This thesis describes neuroimaging techniques to investigate brain networks in healthy aging and dementia. Functional and structural brain networks change with healthy and pathological... Show more This thesis describes neuroimaging techniques to investigate brain networks in healthy aging and dementia. Functional and structural brain networks change with healthy and pathological aging, with differences in network degeneration between different types of dementia. These disease-specific network differences suggest the potential of brain networks to improve diagnostic accuracy. However, at this moment, our findings are only applicable for groups of patients and not yet suitable as a diagnostic tool on an individual basis. Show less
Patients with structural heart disease - e.g. after myocardial infarction or due to a cardiomyopathy - are at increased risk for sudden cardiac death because of arrhythmia. The department of... Show morePatients with structural heart disease - e.g. after myocardial infarction or due to a cardiomyopathy - are at increased risk for sudden cardiac death because of arrhythmia. The department of Cardiology at the Leiden University Medical Center has a strong interest for the underlying substrate and mechanisms of ventricular arrhythmias. Since 2011, research fellow Sebastiaan Piers and his supervisor prof. dr. Katja Zeppenfeld have performed innovative studies, combining advanced electrophysiological data with detailed imaging data derived from CT and MRI. These studies have led to important insights into the substrate and mechanisms of ventricular arrhythmia in patients after myocardial infarction or with a cardiomyopathy. An improved understanding may be the most important prerequisite for the development of effective, individualized and substrate-based therapies for ventricular arrhythmias in the future. Sebastiaan Piers will defend his thesis "Understanding Ventricular Tachycardia: Towards Individualized Substrate-based Therapy" on Thursday January 28th 2016. Show less
This thesis reports on the utility of high permittivity dielectric materials for adjusting the radiofrequency (RF) field in high field MR. The performance-driven trend towards higher static... Show moreThis thesis reports on the utility of high permittivity dielectric materials for adjusting the radiofrequency (RF) field in high field MR. The performance-driven trend towards higher static magnetic field strengths drives MR operation into the regime where the dimensions of the body section being imaged are comparable to the RF wavelength. This results in areas of RF interference within the body, and associated variations in signal intensity and tissue contrast, which can severely reduce the diagnostic image quality. However, the underlying electromagnetic interactions raise the question of whether these mechanisms may also be exploited to establish a remediation. This approach is termed "dielectric shimming," and is the subject of this thesis. The main conclusions from this thesis are that dielectric shimming presents a very simple and effective method for improving MR operation at high field strength. The high permittivity materials allow for tailoring the B1 field without increasing SAR. The technique improves body applications at 3T as well as neuro applications at 7T, and theoretical foundations are presented to harness and exploit this approach. The obtained solutions are low-cost, vendor-independent, do not require any major hardware or software modifications and can therefore be very easily implemented in clinical protocols. Show less
Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) can play a key role in understanding neurobiological mechanisms of diseases that affect the human brain. The specific changes that occur... Show moreDiffusion-weighted magnetic resonance spectroscopy (DW-MRS) can play a key role in understanding neurobiological mechanisms of diseases that affect the human brain. The specific changes that occur within neurons can be reflected as changes in the diffusivity of tNAA, whereas the changes in glial cells can cause pronounced changes in the diffusivities of tCr and tCho. This information combined with that obtained from diffusion tensor imaging (DTI) and other MRI tools can help elucidate various disease processes in the future. The main purposes of this thesis are (i) to investigate neuroanatomy in vivo with DW-MRS, (ii) to develop methodology to enable future clinical applications of the technique in human brain in vivo, and (iii) to characterize the microstructural deficit in neuropsychiatric systemic lupus erythematous (NPSLE) with DW-MRS and other microstructural tools such as DTI and magnetization transfer imaging. The studies presented in this thesis show the robustness and clinical relevance of microstructural information obtained via DW-MRS. The contributions of this thesis such as the optimized acquisition protocols for single volume DW-MRS, the robust DW-CSI and DW-MRS post-processing pipelines that comprise information from DTI, will all facilitate the applications of DW-MRS both for basic neuroscience research and clinical research studies. Show less
