Showing papers by "Giovanni B. Frisoni published in 2007"

The topography of grey matter involvement in early and late onset Alzheimer's disease.

Abstract: Clinical observations have suggested that the neuropsychological profile of early and late onset forms of Alzheimer's disease (EOAD and LOAD) differ in that neocortical functions are more affected in the former and learning in the latter, suggesting that they might be different diseases. The aim of this study is to assess the brain structural basis of these observations, and test whether neocortical areas are more heavily affected in EOAD and medial temporal areas in LOAD. Fifteen patients with EOAD and 15 with LOAD (onset before and after age 65; Mini Mental State Examination 19.8, SD 4.0 and 20.7, SD 4.2) were assessed with a neuropsychological battery and high-resolution MRI together with 1:1 age- and sex-matched controls. Cortical atrophy was assessed with cortical pattern matching, and hippocampal atrophy with region-of-interest-based analysis. EOAD patients performed more poorly than LOAD on visuospatial, frontal-executive and learning tests. EOAD patients had the largest atrophy in the occipital [25% grey matter (GM) loss in the left and 24% in the right hemisphere] and parietal lobes (23% loss on both sides), while LOAD patients were remarkably atrophic in the hippocampus (21 and 22% loss). Hippocampal GM loss of EOAD (9 and 16% to the left and right) and occipital (12 and 14%) and parietal (13 and 12%) loss of LOAD patients were less marked. In EOAD, GM loss of 25% or more was mapped to large neocortical areas and affected all lobes, with relative sparing of primary sensory, motor, and visual cortex, and anterior cingulate and orbital cortex. In LOAD, GM loss was diffusely milder (below 15%); losses of 15-20% were confined to temporoparietal and retrosplenial cortex, and reached 25% in restricted areas of the medial temporal lobe and right superior temporal gyrus. These findings indicate that EOAD and LOAD differ in their typical topographic patterns of brain atrophy, suggesting different predisposing or aetiological factors.

Neuropsychiatric syndromes in dementia: Results from the European Alzheimer disease Consortium: Part I

Abstract: Background/Aims: The aim of this study was to identify neuropsychiatric subsyndromes of the Neuropsychiatric Inventory in a large sample of outpatients with Alzheimer's disease (AD). Methods: Cross-sectional data of 2,354 patients with AD from 12 centres from the European Alzheimer's Disease Consortium were collected. Principal component analysis was used for factor analysis. Results: The results showed the presence of 4 neuropsychiatric subsyndromes: hyperactivity, psychosis, affective symptoms and apathy. The subsyndrome apathy was the most common, occurring in almost 65% of the patients. Conclusion: This large study has provided additional robust evidence for the existence of neuropsychiatric subsyndromes in AD.

Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia

Abstract: Background Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician. Objective To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia. Design A 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study initially designed to evaluate the efficacy of donepezil hydrochloride or vitamin E vs placebo to delay progression of MCI to dementia. Setting Memory assessment centers. Patients A total of 190 individuals with MCI. Main Outcome Measures Ratings of MTA performed using magnetic resonance images obtained at baseline. Log-rank tests and Cox proportional hazards ratios examining the significance of MTA estimates in predicting progression of MCI to dementia. Results A mean MTA score greater than 2.0 was associated with a greater than 2-fold increased likelihood of progression to dementia during the observation period (hazards ratio, 2.30; 95% confidence interval, 1.09-4.92; P = .03) after controlling for age, education, sex, and baseline Mini-Mental State Examination score. Conclusions Adjusted estimates of MTA were associated with significantly increased risk of developing dementia within 3 years, suggesting that obtaining a magnetic resonance image during the evaluation of MCI may offer additional independent information about the risk of progression to dementia. Given the relatively high prevalence of MCI in the general population, use of this method as part of routine clinical evaluation may help identify individuals who might benefit from increased surveillance and future treatment. Trial Registration clinicaltrials.gov Identifier:NCT00000173.

The effect of white matter lesions on cognition in the elderly—small but detectable

Abstract: The extent to which white matter changes affect brain function in elderly individuals is a matter for debate. Although there is a consensus that large confluent white matter lesions (WMLs) can be attributed to small-vessel disease and might denote anatomical damage to axons, the clinical effect of WMLs with regard to cognitive impairment is less certain. In this Review, we argue that WMLs are associated with greater detectable progressive cognitive deterioration than is normal aging, but other causes of progressive cognitive deterioration, such as Alzheimer's disease, are associated with greater cognitive decline than are WMLs. This view has important implications for the development of drugs for the treatment and prevention of cognitive impairment and dementia.

