Magnetic Resonance Imaging Markers Research Articles

Uncovering convolutional neural network decisions for diagnosing multiple sclerosis on conventional MRI using layer-wise relevance propagation.

Machine learning-based imaging diagnostics has recently reached or even surpassed the level of clinical experts in several clinical domains. However, classification decisions of a trained machine learning system are typically non-transparent, a major hindrance for clinical integration, error tracking or knowledge discovery. In this study, we present a transparent deep learning framework relying on 3D convolutional neural networks (CNNs) and layer-wise relevance propagation (LRP) for diagnosing multiple sclerosis (MS), the most widespread autoimmune neuroinflammatory disease. MS is commonly diagnosed utilizing a combination of clinical presentation and conventional magnetic resonance imaging (MRI), specifically the occurrence and presentation of white matter lesions in T2-weighted images. We hypothesized that using LRP in a naive predictive model would enable us to uncover relevant image features that a trained CNN uses for decision-making. Since imaging markers in MS are well-established this would enable us to validate the respective CNN model. First, we pre-trained a CNN on MRI data from the Alzheimer's Disease Neuroimaging Initiative (n = 921), afterwards specializing the CNN to discriminate between MS patients (n = 76) and healthy controls (n = 71). Using LRP, we then produced a heatmap for each subject in the holdout set depicting the voxel-wise relevance for a particular classification decision. The resulting CNN model resulted in a balanced accuracy of 87.04% and an area under the curve of 96.08% in a receiver operating characteristic curve. The subsequent LRP visualization revealed that the CNN model focuses indeed on individual lesions, but also incorporates additional information such as lesion location, non-lesional white matter or gray matter areas such as the thalamus, which are established conventional and advanced MRI markers in MS. We conclude that LRP and the proposed framework have the capability to make diagnostic decisions of CNN models transparent, which could serve to justify classification decisions for clinical review, verify diagnosis-relevant features and potentially gather new disease knowledge.

P.3.24 Structural magnetic resonance imaging markers are associated with Alzheimer's disease pathway-specific polygenic scores

The deficit of cholinergic activity is one of the main findings in Alzheimer’s disease (AD), and is related to the synthesis of acetylcholine, and the hydrolysing enzymes, acetylcholinesterase and butyrylcholinesterase (BuChE). Together with the Apolipoprotein E-ε4 allele (ApoE-ε4), the BuChE-K variant has been proposed to increase AD risk in certain populations. In addition, this polymorphism has been associated with a lower capacity to attenuate β-amyloid aggregation.In the present study we explored the interaction of the BuChE-K variant with its activity in CSF, conventional AD biomarkers and ApoE genotype.217 AD patients and 200 age-matched controls were genotyped for the ApoE and the BuChE-K variant. BuChE activity in CSF, as well as the levels of the CSF-AD biomarkers amyloid-beta 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were determined in 88 of these patients.The results showed no significant differences in the BuChE-K variant distribution between patients and controls. No influence of the BuChE-K variant was seen neither in CSF BuChE activity, nor in the levels of Aβ42, t-tau and p-tau in AD patients. ApoE genotype also did not seem to influence CSF BuChE activity. Interestingly, in AD patients, an association between high CSF BuChE activity and increased levels of CSF Aβ42 was shown, particularly in ApoE-ε4 allele carriers.In our population, the BuChE-K variant does not seem to confer risk for AD or to influence the activity of the enzyme in CSF. However, we demonstrated an association between BuChE activity, ApoE-ε4 genotype and CSF Aβ42 levels, highlighting the importance of assessing BuChE activity as a possible modulator of Aβ load in the brain.

Multiparametric magnetic resonance imaging markers of clinically significant prostate cancer

Authors aimed to assess the correlation between the apparent diffusion coefficient (ADC of the tumor, ADC ratio) and final grade group (GG) after radical prostatectomy (RP), and to determine the threshold values of ADC for detecting clinically significant prostate cancer (PC) with subsequent evaluation in a prospective group. 118 patients with PC were included in the retrospective group. These patients underwent RP from 2012 to 2017 with preoperative 3 Tesla multiparametric MRI (mpMRT) with contrast enhancement in a single center. After analyzing all the MRI studies, the average values of tumor ADC and benign tissue ADC were calculated using the maps of ADC. The prospective part of the study included 60 patients with completed pre-biopsy mpMRI and subsequent RP from January 2018 to March 2019. The prospective part of the study demonstrated the effectiveness of applying the obtained diffusion coefficient thresholds. When used as a criterion for determining clinically significant prostate cancer (GG > 6), threshold value of ADC ratio had sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 84%, 91%, 87%, 94% and 78% respectively.

