𝗣𝗗𝗙 | Against a background of an ever-increasing number of patients, new management options, and novel imaging modalities, neuroimaging is playing an . Structural neuroimaging is a fundamental part of a routine dementia assessment to rule .. vatepatienttariffpdf (accessed 16 March ). guidelines. • Brain imaging cannot diagnose dementia but can suggest the most likely underlying neuropathology in a demented patient. • Alzheimer's disease is .
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Although the diagnosis of dementia still is primarily based on clinical criteria, neuroimaging is playing an increasingly important role. This is in. Neuroimaging, CSF, and genetic biomarkers in Alzheimer's Disease Research Center & Frontotemporal Dementia Unit . us/amyvid-‐portal7.info Positive. A. B. Alzheimer's disease, dementia with Lewy bodies, vascular dementia and frontotemporal lobar degeneration account for the majority. Although detailed clinical assessment forms the basis of evaluating a patient with cognitive impairment, structural and functional imaging techniques.
Free shipping for individuals worldwide Usually dispatched within 3 to 5 business days. Rent the eBook Rental duration: 1 or 6 month low-cost access online reader with highlighting and note-making option can be used across all devices About this book Against a background of an ever-increasing number of patients, new management options, and novel imaging modalities, neuroimaging is playing an increasingly important role in the diagnosis of dementia. This up-to-date, superbly illustrated book aims to provide a practical guide to the effective use of neuroimaging in the patient with cognitive decline. It sets out the key clinical and imaging features of the wide range of causes of dementia and directs the reader from clinical presentation to neuroimaging and on to an accurate diagnosis whenever possible. The imaging findings in normal ageing are then discussed, followed by a series of chapters that carefully present and analyze the key imaging findings in patients with dementias. A structured path of analysis follows the main presenting feature: disorders associated with primary gray matter loss, with white matter changes, with brain swelling, etc.
The target sites in FTD are the ventromedial frontal cortex, the posterior orbital frontal regions, the insula, and the anterior cingulate cortex, which differentiates this illness from AD as these areas are relatively spared in the latter disease, and atrophy in the frontal lobes is often in the lateral frontal lobe [ 10 ] FIG. Patients with the semantic variant of FTD have relative preservation of frontal lobe volumes but marked loss of volumes in the temporal lobes, in particular the neocortex in the temporal pole FIG.
Top row: Sagittal view of a patient with the behavioral variant of frontotemporal dementia bvFTD ; note the anterior atrophy with relative sparing of the parietal and occipital regions. The anterior corpus callosum is also thinned compared to posterior.
Coronal view of patient with semantic dementia showing significant left temporal atrophy. Coronal view of patient with nonfluent variant of FTD showing significant left insular atrophy. Bottom row: VBM study showing that in patients with bvFTD, frontal lobe volumes are reduced compared with age-matched controls.
There is volume loss in the ventromedial frontal cortex, the posterior orbital frontal regions, the insula, and the anterior cingulate cortex. Volumetric studies aimed at gaining an understanding of brain—behavior relationships have demonstrated relationships between focal changes in brain volume and cognitive or behavioral changes in dementia.
Several studies have found correlations between hippocampal volumes and episodic memory performance in AD, consistent with the long-established role for this structure in memory consolidation [ 14 , 15 ]. Studies on focal degeneration in non-AD dementias, particularly FTD, have yielded findings that help identify the anatomical basis of language and word access [ 16 ] and increase our understanding of facial expressions of emotion [ 12 ] and empathy [ 17 ].
Parkinsonian dementias cause damage in different networks within the brain and are also associated with specific patterns of regional volume loss. Characteristic of progressive supranuclear palsy—although not diagnostic of this condition— are third ventricle dilatation and midbrain atrophy with shortening of the anteroposterior length of the midbrain.
This contrasts with corticobasal syndrome, for which frontally predominant atrophy is more typical [ 18 ]. Dementia with Lewy bodies DLB is associated with diffuse atrophy, and no established pattern is characteristic on structural MR images.
