J Neurol DOI 10.1007/s00415-015-7711-x

NEUROLOGICAL UPDATE

Recent imaging advances in neurology Lorenzo Rocchi1 • Flavia Niccolini1 • Marios Politis1

Received: 2 December 2014 / Revised: 13 March 2015 / Accepted: 14 March 2015 Ó Springer-Verlag Berlin Heidelberg 2015

Abstract Over the recent years, the application of neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) has considerably advanced the understanding of complex neurological disorders. PET is a powerful molecular imaging tool, which investigates the distribution and binding of radiochemicals attached to biologically relevant molecules; as such, this technique is able to give information on biochemistry and metabolism of the brain in health and disease. MRI uses high intensity magnetic fields and radiofrequency pulses to provide structural and functional information on tissues and organs in intact or diseased individuals, including the evaluation of white matter integrity, grey matter thickness and brain perfusion. The aim of this article is to review the most recent advances in neuroimaging research in common neurological disorders such as movement disorders, dementia, epilepsy, traumatic brain injury and multiple sclerosis, and to evaluate their contribution in the diagnosis and management of patients. Keywords Magnetic resonance imaging  Positron emission tomography  Movement disorders  Dementia  Epilepsy  Traumatic brain injury  Multiple sclerosis

& Marios Politis [email protected] 1

Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London SE5 8AF, UK

Introduction Several neuroimaging techniques have been deployed over the past decade, to help understand the pathophysiology of complex neurological disorders and to provide us with biological indicators for early diagnosis and response to treatment [1, 2]. Neuroimaging techniques such as magnetic resonance imaging (MRI) and functional MRI (fMRI) have played a critical role in assessing structural and functional changes in the brain, which can be related to the pathophysiology and clinical manifestations of neurological disorders (Table 1). Positron emission tomography (PET) molecular imaging, by measuring the distribution of a radionuclide that is introduced into the body on a biologically active molecule, is a powerful technique for the investigation of in vivo metabolic and biochemical abnormalities in the brain (Table 2). In this article, we review recent neuroimaging advances in common neurological disorders.

Movement disorders Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD), with a life-time risk of 4 % that is predicted to double over the next decades. Although neuroimaging in PD has provided us with important information relating to changes in brain structure and function, metabolic activity and brain neurochemistry, no neuroimaging modalities are specifically recommended for routine use in clinical practice [3]. Despite this, PET studies in PD have significantly contributed to the understanding of the underlying pathology, such as alterations in the dopaminergic network [4].

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J Neurol Table 1 Positron emission tomography techniques in neurologic disorders

PET tracer

Target

Assessment

[11C]AMT

AADC, IDO

Tryptophan synthesis

[11C]CFT

DAT

Presynaptic dopaminergic function

[11C]DAA1106

TSPO

Neuroinflammation

[11C]DASB

SERT

Presynaptic serotonergic function

[11C]Flumazenil

GABAaR

Gabaergic function

[ C]PBB3

TAU

Tau deposits

[11C]PBR28

TSPO

Neuroinflammation

[11C]PiB PET

Ab-amyloid

Ab-amyloid deposits

[11C]PK11195

TSPO

Neuroinflammation

[11C]raclopride

D2/D3 receptors

Postsynaptic dopaminergic receptors/dopamine release

11

18

[ F]AV133

VMAT-2

Presynaptic dopaminergic function

[18F]DTBZ

VMAT-2

Presynaptic dopaminergic function

[18F]FCWAY

5-HT1A

Serotonergic function

[18F]FDG

Glucose metabolism

Brain metabolism

[18F]FEDAA1106 [18F]Florbetaben

TSPO Ab-amyloid

Neuroinflammation Ab-amyloid deposits

[18F]Florbetapir

Ab-amyloid

Ab-amyloid deposits

[18F]Flutametamol

Ab-amyloid

Ab-amyloid deposits

[18F]FP-CIT

DAT

Dopaminergic function

[18F]PBR111

TSPO

Neuroinflammation

[18F]T807

TAU

Tau deposits

[18F]T808

TAU

Tau deposits

[18F]THK5105

TAU

Tau protein deposits

Table 2 Magnetic resonance imaging techniques in neurological disorders MRI technique

