Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

An updated Italian normative dataset for the Stroop color word test (SCWT).

The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3-5; 6-8; 9-13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease.

A normative study of the Italian printed word version of the free and cued selective reminding test.

According to the new research criteria for the diagnosis of Alzheimer's disease, episodic memory impairment, not significantly improved by cueing, is the core neuropsychological marker, even at a pre-dementia stage. The FCSRT assesses verbal learning and memory using semantic cues and is widely used in Europe. Standardization values for the Italian population are available for the colored picture version, but not for the 16-item printed word version. In this study, we present age- and education-adjusted normative data for FCSRT-16 obtained using linear regression techniques and generalized linear model, and critical values for classifying sub-test performance into equivalent scores. Six scores were derived from the performance of 194 normal subjects (MMSE score, range 27-30, mean 29.5 ± 0.5) divided per decade (from 20 to 90), per gender and per level of education (4 levels: 3-5, 6-8, 9-13, >13 years): immediate free recall (IFR), immediate total recall (ITR), recognition phase (RP), delayed free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. This study confirms the effect of age and education, but not of gender on immediate and delayed free and cued recall. The Italian version of the FCSRT-16 can be useful for both clinical and research purposes.

Italian validation of the Wagnild and Young Resilience Scale: a perspective to rheumatic diseases.

OBJECTIVES: Studying the characteristics of resilience may help to explain how, in the face of a chronic disease, people are able to cope in productive and effective ways. The Wagnild and Young Resilience Scale (RS) is an appropriate instrument to study resilience and has already been translated from the original English version into several languages. The aim of this study was to validate the Italian version of the RS, a 25-item scale ranging from 25 to 175 where higher scores indicate stronger resilience. METHODS: The Minimal Translation Criteria were followed to translate the scale which was then filled out by 1090 students to assess the reliability, stability, internal consistency and concurrent validity. RESULTS: Time stability was assessed in a sample of 117 students (M age=20.18 yr, SD 1.25) by test-retest correlation (r=0.78). RS reliability was evaluated in a second sample of 973 students (M age=16.95 yr, SD 1.50) with RS mean of 126.6 (SD 17.4). Concurrent validity was assessed by correlation with General Health Questionnaire (r=-0.51), Ego-Resilience Scale (r=0.63) and Beck Depression Inventory (r=-0.45). Internal consistency was evaluated by Cronbach alpha (α=0.84). Principal component analysis was performed on 24 out of the 25 items and resulted in six components. CONCLUSIONS: Our data indicated that the 24-item Italian version of the RS scale can be considered a useful instrument to measure resilience and can be used by healthcare staff to help patients cope effectively with stressful situations such as rheumatic and other chronic diseases.

The reversed clock drawing test phenomenon in Alzheimer's disease: A perfusion SPECT study.

AIM: To unveil a brain single photon emission computed tomography (SPECT) pattern in Alzheimer's disease (AD) patients, showing a reversed clock drawing test (CDT) phenomenon. PATIENTS AND METHODS: Among 1,005 consecutive subjects, 9 AD patients who drew a reversed CDT (AD-R) underwent SPECT, which was analysed (SPM2) versus a group of 10 AD patients performing the CDT correctly (AD+) and versus 15 controls (CTR). Brain SPECT in 11 AD patients who mistook the CDT in a common way (AD-) was compared with AD+ and CTR groups. RESULTS: Relative hypoperfusion was found in AD-R versus CTR in right medial frontal, parahippocampal and subcallosal gyri, and in left insula and superior temporal gyrus. Hypoperfusion was found in AD-R versus AD+ in the right uncus, superior temporal and parahippocampal gyri. In the AD- versus CTR comparison, hypoperfusion was found in left hippocampus, parahippocampal gyrus and superior parietal lobule. In AD-R versus AD+ and CTR merged together, the analysis showed hypoperfusion in the right parahippocampus, medial frontal gyrus, superior temporal gyrus and uncus, in the left insula and superior temporal gyrus. CONCLUSION: Fronto-temporal dysfunction, especially in the right hemisphere, plays a role in the reversed CDT phenomenon in AD patients, whereas matched AD patients mistaking the CDT in a common way show left posterior temporo-parietal hypoperfusion.

The factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease.

