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.

Volume of interest-based [18F]fluorodeoxyglucose PET discriminates MCI converting to Alzheimer's disease from healthy controls. A European Alzheimer's Disease Consortium (EADC) study.

An emerging issue in neuroimaging is to assess the diagnostic reliability of PET and its application in clinical practice. We aimed at assessing the accuracy of brain FDG-PET in discriminating patients with MCI due to Alzheimer's disease and healthy controls. Sixty-two patients with amnestic MCI and 109 healthy subjects recruited in five centers of the European AD Consortium were enrolled. Group analysis was performed by SPM8 to confirm metabolic differences. Discriminant analyses were then carried out using the mean FDG uptake values normalized to the cerebellum computed in 45 anatomical volumes of interest (VOIs) in each hemisphere (90 VOIs) as defined in the Automated Anatomical Labeling (AAL) Atlas and on 12 meta-VOIs, bilaterally, obtained merging VOIs with similar anatomo-functional characteristics. Further, asymmetry indexes were calculated for both datasets. Accuracy of discrimination by a Support Vector Machine and the AAL VOIs was tested against a validated method (PALZ). At the voxel level SMP8 showed a relative hypometabolism in the bilateral precuneus, and posterior cingulate, temporo-parietal and frontal cortices. Discriminant analysis classified subjects with an accuracy ranging between .91 and .83 as a function of data organization. The best values were obtained from a subset of 6 meta-VOIs plus 6 asymmetry values reaching an area under the ROC curve of .947, significantly larger than the one obtained by the PALZ score. High accuracy in discriminating MCI converters from healthy controls was reached by a non-linear classifier based on SVM applied on predefined anatomo-functional regions and inter-hemispheric asymmetries. Data pre-processing was automated and simplified by an in-house created Matlab-based script encouraging its routine clinical use. Further validation toward nonconverter MCI patients with adequately long follow-up is needed.

Autonomic dysfunction in mild cognitive impairment: a transcranial Doppler study.

OBJECTIVES: The contribution of early microvascular and autonomic derangements to the pathogenesis of mild cognitive impairment (MCI) is unclear. Aim of this study is to evaluate cerebrovascular reactivity (CVR) and cardiac autonomic function in patients with MCI by means of transcranial Doppler (TCD). MATERIAL AND METHODS: Fifteen patients with MCI and 28 controls underwent carotid ultrasound and TCD evaluation, including assessment of mean flow velocity (MFV) in the middle cerebral artery at baseline, after CO(2) inhalation and after hyperpnoea. End-tidal CO(2) , mean arterial blood pressure (MAP), heart rate (HR), and respiratory rate were monitored throughout the procedure, and CVR was calculated. RESULTS: MAP, end-tidal CO(2) , and MFV variations during hypercapnia and hyperventilation showed no between-group differences. CVR was similar in controls and MCI (2.30 vs 2,39, respectively, P = 0.767). HR significantly increased in hypercapnia (+9.4%, P < 0.0001) and hyperventilation (+18.7%, P < 0.0001) in controls, while in MCI it significantly increased in hyperventilation (+10.4%, P = 0.002), but not in hypercapnia (+1.1%, P = 0.635). CONCLUSIONS: This study demonstrates that patients with MCI have a normal CVR, but they exhibit signs of autonomic dysfunction after CO(2) challenge. Should this finding be confirmed in larger studies, HR response to CO(2) challenge could become a marker of MCI.

The new Alzheimer's criteria in a naturalistic series of patients with mild cognitive impairment.