Structural/functional correlate

Use in neurological disorders

Arterial spin labeling Blood oxygenation level-dependent

Magnetically labeled water in the blood stream Difference in hemoglobin saturation

Brain perfusion Estimation of brain activity

Diffusion tensor imaging

Water molecules diffusion in white matter

Characterization of white matter

Fractional anisotropy

Degree of diffusion anisotropy in white matter

Estimation of white matter damage

MR-elastography

Effect of exogenous vibration

Elasticity of brain parenchyma

Magnetization transfer saturation

Pulsed applied at lower frequency

Marker of structural integrity

Mean diffusivity

Diffusion of water molecules irrespective of direction

Estimation of white matter damage

Neuromelanin sensitive MRI

Pulsed applied at lower frequency

Quantification on neuromelanin deposits

Resting state fMRI

Difference in hemoglobin saturation

Estimation of brain activity in resting conditions

Transverse relaxation rate

Relaxation of transverse magnetization

Estimation of iron deposits

Recent studies have shown that novel neuroimaging tools could aid in the early diagnosis and monitoring of PD such as [18F]DTBZ PET, a vesicular monoamine transporter 2 (VMAT-2) marker, for measuring dopaminergic terminal loss [5, 6]. Semi-automated measurement of substantia nigra pars compacta (SNc) volume with 3Dneuromelanin sensitive MRI has been demonstrated to be able to distinguish PD patients from healthy subjects (HS), especially in the early stage of the disease [7]. Ohtsuka and

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coworkers [8] showed that the volume of the SNc and locus coeruleus (LC) as measured with neuromelanin sensitive MRI was able to distinguish early PD patients from those with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). PD patients could also be distinguished from HS based on lower magnetization transfer values of the SNc, which represent a marker of structural integrity [9]. Iron deposition measured with transverse relaxation rate (R2*) in the caudal putamen and substantia

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nigra has been suggested as a biomarker of disease progression in PD [10]. Although the number of patients studied in these reports is limited, quantification of iron and neuromelanin deposition seems to be promising tools for the early diagnosis in PD. Arterial spin labeling (ASL) also appears to be a promising addition in the early diagnosis of PD due to its ability to identify a perfusion covariance pattern, specific for patients with PD, which is consistent with decreased perfusion bilaterally in the temporal, insular, posterior parietal, inferior parietal, lateral occipital and prefrontal cortices, and with relative perfusion increases in the cerebellum, pons, right thalamus, pallidum, sensorimotor cortex, paracentral lobule and supplementary motor area [11]. Diffusion tensor imaging (DTI) has demonstrated a number of white matter abnormalities in PD, such as an increase in mean diffusivity (MD) and a decrease in fractional anisotropy (FA) in the SNc and olfactory tract [12]. Other DTI measures such as radial and axial diffusion have shown changes in PD in the basal ganglia and thalamus [13]. A novel diffusion MRI technique, namely track density imaging, has shown signal changes in areas affected by PD pathology [14]. Although promising, systematic analysis of the contribution of DTI measures as an aid to PD diagnosis is yet to be made. Transcranial sonography (TCS) is a non-invasive technique that has been evaluated as a diagnostic tool in PD. Although echogenicity of the SN has been considered useful to aid PD diagnosis by several studies [15, 16], more recent literature suggests that TCS is less sensitive in detecting early stage PD compared to DAT PET with [11C]CFT [17], and it cannot be recommended for routine clinical use [18]. Nigral lesion load quantification by TCS, which evaluates echogenicity by summing four values, two on each side of SN, could be a more accurate marker for PD diagnosis [19]; however, that needs to be explored further in future studies. Cognitive impairment is one of the most common and important non-motor aspects of PD [20]. PET with [11C]PiB has shown that Ab-amyloid deposition in PD patients at risk for dementia is uncommon [21], and it cannot differentiate PD patients with mild cognitive impairment (MCI) from those without. A study indicated that [11C]PiB PET could be useful only in predicting decline in executive functions in PD [22]. Loss of dopaminergic terminals measured with [18F]FP-CIT, a radioligand tagging DAT, correlates with a glucose specific cognition-related disease network evaluated by [18F]FDG PET. This pattern shows a reduction of metabolic activity in frontal and parietal regions with increases in the cerebellar vermis and dentate nuclei in cognitively impaired PD patients [23]. Inflammation quantified with [11C]PK11195 PET, which evaluates the activity of mitochondrial translocator protein

