Introduction Delirium is common in the older hospital population and is often precipitated by acute illness. Delirium is associated with poor outcomes including subsequent cognitive decline and dementia and may therefore be a modifiable risk factor for dementia. However, the mechanisms underpinning the delirium-dementia relationship and the role of coexisting acute illness factors remain uncertain. Current biomarker studies of delirium have limitations including lack of detailed delirium characterisation with few studies on neurodegenerative or neuroimaging biomarkers especially in the acute setting. The Oxford and Reading Cognitive Health After Recovery from acute illness and Delirium - Prospective Study (ORCHARD-PS) aims to elucidate the pathophysiology of delirium and subsequent cognitive decline after acute illness in older adults, through acquisition of multimodal biomarkers for deep phenotyping of delirium and acute illness, and follow-up for incident dementia. Methods and analysis ORCHARD-PS is a bi-centre, prospective cohort study. Consecutive eligible patients requiring acute hospital admission or assessment are identified by the relevant acute clinical care team. All patients age >65 years without advanced dementia, nursing home residence, end-stage frailty or terminal illness are eligible. Details of potential participants are communicated to the research team and written informed consent or consultee agreement is obtained. Participants are interviewed as soon as possible after admission/assessment using a structured proforma. Data are collected on demographics, diagnosis and comorbidities, social and functional background. Delirium is assessed using the 4A's test, Confusion Assessment Method (long-form), Observational Scale of Level of Arousal, Richmond Agitation-Sedation Scale and Memorial Delirium Assessment Scale and diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Delirium is categorised by time of onset (prevalent vs incident), dementia status, motoric subtype, severity and duration. Cognitive tests include the 10-point Abbreviated Mental Test and Montreal Cognitive Assessment. Participants are reassessed every 48-72 hours if remaining in hospital. Informant questionnaire data and interview are supplemented by hand searching of medical records and linkage to electronic patient records for nursing risk assessments, vital observations, laboratory results and International Classification of Diseases, Tenth Revision diagnostic and procedure codes. In-person follow-up with more detailed cognitive testing and informant interview is undertaken at 3 months, and 1 and 3 years supplemented with indirect follow-up using medical records. Blood banking is performed at baseline and all follow-ups for future biomarker analyses. CT-brain and MRI-brain imaging acquired as part of standard care is obtained for quantification of brain atrophy and white matter disease/stroke supplemented by research CT-brain imaging. Outcomes include length of hospitalisation, change in care needs, institutionalisation, mortality, readmission, longitudinal changes in cognitive and functional status and incident dementia. Biomarker associations with delirium, and with incident dementia on follow-up, will be determined using logistic or Cox regression as appropriate, unadjusted and adjusted for covariates including demographics, baseline cognition, frailty, comorbidity and apolipoprotein E genotype. Ethics and dissemination ORCHARD-PS is approved by the South Central - Berkshire Research Ethics Committee (REC Reference: 23/SC/0199). Results will be disseminated through peer-reviewed publications and conference presentations.
\n \n\n \n \nBACKGROUND: Blood tests used to identify patients at increased risk of undiagnosed cancer are commonly used in isolation, primarily by monitoring whether results fall outside the normal range. Some prediction models incorporate changes over repeated blood tests (or trends) to improve individualized cancer risk identification, as relevant trends may be confined within the normal range. OBJECTIVE: Our aim was to critically appraise existing diagnostic prediction models incorporating blood test trends for the risk of cancer. METHODS: MEDLINE and EMBASE were searched until April 3, 2025 for diagnostic prediction model studies using blood test trends for cancer risk. Screening was performed by 4 reviewers. Data extraction for each article was performed by 2 reviewers independently. To critically appraise models, we narratively synthesized studies, including model building and validation strategies, model reporting, and the added value of blood test trends. We also reviewed the performance measures of each model, including discrimination and calibration. We performed a random-effects meta-analysis of the c-statistic for a trends-based prediction model if there were at least 3 studies validating the model. The risk of bias was assessed using the PROBAST (prediction model risk of bias assessment tool). RESULTS: We included 16 articles, with a total of 7 models developed and 14 external validation studies. In the 7 models derived, full blood count (FBC) trends were most commonly used (86%, n=7 models). Cancers modeled were colorectal (43%, n=3), gastro-intestinal (29%, n=2), nonsmall cell lung (14%, n=1), and pancreatic (14%, n=1). In total, 2 models used statistical logistic regression, 2 used joint modeling, and 1 each used XGBoost, decision trees, and random forests. The number of blood test trends included in the models ranged from 1 to 26. A total of 2 of 4 models were reported with the full set of coefficients needed to predict risk, with the remaining excluding at least one coefficient from their article or were not publicly accessible. The c-statistic ranged 0.69-0.87 among validation studies. The ColonFlag model using trends in the FBC was commonly externally validated, with a pooled c-statistic=0.81 (95% CI 0.77-0.85; n=4 studies) for 6-month colorectal cancer risk. Models were often inadequately tested, with only one external validation study assessing model calibration. All 16 studies scored a low risk of bias regarding predictor and outcome details. All but one study scored a high risk of bias in the analysis domain, with most studies often removing patients with missing data from analysis or not adjusting the derived model for overfitting. CONCLUSIONS: Our review highlights that blood test trends may inform further investigation for cancer. However, models were not available for most cancer sites, were rarely externally validated, and rarely assessed calibration when they were externally validated.
