Sabela C. Mallo

Design of optimal nonlinear network controllers for Alzheimer's disease

Brain stimulation can modulate the activity of neural circuits impaired by Alzheimer’s disease (AD), having promising clinical benefit. However, all individuals with the same condition currently receive identical brain stimulation, with limited theoretical basis for this generic approach. In this study, we introduce a control theory framework for obtaining exogenous signals that revert pathological electroencephalographic activity in AD at a minimal energetic cost, while reflecting patients’ biological variability. We used anatomical networks obtained from diffusion magnetic resonance images acquired by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) as mediators for the interaction between Duffing oscillators. The nonlinear nature of the brain dynamics is preserved, given that we extend the so-called state-dependent Riccati equation control to reflect the stimulation objective in the high-dimensional neural system. By considering nonlinearities in our model, we identified regions for which control inputs fail to correct abnormal activity. There are changes to the way stimulated regions are ranked in terms of the energetic cost of controlling the entire network, from a linear to a nonlinear approach. We also found that limbic system and basal ganglia structures constitute the top target locations for stimulation in AD. Patients with highly integrated anatomical networks–namely, networks having low average shortest path length, high global efficiency–are the most suitable candidates for the propagation of stimuli and consequent success on the control task. Other diseases associated with alterations in brain dynamics and the self-control mechanisms of the brain can be addressed through our framework.

SUBJECTIVE COGNITIVE COMPLAINTS (SCCS) AS A PREDICTOR OF COGNITIVE PERFORMANCE: A LONGITUDINAL STUDY IN PEOPLE WITH SCCS

with nonlinear transformations. The SUVR parametric map was generated using cerebellar grey matter as a reference region for both images. For statistical analysis, we performed voxel-wise analysis to show the association between amyloidosis and NFTs following the model in each group using VoxelStats. [F] MK6240 SUVR w [F]AZD4694 SUVR + age + gender + APOE + education. Results: The unique association between amyloidosis and NFTs was present in entorhinal cortex and PCC in CN; precuneus, PCC, and parahippocampal gyrus in MCI; ACC, entorhinal cortex, parahippocampal gyrus, and orbitofrontal cortex in AD. All groups showed the association in lateral temporal and middle frontal gyrus. Conclusions: Our results revealed both similar and different association patterns between amyloidosis and NFTs across AD stage. Most common association pattern was present at left lateral temporal cortex across all stages while the different association pattern moved from PCC, precuneus, to orbitofrontal cortex in CN, MCI, and AD, respectively. This corroborates the two pathologies spread from the posterior to anterior regions of the brain.

DO BIOMARKERS DIFFERENTIATE COGNITIVE PROFILES IN MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE?

Sr.,, Instituto de Neurociencia Cognitiva y Traslacional (Instituto de Neurologica Cognitiva/National Scientific and Technical Research Council), Buenos Aires, Argentina; Instituto de Neurociencia Cognitiva y Traslacional, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Cient ıficas y T ecnicas, Buenos Aires, Argentina; Neuroscience Institute Favaloro Foundation, Buenos Aires, Argentina; Instituto de Neurologica Cognitiva, Buenos Aires, Argentina. Contact e-mail: mmartinez@ineco.org.ar

MILD BEHAVIORAL IMPAIRMENT CHECKLIST (MBI-C): A PRELIMINARY VALIDATION STUDY

Multiple regression analysis was used to test the predictive value of SCCs at baseline, controlling depression, age and years of schooling on general cognitive performance at follow-up. Results: SCCs correlated significantly with depression, general cognitive performance and episodic memory at baseline (Table 2). General cognitive performance at follow-up was predicted by SCCs from informants at baseline jointly with age and years of schooling explaining 46% of the variance (Model 4 in Table 3), but not by depression (Model 2 in Table 3). Conclusions:SCCs are correlated with depression, general cognitive performance and episodic memory at baseline. SCCs from informants but not depression are relevant in the prediction of cognitive performance over time.

