Highly integrated workflows for exploring cardiovascular conditions: Exemplars of precision medicine in Alzheimer's disease and aortic dissection.

For precision medicine to be implemented through the lens of in silico technology, it is imperative that biophysical research workflows offer insight into treatments that are specific to a particular illness and to a particular subject. The boundaries of precision medicine can be extended using multiscale, biophysics-centred workflows that consider the fundamental underpinnings of the constituents of cells and tissues and their dynamic environments. Utilising numerical techniques that can capture the broad spectrum of biological flows within complex, deformable and permeable organs and tissues is of paramount importance when considering the core prerequisites of any state-of-the-art precision medicine pipeline. In this work, a succinct breakdown of two precision medicine pipelines developed within two Virtual Physiological Human (VPH) projects are given. The first workflow is targeted on the trajectory of Alzheimer's Disease, and caters for novel hypothesis testing through a multicompartmental poroelastic model which is integrated with a high throughput imaging workflow and subject-specific blood flow variability model. The second workflow gives rise to the patient specific exploration of Aortic Dissections via a multi-scale and compliant model, harnessing imaging, computational fluid-dynamics (CFD) and dynamic boundary conditions. Results relating to the first workflow include some core outputs of the multiporoelastic modelling framework, and the representation of peri-arterial swelling and peri-venous drainage solution fields. The latter solution fields were statistically analysed for a cohort of thirty-five subjects (stratified with respect to disease status, gender and activity level). The second workflow allowed for a better understanding of complex aortic dissection cases utilising both a rigid-wall model informed by minimal and clinically common datasets as well as a moving-wall model informed by rich datasets.

Motion artifacts in standard clinical setting obscure disease-specific differences in quantitative susceptibility mapping.

As quantitative susceptibility mapping (QSM) is maturing, more clinical applications are being explored. With this comes the question whether QSM is sufficiently robust and reproducible to be directly used in a clinical setting where patients are possibly not cooperative and/or unable to suppress involuntary movements sufficiently. Twenty-nine patients with Alzheimer's disease, 31 patients with mild cognitive impairment and 41 healthy controls were scanned on a 3 T scanner, including a multi-echo gradient-echo sequence for QSM and an inversion-prepared segmented gradient-echo sequence (T1-TFE, MPRAGE). The severity of motion artifacts (excessive/strong/noticeable/invisible) was categorized via visual inspection by two independent raters. Quantitative susceptibility was reconstructed using 'joint background-field removal and segmentation-enhanced dipole inversion', based on segmented subcortical gray-matter regions, as well as using 'morphology enabled dipole inversion'. Statistical analysis of the susceptibility maps was performed per region. A large fraction of the data showed motion artifacts, visible in both magnitude images and susceptibility maps. No statistically significant susceptibility differences were found between groups including motion-affected data. Considering only subjects without visible motion, significant susceptibility differences were observed in caudate nucleus as well as in putamen. Motion-effects can obscure statistically significant differences in QSM between patients and controls. Additional measures to restrict and/or compensate for subject motion should be taken for QSM in standard clinical settings to avoid risk of false findings.

Modulation of affective symptoms and resting state activity by brain stimulation in a treatment-resistant case of obsessive-compulsive disorder.

The effect of transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) on psychopathological symptoms and resting state brain activity was assessed in a patient with obsessive-compulsive disorder (OCD). tDCS and rTMS had no effect on OC symptoms. tDCS, however, improved depression and anxiety. Functional magnetic resonance imaging at baseline showed an interhemispheric asymmetry with hyperactivation of the left and hypoactivation of the right anterior neural circuits. A reduction of interhemispheric imbalance was detected after tDCS but not after rTMS. tDCS seems to be more effective than rTMS in restoring interhemispheric imbalance and improving anxiety and depression in OCD.

Established donepezil treatment modulates task relevant regional brain activation in early Alzheimer's disease.

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) have shown the different short and long term actions of ChEIs. fMRI studies of the ChEI donepezil have focused on its short to medium term action without exploring the effects of established treatment. In this exploratory study the effect of 20 weeks donepezil treatment on regional brain activity was measured with fMRI in patients with mild AD. Twelve patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association fMRI paradigm and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. After treatment, differences from normal healthy elderly became more pronounced. There was also a spread of deactivation which at retest was detectable in task relevant areas. Behaviourally, however, there were no significant differences between group baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Parametric analyses established that increased behavioural scores at retest correlated significantly with higher activation levels in non task relevant areas. Behavioural stability with donepezil treatment was not paralleled by the pattern of improved task specific brain activation reported in similar studies of other ChEIs. This is arguably related to the different mechanisms of action of the ChEIs and might be a clinical correlate of the reported synaptic upregulation following long term donepezil treatment.

