Isabel Cruz-Orduña

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 Alzheimers 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.

Detecting MCI and dementia in primary care: efficiency of the MMS, the FAQ and the IQCODE

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.

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 Alzheimers 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 (β=0.20, p<0.05).

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.

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 Alzheimers 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.

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

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 Alzheimers disease (AD).

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 Alzheimers 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.

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.

Apathy dimensions evolve differently with levels of dementia severity

Background: Criteria for mild cognitive impairment (MCI) using previously published clinical features and augmenting them with imaging and other biomarkers have been proposed for enhancing the likelihood that the clinical syndrome is due to underlying Alzheimer’s disease (AD) pathophysiology. Levels of certainty are ordered (uninformative, intermediate and highest) according to the availability of biomarkers. The applicability of these criteria in the general population has not been evaluated.Methods: The Mayo Clinic Study of Aging is a population-based cohort of non-demented persons aged 70-89 years at enrollment in Olmsted County, MN. Subjects are evaluated according to existing criteria for normal cognition and MCI. Of these subjects, 143 who received a diagnosis of MCI also received a 3TMRI, FDG PETand Pittsburgh Compound B (PiB) PET scans at the time of the diagnosis of MCI but imaging studies were completed without knowledge of the clinical diagnoses. The subjects were classified as normal or abnormal on indices of amyloid deposition (PiB-PET) and neurodegeneration (MRI hippocampal volume and FDG PET) according to previously published criteria on the cognitively normal subjects and subjects with mild AD from the Mayo Study of Aging or the Alzheimer’s Disease Research Center. Results: The median age of the 143 subjects with MCI was 82 years and 66% of the sample was male. 82% of the subjects were classified as amnestic MCI and 18% as non-amnestic MCI. The APOE-ε4 carrier frequency was 37%. The mean Short Test of Mental Status score was 31 and the mean Clinical Dementia Rating scale sum of the boxes was 1.0. In this sample, 17% of these subjects were biomarker negative (uninformative); 14% had evidence of amyloid deposition only (intermediate); 30% had evidence for neurodegeneration only (intermediate), and 38% showed evidence of amyloid deposition and neurodegeneration (highest). Conclusions: The majority of subjects with MCI have evidence for amyloid deposition, neurodegeneration or both. However, some subjects classified as havingMCI had no evidence of the presence of biomarkers for AD. The utility of these biomarkers for predicting AD will be determined by the clinical outcome of these subjects.

Validation of the apathy scale for institutionalized dementia patients: The APADEM scale

Patients and methods: 100 elderly, institutionalized patients (90% female) with diagnosis of probable Alzheimer Disease (AD) ( 57%), possible AD (13%), AD + cerebral vascular disease (17%), Lewy bodies Dementia (11%) and Parkinson associated to dementia (2%), covering all stages of the disease according to the Global Deterioration Scale (GDS) and Clinical Dementia Rating (CDR). Assessments: Apathy Inventory (AI), Neuropsychiatric Inventory (NPI), Cornell scale for depression, and the tested scale APADEM-NH. Re-test was carried out in 50 patients and inter-rater reliability was explored also in 50 patients. The following attributes were analyzed: feasibility and acceptability, reliability, validity, and measurement precision.