RELATIONSHIP BETWEEN SUBJECTIVE COGNITIVE COMPLAINTS (SCCS), DEPRESSION AND COGNITIVE PERFORMANCE

Background: Neuropsychiatric syndromes have been associated with risk and earlier onset of dementia, but it is unclear whether neuropsychiatric treatment may affect clinical changes in Alzheimer’s disease dementia (AD). This study aimed to investigate whether psychotropics may affect cognitive or functional changes in AD. Methods: Consecutive outpatients with late-onset AD according to National Institute on Aging – Alzheimer’s Association criteria were screened for demographic data and prospectively assessed for psychotropic therapy, the Mini-Mental State Examination (MMSE) and a 15-item Clock Drawing Test (CDT), while caregivers were queried for the Index of Independence in Activities of Daily Living (ADL) and Lawton’s Scale for Instrumental Activities of Daily Living (IADL), and followed for one year. Genotyping for rs7412&rs429358 (APOE gene) was undertaken with TaqMan Real-Time Polymerase Chain Reactions. Baseline behavioral symptoms were assessed according to the Neuropsychiatric Inventory, whereas anti-depressants, anti-psychotics and antiepileptic drugs entered the statistical model, significance at p<0.05. Results:Overall, 193 patients were included (mean age at AD onset 73.2966.4 years-old): 130 were female (67.36%), 103 were APOEε4 carriers (53.37%), 181 used a cholinesterase inhibitor (93.78%), 143 used Memantine (74.09%), 93 used anti-depressants (48.19%), 56 used anti-psychotics (29.02%) and 25 used anti-epileptic drugs (12.95%). Baseline neuropsychiatric burden was not significantly different according to APOE-ε4 carrier status (p1⁄40.9732). Scores in the MMSE, ADL and IADL were significantly lower after one year (p<0.0001), whereas scores in the CDT were marginally significantly lower (p1⁄40.0655). For APOE-ε4 carriers: use of anti-psychotics marginally slowed the decline in IADL (p1⁄40.0611), while use of anti-depressants and anti-epileptic drugs in combination slowed the decline in the MMSE (p1⁄40.0429). For APOE-ε4 non-carriers: use of anti-epileptic drugs accelerated the decline in ADL (p1⁄40.0114), while use of anti-psychotics marginally accelerated the decline in ADL (p1⁄40.0652) and in the MMSE (p1⁄40.0557). Conclusions:The results of this study support the prospective effects of psychotropic drugs over cognitive and functional changes in AD according to APOE-ε4 carrier status, considering a sample in which almost all patients regularly used a cholinesterase inhibitor. Psychotropics differentially affect clinical changes in AD according to APOE-ε4 carrier status, possibly due to genetically-mediated variable efficiency of neural repair mechanisms. (FAPESP grant #2015/10109-5.)

ASSESSING EVERYDAY ACTIVITIES WITH THE SPANISH VERSION OF THE AMSTERDAM IADL QUESTIONNAIRE: GROUP DIFFERENCES AND RELATION WITH COGNITIVE AND PSYCHOSOCIAL MEASURES

was adequate (Pearson’s coefficient 1⁄4. 70, p<. 001) and interrater reliability, excellent (intraclass correlation1⁄4. 99, p<.001). Normative data shown in percentiles were stratified by age and education (See Table). Conclusions: This study suggests that the DCQ is a valid and reliable cognitive screening test. Application of the DCQ on populations with atypical dementias is underway to derive sensitivity and specificity values for various dementias.

COGNITIVE RESERVE (CR) AND COGNITIVE PERFORMANCE IN PEOPLE WITH SUBJECTIVE COGNITIVE COMPLAINTS (SCCS)

Background:Assessment of dementia tends to emphasise irreversible loss of function. However, early diagnosis and effective treatment of dementia will likely requirenewtests that candynamically challenge thebrain’s residual functional capacity. Here we illustrate the feasibility of applying such tests to assess dynamic speech processing capacity in the language cortex of patients with primary progressive aphasia (PPA).Methods:We assessed patients’ ability to understand speech signals under conditions of sinewave replacement (removing spectral detail from speech sounds). Patients representing all major PPA syndromes were compared with healthy age-matched controls. Participants’ performance was measured in terms of how quickly they learned to understand degraded sinewave speech in two tasks, the secondofwhich exploited semantic prediction to boost task performance. Results: Relative to healthy controls, patients with logopenic aphasia (LPA) and progressive nonfluent aphasia (PNFA) showed deficient perceptual learning of sinewave speech, while patients with semantic dementia (SD) showed impaired performance when the task required integration of semantic knowledge. Conclusions:The findings suggest distinct syndromic profiles of dynamic speech decoding: LPA and PNFA are associated with core deficits of ‘bottom-up’ perceptual analysis, whereas SD is associated with a deficit of ‘top-down’ semantic integration. Procedures of this kind could form the basis for future speech-based ‘stress tests’ to assess early language dysfunction, residual cerebral plasticity and treatment response in PPA and potentially other dementias, including Alzheimer’s disease.

LONGITUDINAL CHANGES IN VISUAL MEMORY IN MILD COGNITIVE IMPAIRMENT VERSUS NORMAL AGING IN PEOPLE WITH SUBJECTIVE COGNITIVE COMPLAINT

changes on visual memory performance in individuals complaining of memory deficits and diagnosed with and without MCI. Methods: We evaluated 209 individuals aged +50 years who attended primary care health centers with subjective cognitive complains and without neurological or psychiatric illness. Each participant underwent extensive evaluation, including review of his or her medical history and neuropsychological assessment and was revaluated up to two times at approximately 15 months intervals with an average follow up time of 3.5 years. Of the 209 individuals 170 were diagnosed as Healthy Controls and 39 as MCI at the third evaluation following standard criteria (Albert et al 2011; Petersen 2004). We compared the trajectory of performance of the two groups on the CANTAB tests, Pattern Recognition Memory (PRM. Percent correct), Delayed Matching to Sample (DMS, percent correct), Spatial Span (SSP, span length) Figure 1. Pattern Recognition Memory Performance. Figure 3. Spatial Span Performance.