Our aim was to evaluate the factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease (AD). Five hundred and twenty-four consecutive outpatients at their first diagnostic work-up (age 78.02+/-6.07 years, education 6.62+/-3.48 years, mean MMSE score 20.23+/-4.89) (+/-S.D.) with probable AD (based on DSM-IV and NINCDS-ADRDA criteria) were enrolled in a multicenter, cross-sectional, regional-based study. For the purpose of the present study, the 11 subtests composing the MMSE and the global MMSE score (ranging from 10 to 29, included) were considered. Factor analysis with Varimax rotation method identified two factors that explained about the 85% of total variance. The first factor explained the 65% of variance and mainly included temporal orientation, delayed recall, attention/concentration, and constructional praxia. The second factor explained the 20% of variance and included reading a sentence, writing a sentence, naming, verbal repetition and immediate memory. The first factor was a reliable index of cognitive deterioration along the MMSE score interval between 29 and 10, whereas the second factor was not a suitable marker in this range. The two-factor structure of the MMSE in AD is shown in a large series of patients. The first factor expresses the ability to use new information and is related with working memory. The second factor is related with a more consolidated knowledge, namely verbal abilities, and is essentially useless in mild to moderate AD.

99mTc-HMPAO and 99mTc-ECD brain uptake correlates of verbal memory in Alzheimer's disease.

AIM: Technetium-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO) and technetium-99m N,N-1,2-ethylene diylbis-Lcysteine diethyl ester dihydrochloride ((99m)Tc-ECD) SPECT are widely used in Dementia Clinics for early and differential diagnosis. They have been shown to perform differently in Alzheimer's disease (AD), but the impact of such differences on both research and clinical work is unknown. We investigated the differences between the 2 compounds in research work by assessing correlation between performance on a verbal memory task and cerebral perfusion in 2 matched groups of AD patients. METHODS: Nineteen pairs of patients with mild to moderate AD undergoing SPECT with either 99mTc-HMPAO or (99m)Tc-ECD were retrospectively selected in a Memory Clinic. Patients were matched for sex, age (+/-3 years) and the Mini-Mental State Examination score (+/-2 points) with a case-control procedure, thus obtaining 2 well-matched groups. The score on the Grober-Buschke selective reminding test (SRT) was correlated with SPECT in each group by means of statistical parametric mapping 99 (height threshold: P<0.01). RESULTS: (99m)Tc-HMPAO SPECT yielded 3 significant correlation clusters involving inferior and middle frontal gyri, para-hippocampal gyrus and putamen in the right hemisphere; the middle and superior temporal gyri, insula and claustrum in the left hemisphere. (99m)Tc-ECD gave a significant cluster of correlation in left postcentral gyrus and inferior parietal lobule. CONCLUSION: (99m)Tc-HMPAO SPECT correlation sites seem more consistent than (99m)Tc-ECD ones with the neurophysiological models of verbal memory, as designed both in normal individuals and in pathological conditions. The demonstration of such relevant differences introduces a source of variability among studies performed with either of the 2 compounds, which must be considered when interpreting results.

The Von Restorff effect in ageing and Alzheimer's disease.

The purpose of the study was to evaluate the Von Restorff effect in normal ageing and in Alzheimer's disease (AD). A shortened paradigm was administered to three groups of subjects: young volunteers, elderly volunteers and patients with early-stage AD (MMSE>20). Each subject was presented with 25 lists of 10 words each, the target word appearing in double font size. A free recall phase followed the presentation of each list; after completion of the battery, a size recognition test was administered and subjects were inquired regarding the strategy employed and perception of target words. The total number of recalled words differed significantly among the three groups (young volunteers 144.4+/-38.6, elderly volunteers 86.5+/-17.6, patients 44.2+/-14.6). A significant difference in percentage of recall was found between target and non-target words in young (60.0+/-13.8% vs. 45.7%+/-15.0%, p<0.001) and in elderly (31.2+/-11.4% vs. 20.2+/-6.9%, p<0.001) volunteers, but not in patients (10.7+/-6.9% vs. 11.8+/-7.3%). The present study highlights that the Von Restorff effect can be detected in healthy elderly subjects, and that it is significantly reduced in patients in the early stage of AD. On the basis of the findings of the present study it is not possible to disentangle the contribution of visual-perceptual and encoding impairment, both of them potentially contributing to the observed reduction.

