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.

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.

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.

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.

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.

Transient autobiographic amnesia: EEG and single-photon emission CT evidence of an organic etiology.

We describe a 44-year-old patient who had a transient attack of autobiographic amnesia. When assessed during the attack, her learning abilities were normal, with no sign of anterograde amnesia. In the remote memory domain, she showed a striking dissociation between a detailed knowledge of public events and famous people and a complete loss of autobiographic information. During the attack, EEG recorded bilateral frontotemporal slow waves and single-photon emission CT (SPECT) showed hypoperfusion in the right temporal and parietal lobes; no abnormalities were detected when both EEG and SPECT were repeated 1 week later. This case provides evidence for an organic etiology for the episode and supports the hypothesis that autobiographic memory is independent of other forms of retrograde memory.

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.

Perseverative dysgraphia: a selective disorder in writing double letters.

Models of writing processes postulate that abstract graphemic representations contain information about letter doubling independent of letter identity. We describe a patient, R.T., who made perseverative errors only in handwriting geminate letters, [e.g.: "CORTECCIA" (cortex)-->"CORTECCCIA"]. Perseveration was specific to orthography. To explain R.T.'s errors, we argue that after the selection of the correct graphic motor programs, the geminate feature induced a perseverative graphic behaviour. This form of dysgraphia supports the notion that graphemic representations contain specific information about letter doubling.

Nurturing syndrome: a form of pathological bereavement with delusions in Alzheimer's disease.

We report the history and neuroimaging profile of two patients, CS and KC who developed an unusual bereavement reaction with delusions following the deaths of their husbands. Their neuropsychological profiles met criteria for dementia of Alzheimer type. The delusions about their husbands' existence were persistent despite a considerable passage of time after their deaths. SPECT investigation showed reduction of blood flow in the frontal area in both patients when compared with demented controls and in particular a significant reduction in perfusion was observed in the right frontal regions. We argue that this significant reduction of blood flow in the right frontal area, in the context of severe cognitive deterioration, might be responsible for their delusional reaction to bereavement which we interpret as result of reality monitoring and episodic memory failure.

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.

Precision and accuracy of subjective time estimation in different memory disorders.

The aim of this study was to evaluate how different memory disorders affect subjective time durations. For this purpose we studied prospective time estimations in 4 amnesic (A) and in 15 Alzheimer's disease (AD) patients, and compared their performance with that of 5 matched young normal controls (YC) and 15 elderly subjects (EC). For the short-time durations we asked the subject to repeatedly reproduce a standard interval of 1 s. To test how subjects evaluated longer time durations, we choose a verbal estimation procedure. The subjects' task was to read either 5, 10, 20, or 40 digits appearing one at a time, while concurrently keeping the rhythm of 1 key press per second. At the end of each sequence, subjects had to judge the elapsed time from the beginning of the trial. Results showed that amnesics can correctly reproduce 1-s intervals. However, their accuracy of verbal estimates of longer durations was severely impaired. AD patients showed increased variability on repeated reproduction of 1-s intervals and were both inaccurate and imprecise in their verbal estimate of longer durations. Using the framework of the Scalar Timing Model, we conclude that amnesic patients exhibit a deficit in encoding and storing the current time for intervals that exceed their short-term memory range, while AD patients show a pattern of deficit that is explained by a more widespread involvement of both the clock, the memory, and the decisional mechanisms.

Persistent global amnesia following right thalamic stroke: an 11-year longitudinal study.

The 11-year longitudinal study of a right-handed male patient, L. C., who suffered from a severe amnesic syndrome following a softening in the right thalamus, is reported. Memory impairment involving retrograde and long-term anterograde memory, both verbal and spatial, persisted without modification. Investigation revealed some residual implicit learning ability. Positron emission tomography studies in the resting state displayed a bilateral hypometabolism of the mesial frontal lobes. Evidence suggests that a lesion confined to the thalamus may not on its own account for severe amnesia; that involvement of other structures is necessary for severe amnesia to appear; and that a functional investigation should always be included in cases of small thalamic lesions before drawing conclusions about the structures responsible for a given deficit.

Unilateral spatial neglect in the late stage of Alzheimer's disease.