(TSPO), a marker of microglial activation [24–26], was shown to correlate with mini mental examination scores [27, 28] and with reduced glucose metabolism measured by [18F]FDG PET [28]. Overall, these data suggest a role of neuroinflammation in the development of dementia in PD (PDD), but the clinical impact of a possible anti-inflammatory therapy has not been established yet. A number of morphological brain measures have been used to investigate the pathophysiology of cognitive decline in PD. Cortical thinning, which has been suggested to be linked to overall cognitive performance [47], and to specific cognitive domains [30, 31], may be useful in identifying PDD [32], even at early stages [33]. Cerebral white matter atrophy and volumes of the lateral ventricles and hippocampi have been related to dementia in PD [34]. A faster rate of thinning in various cortical regions has been associated with the early presence of MCI in PD [35], and it has been suggested that hippocampal volume is a major factor in predicting the development of mild cognitive impairment and dementia in PD [36]. Besides cortical alterations, white matter deterioration, and in particular decreases in FA occurring in the left anterior cingulated bundle, corpus callosum splenium [37] or the frontal and interhemispheric connections [38] may underlie progressive cognitive impairment in PD. Impulse control disorders (ICDs) following dopamine replacement therapy represent a significant problem for PD patients and their carers. Using serial [11C]raclopride PET (a specific D2 receptor radioligand) scanning, it was found that patients with ICDs had a greater ventral striatal dopamine release following exposure to reward related cues compared to PD patients without ICDs [39]. One study with fMRI has demonstrated that PD patients with hypersexuality, when exposed to sexual cues, had greater blood oxygen level-dependent (BOLD) signal changes in regions within limbic, paralimbic, temporal, occipital, somatosensory and prefrontal cortices. These changes were present only when patients were ON medication, indicating that dopamine therapy may release inhibition within specific circuits linked to compulsive sexual behaviour [40]. PET and MRI have been used to understand the mechanisms underlying motor signs of PD, which have proven challenging to manage in clinic. Gait disorder is one of the most disabling and treatment resistant symptoms of PD, and has recently been linked to cortical cholinergic denervation [41], in line with the hypothesis that the condition has a largely non-dopaminergic basis [42]. In addition, PD gait disorder seems more common when a substantial Ab-amyloid deposition is present [43]; this finding may explain why the postural instability and gait disorder motor phenotype is considered a risk factor for the development of PDD [44]. In addition to cortical

