Structural correlates of apathy in Alzheimer's disease: a multimodal MRI study.

OBJECTIVE: Apathy is one of the most frequent symptoms of dementia, whose underlying neurobiology is not well understood. The objective was to analyze the correlations of apathy and its dimensions with gray and white matter damage in the brain of patients with advanced Alzheimer's disease (AD). METHODS: The setting of the study was at the Alzheimer Center Reina Sofía Foundation Research Unit. Participants include 37 nursing home patients with moderate to severe AD, 78.4% were women, and mean Standard Deviation (SD) age is 82.7 (5.8). Several measurements were taken: severe mini-mental state examination and Global Deterioration Scale for cognitive and functional status, Neuropsychiatric Inventory for behavioral problems, and Apathy In Dementia-Nursing Home Version Scale for apathy, including total score and subscores of emotional blunting, deficit of thinking, and cognitive inertia. 3T magnetic resonance imaging measures (voxel-based morphometry, fluid-attenuated inversion recovery, and diffusion tensor imaging) were also conducted. RESULTS: Moderate levels of apathy (mean Apathy In Dementia-Nursing Home Version Scale: 31.1 ± 18.5) were found. Bilateral damage to the corpus callosum and internal capsule was associated with apathy severity (cluster size 2435, p < 0.0005, family-wise error [FWE]-corrected). A smaller and more anteriorly located region of the right internal capsule and corpus callosum was associated with higher emotional blunting (cluster size 334, p < 0.0005, FWE-corrected). Ischemic damage in the right periventricular frontal region was associated with higher deficit of thinking (cluster size 3805, p < 0.005, FWE-corrected). CONCLUSIONS: Brain damage related to apathy may have different features in the advanced stages of AD and differs between the three apathy dimensions. Besides atrophy, brain connectivity and vascular lesions are relevant in the study of apathy, especially in the more severe stages of dementia. Further magnetic resonance imaging studies should include multimodal techniques. Copyright © 2016 John Wiley & Sons, Ltd.

A novel rating scale for the measurement of apathy in institutionalized persons with dementia: the APADEM-NH.

OBJECTIVE: Apathy is one of the most frequent symptoms of dementia, still needing better measurement methods. The objective of this study was to validate a new scale for apathy in institutionalized persons with dementia (APADEM-NH). METHODS: The scale includes 26 items distributed in three dimensions: Deficit of Thinking and Self-Generated behaviors (DT): 13 items, Emotional Blunting (EB): 7 items, and Cognitive Inertia (CI): 6 items. The sample included 100 institutionalized patients (90% female) with probable Alzheimer disease (AD) (57%), possible AD (13%), AD + cerebral vascular disease (17%), Lewy body dementia (11%), and Parkinson associated to dementia (2%), covering all stages of dementia severity according to the Global Deterioration Scale and Clinical Dementia Rating. Additional assessments were the Apathy Inventory, Neuropsychiatric Inventory, Cornell Scale for Depression, and the tested scale. Re-test and inter-rater reliability were carried out in 50 patients. RESULTS: All subscales lacked relevant floor and ceiling effects (<15%). Internal consistency for each dimension was (Cronbach's α): DT = 0.88, EB = 0.83, CI = 0.88; item-total correlations were >0.40; and item homogeneity 0.36-0.51. Test-retest reliability for the items was kW = 0.48-0.92; for the subscales, intraclass correlation coefficient (ICC) = 0.80-0.88; and for the total score, ICC = 0.90. Inter-rater reliability reached kW values of 0.84-1.00; subscales ICC, 0.97-0.99, and total score ICC, 0.99. Standard error of measurement for total score was 6.41 and internal validity ranged from rS = 0.69-0.80. CONCLUSIONS: APADEM-NH proved to be feasible, reliable, and valid for apathy assessment in institutionalized patients suffering mild to severe dementia, discerning well between apathy and depression.

[Effectiveness of the Mini-Mental State for detection of cognitive impairment in primary care]. / Efectividad del Mini-Mental en la detección del deterioro cognitivo en Atención Primaria.

