Fernando Henríquez

So Close Yet So Far: Executive Contribution to Memory Processing in Behavioral Variant Frontotemporal Dementia

BACKGROUND Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties. OBJECTIVE This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach. METHOD Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls (among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n = 33) and non-amnestic (n = 38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling. RESULTS Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4% - 12.7%) predicted by EF. DISCUSSION These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD.

Neuroanatomical comparison of the "Word" and "Picture" versions of the free and cued selective reminding test in alzheimer's disease

Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimers disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity.

UTILIDADE DO QUESTIONÁRIO DE INVENTÁRIO NEUROPSIQUIÁTRICO (NPI-Q) NA AVALIAÇÃO DE UMA AMOSTRA DE PACIENTES COM DOENÇA DE ALZHEIMER NO CHILE

The Neuropsychiatric Inventory Questionnaire (NPI-Q) is an informant-based instrument that measures the presence and severity of 12 Neuropsychiatric Symptoms (NPS) in patients with dementia, as well as informant distress. Objective To measure the psychometric properties of the NPI-Q and the prevalence of NPS in patients with Alzheimers disease (AD) in Chile. Methods 53 patients with AD were assessed. Subjects were divided into two different groups: mild AD (n=26) and moderate AD (n=27). Convergent validity was estimated by correlating the outcomes of the NPI-Q with Neuropsychiatric Inventory (NPI) scores and with a global cognitive efficiency test (Addenbrookes Cognitive Examination - Revised - ACE-R). Reliability of the NPI-Q was analysed by calculating its internal consistency. Prevalence of NPS was estimated with both the NPI and NPI-Q. Results Positive and significant correlations were observed between the NPI-Q, the NPI, and the ACE-R (r=0.730; p<0.01 and 0.315; p<0.05 respectively). The instrument displayed an adequate level of reliability (Cronbachs alpha=0.783). The most prevalent NPS were apathy/indifference (62.3%) and dysphoria/depression (58.5%). Conclusion The NPI-Q exhibited acceptable validity and reliability indicators for patients with AD in Chile, indicating that it is a suitable instrument for the routine assessment of NPS in clinical practice.

APATHY IMPAIRS ADVANCED ACTIVITIES OF DAILY LIVING IN VERY MILD ALZHEIMER DISEASE

Background: Chromic inflammation is involved in dysfunction and loss of neurons in neurodegenerative diseases. The complement system is required for activation of microglia, which might induce phagocytosis of Abeta and also neurons in the brain. Activation of the classical complement pathway and the resident microglia in the brain may be related to synapse failure and loss of neurons in pathogenesis of Alzheimer’s disease (AD). We reported the clinical potential of complement C3 (C3), apolipoprotein A1 (apoA1), and transthyretin (TTR) in the assessment of cognitive decline by longitudinal and cross-sectional cohort studies (Alzheimer Dement (Amst) 1: 270-280, 2015). In this study, we measured peripheral levels of both inactivated and activated complement proteins in mild cognitive impairment (MCI), AD, and non-demented healthy control (NDC). Methods: The complement protein is proteolytically cleaved during its activation. We developed immunoassay which differentially detected an inactive (inC3) and active (aC3) forms of C3. Peripheral profiles of them were analyzed immunoassay using specific antibodies raised against each form of C3. We also analyzed complementderived peptides of C3 and C4 in both serum and the brain by LC-MS/MS to assess their clinical potential for evaluation of cognitive impairment. The least absolute shrinkage and selection operator was used to evaluate the combination of multiple biomarkers. Results:A combination of inC3, apoA1, and TTR achieved an area under the curve (AUC) of 0.85 (sensitivity: 75% and specificity: 90%) in MCI vs. NDC, and the combination of aC3/inC3 ratio, apoA1, and TTR improved value of AUC to 0.87 (sensitivity: 90% and specificity: 83%). By LC-MS/MS, we found novel peptide fragments of complement proteins showing clinical potential in diagnosis of MCI and AD. Immunohistochemistry and LC-MS/MS anlyses of serum and the brain tissues, including the hippocampus, frontal lobe, and cerebellum, from definite AD and NDC revealed that levels of fragments of C3 and C4 including novel peptides were significantly elevated in both serum and the brain from AD comparing to NDC subjects. Conclusions:The current study indicates that peripheral profiles of activated fragments and inactivated form of complement proteins are related to cognitive decline in MCI and AD.

FUNCTIONAL NETWORK FOR BASIC, INSTRUMENTAL AND ADVANCED IADL IN ALZHEIMER'S DISEASES: THE TECHNOLOGY-ACTIVITIES OF DAILY LIVING QUESTIONNAIRE

(74.969.3) were collected as part of the Australian Imaging Biomarkers and Lifestyle (AIBL) study. Seven to eight year longitudinal data, acquired at 18-month intervals, included T1W-MRI and C PiB-PET. Cross sectional data at baseline included GRE-MRI scans processed for QSM. Aß-amyloid PET, QSM, and volumetric images were normalized with cerebellar gray matter, middle frontal white matter, and intracranial volume respectively. Participants were classified as being Aß+ when above 1.5 SUVR. Region of interest analysis was conducted using a mixed effect model to investigate the association of hippocampal volume with baseline QSMsusceptibility, controlling for age, gender, APOE ε4 carrier status and SUVR (continuous variable). Results: 41 CN were classified as Aßand 15 as Aß+ while all AD subjects were Aß+. A significant negative association was found between volume and QSM-susceptibility in the hippocampus for Aß+ CN (b1⁄4‒4.2261.3, p 1⁄40.002) and AD (ß1⁄4‒3.5761.5, p1⁄4 0.019), while no significant trend was found for AßCN (Fig. 1). Conclusions: The results suggest that QSM in combination with Aß-amyloid PET imaging could be a valuable tool to predict hippocampal atrophy across the AD spectrum.