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abnormalities, the functional connectivity of basal ganglia [45] and the pedunculopontine nucleus [46] has been suggested to be involved in the pathophysiology of the gait disorder in PD. Another motor feature of advanced PD is the development of levodopa-induced dyskinesias (LIDs), which have been linked to presynaptic dopaminergic denervation as evaluated by [18F]FP-CIT PET [29], and to an immediate hypersensitivity of the pre-supplementary motor area and putamen to levodopa as assessed with functional MRI (fMRI) during a stimulus–response mapping task [48]. Substantial pathology within the serotonergic system in PD has been demonstrated in vivo in recent years with PET and serotonergic markers such as [11C]DASB [49– 51]. Several studies have demonstrated serotonergic dysfunction that correlated with depression levels [52], weight changes [53], development of action-postural tremor [54] and LIDs [55, 56] in PD. Several studies in PD patients with LIDs demonstrated that striatal serotonergic terminals contribute to the development of LIDs through aberrant processing of exogenous levodopa and release of dopamine as a false neurotransmitter in the denervated striatum [55]; these studies also supported the development of selective serotonin receptor type 1A agonists as antidyskinetic agents in PD [56]. [11C]DASB PET has also shown extra-striatal global brain loss of serotonergic function in transplanted PD patients with non-motor symptoms [57] and striatal graft-specific serotonergic hyperinnervation in those who developed graft-induced dyskinesias [58, 59]. Several neuroimaging techniques have been tested for the differential diagnosis of atypical parkinsonism (AP). [18F]FDG PET was superior to [123I]IBZM single photon emission computerized tomography (SPECT) in the differentiation of AP from Lewy body diseases (with the majority of PD) and could differentiate different AP syndromes with high specificity [60]. FA and various diffusivity measures obtained from different structures such as the cerebellum and basal ganglia have been successfully used to discriminate PD from AP and distinguish different types of AP with high sensitivity and specificity [61]. For example, MRI-based segmentation of long variable echotrains [62], supervised machine learning approach [63], automatic pattern recognition [64] and brain viscoelasticity as measured with MR-elastography [65] have been shown to be able to distinguish PSP from PD, although their value as clinical tools has yet to be fully assessed. The parkinsonian variant of MSA, which can be difficult to distinguish from PD, especially at early stages, can be differentiated from PD and PSP by measuring putaminal MD values [66]. Other parameters that could help in discriminating MSA from PD are the relatively preserved volume of olfactory bulbs and tracts [67], and the different

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contrast ratio of the LC [68]. Altogether, these data look promising for aiding the diagnosis of AP; however, they need further validation with larger sample sizes before being integrated into novel therapeutic trials. Huntington’s disease (HD) is a progressive and fatal neurodegenerative disorder caused by an expanded trinucleotide CAG sequence in the huntingtin gene (HTT) on chromosome 4. Over the past years, MRI and PET have provided important advances in our understanding of HD [69]. In a large HD longitudinal study, changes in several imaging measures such as whole-brain, putamen, ventricular and grey matter volume were predictive of decline in total functional capacity and tracked longitudinal change over 36 months after adjustment with respect to age and CAG length [70]. MRI has also shown that there is an inverse correlation between volume and iron levels in the putamen, pallidus and anterior cingulate cortex, while a direct correlation is present between iron deposits and cortical volume in sensorimotor and temporo-occipital cortex [71]; iron deposits in the corpus callosum could be regarded as a marker of disease state, since iron accumulates only in manifest HD [72]. Longitudinal FA change in putamen has been demonstrated to distinguish between premanifest HD and symptomatic HD after a diagnosis was established [73]; premanifest HD also exhibited a longitudinal reduction in functional connectivity, evaluated with BOLD signal, among an extensive prefrontal and motor network during a working memory task [74]. Also, a spatial covariance metabolic pattern investigated with [18F]FDG has been able to evaluate disease progression [75]. Analysis of the BOLD signal has been successfully used to reveal early functional connectivity changes in HD. Premanifest HD exhibited a decrease in the BOLD synchrony between the caudate nucleus and premotor area [76], and in sensorimotor and dorsal attention networks [77], indicating that the BOLD signal may be a useful tool for measuring early neuronal dysfunction in HD. Using structural MRI, [11C]PK11195 and [11C]raclopride PET, one study found that pathologically activated microglia in the associative striatum and other areas related to cognitive function may be a useful predictor of clinical HD onset [78].

Dementia Cognitive decline, particularly in the context of Alzheimer’s disease (AD), has attracted numerous recent imaging studies. Numerous imaging biomarkers have been proposed in these investigations and their clinical applications need to be validated [79]. Alzheimer’s disease is the most common cause of dementia and is characterized by cognitive impairment, progressive neurodegeneration and