The focus of this thesis was to evaluate biomarkers of cardiovascular end organ damage in the metabolic syndrome and diabetes mellitus. We performed cross-sectional studies with biochemical and... Show moreThe focus of this thesis was to evaluate biomarkers of cardiovascular end organ damage in the metabolic syndrome and diabetes mellitus. We performed cross-sectional studies with biochemical and magnetic resonance imaging (MRI) techniques. We have demonstrated that insulin resistance is a strong risk predictor for CVD and we provided a novel link between inflammation and angiopoietin-like protein 4 (ANGPTL4) expression by showing that ANGPTL4 levels in humans are related to systemic inflammation and inflammatory stimuli increased ANGPTL4 expression using human macrophages in vitro. The imaging studies described in this thesis extend the knowledge of end organ damage and explored the relation with aortic stiffness. The impact of type 1 diabetes mellitus (T1DM) on regional grey matter was investigated and showed atrophy of all subcortical grey matter structures but the amygdala. By showing an association of aortic stiffness with subtle microstructural deficits in T1DM and kidney function in patients with hypertension the close link between aortic stiffness and the microcirculation is demonstrated. Furthermore regional and individual differences in response to an oral glucose load in MR assessed aortic stiffness were observed, which may open new future research paths possibly linking inter-individual variation in regional vascular response and CVD. Show less
The general objective of this thesis was to study the causes and consequences of ventricular dilatation in aging and dementia. For this purpose, we used ventricular shape analysis to study... Show moreThe general objective of this thesis was to study the causes and consequences of ventricular dilatation in aging and dementia. For this purpose, we used ventricular shape analysis to study potential new MRI markers of cognitive decline in aging, subjective memory complaints, mild cognitive impairment and Alzheimer's Disease. In addition, we designed a volumetric measure that may objectively quantify the disproportionate ventricular dilatation that is characteristic of Normal Pressure Hydrocephalus (NPH). We investigated the value of this measure for the selection of candidates with NPH for ventricular shunting, studied its association with NPH-like symptoms in the general population and used the measure to explore a possible cardiovascular origin of cerebral ventricular dilatation. Show less
In this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in... Show moreIn this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in muscle of DMD patients with a semi-quantitative method. Dixon MRI showed to be more sensitive to subtle changes. Implementation of a multipeak model to account for multiple lipid spectrum peaks in this method allowed even more sensitive measurements. We evaluated non-contractile and contractile cross-sectional areas in leg muscles of DMD patients. Combined with strength measurements we could measure muscle quality and showed muscle hypertrophy and fatty infiltration to be two distinct processes. We explored the relation between dystrophin levels and fat in BMD patients and found no such relation, but did find a relation between strength and age in a subgroup, demonstrating the location of the mutation to be a major determinant of disease severity. Using T2 MRI as inflammatory marker in DMD/BMD patients and healthy controls we showed an increased T2 in DMD patients. Finally we investigated the muscle energy metabolism in BMD patients with MRS and showed increased PDE/ATP ratios prior to onset of fatty infiltration, consequently 31P MRS could be another potential outcome parameter. Show less
This thesis evaluates morphological and functional vessel wall properties measured by magnetic resonance imaging techniques in healthy volunteers and patients with various diseases (i.e. Marfan... Show moreThis thesis evaluates morphological and functional vessel wall properties measured by magnetic resonance imaging techniques in healthy volunteers and patients with various diseases (i.e. Marfan syndrome patients (MFS), patients with thoracic aortic aneurysm and patients with a previous myocardial infarction.). This thesis shows that imaging of carotid vessel wall morphology can be reproducible assessed by high-field MRI and that carotid vessel wall imaging benefits from imaging at higher field strengths. For a functional imaging parameter, the aorta pulse wave velocity (PWV), improving spatial sampling density resulted in more accurate PWV-assessment, even when temporal resolution decreased. Moreover, a scan-time reduction was achieved. Aortic PWV showed a high specificity for predicting absence of regional aortic luminal growth for all aortic segments in MFS. In patients with thoracic aortic aneurysm, regional PWV showed high specificity in the descending thoracic to abdominal aorta and moderate results in the ascending aorta and aortic arch. Next, PWV-leveling between aorta and carotid artery at older age was associated with a reduction in blood flow volume towards the brain. Furthermore, vessel wall morphology and function were associated in healthy volunteers and in patients with established atherosclerotic disease. Finally, our findings might indicate a link between atherosclerotic large vessel disease and cerebral small vessel disease in patients with established atherosclerotic disease. Show less
