Gaussian Process-based prediction of memory performance and biomarker status in ageing and Alzheimer's disease-A systematic model evaluation.

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as genetic covariates, biomarkers, vascular risk factors, neuropsychological tests etc.) might provide useful predictions of clinical outcomes during the progression towards Alzheimer's disease (AD). The use of multiple features in predictive frameworks for clinical outcomes has become increasingly prevalent in AD research. However, many studies do not focus on systematically and accurately evaluating combinations of multiple input features. Hence, the aim of the present work is to explore and assess optimal combinations of various features for MR-based prediction of (1) cognitive status and (2) biomarker positivity with a multi-kernel learning Gaussian process framework. The explored features and parameters included (A) combinations of brain tissues, modulation, smoothing, and image resolution; (B) incorporating demographics & clinical covariates; (C) the impact of the size of the training data set; (D) the influence of dimensionality reduction and the choice of kernel types. The approach was tested in a large German cohort including 959 subjects from the multicentric longitudinal study of cognitive impairment and dementia (DELCODE). Our evaluation suggests the best prediction of memory performance was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF biomarkers explaining 57% of outcome variance in out-of-sample predictions. The highest performance for Aß42/40 status classification was achieved for a combination of demographics, ApoE4, and a memory score while usage of structural MRI further improved the classification of individual patient's pTau status.

Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

[Pathways of Invasive Ventilated Patients Released into Intensive Home Care: The Perspective of Home Care Providers]. / Wege invasiv beatmeter Patienten in die häusliche Beatmungspflege: Die Perspektive ambulanter Intensivpflegedienste.

INTRODUCTION: Over the past years, many home respiratory care services for invasively mechanically ventilated patients have been set up in Germany. However, little is known about the pathways used by these patients in order to access such specialized care. METHODS: A qualitative, exploratory study was undertaken. Semi-structured interviews with 15 leading experts or employees responsible for care transition were conducted and subjected to content analysis. RESULTS: Invasively ventilated patients' pathways into intensive home care tend to be highly random, risky and uncertain. Coordination and cooperation issues, as well as nontransparent and unclear interests of stakeholders and officials emerged. Rehabilitation opportunities do not seem to be systematically used to their full potential and demands for informed and participatory decision-making processes tend to be neglected. CONCLUSIONS: More attention will have to be paid to research and development needs regarding the provision of care to severely chronically ill and technology-dependent patients beyond the scope of individual health care sectors, organizations or professions.

Resting-state global functional connectivity as a biomarker of cognitive reserve in mild cognitive impairment.

Cognitive reserve (CR) shows protective effects in Alzheimer's disease (AD) and reduces the risk of dementia. Despite the clinical significance of CR, a clinically useful diagnostic biomarker of brain changes underlying CR in AD is not available yet. Our aim was to develop a fully-automated approach applied to fMRI to produce a biomarker associated with CR in subjects at increased risk of AD. We computed resting-state global functional connectivity (GFC), i.e. the average connectivity strength, for each voxel within the cognitive control network, which may sustain CR due to its central role in higher cognitive function. In a training sample including 43 mild cognitive impairment (MCI) subjects and 24 healthy controls (HC), we found that MCI subjects with high CR (> median of years of education, CR+) showed increased frequency of high GFC values compared to MCI-CR- and HC. A summary index capturing such a surplus frequency of high GFC was computed (called GFC reserve (GFC-R) index). GFC-R discriminated MCI-CR+ vs. MCI-CR-, with the area under the ROC = 0.84. Cross-validation in an independently recruited test sample of 23 MCI subjects showed that higher levels of the GFC-R index predicted higher years of education and an alternative questionnaire-based proxy of CR, controlled for memory performance, gray matter of the cognitive control network, white matter hyperintensities, age, and gender. In conclusion, the GFC-R index that captures GFC changes within the cognitive control network provides a biomarker candidate of functional brain changes of CR in patients at increased risk of AD.

Oxytocin's inhibitory effect on food intake is stronger in obese than normal-weight men.

