Magnetic resonance imaging signatures of vascular pathology in multiple sclerosis

Venous vascular contributing factors to multiple sclerosis (MS) have been known for some time. Only recently has the scope of their potential role become more apparent with the theory of chronic cerebrospinal venous insufficiency (CCSVI). As research expands to further explore the role of vascular pathology in the MS population, it is expedient to review the evidence from an imaging perspective. In this paper, we review the current state-of-the-art methods using magnetic resonance imaging (MRI) as applied to imaging MS patients and CCSVI. This includes evaluating imaging signatures of vascular structure and flow as well as brain iron content. Upon review of the literature, we find that extracranial venous anomalies including stenosis, venous malformations, and collateralization of flow in the major veins of the neck have been observed to be prevalent in the MS population. Abnormal flow has been reported in MS patients both in major vessels using phase-contrast flow quantification and in the brain using perfusion-weighted imaging. We discuss the role of quantitative flow imaging and its potential in assessing possible biomarkers for abnormal flow. Finally, it has been suggested that the presence of high iron content may indirectly indicate progression of existing vascular pathology. To that end, we review the use of susceptibility-weighted imaging in monitoring iron in the thalamus, basal ganglia, and MS lesions.     

Magnetic resonance imaging and histopathology in dementia, clinically of frontotemporal type

The magnetic resonance imaging (MRI) and computed tomography findings in 28 patients with the clinical diagnosis of frontotemporal dementia (FTD) were compared with the findings in a control group of 76 individuals without dementia or stroke. A pattern of frontal and temporal atrophy with predominantly frontal white matter changes was found in the FTD patients, and this was significantly different from the radiological findings in the control group. Six of the FTD patients have undergone autopsy. Histopathological evaluation showed a primary cortical degenerative disease (frontal lobe degeneration of non-Alzheimer type) in 3 of them, and primary white matter disorder, mainly frontal, of basically ischemic type (selective incomplete white matter infarction) in 3 of them. MRI could be a helpful tool to support the clinical diagnosis FTD, especially in young patients. MRI may also be helpful for the differentiation of a primary neurodegenerative from a mainly ischemic-vascular type of dementia.     

Magnetic resonance imaging in vascular dementia

Patients with vascular dementia show distinctive white matter lesions on MRI. We performed MRI on 34 patients with documented ischemic cerebrovascular disease to see whether demented and nondemented patients differ with respect to enlarged CSF spaces or white matter lesions. All eight demented patients had white matter lesions on MRI, just as did many borderline and nondemented patients. Enlargement of central CSF spaces was the only radiographic feature that was seen more commonly in demented than in nondemented patients with ischemic cerebrovascular disease.     

Magnetic resonance imaging in dementia of Parkinson''s disease.

The possibility that dementia in Parkinson's disease is associated with specific cerebral abnormalities identifiable by magnetic resonance imaging (MRI) was examined. Sixty eight patients with Parkinson's disease and 28 age and education matched normal controls were evaluated using neuropsychological procedures that included assessment of language, memory, cognition, visuospatial skills and mood. Twenty three patients (34%) were found to have developed significant impairment in at least three of the five areas, thus meeting criteria for a dementia syndrome. Eleven patients (16%) had no intellectual impairment and thirty four patients (50%) had a mild to moderate intellectual disturbance. Patients with (n = 10) and without dementia (n = 20), matched for severity of Parkinson's disease, and normal controls (n = 10) matched for age with the two patients groups, were evaluated by MRI. MRI scans were analysed for evidence of generalised cerebral atrophy, ventricular enlargement, visualisation of the substantia nigra and severity of focal brain lesions. Results indicated that the presence of dementia in patients with Parkinson's disease was not associated with any specific pattern of MRI abnormalities.     

Magnetic resonance imaging and the diagnosis of dementia

We describe seven patients with clinical, laboratory, and CT evidence of primary degenerative dementia (Alzheimer's, Pick's). Magnetic resonance imaging demonstrated regions in the white matter consistent with cerebral infarction. MRI may be a sensitive way to differentiate multi-infarct dementia and primary degenerative dementia.     