Delirium Superimposed on Dementia Predicts 12-Month Survival in Elderly Patients Discharged From a Postacute Rehabilitation Facility

Abstract: Background. Delirium superimposed on dementia (DSD) is highly prevalent and associated with high mortality among hospitalized elderly patients, yet little is known about the effect of DSD on midterm mortality. The purpose of this study was to assess 12-month survival in patients with DSD and matched groups with dementia alone, delirium alone, or neither delirium nor dementia. Methods. Among 1278 consecutively admitted elderly participants (aged >= 65 years) to our Rehabilitation Unit between January 2002 and May 2005, four matched samples of 47 participants each (DSD, dementia alone, delirium alone, or neither delirium nor dementia) were selected. Matching was based on age, gender, and reason for admission. Postdischarge 12-month survival was assessed in the four groups with Kaplan-Meyer analysis and compared with Cox proportional hazard regression models adjusted for confounders. Results. Survival was significantly lower for DSD patients than for the other three groups. After adjustment for comorbidity and Barthel Index score before admission, patients with DSD had significantly higher mortality (hazard ratio, 2.3; 95% confidence interval, 1.1-5.5; p =.04) than did patients with neither delirium nor dementia. Conclusions. Demented patients who experienced delirium during hospitalization had a more than twofold increased risk of mortality in the 12 months following discharge than did patients with dementia alone, with delirium alone, or with neither dementia nor delirium.

Resting EEG sources correlate with attentional span in mild cognitive impairment and Alzheimer's disease.

Abstract: Previous evidence has shown that resting delta and alpha electroencephalographic (EEG) rhythms are abnormal in patients with Alzheimer's disease (AD) and its potential preclinical stage (mild cognitive impairment, MCI). Here, we tested the hypothesis that these EEG rhythms are correlated with memory and attention in the continuum across MCI and AD. Resting eyes-closed EEG data were recorded in 34 MCI and 53 AD subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). These sources were correlated with neuropsychological measures such as Rey list immediate recall (word short-term memory), Rey list delayed recall (word medium-term memory), Digit span forward (immediate memory for digits probing focused attention), and Corsi span forward (visuo-spatial immediate memory probing focused attention). A statistically significant negative correlation (Bonferroni corrected, P < 0.05) was observed between Corsi span forward score and amplitude of occipital or temporal delta sources across MCI and AD subjects. Furthermore, a positive correlation was shown between Digit span forward score and occipital alpha 1 sources (Bonferroni corrected, P < 0.05). These results suggest that cortical sources of resting delta and alpha rhythms correlate with neuropsychological measures of immediate memory based on focused attention in the continuum of MCI and AD subjects.

Cerebral perfusion correlates of conversion to Alzheimer's disease in amnestic mild cognitive impairment.

Abstract: Objective Aim of this study was to find cerebral perfusion correlates of conversion to dementia in patients with amnestic MCI.

The ICTUS Study: A Prospective longitudinal observational study of 1,380 AD patients in Europe. Study design and baseline characteristics of the cohort.

Abstract: The long-term objective of the ICTUS study is to identify milestones in Alzheimer’s disease (AD) progression and to develop a model to predict disease course in individual AD patients in Europe. The s

Brain perfusion correlates of medial temporal lobe atrophy and white matter hyperintensities in mild cognitive impairment

Abstract: To assess the association of Medial Temporal lobe Atrophy (MTA) and White Matter Hyperintensities (WMHs) with gray matter perfusion in Mild Cognitive Impairment (MCI) 56 MCI patients (age = 693 ± 70, 32 females) underwent brain MR scan and 99mTc ECD SPECT We evaluated MTA according to Scheltens' fivepoint scale on T1 MR images, and assessed WMHs using the rating scale for age-related white matter changes on T2-weighted and FLAIR MR images We divided MCI into age-matched subgroups with high and low MTA and high and low WMHs load We processed SPECT images with SPM2 following an optimized protocol and performed a voxel-based statistical analysis comparing high vs low MTA and high vs low WMHs, setting p-value at 0001 uncorrected, thresholding cluster extent at 100 voxels, using proportional scaling and entering age and WMHs or MTA respectively as nuisance covariates MCI with high compared with low MTA showed hypoperfusion in the left hippocampus and in the left parahippocampal gyrus MCI with high compared with low WMHs showed a hypoperfusion area in the left insular region and superior temporal gyrus MTA in MCI is associated with hippocampal gray matter hypoperfusion while WMHs is associated with gray matter hypoperfusion in areas of the insula and temporal neocortex These results confirm that MTA is associated with local functional changes and suggest that WMHs may be associated with remote brain cortical dysfunction