BACKGROUND/OBJECTIVES: Animal studies and pilot experiments in men indicate that the hypothalamic neuropeptide oxytocin limits food intake, and raise the question of its potential to improve metabolic control in obesity. SUBJECTS/METHODS: We compared the effect of central nervous oxytocin administration (24 IU) via the intranasal route on ingestive behaviour and metabolic function in 18 young obese men with the results in a group of 20 normal-weight men. In double-blind, placebo-controlled experiments, ad libitum food intake from a test buffet was examined in fasted subjects 45 min after oxytocin administration, followed by the assessment of postprandial, reward-driven snack intake. Energy expenditure was repeatedly assessed by indirect calorimetry and blood was sampled to determine concentrations of blood glucose and hormones. RESULTS: Oxytocin markedly reduced hunger-driven food intake in the fasted state in obese but not in normal-weight men, and led to a reduction in snack consumption in both groups, whereas energy expenditure remained generally unaffected. Hypothalamic-pituitary-adrenal axis secretion and the postprandial rise in plasma glucose were blunted by oxytocin in both groups. CONCLUSIONS: Oxytocin exerts an acutely inhibitory impact on food intake that is enhanced rather than decreased in obese compared with normal-weight men. This pattern puts it in contrast to other metabolically active neuropeptides and bodes well for clinical applications of oxytocin in the treatment of metabolic disorders.

[Health care and regional disparities]. / Versorgungsgestaltung angesichts regionaler Unterschiede.

Municipalities in Germany have to advance health care structures to be resistant to demographic transitions and to the changing health care needs of the regional population in upcoming years. Therefore, it is important to note that needs vary from region to region and that care structures have to be differentiated according to this. Indeed regionality and community care have been increasingly referred to in current debate on improving care structures. But the discussed approaches remain relatively unclear and, moreover, fail to overcome care fragmentation and legal or sectoral perspectives. This paper points out the current lack of systematic knowledge about regional health disparities as well as knowledge about models of health care that are appropriate especially for disadvantaged communities and also rural regions. Moreover, knowledge of steering mechanisms that enforce the development of regional care systems are not developed yet.

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Subjective memory complaints in community dwelling healthy older people: the influence of brain and psychopathology.

OBJECTIVES: Subjective memory complaints (SMC) are common. We aimed to characterize the relationship between psychiatric illness and white matter disease to SMC in a sample of healthy older people. MEASUREMENTS: Cognitively normal subjects between 55 and 90 years had age-adjusted and education-adjusted Consortium to Establish a Registry for Alzheimer's disease (CERAD) scores ≤1.5 SD from standard mean. ApoE genotyping was performed using polymerase chain reaction. Sixty subjects (30 SMC, 30 controls) underwent 3T MRI, which was rated by two raters blinded to the diagnosis, for periventricular (PVH) and deep white matter hyperintensities (DWMH) using the Fazekas scale. Subjective memory was assessed by asking the participant, Do you feel like your memory or thinking is becoming worse? RESULTS: Two hundred and fifteen volunteers were assessed. Ninety-six were cognitively normal (mean age 62.5 years). SMC were reported by 52/96 subjects (54%). These were compared with subjects who denied SMC. Participants with a history of depression or anxiety were more likely to have SMC (p = 0.02). The frequency distribution of ApoE4 allele and CERAD scores were similar. White matter load was similar (p ≤ 0.47), with a high prevalence of PVH and DWMH seen (100% and 88% of scans, respectively). CONCLUSION: Both SMC and white matter disease were common. SMC were associated with a history of depression or anxiety but not with white matter disease. Evaluation for a history of depression and anxiety in people with SMC is supported by these findings.

Regional differences in effects of APOE ε4 on cognitive impairment in non-demented subjects.

BACKGROUND: The APOE ε4 allele is a risk factor for Alzheimer's disease (AD). APOE ε4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE ε4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. METHODS: Data from 16 centers across Europe were analyzed. RESULTS: A north-south gradient in APOE ε4 prevalence existed in the total sample (62.7% for APOE ε4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE ε4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. CONCLUSION: The APOE ε4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE ε4 allele and cognition is region dependent.

Amygdala reduction in patients with ADHD compared with major depression and healthy volunteers.