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formation of Ab-amyloid containing plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau [80]. One of the most significant developments in AD research has been the development to image the amyloid plaques, whose deposition and accumulation are viewed as fundamental to the pathological process leading to AD [81]. [11C]PiB PET has been shown to be able to image Ab-amyloid plaques in the cortex many years before the clinical onset of the disease in patients with autosomal dominant AD [82], and has shown higher levels of Abamyloid deposits in early onset AD compared to late onset AD [83]. Also, Ab-amyloid deposits measured with [11C]PiB PET are predictive of cognitive decline in healthy individuals and patients with mild cognitive impairment (MCI) [84]. Although [11C]PIB PET can be a promising imaging marker to quantify Ab-amyloid retention, its potential use in clinical practice is limited by the short halflife of C-11 (about 20 min), which requires on-site cyclotron production. This disadvantage can be overcome by the use of more recently established PET ligands such as [18F]Florbetapir, [18F]Florbetaben and [18F]Flutametamol which have a half-life of about 110 min [85]. [18F]Florbetaben has been shown to facilitate accurate detection of prodromal AD [86], and [18F]Flutametamol has yielded results similar to [11C]PIB in Ab-amyloid detection [87]. Similarly, Florbetapir could significantly improve the clinical identification of dementia in AD [88], and has been successfully used to detect Ab-amyloid deposits in presenilin 1vE280A mutation carriers before clinical onset [89]. Ab-amyloid PET imaging such as with [18F]Florbetapir has been shown to be predictive of cognitive and global deterioration over a 3-year follow-up in patients with MCI and probable AD [90]. More recently, several ligands for tau protein have been devised, such as [18F]T807 [91], [18F]T808 [92] [11C]PBB3 [93], [18F]THK5105 [94]; however, their diagnostic role in neurological disorders characterized by accumulation of tau protein has not been investigated yet. Higher Ab-amyloid burden as estimated with [18F]Florbetapir correlates with decreased cerebral blood flow measured with ASL [95] and basal forebrain cholinergic system atrophy [96] in MCI and AD patients. However, Ab-amyloid deposition measured with [11C]PIB has been shown to be independent of hippocampal neurodegeneration [97], suggesting that degeneration of the hippocampus and Ab-amyloid deposits could be at least partially different phenomena. In patients with MCI, the combination of several biomarkers, such as Ab42 concentration in the cerebrospinal fluid, temporoparietal hypometabolism measured with FDG-PET and decreased hippocampal volume, has been shown to be linked to increased incidence of progression to dementia with increased biological severity and decreased conversion time

[98]; cortical volumetry may also predict future decline in cognition in cognitively normal HS [99]. Other types of degenerative dementias have been much less investigated in recent years compared to AD. Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia [100]. Patients affected by DLB exhibit marked reduction of dopaminergic activity in the basal ganglia as evaluated with different PET and SPECT tracers. Also, DLB patients show hypoperfusion of parietal and occipital regions when evaluated with SPECT techniques and structural preservation of medial temporal lobes [31]. DLB can be differentiated from AD based on the lower density of dopamine vesicular transporters as estimated with [18F]AV133 [101] and relatively preserved temporal lobe perfusion as measured with ASL [102]. Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative conditions that share clinical features and pathologic and genetic etiologies [103]. Using a ROI-based classification which combed information from FDG-PET and MRI information, an accuracy of 94 % for the differentiation of AD and FTLD patients was obtained [104]. Also, [18F]Florbetaben has been shown to distinguish patients with FTLD from AD [105]. Other imaging modalities, such as fMRI, have been used as a tool to investigate preclinical alterations in dementia. Several outcome measures have been used, like changes in hippocampal activity during memory-related tasks and resting-state fMRI, which have been reviewed elsewhere [106, 107]. In particular, paradoxically increased hippocampal activity may be an early indicator of AD-related neurodegeneration in a distributed network [108]. From the present data, it seems that imaging techniques, and in particular amyloid imaging, has greatly contributed to the characterization of AD, while the significance of recent imaging literature on other form of dementia seems limited. fMRI, despite technical advancements and interesting pathophysiological investigation, still has a less established clinical role and needs validation in future studies.