OBJECTIVE: To evaluate the diagnostic accuracy (DA) of the Mini-Mental State (MMS) for the detection of cognitive impairment (CI) in Primary Care (PC) and to determine the best conditions of use for that purpose. DESIGN: Pooled analysis of two prospective, double blind, studies on the evaluation of diagnostic tools with complete verification that were conducted in Madrid and Granada (Spain). SETTING: The MMS was administered in PC and the final cognitive diagnosis (gold standard) was made in Specialized Care. PARTICIPANTS: Subjects with cognitive complaints or suspected of having CI were consecutively recruited in the PC clinic. PRINCIPAL MEASURES: The DA of the MMS was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). The best cut-off point was selected according to the ratio of cases correctly classified (RCC) and to the kappa index. Direct (MMSd) and age- and education-adjusted (MMSa) total scores were analyzed separately. RESULTS: In the total sample of 360 subjects (214 CI), the DA of the MMSd was significantly superior to that of the MMSa (0.84±0.02 vs 0.82±0.02, p≤.001). The yield obtained by the best cut-off point of the MMSd (22/23) was modest (RCC 0.77, kappa 0.52±0.05) and was not improved by any MMSa cut-off point. CONCLUSION: The DA of the MMS for detection of CI in PC was modest and did not improve with adjustment of the score by age and education. The best cut-off point was 22/23, inferior to the usually recommended cut-off.

Detecting MCI and dementia in primary care: effectiveness of the MMS, the FAQ and the IQCODE [corrected].

OBJECTIVES: To study the yield of three instruments for detection of patients with cognitive impairment in primary care. To investigate whether combining tests is better for detecting impairment than applying them separately. METHODS: Seven primary care physicians (PCP) systematically recruited individuals aged over 49 years with a complaint or suspicion of cognitive impairment. The tests administered were the Mini-Mental State Test (MMS), the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and the Pfeffer Functional Activities Questionnaire (FAQ). We calculated sensitivity, specificity and the area under the curve (AUC) and applied logistic regression analysis to determine the yield of the tests in combination. The gold standard was the clinical judgement of a neurologist based on a comprehensive assessment, which included a formal neuropsychological workup. RESULTS: Of the 160 study patients, 90 (56%) had cognitive impairment (15 of these had dementia). The MMS had a sensitivity of 77% and a specificity of 70% in screening for cognitive impairment, with an AUC of 0.82. Incorporation of the IQCODE increased the AUC to 0.86 (P = 0.01). As for dementia, the FAQ reached a sensitivity of 87% and a specificity of 82%, with an AUC of 0.91. Incorporation of the MMS increased the AUC to 0.95 (P = 0.03). CONCLUSIONS: Cognitive impairment is probably underdiagnosed in primary care. The combination of the FAQ and the MMS had excellent performance for dementia detection; however, no satisfactory instrument or instrument combination could be found for cognitive impairment.

The Disconnection Hypothesis in Alzheimer's Disease Studied Through Multimodal Magnetic Resonance Imaging: Structural, Perfusion, and Diffusion Tensor Imaging.

According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p <  0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.

[Reliability and validity of the Severe Impairment Battery, short form (SIB-s), in patients with dementia in Spain]. / Fiabilidad y validez de la bateria de evaluacion del deterioro grave, version abreviada (SIB-s), en pacientes con demencia en España.

INTRODUCTION: People with progressive dementia evolve into a state where traditional neuropsychological tests are not effective. Severe Impairment Battery (SIB) and short form (SIB-s) were developed for evaluating the cognitive status in patients with severe dementia. AIM: To evaluate the psychometric attributes of the SIB-s in patients with severe dementia. PATIENTS AND METHODS: 127 institutionalized patients (female: 86.6%; mean age: 82.6 ± 7.5 years-old) with dementia were assessed with the SIB-s, the Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE), Severe Mini-Mental State Examination (sMMSE), Barthel Index and FAST. RESULTS: SIB-s acceptability, reliability, validity and precision were analyzed. The mean total score for scale was 19.1 ± 15.34 (range: 0-48). Floor effect was 18.1%, only marginally higher than the desirable 15%. Factor analysis identified a single factor explaining 68% of the total variance of the scale. Cronbach's alpha coefficient was 0.96 and the item-total corrected correlation ranged from 0.27 to 0.83. The item homogeneity value was 0.43. Test-retest and inter-rater reliability for the total score was satisfactory (ICC: 0.96 and 0.95, respectively). The SIB-s showed moderate correlation with functional dependency scales (Barthel Index: 0.48, FAST: -0.74). Standard error of measurement was 3.07 for the total score. CONCLUSIONS: The SIB-s is a reliable and valid instrument for evaluating patients with severe dementia in the Spanish population of relatively brief instruments.