OBJECTIVE: Results in adult attention deficit hyperactivity disorder (ADHD) on structural brain changes and the clinical relevance are contradictory. The aim of this study was to investigate whether in adult patients with ADHD hippocampal or amygdala volumes differs from that in healthy controls and patients with major depression (MD). METHOD: Twenty patients with ADHD, 20 matched patients with MD and 20 healthy controls were studied with high resolution magnetic resonance imaging. RESULTS: Amygdala volumes in patients with ADHD were bilaterally smaller than in patients with MD and healthy controls. In ADHD, more hyperactivity and less inattention were associated with smaller right amygdala volumes, and more symptoms of depression with larger amygdala volumes. CONCLUSION: This study supports findings that the amygdala plays an important role in the systemic brain pathophysiology of ADHD. Whether patients with ADHD and larger amygdala volumes are more vulnerable to affective disorders needs further investigation.

Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI.

BACKGROUND: The measurement of hyperphosphorylated tau (p-tau) in CSF has been proposed as a biomarker candidate for the prediction of Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). However, a standard quantitative criterion of p-tau has not been evaluated. OBJECTIVE: To assess in a multicenter study the predictive accuracy of an a priori defined criterion of tau phosphorylated at threonine 231 (p-tau(231)) for the prediction of conversion from MCI to AD during a short-term observation interval. METHODS: The study included 43 MCI converters, 45 stable MCI (average follow-up interval = 1.5 years), and 57 healthy controls (at baseline only). Subjects were recruited at four international expert sites in a retrospective study design. Cox regression models stratified according to center were used to predict conversion status. Bootstrapped 95% CIs of classification accuracy were computed. RESULTS: Levels of p-tau(231) were a significant predictor of conversion (B = 0.026, p = 0.001), independent of age, gender, Mini-Mental State Examination, and ApoE genotype. For an a priori-defined cutoff point (27.32 pg/mL), sensitivity ranged between 66.7 and 100% and specificity between 66.7 and 77.8% among centers. The bootstrapped mean percentage of correctly classified cases was 79.95% (95% CI = 79.9 to 80.00%). Post hoc defined cutoff values yielded a mean bootstrapped classification accuracy of 80.45% (95% CI = 80.24 to 80.76%). CONCLUSIONS: An a priori defined cutoff value of p-tau(231) yields relatively stable results across centers, suggesting a good feasibility of a standard criterion of p-tau(231) for the prediction of Alzheimer disease.

[Shoulder pain: image guided management]. / Douleur de l'épaule: apport de la radiologie interventionnelle.

Different interventional radiology techniques used in the management of the painful shoulder will be reviewed in this article. The etiology of shoulder pain is variable, and several image guided procedures are available, from simple to more complex. US and fluoroscopy guided intra-articular and bursal infiltration techniques will be described. Percutaneous needle removal of calcific deposits and capsular distension/infiltration of adhesive capsulitis will be discussed. Cysts in the spinoglenoid or suprascapular notch may cause impingement of the suprascapular nerve and may be aspirated under US guidance. Finally, percutaneous radio-frequency treatment of symptomatic bone metastases under CT guidance may at times be performed. Musculoskeletal radiologists should be familiar with this spectrum of image guided interventional procedures.

[Reliability of multicenter magnetic resonance imaging. Results of a phantom test and in vivo measurements by the German Dementia Competence Network]. / Multizentrische Reliabilität MRT-gestützter Volumetrie des Gehirns. Ergebnisse des Phantomtests und voxelbasierter Morphometrie im Kompetenznetz Demenzen.

BACKGROUND: Whereas a large body of evidence suggests the usefulness of volumetric measurement of cerebral atrophy for diagnosing Alzheimer's disease (AD), the clinical applicability of cerebral volumetry for early detection of AD across multiple clinical sites is not well known. In the current study, we assessed the precision of volumetric measurement of the brain based on magnetic resonance imaging (MRI) in a multicenter setting. METHODS: The reliability of MRI was assessed by a phantom test of the American College of Radiology and voxel-based morphometry applied to the images obtained from a single subject tested at 11 centers of the German Dementia Competence Network. RESULT: Nine of the 11 centers tested met the reliability criteria of the phantom test. Across all centers, a bias was found in the measurements of slice thickness and length. For voxel-based morphometry, the coefficient of variation yielded 5.02% for gray matter volume and 12.81% (SD 9.06%) for gray matter signal intensity in voxels. Power analysis showed that a sample size of 150 subjects is sufficient for statistically valid detection of reduced gray matter volume in patients with mild cognitive impairment. CONCLUSION: The reliability of measurements from multiple centers is sufficient to allow statistically valid analysis of MRI data.

