Eva Hyncicova

Spatial navigation—a unique window into physiological and pathological aging

Spatial navigation is a skill of determining and maintaining a trajectory from one place to another. Mild progressive decline of spatial navigation develops gradually during the course of physiological ageing. Nevertheless, severe spatial navigation deficit can be the first sign of incipient Alzheimers disease (AD), occurring in the stage of mild cognitive impairment (MCI), preceding the development of a full blown dementia. Patients with amnestic MCI, especially those with the hippocampal type of amnestic syndrome, are at very high risk of AD. These patients present with the same pattern of spatial navigation impairment as do the patients with mild AD. Spatial navigation testing of elderly as well as computer tests developed for routine clinical use thus represents a possibility for further investigation of this cognitive domain, but most of all, an opportunity for making early diagnosis of AD.

Spatial navigation in young versus older adults

Older age is associated with changes in the brain, including the medial temporal lobe, which may result in mild spatial navigation deficits, especially in allocentric navigation. The aim of the study was to characterize the profile of real-space allocentric (world-centered, hippocampus-dependent) and egocentric (body-centered, parietal lobe dependent) navigation and learning in young vs. older adults, and to assess a possible influence of gender. We recruited healthy participants without cognitive deficits on standard neuropsychological testing, white matter lesions or pronounced hippocampal atrophy: 24 young participants (18–26 years old) and 44 older participants stratified as participants 60–70 years old (n = 24) and participants 71–84 years old (n = 20). All underwent spatial navigation testing in the real-space human analog of the Morris Water Maze, which has the advantage of assessing separately allocentric and egocentric navigation and learning. Of the eight consecutive trials, trials 2–8 were used to reduce bias by a rebound effect (more dramatic changes in performance between trials 1 and 2 relative to subsequent trials). The participants who were 71–84 years old (p < 0.001), but not those 60–70 years old, showed deficits in allocentric navigation compared to the young participants. There were no differences in egocentric navigation. All three groups showed spatial learning effect (p’ s ≤ 0.01). There were no gender differences in spatial navigation and learning. Linear regression limited to older participants showed linear (β = 0.30, p = 0.045) and quadratic (β = 0.30, p = 0.046) effect of age on allocentric navigation. There was no effect of age on egocentric navigation. These results demonstrate that navigation deficits in older age may be limited to allocentric navigation, whereas egocentric navigation and learning may remain preserved. This specific pattern of spatial navigation impairment may help differentiate normal aging from prodromal Alzheimer’s disease.

Health-related quality of life, neuropsychiatric symptoms and structural brain changes in clinically isolated syndrome

Background Neuropsychiatric symptoms and reduced health-related quality of life (HRQoL) are frequent in multiple sclerosis, where are associated with structural brain changes, but have been less studied in clinically isolated syndrome (CIS). Objective To characterize HRQoL, neuropsychiatric symptoms (depressive symptoms, anxiety, apathy and fatigue), their interrelations and associations with structural brain changes in CIS. Methods Patients with CIS (n = 67) and demographically matched healthy controls (n = 46) underwent neurological and psychological examinations including assessment of HRQoL, neuropsychiatric symptoms and cognitive functioning, and MRI brain scan with global, regional and lesion load volume measurement. Results The CIS group had more, mostly mild, depressive symptoms and anxiety, and lower HRQoL physical and social subscores (p≤0.037). Neuropsychiatric symptoms were associated with most HRQoL subscores (β≤-0.34, p≤0.005). Cognitive functioning unlike clinical disability was associated with depressive symptoms and lower HRQoL emotional subscores (β≤-0.29, p≤0.019). Depressive symptoms and apathy were associated with right temporal, left insular and right occipital lesion load (ß≥0.29, p≤0.032). Anxiety was associated with lower white matter volume (ß = -0.25, p = 0.045). Conclusion Mild depressive symptoms and anxiety with decreased HRQoL are present in patients with CIS. Neuropsychiatric symptoms contributing to decreased HRQoL are the result of structural brain changes and require complex therapeutic approach in patients with CIS.