Global cognitive impairment should be taken into account in SPECT-neuropsychology correlations: the example of verbal memory in very mild Alzheimer's disease.

PURPOSE: To examine the impact of severity of global cognitive impairment on SPECT-neuropsychology correlations, we correlated a verbal memory test with brain perfusion in patients with very mild Alzheimer's disease (AD), taking into account the Mini-Mental State Examination (MMSE) score as an index of global cognitive impairment. METHODS: Twenty-nine outpatients (mean age 78.2+/-5.5 years) affected by very mild, probable AD underwent brain SPECT with 99mTc-ethylcysteinate dimer and a word list learning test. SPM99 was used for voxel-based correlation analysis after normalisation to mean cerebellar counts (height threshold: p<0.01). In a first analysis, only age and years of education were inserted as nuisance covariates, while in a second analysis the MMSE score was inserted as well. RESULTS: In the first analysis, two clusters of significant correlation were found in both hemispheres, mainly including regions of the right hemisphere, such as the inferior parietal lobule, the middle temporal gyrus and the posterior cingulate. Significant correlation in the left hemisphere was observed in the lingual lobule, the parietal precuneus and the posterior cingulate. After taking into consideration the MMSE, the largest cluster of correlation was found in the left hemisphere, including the parietal gyrus angularis, the posterior cingulate and the middle temporal gyrus. CONCLUSION: The wide differences observed between the correlations achieved with and without taking into account the MMSE score indicate that severity of global cognitive impairment should be considered when searching for brain perfusion-neuropsychology correlations. In the present case, this strategy resulted in correlations that more closely matched neuropsychological models of verbal memory deficit.

Psychological and social aspects in management of Alzheimer's patients: an inquiry among caregivers.

A survey in the cities of Genoa and Savona (Italy) was performed to examine stress levels in caregivers of patients with Alzheimer's disease in the context of a project of the Italian Ministry of Health named Cronos. It offered free anticholinesterase inhibitor therapy to patients who addressed dedicated Neurological Units; in this occasion caregivers could be invited to express the main difficulties encountered in managing demented people during an interview conducted by health personnel of the Neurophysiology Service. Caregivers were mainly women, daughters or spouses, with a medium educational level, retired, housekeepers, employees or teachers; they claimed a lowering of economic standard of living of the family owing to extra expenses for assistance. Satisfaction was expressed towards specialists, while support by general practitioners and other sanitary services was usually lacking and money contribution from the government or territorial services was considered inadequate. From the emotional point of view, caregivers claim loss of free time, friendships and hobbies, and feel isolated in the social context; sometimes the patient's death is thought of as a solution. A strong need for information and support is clearly emerging and any further interventions should take these requirements into consideration.

Clinical correlative evaluation of an iterative method for reconstruction of brain SPECT images.

BACKGROUND: Brain SPECT and PET investigations have showed discrepancies in Alzheimer's disease (AD) when considering data deriving from deeply located structures, such as the mesial temporal lobe. These discrepancies could be due to a variety of factors, including substantial differences in gamma-cameras and underlying technology. Mesial temporal structures are deeply located within the brain and the commonly used Filtered Back-Projection (FBP) technique does not fully take into account either the physical parameters of gamma-cameras or geometry of collimators. In order to overcome these limitations, alternative reconstruction methods have been proposed, such as the iterative method of the Conjugate Gradients with modified matrix (CG). However, the clinical applications of these methods have so far been only anecdotal. The present study was planned to compare perfusional SPECT data as derived from the conventional FBP method and from the iterative CG method, which takes into account the geometrical and physical characteristics of the gamma-camera, by a correlative approach with neuropsychology. METHODS: Correlations were compared between perfusion of the hippocampal region, as achieved by both the FBP and the CG reconstruction methods, and a short-memory test (Selective Reminding Test, SRT), specifically addressing one of its function. A brain-dedicated camera (CERASPECT) was used for SPECT studies with 99mTc-hexamethylpropylene-amine-oxime in 23 consecutive patients (mean age: 74.2 +/- 6.5) with mild (Mini-Mental Status Examination score > or =15, mean 20.3 +/- 3), probable AD. Counts from a hippocampal region in each hemisphere were referred to the average thalamic counts. RESULTS: Hippocampal perfusion significantly correlated with the MMSE score with similar statistical significance (p < 0.01) between the two reconstruction methods. Correlation between hippocampal perfusion and the SRT score was better with the CG method (r = 0.50 for both hemispheres, p < 0.01) than with the FBP method (r = 0.37 and 0.43, respectively for the right and left hemisphere, p < 0.05 and p < 0.02). The bootstrap procedure showed that such correlation indexes were statistically different both in the right (p < 0.01) and in the left (p < 0.05) hemisphere. CONCLUSION: These results are interpreted as a better performance of the CG reconstruction method in correctly detecting counts from hippocampal ROI. By using the same gamma-camera or collimator, alternative methods for brain SPECT reconstruction may improve quality of data and then help SPECT diagnostic accuracy.