Proton magnetic resonance spectroscopy in frontotemporal dementia

This study of frontotemporal dementia (FTD) was carried out to determine whether MR spectroscopy can provide an in vivo marker for the neuronal loss and gliosis that occur in this condition. We compared spectra in frontal and temporal regions known to be affected early in the course of the disease with spectra in the parietal lobe that is spared until late stages of FTD. We were interested in the relative concentrations of two compounds, NAA (a marker of neuronal integrity) and mI (a marker of gliosis), expressed as ratios to creatine (a relatively stable brain constituent). MR spectroscopy was performed on the temporal, parietal, and anterior cingulate cortices of five patients with the established semantic dementia form of FTD, two patients with the frontal form of FTD and 13 age matched controls. Structural MRI and neuropsychometry were also performed. Patients with FTD had reduced NAA/Cr in frontal and temporal, but not parietal lobes. The two patients with the frontal form of FTD had increased mI/Cr in their cingulate cortices. These data show for the first time that MR spectroscopy can reveal regionally selective abnormalities in patients with FTD. This opens up the possibility of using MR spectroscopy as a clinical tool to identify earlier presentations of the condition.     

Magnetic resonance spectroscopic study of Alzheimer's disease and frontotemporal dementia/Pick complex

Disease-specific metabolic changes in Alzheimer's disease and frontotemporal dementia/Pick complex were examined by proton magnetic resonance spectroscopy at 3.0 T. Spectra were acquired from posterior and anterior cingulate cortices and the parieto-occipital and frontal white matter. This study included eight Alzheimer's disease patients, 10 frontotemporal dementia/Pick complex patients and 14 healthy volunteers. N-acetylaspartate/creatine+phosphocreatine ratio was reduced in the posterior cingulate cortex in the Alzheimer's disease and frontotemporal dementia/Pick complex patients. The Alzheimer's disease patients, however, showed a posterior dominant decrease, whereas the frontotemporal dementia/Pick complex patients showed a frontal predominant decrease. These different distributions of metabolic changes may represent the underlying pathological processes in each disease. Our standardized protocol of proton magnetic resonance spectroscopy measurement may be helpful in differentiating these dementia subtypes.     

Usefulness of functional magnetic resonance imaging and spectroscopy in the diagnosis of frontotemporal dementia

Early diagnosis of frontotemporal dementia is difficult, especially at its early stages, being mainly misdiagnosed as a psychiatric condition. The main source of uncertainty comes from the primacy of behavioral disturbances, for which sufficiently validated detection tools are not available. The increasing development of magnetic resonance (MR) techniques permits a triple approach that combines morphology, biochemistry and perfusion in the study of dementing neurodegenerative conditions. A 64-year-old male patient is described with prominent behavioral disturbances and a frontotemporal pattern of cognitive impairment. He met criteria for frontotemporal dementia. Conventional MR imaging showed minimal frontotemporal atrophy. A moderate hypoperfusion of the frontal lobes was observed in the MR perfusion study. The spectroscopy showed a decrease of the n-acetyl-aspartate peak in the medial frontal region with normal values in the medial parietal region. The whole MR imaging study aided to distinguish frontotemporal dementia from other conditions, such as brain structural processes and depression, offering relevant information for prognostic and therapeutic purposes. The usefulness of the new MR imaging techniques in the early diagnosis of dementing neurodegenerative conditions must be confirmed by larger studies accompanied by pathological material.     

Profiles of white matter tract pathology in frontotemporal dementia

Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template‐based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co‐localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies. Hum Brain Mapp 35:4163–4179, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.     

Progression in frontotemporal dementia: identifying a benign behavioral variant by magnetic resonance imaging

OBJECTIVE: To assess the clinical course and prognosis in patients with behavioral-variant frontotemporal dementia (FTD) lacking evidence of brain atrophy on magnetic resonance imaging (MRI). DESIGN: Patients were enrolled into this prospective cohort study over a period of 15 years; cognitive status, duration of symptoms, and behavioral indexes were recorded. Brain MRIs were rated using a standardized scale. SETTING: Regional early-onset dementia clinic. PARTICIPANTS: Thirty-one participants diagnosed clinically with behavioral-variant FTD. Intervention Rating of MRIs. MAIN OUTCOME MEASURES: Death or institutionalization after a minimum of 3 years' follow-up indicated poor prognosis, while the ability to live independently was regarded as a good prognosis for the purpose of survival (Kaplan-Meier) and discriminant function analysis. RESULTS: Patients with normal or borderline MRI findings (n = 15) showed significantly longer survival to institutionalization or death than those (n = 16) with definite frontotemporal atrophy (mean +/- SE, 9.3 +/- 1.7 years vs 3.0 +/- 0.7 years; P<.01). Using groups defined by 3-year outcome (good or bad prognosis), cerebral atrophy predicted poor outcome while age, symptom duration, cognitive performance, behavioral impairment, and overall disability at baseline did not. CONCLUSIONS: Patients with FTD with normal MRI results follow a more benign course than cases with atrophy at presentation. The substrate of the behavioral symptoms in such cases may differ from the neurodegenerative pathological features typically associated with FTD.     