People of South Asian origin have an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people of Western European descent. Not only is the prevalence... Show morePeople of South Asian origin have an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD) compared to people of Western European descent. Not only is the prevalence of these diseases higher in South Asians, they also occur at a younger age and lower BMI, and have a more severe course. The high prevalence of T2D and CVD in South Asians, who comprise one fifth of the total world__s population, poses a major health and socioeconomic burden worldwide. The underlying cause of this excess risk is, however, still poorly understood. The studies described in this thesis were performed to gain more insight in the pathogenesis of T2D and CVD in South Asians and to provide new leads for preventive strategies and treatment options. For this purpose sophisticated techniques were used such as hyperinsulinemic-euglycemic clamp with stable isotopes, indirect calorimetry, skeletal muscle biopsies, MRI and spectroscopy, and brown fat quantification using PET-CT-imaging, combined with short-term dietary interventions, in healthy lean young adult men and overweight adult men. These studies have led to a number of promising areas for further research. It seems that not one, but multiple metabolic mechanisms have been affected, most likely due to gene-environment interactions. Show less
The main objective of this thesis is to compare bony decompression with implantation of interspinous process devices (IPDs) in patients with intermittent neurogenic claudication (INC) caused by... Show moreThe main objective of this thesis is to compare bony decompression with implantation of interspinous process devices (IPDs) in patients with intermittent neurogenic claudication (INC) caused by lumbar spinal stenosis (LSS). A national survey among Dutch spine surgeons is presented about the usual care of patients with intermittent neurogenic claudication caused by lumbar spinal stenosis. Surgeons' expectations of different treatment options are presented. The existing evidence on interspinous implant surgery will be systematically reviewed. Results of treatment with IPDs are compared with other (conservative) treatment options. The Foraminal Enlargement Lumbar Interspinosus distraXion (FELIX) trial is described. This double-blind, multicenter, randomized (cost)effectiveness study was designed to answer the question whether treatment with IPDs would be more (cost) effective compared with conventional bony decompression. Short-term results (eight weeks), long-term results (one and two year) and results in different subgroups are described in this thesis. The analysis based on total direct and indirect costs of both procedures (treatment with IPD and bony decompression) are also presented. INC suitable for surgical treatment. The compression on MR images was evaluated and correlated with baseline complaints and long-term clinical outcome. Show less
Spondyloarthritis (SpA) is a heterogeneous group of rheumatic diseases, characterized by sacroiliac-joint inflammation (sacroiliitis), peripheral and extra-articular complaints. The lack of... Show moreSpondyloarthritis (SpA) is a heterogeneous group of rheumatic diseases, characterized by sacroiliac-joint inflammation (sacroiliitis), peripheral and extra-articular complaints. The lack of diagnostic criteria makes diagnosing SpA challenging, yet, classification criteria are available. We tested the performance (sensitivity, specificity) of various classification criteria; the recently developed Assessment of SpondyloArthritis international Society (ASAS) criteria outperformed all other criteria. We investigated the discrepancies in interpretation MRIs and conventional radiographs on the presence of sacroiliitis; agreement on radiographic sacroiliitis between different readers is only moderate, but agreement regarding sacroiliitis on MRI is substantial. Rheumatologists take into account all clinical and laboratory results in addition to the imaging results in the diagnostic process. The diagnostic Berlin algorithm - in which all relevant results are taken into account __ can assist rheumatologists. We proposed a modification of this algorithm, which is accepted by ASAS and also included in the recently published guidelines for the diagnosis and treatment of SpA by the Dutch Society for Rheumatology. Besides, we performed systematic literature reviews, forming the base for the update of the ASAS management recommendations. With these results, SpA-patients can be recognized earlier, offering better treatment options and better outcomes. However, further improvements of care for SpA-patients are necessary. Show less