Regional cerebral blood flow and prognostic evaluation in Alzheimer's disease.

The present investigation reports the application of regional cerebral blood flow (rCBF; (133)Xe method) to prognostic purposes in a consecutive series of 76 patients (mean age 68.4 +/- 8.7 years) with probable Alzheimer's disease (AD; NINCDS-ADRDA criteria). The likelihood that rCBF from a posterior temporal-inferior parietal area in each hemisphere at the first visit may predict timing of achievement of three endpoints (i.e. loss of activity of daily living, ADL, incontinence and death due to end-stage AD) was tested by the 'lifereg' procedure of the Statistical Analysis System package. With respect to baseline evaluation, 32 patients lost ADL 20.6 +/- 17.4 months later, 31 developed incontinence 27.1 +/- 19.0 months later, and 16 patients died after 40.9 +/- 23.8 months of follow-up. Baseline rCBF significantly predicted all end-points: the loss of ADL (left hemisphere: p = 0.04; right hemisphere: p = 0.02), incontinence (p = 0.02 in both hemispheres) and death (p = 0.01 in both hemispheres). Statistical significance was maintained for the loss of ADL and incontinence both in a subgroup of mildly demented patients, in whom death was not considered due to the low number of patients who died, and in a multivariate analysis including patient age, age at onset, sex, duration of illness, Mini-Mental State Examination score and presence of extrapyramidal signs and psychotic symptoms at the first visit. This study shows that rCBF measurement in a posterior temporal-inferior parietal area may give prognostic information on timing of evolution of AD, whenever performed during the course of the disease, and may be utilized both in clinical practice and for social planning.

Hippocampal perfusion in mild Alzheimer's disease.

Perfusion and metabolic studies in patients with Alzheimer's disease (AD) have so far yielded conflicting results on the functional status of the hippocampal region, whose deep location in the brain makes it critical to optimize the image-reconstruction technique employed in emission tomography. We used a brain-dedicated device (CERASPECT) to perform single photon emission computed tomography (SPECT) studies with 99mTc-hexamethylpropylene-amine-oxime in 22 consecutive patients (mean age: 74+/-6.5 years) with mild [mini-mental status examination (MMSE) score > or =15, mean 20.8+/-3.2], probable AD. The control subjects were 11 healthy elderly people (mean age: 70.5+/-6.5 years). In patients, the total score on the selective reminding test (SRT) was used as an index of memory function. Counts from a hippocampal and a temporoparietal region of interest in each hemisphere were referred to the average thalamic counts. To optimize SPECT images, we used conventional filtered back-projection (FBP) reconstruction and a new iterative method of conjugate gradients (CG), which takes into account the geometrical and physical characteristics of the gamma-camera. Hippocampal perfusion in the two hemispheres was significantly lower in patients than in control subjects, regardless of which reconstruction method was used, and correlated with the MMSE score. The correlation between hippocampal perfusion and the SRT score was significantly (bootstrap procedure) higher with the CG method than with the FBP method (CG: r=0.52 and 0.54; FBP: r=0.39 and 0.47, for the right and left hemisphere, respectively). These results show hippocampal hypoperfusion in patients with mild AD, a correlation between hippocampal perfusion and the severity of cognitive impairment, and enhanced identification of these subtle perfusional changes with the use of an alternative image-reconstruction method that improves the spatial resolution of SPECT images.