Some forms of spinocerebellar atrophy are associated with cognitive impairment and display both cerebellar and cerebral atrophy along with caudate and putamen atrophy in some variants [ 19 ]. The hippocampus and its subfields cannot be well visualized using most clinical or research scanners, which are 1. The introduction of 7T MRI, currently only used in research, holds promise for better visualization of the macrostructures of subcortical structures, including the hippocampus and basal ganglia.
Postmortem studies have shown that the CA1 apical neuropil is an early target of AD pathology [ 21 ]. Neurofibrillary tangles appear in the entorhinal cortex first, but the perforant pathway axons project from the entorhinal cortex to the outer molecular layer of the dentate gyrus and the distal apical dendrites of CA1 neurons in the stratum lacunosum-moleculare [ 22 , 23 ].
These two neuropil areas of the hippocampus are among the next sites for tau pathology to appear, but as clinical signs of AD become more pronounced, the varicose, tau-filled CA1 dendrites in the stratum lacunosum-moleculare disappear, possibly corresponding to the thinning of the CA1—SRLM observed in vivo in this study and in prior postmortem studies [ 24 , 25 ].
Cross-section through the hippocampus at the level of the red nucleus in a normal control, obtained using a 7T gradient-recalled echo sequence. Image has been reproduced courtesy of Dr. Geoffrey A. MRI of vascular damage Hyperintensity, or increased bright signal, on T2—weighted and fluid-attenuated inversion recovery FLAIR images is associated with cerebral pathology characterized by edema and gliosis. The results of a quantitative MRI study in non-demented elderly subjects suggested that this subcortical injury impacts brain function and correlates with frontal executive impairment [ 27 ].
A Axial section through fluid-attentuated inversion recovery image from a patient with vascular dementia, showing multiple patchy areas of high signal in periventricular white matter.
B Coronal gradient echo MR image showing multiple microhemorrhages. Amyloid angiopathy, unlike hypertension-related lesions, is usually associated with microhemorrhages in the cortico—subcortical junctions of the frontomesial, fronto-orbital, and parietal regions [ 29 ].
Many rapidly progressive dementias can cause leukoencephalopathy, including progressive multifocal leukoencephalopathy and leukodystrophies, limbic encephalitis, infections and toxic conditions, or mixed gray and WM involvement, such as mitochondrial diseases and intravascular lymphoma [ 30 ]. MRI with contrast should be used in the evaluation of most rapidly progressing dementias. Diffusion-weighted imaging and diffusion-tensor imaging Diffusion-weighted imaging DWI is based on the analysis of the random motion of water molecules in the brain and is an integral part to any assessment of acute stroke victims, as it shows all acute injury extremely well.
Variant CJD is often associated with high signals in the pulvinar and dorsomedial thalamic region [ 32 ]. Axial diffusion-weighted imaging showing cortical ribboning, left more than right, in a patient with Creutzfeldt—Jakob disease.
Diffusion tensor imaging DTI , is a novel MRI technique that enables the integrity of WM tracts to be better evaluated, revealing injury that may not be apparent with other imaging techniques. Diffusion of water is anisotropic directionally dependent in WM fiber tracts because axons and myelin sheaths act as barriers; consequently, in axons, the diffusion of water diffusivity is significantly greater along the axis of those fibers, thereby providing a tensor measurement [ 33 ]. Fractional anisotropy FA is a measure of the degree of anisotropy of a diffusion process and ranges from zero, when diffusion is isotropic i.
FA can therefore provide information on the orientation and integrity of fibers. Until recently, the focus of research in neurodegenerative disease was restricted to the gray matter. However, it has become evident that although there is significant gray matter pathology in neurodegenerative diseases and particularly in AD , WM pathology is also present in AD, specifically in temporal lobe and posterior cerebral WM and the corpus callosum [ 34 ].
Reduced FA was recently identified in the portion of the cingulum bundle connecting the hippocampus to the posterior cingulate region in patients with MCI and AD compared with controls [ 35 ]. DTI may also be useful for differentiating amongst the different dementias. One recent study reported decreased FA in the parietal lobes of patients with DLB compared to those with AD, which is in keeping with metabolic studies and the prominent visuospatial difficulties often seen in these patients [ 37 ].