\n \n\n \n \nBehavioural experiments are experiential exercises used in Cognitive Behavioural Therapy to drive cognitive change by testing patients' idiosyncratic, emotionally linked beliefs. In this paper, we provide clinical guidance on how to deliver effective behavioural experiments that maximise cognitive change based on lessons learnt over the last 30\u2009years from our work using Cognitive Therapy to treat Panic Disorder (CT-PD), Social Anxiety Disorder (CT-SAD) and Post-Traumatic Stress Disorder (CT-PTSD). We describe key steps for setting up and carrying out powerful experiments, including common blocks and barriers patients and therapists come across when using them.
\n \n\n \n \nWhile with methodological advances a connectivity-based parcellation of the \nentire ... Relating connectional architecture to grey matter function using ...
\n \n\n \n \nLittle is known about the spatiotemporal dynamics of cortical responses that integrate slightly asynchronous somatosensory inputs from both hands. This study aimed to clarify the timing and magnitude of interhemispheric interactions during early integration of bimanual somatosensory information in different somatosensory regions and their relevance for bimanual object manipulation and exploration. Using multi-fiber probabilistic diffusion tractography and MEG source analysis of conditioning-test (C-T) median nerve somatosensory evoked fields in healthy human subjects, we sought to extract measures of structural and effective callosal connectivity between different somatosensory cortical regions and correlated them with bimanual tactile task performance. Neuromagnetic responses were found in major somatosensory regions, i.e., primary somatosensory cortex SI, secondary somatosensory cortex SII, posterior parietal cortex, and premotor cortex. Contralateral to the test stimulus, SII activity was maximally suppressed by 51% at C-T intervals of 40 and 60 ms. This interhemispheric inhibition of the contralateral SII source activity correlated directly and topographically specifically with the fractional anisotropy of callosal fibers interconnecting SII. Thus, the putative pathway that mediated inhibitory interhemispheric interactions in SII was a transcallosal route from ipsilateral to contralateral SII. Moreover, interhemispheric inhibition of SII source activity correlated directly with bimanual tactile task performance. These findings were exclusive to SII. Our data suggest that early interhemispheric somatosensory integration primarily occurs in SII, is mediated by callosal fibers that interconnect homologous SII areas, and has behavioral importance for bimanual object manipulation and exploration. \u00a9 2012 the authors.
\n \n\n \n \nObjective: Deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM) is a treatment option in medically intractable tremor, such as essential tremor or tremor-dominant Parkinson disease (PD). Although functional studies demonstrated modulation of remote regions, the structural network supporting this is as yet unknown. In this observational study, we analyzed the network mediating clinical tremor modulation. Methods: We studied 12 patients undergoing VIM stimulation for debilitating tremor. We initiated noninvasive diffusion tractography from tremor-suppressive VIM electrode contacts. Moreover, we tested for the contribution of primary motor projections in this structural correlate of a functional tremor network, comparing the connectivity of effective DBS contacts with those of adjacent, but clinically ineffective, stimulation sites. Results: VIM stimulation resulted in decrease of tremor and improvement in quality of life. Tractography initiated from the effective stimulation site reconstructed a highly reproducible network of structural connectivity comprising motor cortical, subcortical, and cerebellar sites and the brainstem, forming the anatomic basis for remote effects of VIM stimulation. This network is congruent with functional imaging studies in humans and with thalamic projections found in the animal literature. Connectivity to the primary motor cortex seemed to play a key role in successful stimulation. Conclusions: Patients undergoing DBS provide a unique opportunity to assess an electrophysiologically defined seed region in human thalamus, a technique that is usually restricted to animal research. In the future, preoperative tractography could aid with stereotactic planning of individual subcortical target points for stimulation in tremor and in other disease entities. Copyright \u00a9 2012 by AAN Enterprises, Inc.