TITLE: Fiabilidad y validez de la bateria de evaluacion del deterioro grave, version abreviada (SIB-s), en pacientes con demencia en España.Introduccion. Las personas con demencia progresiva evolucionan hacia un estado donde los tests neuropsicologicos tradicionales dejan de ser eficaces. La bateria de evaluacion del deterioro grave, en su forma completa (SIB) y abreviada (SIB-s), se desarrollo para evaluar el estado cognitivo de pacientes con demencia avanzada. Objetivo. Evaluar los atributos psicometricos de la SIB-s en poblacion española. Pacientes y metodos. Estudio transversal de 127 pacientes con demencia (86,6%, mujeres; edad media: 82,6 ± 7,5 años) evaluados con la SIB-s y las siguientes medidas: escala de deterioro global, miniexamen cognitivo (MEC), miniexamen del estado mental grave (sMMSE), indice de Barthel y escala del estado funcional. Resultados. La puntuacion media total de la SIB-s fue de 19,1 ± 15,34 (rango: 0-48). Efectos suelo y techo < 20%. El analisis factorial identifico un unico factor que explica el 68% de la varianza total de la escala. La consistencia interna fue alta (alfa de Cronbach: 0,96). La correlacion item-total corregida oscilo entre 0,27 y 0,83, y la homogeneidad de los items fue de 0,43. La fiabilidad test-retest e interevaluador fue satisfactoria (coeficiente de correlacion intraclase: 0,96 y 0,95, respectivamente), asi como la validez de constructo convergente con otras medidas cognitivas (MEC: 0,83; sMMSE: 0,9). La SIB-s mostro una correlacion moderada con escalas cognitivas de dependencia funcional (indice de Barthel: 0,48; FAST: ­0,74). El error estandar de la medida fue de 3,07 para el total de la escala. Conclusiones. La SIB-s es un instrumento fiable y valido, relativamente breve, para evaluar a pacientes con demencia avanzada en la poblacion española.

Cerebral blood flow is an earlier indicator of perfusion abnormalities than cerebral blood volume in Alzheimer's disease.

The purpose of this study was to elucidate whether cerebral blood flow (CBF) can better characterize perfusion abnormalities in predementia stages of Alzheimer's disease (AD) than cerebral blood volume (CBV) and whether cortical atrophy is more associated with decreased CBV or with decreased CBF. We compared measurements of CBV, CBF, and mean cortical thickness obtained from magnetic resonance images in a group of healthy controls, patients with mild cognitive impairment (MCI) who converted to AD after 2 years of clinical follow-up (MCI-c), and patients with mild AD. A significant decrease in perfusion was detected in the parietal lobes of the MCI-c patients with CBF parametric maps but not with CBV maps. In the MCI-c group, a negative correlation between CBF values and cortical thickness in the right parahippocampal gyrus suggests an increase in CBF that depends on cortical atrophy in predementia stages of AD. Our study also suggests that CBF deficits appear before CBV deficits in the progression of AD, as CBV abnormalities were only detected at the AD stage, whereas CBF changes were already detected in the MCI stage. These results confirm the hypothesis that CBF is a more sensitive parameter than CBV for perfusion abnormalities in MCI-c patients.

Utility of the mini-cog for detection of cognitive impairment in primary care: data from two spanish studies.

Objectives. To study the utility of the Mini-Cog test for detection of patients with cognitive impairment (CI) in primary care (PC). Methods. We pooled data from two phase III studies conducted in Spain. Patients with complaints or suspicion of CI were consecutively recruited by PC physicians. The cognitive diagnosis was performed by an expert neurologist, after formal neuropsychological evaluation. The Mini-Cog score was calculated post hoc, and its diagnostic utility was evaluated and compared with the utility of the Mini-Mental State (MMS), the Clock Drawing Test (CDT), and the sum of the MMS and the CDT (MMS + CDT) using the area under the receiver operating characteristic curve (AUC). The best cut points were obtained on the basis of diagnostic accuracy (DA) and kappa index. Results. A total sample of 307 subjects (176 CI) was analyzed. The Mini-Cog displayed an AUC (±SE) of 0.78 ± 0.02, which was significantly inferior to the AUC of the CDT (0.84 ± 0.02), the MMS (0.84 ± 0.02), and the MMS + CDT (0.86 ± 0.02). The best cut point of the Mini-Cog was 1/2 (sensitivity 0.60, specificity 0.90, DA 0.73, and kappa index 0.48 ± 0.05). Conclusions. The utility of the Mini-Cog for detection of CI in PC was very modest, clearly inferior to the MMS or the CDT. These results do not permit recommendation of the Mini-Cog in PC.