Myxovirus Resistance Protein A mRNA Expression Kinetics in Multiple Sclerosis Patients Treated with IFNβ

Introduction Interferon-β (IFNß) is the first-line treatment for relapsing-remitting multiple sclerosis. Myxovirus resistance protein A (MxA) is a marker of IFNß bioactivity, which may be reduced by neutralizing antibodies (NAbs) against IFNß. The aim of the study was to analyze the kinetics of MxA mRNA expression during long-term IFNβ treatment and assess its predictive value. Methods A prospective, observational, open-label, non-randomized study was designed in multiple sclerosis patients starting IFNß treatment. MxA mRNA was assessed prior to initiation of IFNß therapy and every three months subsequently. NAbs were assessed every six months. Assessment of relapses was scheduled every three months during 24 months of follow up. The disease activity was correlated to the pretreatment baseline MxA mRNA value. In NAb negative patients, clinical status was correlated to MxA mRNA values. Results 119 patients were consecutively enrolled and 107 were included in the final analysis. There was no correlation of MxA mRNA expression levels between baseline and month three. Using survival analysis, none of the selected baseline MxA mRNA cut off points allowed prediction of time to first relapse on the treatment. In NAb negative patients, mean MxA mRNA levels did not significantly differ in patients irrespective of relapse status. Conclusion Baseline MxA mRNA does not predict the response to IFNß treatment or the clinical status of the disease and the level of MxA mRNA does not correlate with disease activity in NAb negative patients.

DIFFERENCES IN SPATIAL AND TEMPORAL ORDER MEMORY IN VARIOUS NEURODEGENERATIVE DEMENTIAS

memory (MOD-MEM) included 43% of patients. On visual inspection these patients had more severe MTA and were more often APOE e4 positive. Memory-spared clusters mild-executive (MILD-EXE), mild-visuoperception-language (MILD-VILA) and moderate-visuospatial (MOD-VISP) included 30% of patients. Using MILD-MEM as reference cluster, younger age was associated with higher likelihood for membership of MOD-VISP (Odds Ratio [OR] 6.21, 95% confidence interval [CI] 3.56-10.83) and MILD-EXE (OR 2.06, CI 1.32-3.23). Membership of MOD-VISP was more likely when APOE e4 was absent (OR 1.82, CI 1.04-3.20) and PA and GCAwere more severe (resp. OR 2.17, CI 1.15-4.10 and OR 2.64, CI 1.44-4.84). On visual inspection, MTA was less severe in memory-spared clusters than in other clusters. Finally, mild-diffuse (MILD-DIFF), moderate-language (MOD-LAN) and severe-diffuse (SEV-DIFF) were characterized by a memory-indifferent profile and included 28% of patients. Using MILD-MEM as reference, membership of SEV-DIFF was more likely when patients were younger (OR 2.77, CI 1.65-4.63), had longer duration of complaints (OR 2.18, CI 1.04-4.57) and had more severe PA and GCA (resp. OR 2.10, CI 1.07-3.76 and OR 2.28, CI 1.29-4.03). Conclusions: We demonstrated that LCA is an eligible method to identify cognitive subtypes in AD dementia using an extensive neuropsychological test battery. The cluster characteristics we found corresponded with earlier findings regarding the association between neurobiological characteristics and cognition.

Effect of age on spatial navigation

Methods: From April 2007 to June 2011, in the neurology department of Seoul National University Bundang Hospital, patients diagnosed as probable Alzheimer’s disease according to NINDS-ADRDA were included. And those with extreme cognitive impairment (CDR 2, 3) were excluded. The Geriatric depression scale was used as a symptom checklist to diagnose depression. And Korean Neuropsychiatric Inventory (NPI) and Seoul-Instrumental Activities of Daily Living (SIADL) score were assessed. Results: Among 229 patients with probable Alzheimer’s disease, 127 patients (54.46%) were female. There were no differences in CDR, CDRSOB, underlying disease such as hypertension, stroke between two groups. Education years, age, total MMSE score, and diabetes were higher in the male group. The Chi-square test and independent t-test were used to check the significance of association. Geriatric depression scale was higher in female patients, but it was not significant (13.67 vs 12.54, P1⁄4.291). But depression in NPI was higher in female patients (64% vs. 36%, P1⁄4.015). The current and possible SIADL total scores were lower in female patients (13.14 vs. 16.40, P1⁄4.013), (11.79 vs 15.10, P1⁄4.009).Conclusions: There is a higher tendency of depression among patients of Alzheimer’s disease, particularly female patients. And daily performance was relatively better in female patients. We suggested that social-living status and previous daily activity were related to these results.