Epilepsy With 65 million people affected worldwide, epilepsy is a very common and chronic neurological disease [109]. Recent use of neuroimaging in epilepsy has indicated that seizure activity propagates along specific anatomical pathways that characterize the underlying epilepsy syndrome [110]. For instance, temporal lobe epilepsy (TLE) appears to chronically alter the activity of several brainwide neural networks involved in the control of higher

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order brain functions and not traditionally linked to epilepsy, like the default mode network (DMN), attention networks, executive control network and reward network when investigated with resting-state fMRI [111]. Connectivity alterations within these networks have been suggested to be responsible for the cognitive and psychiatric symptoms of TLE like depression [112]. In particular, auditory memory deficits have been linked to diminished 5-HT1A receptor binding measured with [18F]FCWAY [113], while depression was associated with decreased serotonin transporter activity in the insular cortex evaluated with [11C]DASB [114]. Neuroimaging techniques have also proven to be useful in the setting of surgical evaluation of TLE. In this context, the combined use of electrical source imaging, perfusion evaluated with ASL and [18F]FDG PET may play an increasingly important role in the non-invasive evaluation of patients with refractory focal epilepsy [115]. In particular, patients free of seizures after surgery had significantly different mesial temporal asymmetry for 5-HT1A receptor densities as evaluated with [18F]FCWAY and glucose metabolism measured with [18F]FDG PET [116]. [11C]Flumazenil PET provides evidence for a more restricted region of abnormality in patients with drug-resistant temporal lobe epilepsy and thus give localizing information which is complimentary to [18F]FDG PET [117]. Overall, it seems that surgical approaches to intractable epilepsy could benefit from the use of PET, although more studies in conjunction with electroencephalographic mapping of epileptogenic areas are needed. Recent studies have also shed light on the genetic and malformative causes of epilepsy. In patients with tuberous sclerosis complex and intractable epilepsy, the more hotspots of a-[11C]-methyl-L-tryptophan ([11C]AMT), which is used for the measurement of serotonin synthesis, correlated with longer duration of seizure intractability [118]; in another study, higher binding of [11C]AMT correlated negatively with FA values [119]. PET using [11C]PK11195 was able to detect neuroinflammation associated with subtle focal cortical dysplasia in one study [120]. Cortical dysplasia also displays hyperperfusion, which can be related to increased microvessel density and can be monitored with ASL [121].

Traumatic brain injury The incidence of traumatic brain injury (TBI) is increasing worldwide, and consequences of severe TBI such as permanent disability can be detrimental, especially in children [122]. Ab-amyloid depositions are very often found in post mortem examination of subjects who had severe TBI; although Ab-amyloid deposits are gradually cleared during

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the days and months following acute TBI, autopsy studies indicate that Ab plaques (often of the AD-associated form, Ab 42) are present in up to 30 % of patients with a history of TBI, regardless of age [123]. These findings are in line with epidemiological data suggesting that TBI results in a substantial increase in the risk for developing AD later in life [124]. PET with [11C]PiB following acute TBI is in agreement with the distribution of Ab-amyloid deposition in the postmortem tissue of patients with TBI [124]. However, the relationship between acute traumatic brain injury (TBI) and Ab-amyloid deposition is still incompletely understood. A subcortical tauopathy with a distribution that mimics that of PSP, with the addition of hippocampal involvement, was observed in a case of chronic traumatic encephalopathy; also, focal Ab-amyloid aggregation after a single, severe TBI has been found [125]. Moreover, one study found that not all patients who had undergone TBI showed [11C]PiB binding; in patients, in whom [11C]PiB binding was present, binding was not correlated with chronic neuropsychological impairment, severity of injury, computed tomography findings, elapsed time from the injury, and cognitive performance [126]. Despite the importance of defining the relationship between TBI and Ab-amyloid depositions, the clinical application of Ab-amyloid imaging needs further clarification. Important information about the role of the inflammatory response after TBI came from a study which showed an increase in binding of [11C]PK11195 months or years after TBI, suggesting that the traumatic event triggers a chronic inflammatory response, associated with a greater cognitive deficit [127]. Several recent studies used different MRI techniques in the investigation of the underlying pathophysiology of TBI. Analysis of resting-state fMRI demonstrated alterations of multiple brain networks in patients with mild TBI in the acute stage, suggesting that fMRI could be used as a potential biomarker for improved detection of TBI in the acute setting [128, 129]. Connectivity alterations of neural structures included in the DMN has been also reported in repetitive sub-concussive events in athletes [130] and in animal models of TBI [131]. FA has received attention in the clinical context of TBI. Patients with mild TBI showed evidence of increased FA in the bilateral superior frontal cortices during the semiacute phase [132]. One metaanalysis study suggested that acute mild TBI is associated with elevated FA values and that complaints due to chronic mild TBI are correlated with depressed anisotropy [133]. According to other data, FA was predictive of functional recovery after TBI [134]. However, the clinical usefulness of FA in TBI has been questioned by a large study in patients with mild TBI [135], which showed that acute mild TBI was not associated with DTI abnormalities. Entropy measurement, which is more sensitive to axonal