Ultrasound-guided radiofrequency-assisted segmental arterioportal vascular occlusion in laparoscopic segmental liver resection.

BACKGROUND: Studies have shown laparoscopic liver resection to be feasible and safe. Segmental hepatectomy is appealing because it allows a reduction of intraoperative blood loss and blood replacement by dividing tissues along the anatomic planes. However, an effective technique that allows the closure of segmental vessels during systematic segmentectomies before resection still is lacking in laparoscopic surgery. METHODS: A simple technique guided by intraoperative ultrasound to facilitate laparoscopic liver segmentectomies is described. Coagulative desiccation of the vessels feeding the segment to be resected was induced by introduction of a "cooled-tip" radiofrequency electrode percutaneously under intraoperative ultrasound guidance at the level of the vessels. The intrahepatic parenchymal change induced by the radiofrequency was monitored using intraoperative ultrasound. After the application of energy to destroy the vessels feeding that segment, an area of marked discoloration on the surface of the liver became obvious. Liver parenchymal transection followed without any form of hepatic inflow occlusion. RESULTS: For this study, 10 patients underwent a segmental resection using the described technique. The resection time ranged from 40 to 60 min including the time required to destroy the feeding vessels with radiofrequency. The intraoperative blood loss was less than 50 ml and did not necessitate intra- or postoperative blood transfusion. The surgical margins of the specimen were free of disease. There was no morbidity or mortality. CONCLUSIONS: The preliminary experience shows that the reported technique is safe and effective, with the potential to make even difficult laparoscopic liver segmentectomies for segments such as VII and VIII, easier to manage.

Palliative antecolic isoperistaltic gastrojejunostomy: a randomized controlled trial comparing open and laparoscopic approaches.

Gastric outlet obstruction is a common, often preterminal, event for patients with inoperable neoplasms of the distal stomach, duodenum, and biliopancreatic area. It can be surgically managed by open or laparoscopic gastrojejunostomy. This study aimed to compare the results of open and laparoscopic palliative gastrojejunostomy for patients with gastric outlet obstruction resulting from inoperable neoplasms. A total of 24 patients were randomized prospectively to undergo laparoscopic (12 patients) or open (12 patients) palliative laterolateral antecolic isoperistaltic gastrojejunostomy. All the procedures were completed as planned. The mean duration of surgery was not significantly different between the two groups (p = 0.75). The mean intraoperative blood loss was significantly less after laparoscopic gastrojejunostomy (LGJ) (p = 0.0001). Time to oral solid food intake was longer after open gastrojejunostomy (OGJ) (p = 0.04). Two patients in the OGJ group experienced postoperative delayed gastric empting, whereas no patients in the LGJ group experienced such a complication (p = 0.04). The mean postoperative stay was shorter in the LGJ group, but the difference did not reach statistical significance (p = 0.65). No readmissions were registered after a minimum follow-up period of 2 months. The findings show that LGJ is a safe, feasible, and effective alternative to OGJ. However, because the current data involved only a small number of patients, large studies still are required for further evaluation of the this operation's effectiveness.

Traces of vocabulary acquisition in the brain: Evidence from covert object naming.

One of the strongest predictors of the speed with which adults can name a pictured object is the age at which the object and its name are first learned. Age of acquisition also predicts the retention or loss of individual words following brain damage in conditions like aphasia and Alzheimer's disease. Functional Magnetic Resonance Imaging (fMRI) was used to reveal brain areas differentially involved in naming objects with early or late acquired names. A baseline task involved passive viewing of non-objects. The comparison between the silent object naming conditions (early and late) with baseline showed significant activation in frontal, parietal and mediotemporal regions bilaterally and in the lingual and fusiform gyri on the left. Direct comparison of early and late items identified clusters with significantly greater activation for early acquired items at the occipital poles (in the posterior parts of the middle occipital gyri) and at the left temporal pole. In contrast, the left middle occipital and fusiform gyri showed significantly greater activation for late than early acquired items. We propose that greater activation to early than late objects at the occipital poles and at the left temporal pole reflects the more detailed visual and semantic representations of early than late acquired items. We propose that greater activation to late than early objects in the left middle occipital and fusiform gyri occurs because those areas are involved in mapping visual onto semantic representations, which is more difficult, and demands more resource, for late than for early items.

Detecting subtle spontaneous language decline in early Alzheimer's disease with a picture description task.