The first part of this thesis focuses on assessing end-organ damage in individuals with the metabolic syndrome and diabetes mellitus using magnetic resonance imaging (MRI) and spectroscopy (1H-MRS)... Show moreThe first part of this thesis focuses on assessing end-organ damage in individuals with the metabolic syndrome and diabetes mellitus using magnetic resonance imaging (MRI) and spectroscopy (1H-MRS). We performed cross sectional and intervention studies to investigate the contribution of obesity, dietary conditions, metabolic environment and exogenous disruptors (chemotherapy) to cardiovascular end-organ damage and the reversibility of this damage with a low caloric diet. The effects of interventions, dietary as well as non-dietary, were explored using imaging technology. As ethnicity is an important aspect of the pathophysiology in diabetes mellitus, we also examined the influence of ethnic factors on diabetes mellitus and its complications. The second part of this thesis focuses on safety, feasibility and implementation of innovative MR techniques at higher field strengths for assessment of cardiovascular disease. Show less
Newborn infants requiring intensive care treatment are at risk of cerebellar injury. This can have important consequences for long-term neurodevelopmental outcome. The aim of this thesis was to... Show moreNewborn infants requiring intensive care treatment are at risk of cerebellar injury. This can have important consequences for long-term neurodevelopmental outcome. The aim of this thesis was to study the incidence and characteristics of cerebellar injury, and to investigate the role of different neuroimaging techniques (cranial ultrasound (CUS) with additional mastoid fontanelle (MF) views and MRI) for its detection in both preterm and high-risk term infants. Part I describes the standard CUS procedure and supplementary imaging techniques to optimize its performance, including the use of additional acoustic windows. Part II focuses on the detection, risk factors and prognostic implications of cerebellar injury in preterm infants. Part III focuses on CUS and MRI findings of posterior fossa abnormalities in full-term infants with various neonatal disorders. Part VI reviews the main findings and conclusions of this thesis, and discusses future perspectives and proposals for further research. Based on the findings of this thesis, we conclude that in both preterm and critically ill full-term infants CUS protocols should include MF views. This enables early detection of most major and clinically relevant posterior fossa abnormalities. Routine MRI for the detection of small hemorrhagic lesions is not warranted, as these lesions have a favorable prognosis Show less
The main goal of this thesis was to develop methods for automated segmentation, registration and classification of the carotid artery vessel wall and plaque components using multi-sequence MR... Show moreThe main goal of this thesis was to develop methods for automated segmentation, registration and classification of the carotid artery vessel wall and plaque components using multi-sequence MR vessel wall images to assess atherosclerosis. First, a general introduction into atherosclerosis and different stages of the disease were described including the importance to differentiate between stable and vulnerable plaques. Several non-invasive imaging techniques were discussed and the advantages of multi-sequence MRI were highlighted. Different novel automated image segmentation and registration techniques for analysis of the MRI images have been developed. A 3D vessel model to automatically segment the vessel wall was presented. Automated image registration was applied to correct for patient movement during the acquisition of an MRI scan and between MRI scans. The last topic is the automatic classification of the different plaque components which can be present inside the vessel wall. All techniques were developed and validated using relevant patient data and reference standards. The work presented is an important contribution to the automated analysis of multi-sequence MR vessel wall imaging of the carotid artery. These techniques can speed up the current manual analysis and are potentially more accurate and more reproducible. Show less
The general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were... Show moreThe general objective of this thesis was to investigate new (quantitative) MR techniques and MR markers in the light of both AD and cerebral aging. The quantitative MR techniques that we used were MTI, tCBF and WSS measurements. The new markers we studied were cerebral microbleeds and iron accumulation in the basal ganglia. In chapter 2 we investigated whether MTI changes could be detected in the GM, WM or both in patients suffering from MCI or AD. Using MTI we found evidence for structural brain changes in both GM and WM of patients with MCI and AD. Furthermore, these MTI changes were related to cognitive impairment as expressed by the mini mental state examination (MMSE) score. These findings imply that cerebral changes can be detected in both GM and WM even before patients are clinically demented. The finding of MTI changes in the GM might relate to classical AD type pathology, whereas WM MTI changes could indicate concomitant vascular pathology. The findings in chapter 2 raised the question of how the MTI changes found in this study are distributed over the GM and WM. This was investigated in chapter 3. In this study we showed that brain damage, as detected by MTI, is widespread over the lobes in both AD and MCI patients whereas GM