We report two patients with presumptive diagnosis of dementia of the Alzheimer's type (AD) who manifested a clear unilateral neglect syndrome in the late stage of the disease. At onset, their cognitive profiles were broadly similar to the usual cases of degenerative dementia, but, as the disease progressed, neglect appeared, becoming gradually more severe. MRI showed more pronounced cerebral atrophy in the right hemisphere in both patients and larger ventricles on the right in one of them. These two longitudinal single case studies show that neglect can occur in AD despite the insidious and progressive nature of this disease, and in spite of the fact that the underlying pathology affects the brain bilaterally. The appearance of neglect in the late stages of the patients' illness is interpreted as resulting from both the asymmetry in the atrophy and the disruption of compensatory mechanisms caused by the progressively worsening of the atrophy in the left hemisphere.

Delusions in Alzheimer's disease: spet evidence of right hemispheric dysfunction.

Delusional thinking and related behaviours are common symptoms in Alzheimer's disease (AD). The aim of the study was to determine if any consistent cerebral image pattern can be identified using Tc99m-hexamethylpropyleneamine (HMPAO) SPET in AD patients with and without delusions. 18 AD patients with delusion and 15 AD patients without delusion underwent neuropsychological testing and regional cerebral blood flow imaging using Tc99m-HMPAO SPET. The reconstructed data was compared using regions of interest drawn over each cerebral lobe and a statistical parametric mapping (SPM) approach. The neuropsychological testing showed that there was no difference in the profiles of the deluded and non deluded AD patients. The imaging results showed a significant degree of image asymmetry. This took the form of a right hemisphere hypoperfusion mainly in the right frontal and limbic regions. The results do not indicate a specific focal site of hypoperfusion in the patients with delusion. They do, however, indicate that delusions in AD may be associated with areas of hypoperfusion in the right anterior hemisphere.

Changes in the rCBF images of patients with Alzheimer's disease receiving Donepezil therapy.

Alzheimer's disease is associated with a loss in presynaptic cholinergic function. It has been suggested that cholinergic inhibitors such as donepezil hydrochloride (Donepezil) could restore this function and improve some of the symptoms of Alzheimer's disease. Previous work has shown that Donepezil improves cognitive and global function in patients with mild to moderate Alzheimer's disease. This study reviewed retrospectively 12 patients who had previously had a 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography (SPET) regional cerebral blood flow (rCBF) examination and had gone on to receive Donepezil therapy. These patients were recalled for a further 99Tcm-HMPAO SPET rCBF examination and the image data sets were compared. The results showed an overall increase in global cerebral blood flow (P = 0.04) averaged over the group with a percentage change in blood flow ranging from -1.8% to 6.4%. However, some patients showed a slight decrease in blood flow. When the data were analysed in terms of regional cerebral blood flow, we found that the most significant increase in blood flow occurred in the frontal lobes (P = 0.02).

Horizontal and vertical neglect dyslexia.

This case study concerns a 25-year-old right-handed male patient (G.G.) with post-traumatic lesions involving the right temporal and occipital lobe as well as the basal forebrain of the same side. G.G., who had a visual field defect almost limited to the upper left quadrant, showed both left horizontal and lower vertical neglect dyslexia, disproportionately severe when compared with left and lower visuo-spatial neglect. This is the first case report of a patient whose neglect dyslexia for vertical stimuli depended upon stimulus orientation, i.e., errors affected the final letters of top-down words and the initial letters of the bottom-up ones. This implies that neglect dyslexia can affect the internal letter shape map not only along the horizontal, but also along the vertical axis.

Bisection of shapes and lines: analysis of the visual and motor aspects of pseudoneglect.

This study examined the visual and motor components of pseudoneglect as expressed on horizontal bisection tasks. Ten participants were tested on bisection of lines and elliptical shapes and judgement of pretransected lines. Results showed the same magnitude of leftward error on all three tasks, in contrast to previous findings for patients with visuospatial neglect who are known to bisect ellipses and circles much more accurately than lines. Participants' mean line bisection error was significantly further to the left than the mean subjective midpoint found on the judgement task. The findings contradict the claim that the visual component of pseudoneglect is caused by the same mechanism that causes visuospatial neglect but support the hypothesis that the motor component of pseudoneglect is similar to directional hypometria.

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.