Another recent study compared AD and FTD and found that patients with FTD had reduced FA in frontal and temporal regions, including the anterior corpus callosum, bilateral anterior, and descending cingulum Cg tracts, and in the uncinate UNC fasciculus compared to controls, while patients with AD had reduced FA in the parietal, temporal, and frontal regions, including the left anterior and posterior Cg tracts, bilateral descending Cg tracts, and left UNC fasciculus [ 38 ].
This study highlights the fact that the WM pathology is focal and that it may play a more important role in the pathophysiology of FTD than in that of AD. The different syndromes in FTD have a predilection for different tracts.
Studies have also evaluated the contribution of WM injury to the cognitive and behavioral changes observed in the different dementias [ 40 , 41 ]. Diffusion tensor imaging-derived tracts in normal controls. Sebastiano Galantucci. MR spectroscopy and biochemical information In vivo proton MR spectroscopy 1H MRS allows the noninvasive evaluation of brain biochemistry by measuring the levels of specific metabolites, including N-acetylaspartate NAA , choline, creatine, lactate, myoinositol, and glutamate.
NAA is thought to be a marker of neuronal integrity, and many studies have reported on NAA content in patients with dementia.
NAA is consistently reported as being lower in the parietal gray matter and hippocampus of patients with AD than in cognitively normal elderly subjects [ 42 ]. In vascular dementia, the greatest deficits occur in the frontal and parietal cortex [ 43 ].
Functional activation using MRI fMRI is based on the principle that increased neuronal activity is associated with a local hemodynamic response involving an increase in both cerebral blood flow and blood volume.
The increase in blood flow, however, is greater than is necessary for oxygen delivery to match increased consumption, so the ratio of deoxy-to-oxyhemoglobin is altered. Deoxyhemoglobin is paramagnetic and distorts an applied static magnetic field, and since magnetic field inhomogeneities are found around blood vessels, their magnitude increases with the amount of paramagnetic deoxyhemoglobin [ 47 ]. A consequence of this increase in blood flow above that required for the increased tissue demands in response to neuronal activation is that the oxygen extraction fraction decreases.
The lower ratio of deoxy-to-oxyhemoglobin in draining blood is associated with a small increase in MRI signal, and this is the basis of blood—oxygen-level-dependent contrast fMRI. An fMRI study of memory showed decreased regional function in the medial temporal lobe in patients with AD [ 48 ] and in elderly patients with isolated memory decline.
Rombouts et al. These researchers found that in FTD, brain activation in the frontal and parietal cortex was significantly decreased. Frontal regions in patients with FTD showed less of a linear activation increase with working memory load than did these regions in patients with AD.
The FTD group displayed a stronger response in the cerebellum, leading the authors to postulate that this might be a compensatory mechanism. A recent study on a visual motion processing task also showed increased temporal lobe activation in DLB patients compared with AD patients [ 50 ].
Since the significance of increased activation is still only incompletely understood, the role of fMRI in the diagnosis or monitoring of patients with dementia remains unclear. Resting state fMRI Resting-state fMRI examines spatial synchronization of intrinsic fluctuations in blood—oxygen-level-dependent signals arising from neuronal and synaptic activity that is observed independent of overt cognitive information processing.
Resting-state fMRI has been used to elucidate coherent large-scale brain networks subserving vision, audition, language, and attention, and a frontal opercular network that has been related to stimulus salience [ 51 , 52 , 53 ].
One of the resting-state networks, referred to as the default mode network, involves a set of regions that routinely decrease their activity during attention-demanding tasks [ 54 , 55 ].
The default mode network, which includes the posterior cingulate, inferior parietal, inferolateral temporal, ventral anterior cingulate, and hippocampal regions, has received considerable attention in AD and has been shown to have decreased activity in AD and MCI.