Multicenter assessment of reliability of cranial MRI.

Clinical utility of magnetic resonance imaging (MRI) for the diagnosis and assessment of neurodegenerative diseases may depend upon the reliability of MRI measurements, especially when applied within a multicenter context. In the present study, we assessed the reliability of MRI through a phantom test at a total of eleven clinics. Performance and entry criteria were defined liberally in order to support generalizability of the results. For manual hippocampal volumetry, automatic segmentation of brain compartments and voxel-based morphometry, multicenter variability was assessed on the basis of MRIs of a single subject scanned at ten of the eleven sites. In addition, cranial MRI scans obtained from 73 patients with Alzheimer's disease (AD) and 76 patients with mild cognitive impairment were collected at subset of six centers to assess differences in grey matter volume. Results show that nine out of eleven centers tested met the reliability criteria of the phantom test, where two centers showed aberrations in spatial resolution, slice thickness and slice position. The coefficient of variation was 3.55% for hippocampus volumetry, 5.02% for grey matter, 4.87% for white matter and 4.66% for cerebrospinal fluid (CSF). The coefficient of variation was 12.81% (S.D.=9.06) for the voxel intensities within grey matter and 8.19% (S.D.=6.9) within white matter. Power analysis for the detection of a difference in the volumes of grey matter between AD and MCI patients across centers (d=0.42) showed that the total sample size needed is N=180. In conclusion, despite minimal inclusion criteria, the reliability of MRI across centers was relatively good.

Inflammatory myofibroblastic tumour of the spinal cord: case report and review of the literature.

Inflammatory myofibroblastic tumours (IMT), also called inflammatory pseudotumours, nodular lymphoid hyperplasia, plasma-cell granuloma and fibrous xanthoma, are rare soft-tissue lesions characterised by inflammatory cells and a fibrous stroma. Clinically and radiologically, they may look like malignant tumours. They rarely affect the central nervous system and are very rare in the spinal cord. We report an IMT of the spinal cord in a 22-year-old woman presenting with spinal cord compression and a cauda equina syndrome. MRI showed a lesion at T9 with extramedullary and intramedullary components giving low signal on T2-weighted images and enhancing homogeneously. Pial lesions on the lumbar enlargement and thoracic spinal were present 11 months after surgery, when the lesion recurred. We present the radiological, operative and pathological findings and review the literature.

MRI-assessed volume of cerebellum correlates with associative learning.

Richard F. Thompson's cerebellar model of classical eyeblink conditioning highlights Purkinje cells in cerebellar cortex and principal cells in the deep cerebellar nucleus as the integrating cells for acquisition of conditioned responses (CRs). CR acquisition is significantly slower in rabbits with lesions to cerebellar cortex and in Purkinje cell-deficient mice that lose all cerebellar cortical Purkinje cells. Purkinje cells are the largest neurons in the cerebellum and contribute significantly to cerebellar volume. Magnetic resonance imaging (MRI) was used to assess cerebellar volume in humans. Cerebellar volume was related to eyeblink conditioning (400-ms delay procedure) in 8 adults (21-35 years) and compared to 8 older adults (77-95 years) tested previously (Woodruff-Pak, Goldenberg, Downey-Lamb, Boyko, & Lemieux, 2000). In the young adult sample, there was a high correlation between percentage of CRs in a session and cerebellar volume (corrected for total intracranial volume [TIV], r =.58, p =.066). There were statistically significant age differences in cerebellar volume, t(14) = 8.96, p <.001, and percentage of CRs, t(14) = 3.85, p <.002, but no age difference in TIV. Combining the young and older adult sample, the correlation between percentage of CRs and cerebellar volume (corrected for TIV) was.832 (p <.001). Cerebellar volume showed age-related deficits likely due to Purkinje cell loss. Individual differences in classical eyeblink conditioning are associated with differences in cerebellar volume, supporting Thompson's model of a cerebellar cortical role in facilitating this form of associative learning.