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density and orientation, could be more effective in distinguishing axonal remodeling after injury when compared with FA [136]. Several studies have investigated the DMN in patients with TBI. Patients who have undergone TBI showed an increase in functional connectivity in the DMN, with higher DMN functional connectivity being associated to lesser cognitive impairment [137]. A lower DMN connectivity was found in patients who showed more diffuse axonal injury within the corpus callosum measured with DTI [137]. TBI patients with impaired cognitive control showed reduced functional connectivity on fMRI between DMN and right anterior insula, an area critically involved in the salience network, during a response inhibition and switching task [138].

Multiple sclerosis Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease, often resulting in considerable disability among affected patients. Imaging research in MS has recently evolved to address the issue of visualizing neuroinflammation and changes in myelin content in vivo. [11C]PK11195 PET has showed increased microglial activation in the cortical grey matter (GM) of relapsingremitting (RR) and secondary progressive (SP) MS patients, which correlated with levels of neurological disability [139]. Patients with clinically isolated syndrome showed a global increase of [11C]PK11195 binding in normal-appearing white matter (NAWM), and the binding was higher in subjects who developed lesions that were disseminated in space or MS at 2 years follow-up [140]. [11C]PK11195 PET has been found to be increased in chronic hypointense T1-weighted MRI lesions (black holes) and this has been associated with worse prognosis at 2 years of follow-up in progressive MS [141]. [11C]PK11195 PET was also able to show decreases in microglial activation after 1 year of treatment with glatiramer acetate in RRMS patients [25]. These findings suggest that [11C]PK11195 PET is able to detect diffuse widespread inflammation and chronic active plaques, which are two characteristics associated with progressive disease, and may predict disability progression. These promising studies could help in the future towards better management of MS patients, through monitoring disease progression and testing of anti-inflammatory drugs. Second generation TSPO radioligands such as 11 [ C]DAA1106, [18F]FEDAA1106, [11C]PBR28 and [18F]PBR111 have recently been developed to address the limitations associated with [11C]PK11195 such as low signal to noise ratio [142–144]. Increased [18F]PBR111 binding has been found in MS lesions and in perilesional