\n \n\n \n \nEpisodic memory dysfunction, commonly assessed with word list recall, is the main characteristic of amnestic Mild Cognitive Impairment (aMCI). While brain pathology underlying this kind of memory impairment is well established in aMCI, little is known about the effect of neurodegeneration on autobiographical memory. The present study investigated neuronal correlates of autobiographical memory in aMCI patients (n= 12) and healthy elderly controls (n= 13) using functional magnetic resonance imaging (fMRI). Additionally, voxel-based morphometry (VBM) was employed to reveal brain pathology in aMCI patients. Neuropsychological assessment showed significant impairment in episodic memory tasks (immediate and delayed word list recall) in aMCI patients. Moreover, VBM revealed significantly reduced gray matter concentration, which was most pronounced in the temporal lobes of aMCI patients. Despite episodic memory impairment and atrophy in areas that are associated with encoding and recall of episodic memories, aMCI patients showed no alterations in brain activation associated with autobiographical memory retrieval. These findings could suggest that autobiographical memory is subserved by a different neuronal network than episodic memory and that the two memory systems are differently affected by aMCI. \u00a9 2011 Elsevier Ireland Ltd.
\n \n\n \n \nThis study set out to determine whether there is white matter involvement in essential tremor (ET), the most common movement disorder. We collected diffusion MRI and analysed differences in fractional anisotropy (FA) and mean diffusivity (MD) between ET patients and control subjects as markers of white matter integrity. We used both classical ROI-based statistics and whole-brain analysis techniques, including voxel-wise analysis with SPM5 and tract-based spatial statistics (TBSS). Using region of interest (ROI) analysis, we found increased MD bilaterally in the inferior cerebellar peduncles (ICP) and reduced FA in the right-sided ICP of ET patients. Whole-brain analyses with TBSS detected increased MD distributed in both motor and nonmotor white matter fibers of ET patients predominantly in the left parietal white matter, while there were no significant FA differences in these areas between ET patients and controls. Voxel-wise analysis with SPM detected significant increase of MD congruent with the highest probability of difference as detected by TBSS. VBM analysis of T1 images did not detect significant differences in either gray or white matter density between our study groups. In summary, we found evidence for changes in white matter MRI properties in ET. The circumscript pathology of the ICP corroborates the pathogenetic concept of the cerebellum and its projections as key structures for tremor generation in ET. Moreover, increased diffusivity in white matter structures of both hemispheres suggests widespread alterations of fiber integrity in motor and nonmotor networks in ET patients. The underlying cause of the DTI changes observed remains to be elucidated. \u00a9 2010 Wiley-Liss, Inc.
\n \n\n \n \nParkinson's disease (PD) is associated with abnormal hypersynchronicity in basal ganglia-thalamo-cortical loops. The clinical effectiveness of subthalamic nucleus (STN) high frequency stimulation indicates a crucial role of this nucleus within the affected motor networks in PD. Here we investigate alterations in the functional connectivity (FC) profile of the STN using resting state BOLD correlations on a voxel-by-voxel basis in functional magnetic resonance imaging (fMRI). We compared early stage PD patients (n. =31) during the medication-off state with healthy controls (n. =44). The analysis revealed increased FC between the STN and cortical motor areas (BA 4 and 6) in PD patients in accordance with electrophysiological studies. Moreover, FC analysis of the primary motor cortex (M1) hand area revealed that the FC increase was primarily found in the STN area within the basal ganglia. These findings are in good agreement with recent experimental data, suggesting that an increased STN-motor cortex synchronicity mediated via the so called hyperdirect motor cortex-subthalamic pathway might play a fundamental role in the pathophysiology of PD. An additional subgroup analysis was performed according to the presence (n. =16) or absence (n. =15) of tremor in patients. Compared to healthy controls tremor patients showed increased STN FC specifically in the hand area of M1 and the primary sensory cortex. In non-tremor patients, increased FC values were also found between the STN and midline cortical motor areas including the SMA. Taken together our results underline the importance of the STN as a key node for the modulation of BG-cortical motor network activity in PD patients. \u00a9 2011 Elsevier Inc.
\n \n\n \n \nBrain imaging enables the investigation of brain morphology and function in patients with Parkinson's disease (PD). Innovative magnetic resonance imaging (MRI) techniques have recently been established as a new research tool in PD. They are based on the investigation of neuronal tissue properties (MR relaxometry, SWI, DWI, DTI, VBM) and of cerebral perfusion and neuronal activity (ASL, fcMRI). Besides a better understanding of the pathophysiology of PD, these innovative MR techniques might be suitable for measuring progression of PD and the effect of therapeutic interventions on brain functioning. In the clinical setting, they could help to advance the differential diagnosis of parkinsonian disorders. \u00a9 2010 Springer-Verlag.