To test the validity of the new diagnostic criteria for Alzheimer's disease (AD) in a naturalistic series of patients with mild cognitive impairment (MCI). Ninety consecutive MCI patients were enrolled in a longitudinal study on the natural history of cognitive impairment. Medial temporal (MT) atrophy on MRI was defined as hippocampal volume below the fifth percentile of the distribution in healthy elders, abnormal CSF was based on Sjogren's cutoffs for Abeta42 and tau, and temporoparietal hypometabolism on 18F-FDG PET based on Herholz's t sum score. Patients were followed clinically to detect conversion to AD (MCI-AD), non-AD dementia (MCI-nAD), or no conversion (MCI-NC). The 24 MCI-AD and 15 MCI-nAD patients had sociodemographic, clinical, and neuropsychological baseline features similar to the 51 MCI-NC patients. All MCI patients with MT atrophy converted to AD, as did all those with abnormal CSF, but only 48 and 35% of those without MT atrophy or abnormal CSF converted (p on logrank test = 0.0007 and 0.001). Prediction of AD conversion was enhanced when positivity to either MT atrophy or abnormal CSF was considered, with only 15% of those MCI patients negative on both converting to AD (p < 0.0005). Markers were not predictive of non-AD dementia conversion. The accuracy of either MT atrophy or abnormal CSF in discriminating MCI-AD from MCI-NC was good (AUC 0.82, 95% CI 0.70-0.95). MT atrophy and abnormal CSF are the single most robust predictors of conversion to AD in MCI patients, and their combination enhances prediction. AD markers are not predictive of conversion to non-AD dementia.

Mapping the effect of APOE epsilon4 on gray matter loss in Alzheimer's disease in vivo.

Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E (APOE) epsilon4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (epsilon4+, age: 72+/-10 SD years, MMSE: 20+/-3 SD) and 14 non-carriers (epsilon4-, age: 69+/-9, MMSE: 20+/-5) of the epsilon4 allele and compared them to 29 age-and-sex matched controls (age: 70+/-9, MMSE: 28+/-1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. epsilon4+ and epsilon4- patients showed similar performance on neuropsychological tests (p>.05, t-test). Diffuse cortical atrophy was detected for both epsilon4+ (p=.0001, permutation test) and epsilon4- patients (p=.0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5-15% greater loss in non-carriers). APOE effect in AD was not significant (p>.74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected (p=.002, ANOVA), in both early and late-onset patients (p<.05, ANOVA). We conclude that the epsilon4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.

Hippocampal shape differences in dementia with Lewy bodies.

To assess the morphological changes of the hippocampus in Lewy body dementia (LBD) patients we used radial atrophy mapping, a mathematical modeling method sensitive to subtle differences in hippocampal shape. T1-weighted high resolution magnetic resonance (MR) scans were acquired from 14 LBD and 28 controls of similar age and gender, and were compared to those of 28 patients with Alzheimer's disease (AD) described previously. MR images were normalized by linear (12 parameter) transformation to a customized template. The hippocampal formation was isolated by manual tracing. Group differences were assessed with algorithms that average hippocampal shapes across subjects, using three-dimensional parametric surface mesh models. In LBD patients, significant tissue loss amounting to 10-20% was found in the hippocampal subregions corresponding to the anterior portion of the CA1 field on both sides, along the longitudinal midline in the dorsal aspect within the CA2-3 field, and in the subiculum and presubiculum. The direct comparisons between LBD and AD patients showed that this pattern of local atrophy is different from that characteristic of AD. LBD pattern of hippocampal atrophy might be related to the peculiar neuropathology of the disease.

Imaging, subjective complaints, and MCI: 30 years before.

The neuropathological and cognitive changes preceding Alzheimer's disease (AD) appear to begin decades before disease symptoms make the clinical diagnosis obvious. Clinical trials have begun to focus on preventive treatments aimed to slow cognitive decline in people with only subjective memory complaints. However, it is not clear how many years before clinical diagnosis of Alzheimer's disease is possible to recognize early signs of neurodegeneration. We report evidence from the literature showing feasibility to diagnose AD at the stage of mild cognitive impairment (MCI) and also a few years before the MCI stage with imaging markers. However, we showed that neuroimaging brain changes evidenced decades before MCI are not early signs of neurodegeneration but expression of genetic risk states for AD or markers of inter-individual variability of cognitive performance due to genetic or environmental factors.

Vascular damage and EEG markers in subjects with mild cognitive impairment.