white matter (WM) volumes of MS patients compared to healthy controls [144]. Within-subject analysis showed higher [18F]PBR111 binding in WM lesions and perilesional regions compared to the normal WM, which was associated with worse disability scores [144]. These data suggest that TSPO PET with second generation radioligands can be used to assess in vivo inflammatory response in MS and provides further evidence supporting the role of microglial activation in disease progression. PET imaging with the development of new radiolabelled ligands may also allow further applications in MS [145]. For example, PET could be used for the quantitative assessment of myelination, using a family of Congo red derivatives. A recent in vivo PET study has assessed [11C]PiB as a suitable biomarker for imaging myelin in normal nonhuman primates and in two patients with RRMS [146]. [11C]PiB has shown high affinity for CNS myelin in the normal nonhuman primates. In RRMS patients, higher [11C]PiB binding was detected in the normal appearing WM compared to GM structures, and showed reduced uptake in WM lesions compared to normal appearing WM. Interestingly, [11C]PiB uptake in gadolinium-enhancing lesions tends to be higher than in non-enhancing lesions, suggesting a different magnitude of myelin loss between chronically demyelinated lesions and more recent plaques that do not achieve complete demyelination [146]. Imaging remyelination would be very important in MS to monitor the disease evolution and to assess putative remyelinating strategies. MRI provides valuable support in clinical management of MS, but an increment in lesion load on conventional MRI is not necessarily associated with clinical manifestations; thus, nonconventional MRI techniques as biomarkers of MS are increasingly been considered [147]. Currently, new MRI techniques are mostly aimed to increasing the specificity for the type of underlying pathology, to developing improved predictive markers for disease activity and disability, and to studying grey matter pathology [148]. Recently, quantitative MRI techniques have been developed with the prospect of direct assessment of myelination status. Multi-component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) allows quantitative estimation of the myelin water fraction (MWF) in scan times of less than 15 min [149–151]. In primary progressive (PP) MS, RRMS and SPMS lower MWF values were associated with higher disability measures, including cognitive assessments and sensory scores [151]. The morphological correlates of disability in MS have been addressed with several MRI applications. Disability shows correlations with brain T2 lesion load, but correlates less consistently with grey matter atrophy [152]. Disability correlated with lesion load quantified with gradient echo plural contrast imaging in one study [153].

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DTI is an effective means of quantifying parameters of demyelination and axonal loss, and its application in MS has yielded noteworthy results in recent years [154]. MS patients have significantly lower FA and higher MD values in their NAWM and cerebral cortex; these changes are more marked in SPMS than in RRMS patients [155]. DTI indices in the optic radiations have also been suggested to correlate with disability [156]. By contrast, DTI measures obtained by areas around lesions and NAWM have shown no correlation with clinical status [157]. The proton magnetic resonance spectroscopy imaging (1H-MRSI) allows the evaluation of different cerebral metabolites in vivo [157]. A decreased ratio between Nacetylaspartate (NAA) and creatine, suggestive of axonal damage, has been reported in patients with radiologically isolated syndrome [158]. Choline, a marker of membrane phospholipids synthesis and degradation, correlates with phosholipid release during active demyelination and can as well be quantified with 1H-MRSI [159, 160]. Myo-inositol (mI), synthesized in glial cells and associated with gliosis [159], can be also investigated with 1H-MRSI. The mI/ NAA ratio in NAWM has been shown to predict brainvolume loss and clinical disability in patients with various subtypes of MS [161]. Other interesting molecules investigated by 1H-MRSI in the MS setting are glutathione, which is useful for the evaluation of oxidative stress and which has been found to be reduced in patients with SPMS [162]; lipids, used as a putative index of remyelination, have been studied in NAWM of patients with PPMS [160]; and macromolecules, which may represent markers of myelin fragments [160]. Overall, although the use of 1HMRSI is not common because of technical demands [160], the ability to study many different molecules in vivo makes it a very promising tool to investigate the biochemical alterations linked to demyelination.

Conclusions Over the recent years, a significant number of novel or established MRI and PET techniques have been applied to common neurological disorders. These techniques have been extensively used to study the pathophysiology of complex mechanisms and to aid in the diagnosis and management of patients. Some of these techniques, such as novel PET tracers in AD, have gained an established clinical role. The recent literature also discloses very promising role for imaging techniques in the differential diagnosis of different parkinsonian syndromes and in the investigation of the mechanisms underlying MS. Other imaging modalities, such as resting-state fMRI, have a less established clinical role and their contribution to the

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management of patients needs to be systematically evaluated. Acknowledgments There is no funding related to this article. L.R. has been supported by the Edmond J. and Lily Safra Foundation. F.N. has been supported by the Parkinson’s UK. M.P. research has been supported by the Edmond J. Safra Foundation, Michael J. Fox Foundation, Parkinson’s UK, Imanova Ltd, and the National Institute for Health Research Biomedical Research Centre. Conflicts of interest of interest.

The authors declare that they have no conflict

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Recent imaging advances in neurology.

Over the recent years, the application of neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) has ...
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