Does cognitive performance affect physical therapy regimen after hip fracture surgery

Abstract: Background and aims: To evaluate whether and which clinical factors affect the regimen of physical therapy (PT) treatment in elderly patients after hip fracture (HF). Methods: HF patients consecutively admitted to a rehabilitation unit (from January 2002 to May 2004) without adverse clinical events on admission or during hospital stay were considered (n=80). All patients underwent multidimensional assessment including demographic, clinical, cognitive, affective and functional status. Outcome measure was the number of rehabilitative procedures (NRP), computed as the ratio between sum of rehabilitative procedures and length of hospital stay. Results: Patients received 3.8± 1.3 NRP on average, although with large variability. Age and impairment of cognitive and pre-fracture functional status were significantly higher in those receiving fewer NRP. In a multiple regression model, only the Mini Mental State Examination (MMSE) significantly predicted NRP: compared with patients with MMSE ≤ 17, those with MMSE = 18–23, 24–26 and ≥ 27 received 0.3 (95% CI-0.5–1.1, p=0.46), 1.5 (95% CI 0.6–2.4, p=0.001 ), and 1.6 (95% CI 0.7–2.5, p=0.001) more NRP. Conclusions: Cognitive performance affects NRP in elderly HF patients. Specific rehabilitative approaches, according to baseline cognitive performance, should be considered.

Clinical and neuropsychological features associated with structural imaging patterns in patients with mild cognitive impairment.

Abstract: Aim: To describe the clinical and neuropsychological features of mild cognitive impairment (MCI) patients with medial temporal atrophy (MTA), white matter hyperintensities (WMH), both, and neither and to assess whether the rate of progression differs among groups. Methods: Ninety-five MCI patients were divided into 4 groups based on the presence of MTA and WMH: 29 were MTA– WMH–, 11 MTA– WMH+, 23 MTA+ WMH–, and 32 MTA+ WMH+. MCI patients were compared with 30 normal subjects. MTA and WMH were assessed with MR-based visual rating scales. Subjects underwent an extensive clinical and neuropsychological investigation. Fifty-six underwent follow-up evaluation. Results: MTA– WMH– had relatively good neuropsychological performance, little vascular and physical comorbidity. MTA– WMH+ performed poorly only on executive neuropsychological tests. MTA+ WMH– patients had poor neuropsychological performances (mainly on memory tests), high physical and vascular comorbidity. MTA+ WMH+ were impaired in neuropsychological performances, had a high number of physical diseases and severe vascular comorbidity. On follow-up, 25% of MTA+ WMH– and 32% of MTA+ WMH+ and none in MTA– WMH– and in MTA– WMH+ converted to dementia (p = 0.05, log rank test). Conclusion: Structural neuroimaging can identify subgroups of MCI patients with specific clinical and neuropsychological features.

Prescription patterns and efficacy of drugs for patients with dementia: physicians' perspective in Italy.

Abstract: Background and aims: The aim of this study was to assess the prescription practices and judgment of efficacy of physicians of drugs used for the cognitive and non-cognitive symptoms of dementia. Methods: Physicians from 88 Italian Alzheimer Evaluation Units were surveyed by means of a structured questionnaire assessing the proportion of patients with four different types of dementia prescribed with drugs for cognitive and non-cognitive symptoms, and physicians’ perceived efficacy of cholinesterase inhibitors. The Units prescribed cholinesterase inhibitors for 73 patients per year on average. Results: Cholinesterase inhibitors are prescribed to 90% of patients with Alzheimer’s disease (AD), 80% with with Lewy body dementia (LBD), and 35–45% with vascular dementia (VD) and frontotemporal lobar degeneration (FTLD). Selective serotonin uptake inhibitors (SSRIs) are prescribed for 28–45% of patients with all dementias except LBD (16%). Atypical neuroleptics were prescribed for 23–31% of patients, with no difference across types of dementia. Other drugs, such as ginkgo and nootropics, were prescribed less frequently, except in VD (20%). The perceived efficacy on cognitive and non-cognitive symptoms, assessed on a 0-to-10 ordinal scale, was highest in AD (4.3–6.1), intermediate in LBD (3.5–5.3) and VD (3.3–4.7), and lowest in FTLD (2.0–2.7). Conclusions: The data indicate that, in specialized Italian centers, cholinesterase inhibitors and atypical neuroleptics are largely used in patients with AD and LBD, but the former are prescribed off-label to a remarkable proportion of patients with VD and FTLD. The efficacy of cholinesterase inhibitors is perceived to be highest in AD and poorest in FTLD. Perceived efficacy is affected more by whom is treated than by what is used.