\n \n\n \n \nBACKGROUND: While homozygous mutations in the PINK1 gene cause recessively inherited early-onset Parkinson disease (PD), heterozygous mutations have been suggested as a susceptibility factor. METHODS: To evaluate this hypothesis, 4 homozygous PINK1 patients with PD and 10 asymptomatic carriers of a single heterozygous mutation from a large German family (family W) were included in this study. Clinical follow-up of the heterozygous mutation carriers 3 years after the initial visit included a detailed videotaped neurologic examination using the Unified Parkinson's Disease Rating Scale III protocol and smell and color discrimination testing. At follow-up, PET with 18-fluorodopa (FDOPA) of 13 family members was obtained in order to evaluate the clinical phenotype in light of nigostriatal dopaminergic functioning. The clinical and PET data were compared to those of healthy controls. RESULTS: While there was mild worsening of clinical signs in previously affected heterozygous mutation carriers upon follow-up, 3 additional individuals had newly developed signs of possible PD. Hyposmia was found in 7 of the heterozygous mutation carriers, diminished color discrimination in 4. The homozygous mutation carriers who were all definitely affected with PD showed a severe, 60% decrease of caudate and putaminal FDOPA uptake; heterozygous offspring also had a significant 20% putaminal FDOPA uptake reduction compared to controls. CONCLUSIONS: Our findings strengthen the hypothesis that heterozygous PINK1 mutations act as a susceptibility factor to develop at least subtle Parkinson disease motor and nonmotor signs, as supported by the finding of a reduced striatal dopaminergic FDOPA uptake not only in homozygous but also, albeit to a lesser extent, in heterozygous mutation carriers. \u00a9 2010 by AAN Enterprises, Inc.
\n \n\n \n \nObjective: Although Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) show a wide clinical and neuropathologic overlap, they are differentiated according to the order and latency of cognitive and motor symptom appearance. Whether both are distinct disease entities is an ongoing controversy. Therefore, we directly compared patients with DLB and PDD with multitracer PET. Methods: PET with 18fluorodopa (FDOPA), N -11C-methyl-4-piperidyl acetate (MP4A), and 18flu- orodeoxyglucose (FDG) was performed in 8 patients with PDD, 6 patients with DLB, and 9 patients with PD without dementia vs age-matched controls. Data were analyzed with voxel-based statistical parametric mapping and region of interest-based statistics.Results: We found a reduced FDOPA uptake in the striatum and in limbic and associative prefrontal areas in all patient groups. Patients with PDD and patients with DLB showed a severe MP4A and FDG binding reduction in the neocortex with increasing signal diminution from frontal to occipital regions. Significant differences between PDD and DLB were not found in any of the radioligands used. Patients with PD without dementia had a mild cholinergic deficit and no FDG reductions vs controls.Conclusions: Patients with dementia with Lewy bodies and Parkinson disease dementia share the same dopaminergic and cholinergic deficit profile in the brain and seem to represent 2 sides of the same coin in a continuum of Lewy body diseases. Cholinergic deficits seem to be crucial for the development of dementia in addition to motor symptoms. The spatial congruence of cholinergic deficits and energy hypometabolism argues for cortical deafferentation due to the degeneration of projection fibers from the basal forebrain. Copyright \u00a9 by AAN Enterpnsos, Inc.
\n \n\n \n \nQuantitative magnetic resonance imaging is a promising in vivo imaging technique revealing insights into different aspects of brain morphology in neurodegenerative diseases based on the determination of physical tissue parameters. Using combined T1- and T2-mapping, we investigated changes of local relaxation times in the midbrain and lower brainstem of 20 patients with early Parkinson's disease (PD) compared to 20 healthy controls. Voxelwise statistical parametric mapping disclosed a widespread reduction of midbrain T1 values contralateral to the clinically more severely affected limbs. Within the SN, the T1 decrease matched the known pattern of selective neuronal loss as examined in various post-mortem studies, suggesting that T1 is a marker for PD related tissue pathology. However, the spatial extent of T1 reductions exceeded the SN and reached non-dopaminergic areas in the pontomesencephalic junction potentially involved in early non-motor symptoms of PD. In contrast, T2-mapping revealed a bilateral decrease of T2 values restricted to the SN, indicating a local increase in total iron content. We conclude that, particularly in longitudinal studies, quantitative T1 may be a valuable marker for the monitoring of progressive neuronal loss in PD, whereas nigral T2 reductions might be more closely associated with an increased general vulnerability for the development of the disorder. \u00a9 2010 Elsevier Inc.
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