinical practice is challenging due to the high variability found between centers in the concentrations of both AD CSF biomarkers (Aβ42, total tau and phosphorylated tau) and PD CSF biomarker (α-synuclein). Such a variability has been partially attributed to different preanalytical procedures between laboratories, thus highlighting the need to establish standardized operating procedures. Here, we merge two previous consensus guidelines for preanalytical confounding factors in order to achieve one exhaustive guideline updated with new evidence for Aβ42, total tau and phosphorylated tau, and α-synuclein. The proposed standardized operating procedures are applicable not only to novel CSF biomarkers in AD and PD, but also to biomarkers for other neurodegenerative disorders.
The term cognitive reserve describes the capacity of the adult brain to minimise the clinical manifestation of a neurodegenerative process. The acquisition of cognitive reserve has been linked to the ...performance of certain intellectual and cognitive activities throughout the whole of the individual's life.
To create a new cognitive reserve questionnaire (CRQ), to establish its relation with the cognitive functions and to obtain the standard values in the cognitively healthy elderly Spanish population.
The sample consisted of 55 cognitively healthy controls and 53 patients with Alzheimer's disease. All the subjects were asked to complete the CRQ, which consists of eight items with several different possible answers, together with a brief neuropsychological battery.
Age had no significant influence on the score obtained on the CRQ in either of the groups, yet the number of years of schooling did exert a significant effect. In both groups significant correlations were found between the score on the CRQ and performance in neuropsychological tests that measure executive functioning.
The CRQ is a useful questionnaire for assessing the degree of cognitive reserve in healthy controls and in patients in the early stages of Alzheimer's disease. The CRQ is associated with the cognitive performance of executive functioning.
OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer's disease (OPTIMA) was a randomized, double-blind comparison of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch in patients with ...mild-to-moderate Alzheimer's disease who declined despite open-label treatment with 9.5 mg/24 h patch. Over 48 weeks of double-blind treatment, high-dose patch produced greater functional and cognitive benefits compared with 9.5 mg/24 h patch.
Using OPTIMA data, a post-hoc responder analysis was performed to firstly, compare the proportion of patients demonstrating improvement or absence of decline with 13.3 mg/24 h versus 9.5 mg/24 h patch; and secondly, identify predictors of improvement or absence of decline. 'Improvers' were patients who improved on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) by ≥4 points from baseline, and did not decline on the instrumental domain of the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-IADL). 'Non-decliners' were patients who did not decline on either scale.
Overall, 265 patients randomized to 13.3 mg/24 h and 271 to 9.5 mg/24 h patch met the criteria for inclusion in the intention-to-treat population and were included in the analyses. Significantly more patients were 'improvers' with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Weeks 24 (44 (16.6%) versus 19 (7.0%); P < 0.001) and 48 (21 (7.9%) versus 10 (3.7%); P = 0.023). A significantly greater proportion of patients were 'non-decliners' with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Week 24 (71 (26.8%) versus 44 (16.2%); P = 0.002). At Week 48, there was a trend in favor of 13.3 mg/24 h patch. Functional and cognitive assessment scores at double-blind baseline did not consistently predict effects at Weeks 24 or 48.
More patients with mild-to-moderate Alzheimer's disease who are titrated to 13.3 mg/24 h rivastigmine patch at time of decline are 'improvers' or 'non-decliners' i.e. show responses on cognition and activities of daily living compared with patients remaining on 9.5 mg/24 h patch.
Clinicaltrials.gov identifier: NCT00506415; registered July 20, 2007.
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