OBJECTIVE: We evaluated the changes induced by cerebrovascular (CV) damage on brain rhythmicity recorded by electroencephalography (EEG) in a cohort of subjects with mild cognitive impairment (MCI). METHODS: We enrolled 99 MCI subjects (Mini-Mental State Examination [MMSE] mean score 26.6). All subjects underwent EEG recording and magnetic resonance imaging (MRI). EEGs were recorded at rest. Individual EEG frequencies were indexed by the theta/alpha transition frequency (TF) and by the individual alpha frequency (IAF) with power peak in the extended alpha range (5-14 Hz). Relative power was separately computed for delta, theta, alpha1, alpha2, and alpha3 frequency bands on the basis of the TF and IAF values. Subsequently, we divided the cohort in four sub-groups based on subcortical CV damage as scored by the age-related white matter changes scale (ARWMC). RESULTS: CV damage was associated with 'slowing' of TF proportional to its severity. In the spectral bandpower the severity of vascular damage was associated with increased delta power and decreased alpha2 power. No association of vascular damage was observed with IAF and alpha3 power. Moreover, the theta/alpha1 ratio could be a reliable index for the estimation of the individual extent of CV damage. CONCLUSIONS: EEG analysis may show physiological markers sensitive to CV damage. The appropriate use of this EEG index may help the differential diagnosis of different forms of cognitive decline, namely primary degenerative and secondary to CV damage. SIGNIFICANCE: The EEG neurophysiological approach, together with anatomical features from imaging, could be helpful in the understanding of the functional substrate of dementing disorders.

Topographic correspondence between white matter hyperintensities and brain atrophy.

White matter hyperintensities (WMHs) are a common finding in normal elderly persons. We studied the biological damage associated with WMHs by assessing the correspondence between WMH location and regional gray matter loss.Voxel-based morphometry of the gray matter was carried out with statistical parametric mapping on high resolution MR images.Neurologically intact persons with mainly anterior (frontal>parieto-occipital; N = 39) and mainly posterior WMHs (parieto- occipital>frontal; N = 14) were compared with a group devoid of WMHs (N = 80). Subjects with mainly frontal WMHs had bilateral frontal (medial, superior, and inferior gyri) atrophy in gray matter, while subjects with mainly posterior WMHs had more diffuse atrophy, involving mainly the frontal but also the right insular region. Our findings suggest that frontal WMHs are associated with frontal gray matter damage while parietooccipital WMHs seem to have a weaker and more diffuse impact on gray matter.

Neuroimaging tools to rate regional atrophy, subcortical cerebrovascular disease, and regional cerebral blood flow and metabolism: consensus paper of the EADC.

Neuroimaging is a mainstay in the differential diagnosis of patients with cognitive impairment. The often equivocal clinical pictures, the prognostic uncertainty of the earliest stages of mild cognitive impairment, and the subtle brain changes mean that neuroimaging techniques are of potentially great incremental diagnostic value. A number of methods, ranging from very simple subjective visual ratings to highly sophisticated computerised tools, have been developed, which allow rating of structural and functional brain changes. The choice of the method is not obvious, and current guidelines provide no indications on which tools should be preferred. In this paper, we give indications for tools with demonstrated accuracy for detecting regional atrophy, cerebrovascular disease, and regional brain function, and discuss these according to increasing technological complexity, ranging from those with high feasibility that can be used at the patient's bedside to highly technological ones that require trained personnel and specific hardware and software.

Prescription practices of diagnostic imaging in dementia: a survey of 47 Alzheimer's Centres in Northern Italy.

BACKGROUND: To date, there are no data at the national or European level on the prescription practices of imaging (CT, MR, and SPET) in the diagnosis of cognitively impaired elderly patients. METHODS: We addressed prescription practices of diagnostic imaging in 47 Alzheimer's Centres in Northern Italy, with an ad-hoc questionnaire. RESULTS: The use of imaging in new cases was relatively intensive: 62% of the Alzheimer's Centres prescribed CT to more than 95% of cases, 24% prescribed MR to more than 33% of cases, and 33% prescribed SPET to more than 5% of cases. A minority of Alzheimer's Centres (n = 3, 6%) prescribed imaging to less than 100% of new cases. The association between onsite scanner availability and frequency of prescription increased from CT (Odds ratio (OR) = 1.8) through MR (OR = 2.4) to SPET (OR = 4.6), although only the latter was significant (95% confidence interval (CI) 1.2-17.7, p = 0.003). Patient-related factors (age, severity of cognitive impairment, and clinical suspicion of cerebrovascular disease) influenced prescription of structural imaging in 30-53% of Alzheimer's Centres and organizational factors (onsite scanner availability, and waiting list) in a similar proportion (32 and 43% respectively). CONCLUSIONS: Organizational factors play a relevant role in the prescription of imaging exams in patients with cognitive impairment and, at least for CT, the perceived diagnostic added value is rather low, suggesting a high degree of uncertainty in the clinical use of imaging techniques.