Is the cerebellum the optimal reference region for intensity normalization of perfusion MR studies in early Alzheimer's disease?

The cerebellum is the region most commonly used as a reference when normalizing the intensity of perfusion images acquired using magnetic resonance imaging (MRI) in Alzheimer's disease (AD) studies. In addition, the cerebellum provides unbiased estimations with nuclear medicine techniques. However, no reports confirm the cerebellum as an optimal reference region in MRI studies or evaluate the consequences of using different normalization regions. In this study, we address the effect of using the cerebellum, whole-brain white matter, and whole-brain cortical gray matter in the normalization of cerebral blood flow (CBF) parametric maps by comparing patients with stable mild cognitive impairment (MCI), patients with AD and healthy controls. According to our results, normalization by whole-brain cortical gray matter enables more sensitive detection of perfusion abnormalities in AD patients and reveals a larger number of affected regions than data normalized by the cerebellum or whole-brain white matter. Therefore, the cerebellum is not the most valid reference region in MRI studies for early stages of AD. After normalization by whole-brain cortical gray matter, we found a significant decrease in CBF in both parietal lobes and an increase in CBF in the right medial temporal lobe. We found no differences in perfusion between patients with stable MCI and healthy controls either before or after normalization.

Quality of life (QoL) in community-dwelling and institutionalized Alzheimer's disease (AD) patients.

The purpose of this study was to describe and compare QoL and its determinants in two groups of patients with AD that differed in place of residence: community or nursing home. This study covered 200 patients with AD (mean age 79.3 ± 8.2 years, 74% female). Fifty-four per cent of the subjects were living in a nursing home and 46% lived at home. QoL was measured using the Alzheimer's Disease Related Quality of Life Scale (ADRQL). The ADRQL was answered by the family caregiver (community group) or the professional caregiver (nursing home group). Descriptive statistics, Chi-square test, Mann-Whitney test and multiple regression analysis were used to compare sociodemographic and clinical variables between the two study groups. The institutionalized patients were predominantly women (87.0% vs. 58.7%, p<0.001), were older (84 years vs. 74 years, p<0.001), and had more advanced dementia (Global Deterioration Scale (GDS)>5 79.6% vs. 19.6%, p<0.001). ADRQL total score was higher (i.e., better QoL) for patients living at home than for institutionalized patients (72.6 ± 19.9 vs. 64.8 ± 18.2, p<0.01). Neuropsychiatric symptoms, severity of dementia, depression and functional dependence were significant predictors of worst QoL. Once those variables were controlled a marginal effect of setting on QoL was found, which favored the nursing home (ß=0.20, p<0.05).

Promoting research in advanced dementia: early clinical results of the Alzheimer Center Reina Sofía Foundation.

The Alzheimer Center Reina Sofía Foundation (ACRSF) was envisaged to address the complex and multi-disciplinary research and care needs posed by Alzheimer's disease (AD) and other neurodegenerative dementias. Patients may be admitted at ACRSF either as inpatients (i.e., nursing home) or outpatients (i.e., day-care center). The research program includes clinical, social, biochemical, genetic, and magnetic resonance investigations, as well as brain donation. We present the inception of the clinical research protocol for the ACRSF, the early results, and the amendments to the protocol. Foreseen as distinct populations, inpatient and outpatient results are presented separately. Data were collected from 180 patients (153 inpatients, 27 outpatients) (86% AD), with informed consent for participation in the research program of the ACRSF. Most patients (95%) had moderate to severe dementia. Nursing home patients were older, displayed marked gait dysfunction, and were significantly more dependent in the activities of daily living (ADL), compared to the day-care patients (p < 0.05). Some cognitive, ADL, and quality of life (QoL) scales were eliminated from the protocol due to floor effect or lack of specificity of contents for advanced dementia. New measurements were added for evaluation of cognition, apathy, agitation, depression, ADL, motor function, and QoL. The final assessment is expected to be sensitive to change in all the clinical aspects of advanced degenerative dementia, to promote multidisciplinary and, desirably, inter-center collaborative research and, eventually, to contribute to the improvement of treatment and care for these patients.