Interleukin-17 affects synaptic plasticity and cognition in an experimental model of multiple sclerosis.

Cognitive impairment (CI) is a disabling concomitant of multiple sclerosis (MS) with a complex and controversial pathogenesis. The cytokine interleukin-17A (IL-17A) is involved in the immune pathogenesis of MS, but its possible effects on synaptic function and cognition are still largely unexplored. In this study, we show that the IL-17A receptor (IL-17RA) is highly expressed by hippocampal neurons in the CA1 area and that exposure to IL-17A dose-dependently disrupts hippocampal long-term potentiation (LTP) through the activation of its receptor and p38 mitogen-activated protein kinase (MAPK). During experimental autoimmune encephalomyelitis (EAE), IL-17A overexpression is paralleled by hippocampal LTP dysfunction. An in vivo behavioral analysis shows that visuo-spatial learning abilities are preserved when EAE is induced in mice lacking IL-17A. Overall, this study suggests a key role for the IL-17 axis in the neuro-immune cross-talk occurring in the hippocampal CA1 area and its potential involvement in synaptic dysfunction and MS-related CI.

T2*-weighted MRI values correlate with motor and cognitive dysfunction in Parkinson's disease.

Brain iron load is one of the main neuropathologic hallmarks of Parkinson's disease (PD). Previous studies indicated that iron in the substantia nigra (SN) is related to disease duration and motor impairment. We explore, through a cross-sectional study, the association between brain iron distribution, evaluated by T2*-weighted magnetic resonance imaging (T2*), and clinical features in a cohort of patients with PD. Thirty-two patients with PD, compared with 10 control subjects, were evaluated for motor and cognitive features (attention and working memory, executive functions, language, memory, and visuospatial function). They underwent a magnetic resonance imaging protocol including T2* analysis of specific brain regions of interest to measure iron load compared with healthy control subjects. We found that iron content of the SN correlated positively with both disease duration and Unified Parkinson's Disease Rating Scale III off score. Montreal Cognitive Assessment, Spatial Span, and Graded Naming Test scores were inversely associated with iron load of the SN, whereas Wechsler Adult Intelligence Scale-IV Similarities score showed an inverse relationship with iron content in all the regions of interest examined. Our findings suggest a relationship between topographic brain iron distribution and cognitive domain impairment.

Cerebrospinal fluid neurofilament light chain tracks cognitive impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) is a disabling symptom of multiple sclerosis (MS). Axonal damage disrupts neural circuits and may play a role in determining CI, but its detection and monitoring are not routinely performed. Cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a promising marker of axonal damage in MS. OBJECTIVE: To retrospectively examine the relationship between CSF NfL and CI in MS patients. METHODS: CSF NfL concentration was measured in 28 consecutive newly diagnosed MS patients who underwent a neuropsychological evaluation with the Brief Repeatable Battery of Neuropsychological tests (BRBN). RESULTS: CSF NfL was higher in patients with overall CI (947.8 ± 400.7 vs 518.4 ± 424.7 pg/mL, p < 0.01), and with impairment in information processing speed (IPS) (820.8 ± 413.6 vs 513.6 ± 461.4 pg/mL, p < 0.05) and verbal fluency (1292 ± 511 vs 582.8 ± 395.4 pg/mL, p < 0.05), and it positively correlated with the number of impaired BRBN tests (r = 0.48, p = 0.01) and cognitive domains (r = 0.47, p = 0.01). Multivariate analyses taking into account potential confounders confirmed these findings. CONCLUSION: CSF NfL is higher in MS patients with CI and impaired IPS and verbal fluency. Large myelinated axons injury, causing neural disconnection, may be an important determinant of CI in MS and can be reliably measured through CSF NfL.

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

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.

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

The variability of Alzheimer's 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-ß 1-40 (Aß1-40), amyloid-ß 1-42 (Aß1-42), 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 Aß1-42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aß1-42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aß1-42/Aß1-40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aß1-42 (area under the curve = 0.93). In MCI patients, the Aß1-42/Aß1-40 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 Aß1-42/Aß1-40 ratio in AD diagnosis need to be validated in large multi-center studies.

Differential role of CSF alpha-synuclein species, tau, and Aß42 in Parkinson's Disease.

There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinson's 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 Alzheimer's disease (AD) biomarkers-ß-amyloid 1-42 (Aß42), total tau (t-tau), phosphorylated tau (p-tau)-differentiate PD patients from controls, and that reduced levels of Aß42 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 Aß42/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 Aß42 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 Aß42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aß42 levels at baseline are more prone to develop cognitive decline.

Performance of aß1-40, aß1-42, 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 Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-ß 1-42 (Aß1-42), 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 Aß1-40, Aß1-42, 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. Aß1-42 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 Aß1-42/Aß1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aß1-42/t-tau and Aß1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aß1-42/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 Aß1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aß1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aß1-42 and p-tau reliably predict conversion to AD in MCI patients.