Neuroimaging outcomes for clinical trials.

Abstract: A wide range of drugs is currently under development for treating Alzheimer's Disease (AD). Clinical trials traditionally use rating scales, such as neuropsychological tests and disability scales, as outcome measures. However, their intrinsic measurement variability, the slow disease progression, and the low effectiveness of the drugs developed so far have led to trial designs with hundreds of subjects per treatment arm. Furthermore, a key issue is to establish what effect are these compounds having on the biological progression of the disease, beyond delaying symptomatic progression. The development of imaging markers, either structural, functional, or amyloid, with proven sensitivity to disease progression has recently paved the way for their use as outcome measures in clinical trials. The use of imaging measures has the double advantage of decreasing the number of subjects per treatment arm whilst also providing a direct measure of the degree of disease modification induced by the "active" molecules. The reviewed techniques, except for the most recent amyloid imaging, are those applied to prospective studies investigating changes of imaging markers over time.

Tau missing from CSF: a case report.

Abstract: Received: 21 December 2005 Received in revised form: 14 April 2006 Accepted: 27 April 2006 Published online: 3 February 2007 Sirs: Most of the neurodegenerative diseases known collectively as tauopathies, such as Frontotemporal Lobar Degeneration (FTLD), have excessive deposits of hyperphosphorylated tau in affected neurons and glia [6]. Paradoxically, the general label of tauopathy has been expanded to include cases in which tau was not identified in the brain and therefore were named as tau-less dementia [7, 12, 13]. In addition, cerebrospinal fluid (CSF) studies have reported very low levels of tau in cases of FTLD, but still uncertain is 1) how common these cases are, and 2) how to distinguish tau positive from tau negative patients [5]. The present case contributes to answering these questions, describing an early onset FTLD patient who lacked detectable levels of tau in the CSF. The proband is a right-handed woman with 8 years of education who, at age 41 developed depression with no previous history of alcohol or substance abuse, prior psychiatric or neurological disease. Family history indicated that her mother had been diagnosed with Alzheimer’s disease at age 67, but further details were not accessible. The patient received antidepressant medication, with no benefit. Six months later, she was admitted to the neurology department because of the reduction of her speech output. She was found to be depressed and apathetic. Spontaneous speech was sparse and non fluent. The MMSE score was 22/30. Metabolic and infectious causes of dementia were excluded by laboratory tests. Brain MRI is reported in Fig. 1A. At the age of 43, the patient displayed severe behavioural disturbances along with global aphasia, and brain SPECT was performed (Fig. 1B). A blood sample was drawn from the patient and DNA was isolated according to standard procedures. Genetic analyses were performed as previously described [3]. In addition, different pairs of primers were used to sequence overlapping fragments of exon 0 (position g.7757 to g.8061, GenBank Accession Number AC091628.2 ) and of the 3’ UTR region of the MAPT gene (position g.137583 to g.138810, GenBank Accession Number AC091628.2). Patient APOE genotype was e3e4. No mutations were found in the analysed sequences of MAPT, PSEN1, PSEN2, APP, PRNP. CSF levels of Abeta1-42 and tau protein were determined by ELISA (Innogenetics, Belgium) (Table 1). Comparisons were made with normative data [10]. Routine CSF analyses were normal (total proteins 0.27 g/l), and 14.3.3 protein was not detected. SPECT neuroimaging for the patient was analysed with statistical parametric mapping (SPM01). Genetic analyses, CSF measurements, and brain SPECT were performed in accordance with the Declaration of Helsinki and informed consents were obtained from patients and control subjects. In the present report, clinical and imaging features appear to indicate a rapidly progressive form of FTLD. Indeed, the CSF findings with low Abeta-42 and absence of tau protein constituted M. Cotelli, MSC Center for Cognitive Science Dept. of Psychology University of Turin, Turin, Italy