Mild cognitive impairment: clinical features and review of screening instruments.

Clinical criteria to recognize subjects with cognitive impairment in the pre-dementia stage are becoming available. These are frail subjects, at risk of adverse outcomes, such as death, institutionalization, and functional and cognitive deterioration. Early identification of these subjects has a great importance in order to start rehabilitative or pharmacological interventions that could slow the progression of cognitive impairment, and the onset of disability. In this regard, cognitive screening tests might be helpful in different clinical settings (general practice, acute care, rehabilitation, and nursing home). We describe the most frequent clinical presentations of cognitive impairment in the pre-dementia stage, and review eleven screening tests to provide recommendations on which should be preferred in each setting.

Temporal lobe asymmetry in patients with Alzheimer's disease with delusions.

OBJECTIVE: To test the hypothesis that delusions are associated with asymmetric involvement of the temporal lobe regions in Alzheimer's disease. METHODS: Temporal lobe atrophy was assessed with a linear measure of width of the temporal horn (WTH) taken from CT films. Temporal asymmetry was computed as the right/left (R/L) ratio of the WTH in 22 non-delusional and 19 delusional patients with Alzheimer's disease. Delusional patients had paranoid delusions (of theft, jealousy, persecution). None of the patients had misidentifications or other delusions of non-paranoid content. RESULTS: The R/L ratio indicated symmetric temporal horn size in the non-delusional (mean 1. 05 (SD 0.20), and right greater than left temporal horn in the delusional patients (mean 1.30, (SD 0.46); t=2.27, df=39, p=0.03). When patients were stratified into three groups according to the R/L ratio, 47% of the delusional (9/19) and 14% of the non-delusional patients (3/21; chi(2)=5.6, df=1, p=0.02) showed right markedly greater than left WTH. CONCLUSIONS: Predominantly right involvement of the medial temporal lobe might be a determinant of paranoid delusions in the mild stages of Alzheimer's disease.

[MacLeod's syndrome. Observations on 6 cases]. / Sindrome di MacLeod. Osservazioni su sei casi.

Mac Leod's syndrome is a rarely diagnosed disease; that is why an accurate differential diagnosis is needed by means of radiological imaging. This paper is aimed at discussing the differential diagnosis, with a special emphasis on the pathogenesis of the syndrome. The phenomenon of air trapping in absence of central bronchial lesions is a typical radiographic finding. Chest X-ray is performed in both inspiration and expiration. Posterior oblique tomography at 55 degrees of the affected side is also performed. Diffuse bronchiolitis obliterans in infancy or early childhood is a widely accepted pathogenetic pattern. Pulmonary hypoventilation causes vasoconstriction and underdevelopment of pulmonary vessels, that are reduced in caliber. Differential diagnosis includes all the diseases resulting in pulmonary hyperlucency, i.e. pulmonary and pleural alterations, and skeletal anomalies.

Radiologic staging of granulomatous enteritis.

A staging of granulomatous enteritis (Crohn's disease) based only on roentgen findings is proposed. This would provide a common base to the analysis of different groups of patients and to the evaluation of management results. Twenty of the most relevant signs have been selected and divided into four stages, each referring to an increasing involvement of the bowel. Every case of disease should be classified in the stage to which its more advanced sign belongs.

[Farmer's lung: comparison of the teleradiographic images and computerized tomographic (CT) images]. / Farmer's lung: confronto tra immagini teleradiografiche ed immagini TC.

A critical and comparative analysis between chest radiograms and CT pictures in pulmonary fibrosis of various degree, occurring in farmer's lung, reveal that the latter are apt to give a somewhat more diversified informations about pulmonary changes as simple radiography. This would prove useful in evaluating the extension and distribution of anatomical changes due to fibrotic process, although as far not able to allow an earlier diagnosis.