The objective was to collect normative data for a simple and a complex version of a picture description task devised to assess spontaneous speech and writing skills in patients with Alzheimer's disease (AD), and to test whether some aspects of spontaneous language can discriminate between normal and pathological cognitive decline. Two hundred and forty English-speaking healthy volunteers were recruited to participate in this normative study. Thirty patients with a clinical diagnosis of minimal to moderate probable AD were also recruited. Age and education influenced some aspects of spontaneous oral and written language whereas sex had no influence on any of the variables assessed. A high proportion (>70%) of AD patients performed below cut-off on those scales that measured semantic processing skills. Deficits were detected even amongst those in the very early stage of the disease when the complex version of the task was used. Prospective assessment of spontaneous language skills with a picture description task is useful to detect those subtle spontaneous language impairments caused by AD even at an early stage of the disease.

Walking difficulties in patients with Alzheimer's disease might originate from gait apraxia.

OBJECTIVES: To investigate whether gait apraxia is a possible cause for some of the walking abnormalities shown by patients with Alzheimer's disease. METHODS: 60 patients with Alzheimer's disease, selected as being free from overt extrapyramidal impairment or other potential causes of walking deficits, were assessed with a new test evaluating aspects of walking and related movements. Norms for this test were collected from a sample of 182 healthy volunteers. RESULTS: 40% of the Alzheimer group performed below the cut off score on this test, and half performed poorly. Performance of the Alzheimer group in the walking skills test correlated highly with scores in a test assessing limb apraxia and with dementia severity. CONCLUSIONS: Gait apraxia may be the cause of walking disorders found in a subgroup of patients with Alzheimer's disease. Its detection is made easier by the use of a standardised test, but still relies heavily on the exclusion of other causes of walking deficits. It is a recognisable and independent form of apraxia.

Short-term longitudinal evaluation of cerebral blood flow in mild Alzheimer's disease.

The aim of this study was to estabilish whether subtle changes in regional cerebral blood flow (rCBF) can be detected in patients with mild Alzheimer's disease (AD) over a period as short as three months. Aprospective evaluation of rCBF changes with HMPAO SPECT at baseline and after 3 and 6 months was carried out. Standard clinical dementia tests were performed in parallel. The study enrolled 13 patients with mild probable AD from an outpatient memory clinic. SPECT data collected at baseline and after three months were compared using Statistical Parametric Mapping (SPM). Significant clusters of rCBF decrement in the medial part of the temporal lobe in both hemispheres, in the orbital part of the right frontal lobe and in the inferior part of the right parietal lobe were observed. No significant differences were found using a region of interest (ROI) analysis. After six months SPM analysis showed larger clusters of significant decrement in the same areas. ROI analysis was now sensitive to the rCBF changes and significant differences were shown in all brain regions except the temporal lobes. SPM analysis of SPECT data can detect significant changes in rCBF in mild AD over a short time interval. This method might be of potential advantage for the early diagnosis of AD and for its differentiation from stable cognitive impairments.

A normative study of a shorter version of Raven's progressive matrices 1938.

A shorter four-set (A, B, C, D) version of Raven's progressive matrices 1938 (PM38) has gained increasing use in neuropsychological assessment. No normative data spanning across a wide age range are, however, available. This study collected norms for the shorter version of PM38, established an inferential cut-off value and derived equivalent scores in a sample of 248 individuals from 20 to 89 years of age, evenly distributed across sex, age and education levels. Results showed significant effects of age and education but no effect of sex on performance. These normative data will complement existing norms for other tests, will increase the wealth of neuropsychological tools for which normative data are available for the Italian population, and may be useful in the early detection of individuals at risk of developing dementia.

Rey-Osterrieth complex figure: normative values in an Italian population sample.

The Rey-Osterrieth complex figure test (ROCF) is a neuropsychological test extensively used in clinical practice to investigate visuospatial constructional functions, visuographic memory and some aspects of planning and executive function. The aim of the present study was to collect normative values in an Italian normal population sample (n=280) for the direct copying and delayed (10 min) reproduction of the ROCF. Multiple regression analysis revealed significant effects of age and education on performance of both copying tasks, whereas sex appeared to affect only performance on the delayed copying task. Inferential cut-offs have been determined and equivalent scores computed. The availability of equivalent scores for the ROCF will prove useful in clinical assessment since it allows the comparison of a subject's performance on the ROCF with that on other neuropsychological tests for which normative values collected with similar methods are already available for the Italian population.

Famous face recognition and naming test: a normative study.