damage is more focally present in the temporal and frontal lobe of MCI patients. These findings are compatible with the knowledge that GM damage originates from the temporal lobe in AD. This interpretation is further supported by the observed independent association between temporal GM peak height and cognitive decline. MTI changes were found in all four lobes of the MCI patients investigated in this study and show the involvement of a diffuse process affecting the WM even before patients are clinically demented, a finding potentially explained by the presence of diffuse vascular pathology. Chapter 4 shows that the tCBF is strongly associated with parenchymal volume rather than age and, although much weaker, with the severity of WMHs. Although the association between tCBF and parenchyma volume seems straightforward, this finding has important implications for future studies. Volume flow measurements should be corrected for parenchymal volume ratherthan age in all future studies in which flow measurements are being used as a diagnostic tool. In addition, studies including elderly patients or patients with a pathological increase of WMHs, such as diabetic type II subjects, should also correct their tCBF measurements for WMH volumes. Chapter 5 shows that hemodynamic conditions of the carotid and basilar arteries, as expressed in lower WSS parameters, are worse in both MCI and AD compared to controls. In addition, the WSS parameters were found to correlate strongly with cognition. Again, this study is additional evidence for an important role of vascular pathology in the development of AD. In chapter 6, we found a high prevalence of microbleeds in a population of patients suffering from vascular disease or at high risk of developing this condition. Age, hypertension and WMH were the most important risk factors for microbleeds, especially when located in the cortico-subcortical junction and basal ganglia. Regarding the associations between the presence and location of microbleeds on the one hand and parameters of cognitive functioning on the other, chapter 7 shows that microbleeds located infratentorially are associated with impaired cognitive functioning in the aging population with increased vascular risk factors. This suggests that in elderly individuals microbleeds in the posterior fossa should be considered a sign of small vessel disease with potential functional consequences. The semi-quantative scale for scoring basal ganglia hypo-intensity on T2*- weighted imaging presented in chapter 8 was associated with markers of neurodegeneration. This study showed that low signal intensity of the caudate nucleus T2*-weighted MR is a frequent finding which is associated with more cerebral atrophy, a higher load of WMH and a higher load of invisible changes in both cortical GM and NAWM non-demented elderly. Furthermore, hypo- intensity limited to the globus pallidus and putamen was not associated with any of these parameters of neurodegeneration. In chapter 9 we present a method for automated detection and classification of hypo-intense regions on T2-weighted MR images of the basal ganglia. In this chapter we not only show an association between basal ganglia hypo-intensity and cardiovascular risk factors but also with measures of cognitive functioning. From this we conclude that hypo-intensity of the basal ganglia on T2-weighted MR is not only a radiological finding accompanying cerebral aging but also an independent marker of neurodegeneration. Show less
In contrast with the intuitive feeling of physicians many worrisome MRI findings do not correlate with patient outcome in patients with sciatica. Physicians should for example not automatically... Show moreIn contrast with the intuitive feeling of physicians many worrisome MRI findings do not correlate with patient outcome in patients with sciatica. Physicians should for example not automatically ascribe persistent or recurrent symptoms of sciatica to the presence of abnormalities visible on MRI. This thesis enables physicians to reshape the mindset of many persons thinking that knowing imaging findings can only be good. Seeing MRI abnormalities of patients with sciatica should not always be believing. Show less
In pre-clinical research, whole-body small-animal imaging is widely used for in vivo visualization of functional and anatomical information to study cancer, neurological and cardiovascular diseases... Show moreIn pre-clinical research, whole-body small-animal imaging is widely used for in vivo visualization of functional and anatomical information to study cancer, neurological and cardiovascular diseases and help with a faster development of new drugs. Functional information is provided by imaging modalities such as PET, SPECT and specialized MRI. Structural imaging modalities like CT, MRI and ultrasound provide detailed depictions of anatomy. Optical imaging modalities, such as BLI and near-infrared-fluorescence offer a high sensitivity in visualizing molecular processes in vivo. Combining these modalities enables to follow the subject(s) and molecular processes in time, in living animals. With these advances in image acquisition, the problem has shifted from data acquisition to data processing: organization, analysis and interpretation of this heterogeneous whole-body imaging data has become a demanding task. Here, our data processing approach is based on an articulated whole-body atlas as a common reference to normalize the geometric heterogeneity caused by postural and anatomical differences between individuals and geometric differences between imaging modalities. Mapping to this atlas has the advantage that all the different imaging modalities can be registered to a common anatomical reference; postural variations can be corrected, and the different animals can be scaled properly while allowing for proper management of this high-throughput data. Show less