Magnetic resonance imaging and the severity of dementia in older adults

Periventricular white-matter lesions were visualized in the brains of elderly patients being assessed for possible Alzheimer's disease. The magnitude of these lesions, expressed as lesion-brain ratios, correlated closely with the severity of dementia indicated by scores on the Blessed Dementia Scale and the Folstein Mini-Mental State Examination. Impairment in several domains of cognitive functioning tested by the Mini-Mental State Examination was also correlated with the relative quantity of periventricular lesions. Correlations were significant with systolic blood pressure, approached significance with age, and were not significant with duration of dementia or the magnitude of the lateral ventricles. These findings indicate the potential utility of structure-function correlations that are possible with magnetic resonance imaging in identifying mechanisms underlying dementia. They suggest that magnetic resonance imaging may be more useful than computed tomography in following the course of dementia.     

Review: Modelling the pathology and behaviour of frontotemporal dementia

Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.     

Magnetic resonance imaging in Alzheimer's disease, multi-infarct dementia, alcoholic dementia and Korsakoff's psychosis

Regional spin lattice relaxation times (T1) measured during nuclear magnetic resonance imaging of the brain were compared in patients with Alzheimer's disease, multi-infarct dementia, alcoholic dementia, Korsakoff's psychosis and control subjects. Regional differences were found between all patient groups compared with controls and within patient groups, with the exception of the comparison between Korsakoff's psychosis and alcoholic dementia. Correlations between regional T1 change and cognitive test scores were also found, with particular emphasis between visuospatial deficits and parietal T1. The possible role of T1 measures in the pathophysiology of these disorders is discussed.     

Neuroimaging in frontotemporal dementia

Abstract

The term frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are associated with atrophy of the frontal and temporal lobes, and present clinically with impairments of behaviour or language. Three main subtypes are described, behavioural variant FTD (bvFTD) and two subtypes of the language presentation (known as primary progressive aphasia or PPA) called semantic variant of PPA and non-fluent variant of PPA. Most imaging studies of FTD have used volumetric T1 magnetic resonance imaging (MRI) or positron emissions tomography imaging to identify patterns of grey matter atrophy or hypometabolism in these different subtypes, but more recently newer imaging techniques have been used to help define abnormalities in structural connectivity (white matter tract integrity using diffusion tensor imaging), functional connectivity (resting state networks using resting state functional MRI) and perfusion (using arterial spin labelling perfusion MRI) in FTD. These techniques have the potential to improve the differential diagnosis of FTD from other disorders and to provide more informative imaging signatures of FTD syndromes.     

TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations

Frontotemporal dementia with inclusion body myopathy and Paget disease of bone is a rare, autosomal-dominant disorder caused by mutations in the gene valosin-containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) without VCP mutations. TAR DNA binding protein 43 (TDP-43) was recently identified as a major disease protein in the ubiquitin-positive inclusions of sporadic and familial FTLD-U. To determine whether the ubiquitin pathology associated with mutations in VCP is characterized by the accumulation of TDP-43, we analyzed TDP-43 in the CNS pathology of five patients with VCP gene mutations. Accumulations of TDP-43 colocalized with ubiquitin pathology in inclusion body myopathy and Paget disease of bone, including both intranuclear inclusions and dystrophic neurites. Similar to FTLD-U, phosphorylated TDP-43 was detected only in insoluble brain extracts from affected brain regions. Identification of TDP-43, but not VCP, within ubiquitin-positive inclusions supports the hypothesis that VCP gene mutations lead to a dominant negative loss or alteration of VCP function culminating in impaired degradation of TDP-43. TDP-43 is a common pathologic substrate linking a variety of distinct patterns of FTLD-U pathology caused by different genetic alterations.