Tests of famous face recognition and naming, and tasks assessing semantic knowledge about famous people after presentation either of their faces or their names are often used in the neuropsychological examination of aphasic, amnesic and demented patients. A total of 187 normal subjects took part in this study. The aim was to collect normative data for a newly devised test including five subtests: famous face naming, fame judgement after face presentation and after name presentation, semantic knowledge about famous people after face presentation and after name presentation. Norms were calculated taking into account demographic variables such as age, sex and education and adjusted scores were used to determine inferential cut-off scores and to compute equivalent scores. Multiple regression analyses showed that age and education influenced significantly the performance on most subtests, but sex had no effect on any of them. Scores of the subtest evaluating fame judgements after name presentation were significantly influenced only by education. The only subtest whose scores were not influenced by any demographic variable was fame judgement after face presentation.

General Knowledge of the World: a standardised assessment.

An entirely verbal enquiry of "General Knowledge of the World" made up by 168 questions exploring 14 domains of knowledge (12 questions each) has been standardised on 175 (97 women and 78 men) healthy Italian subjects with at least 8 years of formal education. Norms for each set of questions are provided. An unexpected finding is that age did not play an influential role on performance, whereas education did: the higher it was, the better the score. Women proved to fare significantly worse than men. A feasibility check on 30 Alzheimer patients with very mild overall cognitive impairment showed that the general knowledge enquiry was relatively easy to administer. The discrimination power between normal controls and Alzheimer patients for each subtest has been calculated.

Preservation of golf skills in a case of severe left lobar frontotemporal degeneration.

The authors report the longitudinal study of a 53-year-old man with severe lobar atrophy confined to the left frontal and temporal lobes, including the left hippocampus, but sparing other cortical regions. He experienced profound cognitive deterioration, sparing only visuospatial memory. Despite these deficits, he could play golf at a high level of competence, following rules and etiquette as well as monitoring the ongoing game. The patient's golf performance may have been supported by residual visuospatial declarative memory and complex flexible implicit memory programs.

Quality of spelling breakdown in Alzheimer's disease is independent of disease progression.

There is a convergence of evidence from recent studies that spelling is impaired in Alzheimer's Disease (AD) relative to normal aging. However, the literature is more divided over whether there is a logical pattern in spelling deterioration with disease progression. The present study reviewed performance of participants with mild AD, moderate AD, and control participants on a written and oral spelling task. Results suggest that spelling in individuals with AD is impaired relative to controls. Comparison between those with mild AD and moderate AD failed to find evidence of a logical pattern of deterioration. We further examined the effects of word characteristics on spelling performance. Although increasing in quantity with disease progression, analysis of quality of spelling errors reveal a multi-componential disruption of spelling ability, which is independent of disease progression.

Upper and lower face apraxia: role of the right hemisphere.

The aim of this study was to evaluate face apraxia in left- and right-hemisphere-damaged patients both in the acute and chronic stage of their disease. Two newly devised tests that assess movements of the upper and lower face districts were employed. On the whole, the proportion of left-hemisphere-damaged patients showing face apraxia were 46 and 68% for upper and lower face, respectively. A substantial proportion of right-hemisphere-damaged patients also showed face apraxia, i.e. 44% upper face and 38% lower face. Concomitant variables such as general severity, locus of lesion, language or visuo-spatial impairments, presence of neglect, interval from stroke, peculiarity of clusters of items or scoring procedures did not account for these results. These findings suggest that face apraxia in some patients may affect movements of the upper face district and that the right hemisphere plays a significant part in both upper and lower face praxis.

HMPAO SPECT imaging of Alzheimer's disease patients with similar content-specific autobiographic delusion: comparison using statistical parametric mapping.

UNLABELLED: Delusional behavior and thinking are common symptoms in Alzheimer's disease (AD). In the past, these delusions have been considered to be psychotic complications of global neurologic dysfunction. Recently, authors have suggested that content-specific delusions in AD are associated with discrete regional abnormalities of the right hemisphere. METHOD: This study compared 99mTc-hexamethyl propyleneamine oxime (HMPAO) SPECT images of a group of AD patients with a similar autobiographic delusion with a group of AD patients without delusions and a group of AD patients with a range of delusions but without autobiographic content. The reconstructed SPECT data were compared using a statistical parametric mapping technique. RESULTS: The autobiographic AD group had a significant area of hypoperfusion in the right frontal lobe when compared with the 2 other groups. The area of hypoperfusion included parts of Brodmann's areas 9 and 10. Region 9 has been identified previously as having a role in episodic memory retrieval. CONCLUSION: This result suggests that autobiographic delusions in AD may have an identifiable neuropsychologic mechanism and that it may be possible to identify an organic cause in some patients using 99mTc-HMPAO SPECT.