This thesis focuses on epidemiological studies of hand OA in secondary care, erosive OA as a subset of hand OA and the added value of imaging in hand OA to understand better the pathophysiology of... Show moreThis thesis focuses on epidemiological studies of hand OA in secondary care, erosive OA as a subset of hand OA and the added value of imaging in hand OA to understand better the pathophysiology of hand OA and seek for opportunities to define progression in an earlier stage. Chapter 2 gives an overview about the current knowledge on hand OA and it is clear that hand OA is a prevalent, heterogeneous disorder (including several hand OA subsets) that can cause considerable pain and disability. Much less is known about the risk factors of progression in hand OA. Moderate evidence for an abnormal scintigram at baseline was found as a risk factor for radiographic progression in a systematic review as described in chapter 3. In rheumatology practice, the most prevalent phenotype of OA is hand OA as depicted in chapter 4. This symptomatic population experience a substantial lower health-related quality of life compared to the general population. The collaborations with the Rotterdam Study and NorStOP Study (chapter 5, 6, 7) revealed that 2.8% of the general population rising to 10.2% in the symptomatic population is affected by erosive disease in the interphalangeal joints (IPJs). Furthermore, erosions are not present in IPJs only and prevalence of erosive disease in 1st carpometacarpal joints (CMCJs) is also given. Persons with erosive OA in the interphalangeal joints report more pain and functional limitations, however to a lesser extent than persons with other rheumatic inflammatory diseases. Inflammation does play a role in OA joints with erosions, as assessed with Power Doppler Signal, greyscale synovitis and effusion on ultrasound (chapter 8). Also in OA joints without erosions, inflammatory signs are visible on ultrasound (chapter 9). Regarding other imaging modalities used in hand OA research, quantitative joint space width (JSW) measurements in hand OA joints have been shown to be associated with self-reported pain, functional ability and structural abnormalities (chapter 10), whereas features on Magnetic Resonance Imaging (MRI, such as abnormal collateral ligaments and bone marrow lesions) are also associated with pain upon palpation in individual joints (chapter 11). Finally, the health-related quality of life in hand OA patients in rheumatology practice can be improved with a protocol-led consultation about increasing the use of helping aids and acetaminophen given by a clinical nurse specialist (chapter 12). Show less
The aim of this thesis was to develop methods to enable the use of 7 Tesla MRI in clinical practice. A number of technical developments have been performed to facilitate clinical studies and to... Show moreThe aim of this thesis was to develop methods to enable the use of 7 Tesla MRI in clinical practice. A number of technical developments have been performed to facilitate clinical studies and to achieve the full potential of high field. Studies have been performed for imaging of different anatomies of the human body, including visualization of the right coronary artery and high resolution imaging of the brain in patients with neurodegenerative diseases Show less
The aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain... Show moreThe aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain characteristics and intrinstic functional brain connectivity of premanifest and early HD subjects were examined. Cortical, subcortical and the intermediate white matter brain tissue shows evidence of structural and functional decline. We found evidence that disease processes, such as altered metabolism, excessive iron accumulation and cell loss, play a role in the changes. We conclude that changes occur throughout the brain from the earliest disease phase onwards. Hence, both premanifest and manifest HD should not be regarded as a disorder of the basal ganglia, but as a disease affecting the whole brain. Candidate biomarkers that have the potential to objectively reflect the early changes and the progressive nature of the disease are measures of subcortical atrophy, integrity of white matter pathways and of intrinsic functional brain connectivity. Iron, creatine, and N-acetylaspartate concentrations in the caudate nucleus and putamen may prove to be useful as markers of disease state for objectifying transitional disease processes from premanifest to manifest HD. Visuospatial working memory could be applied as a state marker for stage two HD. Show less
