Viviana Lisetti

Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's disease

There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinsons disease (PD). CSF alpha synuclein (α-syn) species, namely total and oligomeric α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis. Preliminary evidences show that the combination of CSF t-α-syn and classical Alzheimers disease (AD) biomarkers—β-amyloid 1–42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau)—differentiate PD patients from controls, and that reduced levels of Aβ42 represent a predictive factor for development of cognitive deterioration in PD. In this prospective study carried out in 44 PD patients and 25 neurological controls we wanted to verify whether the combination of CSF α-synuclein species—t-α-syn and o-α-syn—and classical AD biomarkers may help in differentiating PD from neurological controls, and if these biomarkers may predict cognitive decline. The median of follow-up duration was 3 years (range: 2–6 years). Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used for monitoring cognitive changes along time, being administered once a year. Oligo/total α-syn ratio (o/t-α-syn ratio) confirmed its diagnostic value, significantly contributing to the discrimination of PD from neurological controls. A greater diagnostic accuracy was reached when combining o/t-α-syn and Aβ42/tau ratios (Sens = 0.70, Spec = 0.84, AUC = 0.82; PPV = 0.89, NPV = 0.62, LR+ = 4.40, DOR = 12.52). Low CSF Aβ42 level was associated with a higher rate of MMSE and MoCA decline, confirming its role as independent predictive factor for cognitive decline in PD. None of the other biomarkers assessed (t-tau, p-tau, t-α-syn and o-α-syn) showed to have prognostic value. We conclude that combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive decline.

Performance of Aβ1-40, Aβ1-42, Total Tau, and Phosphorylated Tau as Predictors of Dementia in a Cohort of Patients with Mild Cognitive Impairment

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimers disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination annual change rate score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.

Performance Evaluation of an Automated ELISA System for Alzheimer’s Disease Detection in Clinical Routine

The variability of Alzheimers disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1-40), amyloid-β 1-42 (Aβ1-42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1-42/Aβ1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1-42 (area under the curve = 0.93). In MCI patients, the Aβ1-42/Aβ1-40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1-42/Aβ1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

Evidence of practice effect in CANTAB spatial working memory test in a cohort of patients with mild cognitive impairment

ABSTRACT The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a system of neuropsychological tests frequently used to track the progression of cognitive deficits in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). We investigated test–retest reliability in seven CANTAB tests. Twenty-five MCI patients, with either AD-like or conflicting/normal cerebrospinal fluid profiles underwent three testing sessions at 6-month intervals, including the following tests: Reaction Time and Rapid Visual Information Processing (assessing attention and reaction times); Delayed Matching-to-Sample, Paired Associates Learning, Spatial Recognition Memory and Pattern Recognition Memory (assessing memory); Spatial Working Memory (assessing executive functions). No significant difference was found when comparing the two groups. Many CANTAB measures obtained low or marginal test-retest coefficients. We observed a marked improvement in Spatial Working Memory (SWM) in both groups when comparing the baseline performance with the 6-month follow-up, but no difference in performance between 6- and 12-month follow-ups. A similar trend was documented in Paired Associates Learning (PAL), but the effect size was small. Such improvement may result from a practice effect, likely due to the learning of an effective strategy. Our evidence raised an important issue concerning the need for methodological caution when interpreting the results of longitudinal studies using SWM and PAL.

ROLE OF THE PAIRED ASSOCIATES LEARNING TASK FROM CANTAB IN THE ASSESSMENT OF INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE AND MCI PATIENTS

the anti-saccade task). Thus, participants with AD are expected to show a greater number of eye movements towards salient, task-unrelated stimuli. This should also be reflected in the MCI group but will be mediated by performance on cognitive assessments. Results: All the saccades of different groups of participants collected during the video watching tasks were filtered and then generated density maps based on their direction and amplitude. Each map was then condensed into two values using a feature extraction analysis using kernel principal component analysis (KPCA). Conclusions:Preliminary findings suggest that the distribution of the saccades for MCI and AD groups are different than old and younger groups.

NOT YET MCI: HOW TO DETECT SUBTLE COGNITIVE IMPAIRMENT?

model for FR from the Baltimore Longitudinal Study of Aging (Grober et al, 2008). FR was stable up to 7 years before AD diagnosis, then declined steadily until 3 years when the rate doubled. Impaired TR, the core clinical phenotype of the IWG-2 criteria for prodromal AD, emerges at this time. The OMICs was applied to the FR and TR scores of 148 AD cases that developed out of 1448 Einstein Aging Study participants initially dementia-free. Each data wave was assigned to the stage predicted by the OMICs according to when in the preclinical or clinical period the assessment was conducted. Descriptive statistics were computed for FR and TR at each OMICs stage and spaghetti plots displayed the trajectory of FR and TR decline. Results:The prescribed ranges for FR and TR at each OMICs stage fell within the 95% CI of the mean FR and TR scores assigned to that stage (Table). Trajectories for FR and TR appear consistent with expectations: FR declined at 7-8 years with more rapid decline at 3 years (Figure 1); TR was unimpaired (>46) until 3 years before diagnosis when decline began (Figure 2). The look-up-table (Figure3) classifies patients into OMICs stages based on their FR and TR scores. A patient with 28 in FR and 47 in TR would be assigned to the pre-aMCI stage; a patient with 23 in FR and 45 in TR would be assigned to the prodromal stage. Conclusions:The results support our proposed OMICs model. Analyses are underway to determine how well the model prospectively classifies individuals into the prescribed stages. The ultimate objective is to enable more accurate diagnosis and serve as a cost-effective screening tool for secondary AD clinical trials. Grober, 2008, JINS, 14,266.