Resting-state data provide a means of evaluating and following patients who may be too impaired to perform cognitive tasks, and so will likely become increasingly more routine in both research and clinical settings [ 56 ]. The ideal test would allow for disease to be detected in the presymptomatic stage, and thus for treatment, if available, to be initiated before there is evidence of damage.
In both techniques, various chemical compounds can be used to measure a variety of physiologic parameters in the brain. These techniques can reveal metabolic abnormalities in the structurally normal brain. Very early metabolic deficits occur in AD and MCI in the medial portion of the parietal cortex, in the posterior cingulate or retrosplenial region [ 57 ].
It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement.
Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging MRI , providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion.
Atrophy rates either hippocampal or whole brain , which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification.
Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities ARIA. Tau PET to measure neurofibrillary tangle burden is currently under development.
Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation.
To date, treatments have only been approved for the dementia stage of the disease and provide modest symptomatic benefit but no slowing of progression. A global research priority is to find therapies to prevent or delay symptom onset and functional decline [ 6 ], and a number of candidate agents have shown promise in cell or animal models.
Despite this, clinical trials of potential disease-modifying treatments have proven unsuccessful thus far.
This may be partly due to limitations of the treatments e. However, the failures could also reflect inappropriate trial populations. Typically, trials have recruited patients with mild to moderate dementia in whom the disease process may be too advanced to be amenable to treatment. An alternative approach is to treat subjects at risk of AD dementia, which is the aim of secondary prevention—preventing neurodegeneration, cognitive decline, and dementia [ 7 , 8 ].
Mild cognitive impairment MCI is used to denote an intermediate stage between normal cognition and dementia in which subjects have objective cognitive impairment in the absence of functional disability interfering with daily activities. Non-demented subjects with evidence of amyloid pathology, i.
Designing trials for subjects in pre-dementia stages of AD is greatly facilitated by the ability to identify subjects at increased risk of cognitive decline and progression to dementia. In the earliest stage, neuropsychological testing to detect subtle cognitive abnormalities in the absence of obvious symptoms has some predictive value [ 15 ], but biomarkers that are sensitive to underlying pathological change could further increase prognostic accuracy.
Ideally, early-stage biomarkers should predict risk and likely timing of cognitive decline and progression to dementia in a reliable, non-invasive, and cost-effective manner. Secondly, trials in non-demented subjects would benefit from biomarkers that can monitor treatment effects and should thus reflect disease progression, be sensitive to detect pathologically significant changes over time and in response to treatment, and be highly reproducible and reliable in a multi-centre setting.
Neuroimaging techniques have developed rapidly over the past decade and they currently offer a comprehensive armamentarium that can be employed to address this unmet need. Over and above structural neuroimaging markers that are widely available and used to support AD diagnosis at the dementia stage, advances in imaging techniques allow the detection and quantification of molecular, functional, and structural brain changes that precede gross atrophy.
In this paper, we discuss the use of neuroimaging markers in subject selection for inclusion or stratification in secondary prevention trials, their potential to serve as outcome markers in trials, and for monitoring trial safety.
The overall aim is to devise a neuroimaging strategy that will maximise the information required to enrol and monitor secondary prevention trials in AD including progression from MCI to dementia. To identify potential imaging markers, a comprehensive review of the existing literature was performed. Based on the evidence from the literature and the personal experience of the authors, recommendations are centred around three domains: 1 imaging markers for subject selection and stratification; 2 imaging markers with potential to be used as outcome measures in clinical trials; and 3 imaging markers for monitoring trial safety.
The utility of longitudinal imaging as a run-in for clinical trials, identification of exclusion criteria, and vascular comorbidity were also taken into account. Methods Neuroimaging modalities: from molecular changes to structural damage The past two decades have seen major advances in neuroimaging. Different imaging modalities are now able to track different aspects of the hypothesised pathological cascade of events in AD in vivo [ 3 ] Box 1, Figs. Positron emission tomography PET with amyloid-specific tracers, and more recently also tau-binding ligands, can visualise and quantify molecular pathology at an early stage.