Intracranial Vessel Wall Lesions on 7T MRI (Magnetic Resonance Imaging).

Background and Purpose- Intracranial vessel wall lesions are a novel imaging marker of intracranial atherosclerosis (ICAS), but data on their occurrence and risk factors are lacking. Our aim was to study the frequency, distribution, and risk factors of intracranial vessel wall lesions on 7T magnetic resonance imaging in patients with a history of vascular disease. Methods- Within the SMART-MR study (Second Manifestations of Arterial Disease-Magnetic Resonance), cross-sectional analyses were performed in 130 patients (68±9 years) with assessable 7T intracranial vessel wall-magnetic resonance imaging data. Associations between vascular risk factors and ICAS burden, defined as the total number of vessel wall lesions, were estimated using linear regression analyses with ICAS burden as the dependent variable, adjusted for age and sex. Results- Ninety-six percent of patients had ≥1 vessel wall lesion. The mean±SD (range) ICAS burden was 8.5±5.7 (0-32) lesions. Significant associations were found between ICAS burden and age ( b=2.0 per +10 years; 95% CI, 0.81- 3.10), systolic blood pressure ( b=0.9 per +10 mm Hg; 95% CI, 0.27-1.42), diabetes mellitus ( b=3.2 for presence of diabetes mellitus; 95% CI, 0.79-5.72), hemoglobin A1c level ( b=1.2 per +1%; 95% CI, 0.19-2.26), apoB (apolipoprotein-B) ( b=4.7 per +1 g/L; 95% CI, 0.07-9.35), and hs-CRP (high-sensitivity C-reactive protein) level ( b=2.7 for hs-CRP >3 mg/L; 95% CI, 0.22-5.11). No significant associations were found with sex, smoking, and other lipid-factors. Conclusions- Vessel wall lesions are a novel and direct magnetic resonance imaging marker of ICAS. In this cohort, 96% of patients had at least 1 lesion on 7T vessel wall-magnetic resonance imaging. More lesions were found with older age, higher systolic blood pressure, diabetes mellitus, and higher levels of hemoglobin A1c, apoB, and hs-CRP.

Waves of Maturation and Senescence in Micro-structural MRI Markers of Human Cortical Myelination over the Lifespan.

Seminal human brain histology work has demonstrated developmental waves of myelination. Here, using a micro-structural magnetic resonance imaging (MRI) marker linked to myelin, we studied fine-grained age differences to deduce waves of growth, stability, and decline of cortical myelination over the life-cycle. In 484 participants, aged 8–85 years, we fitted smooth growth curves to T1- to T2-weighted ratio in each of 360 regions from one of seven cytoarchitectonic classes. From the first derivatives of these generally inverted-U trajectories, we defined three milestones: the age at peak growth; the age at onset of a stable plateau; and the age at the onset of decline. Age at peak growth had a bimodal distribution comprising an early (pre-pubertal) wave of primary sensory and motor cortices and a later (post-pubertal) wave of association, insular and limbic cortices. Most regions reached stability in the 30-s but there was a second wave reaching stability in the 50-s. Age at onset of decline was also bimodal: in some right hemisphere regions, the curve declined from the 60-s, but in other left hemisphere regions, there was no significant decline from the stable plateau. These results are consistent with regionally heterogeneous waves of intracortical myelinogenesis and age-related demyelination.

Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions

Background: Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). Objective: To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. Methods: We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. Results: Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time. Conclusion: We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS.

Toxicity Evaluation of a Novel Magnetic Resonance Imaging Marker, CoCl2-N-Acetylcysteine, in Rats.

C4 (cobalt dichloride-N-acetylcysteine [1% CoCl2:2% NAC]) is a novel magnetic resonance imaging contrast marker that facilitates visualization of implanted radioactive seeds in cancer brachytherapy. We evaluated the toxicity of C4. Rats were assigned to control (0% CoCl2:NAC), low-dose (0.1% CoCl2:2% NAC), reference-dose (C4), and high-dose (10% CoCl2:2% NAC) groups. Agent was injected into the left quadriceps femoris muscle of the rats. Endpoints were organ and body weights, hematology, and serum chemistry and histopathologic changes of tissues at 48 hours and 28 and 63 days after dosing. Student's t tests were used. No abnormalities in clinical signs, terminal body and organ weights, or hematologic and serum chemistry were noted, and no gross or histopathologic lesions of systemic tissue toxicity were found in any treatment group at any time point studied. At the site of injection, concentration-dependent acute responses were observed in all treatment groups at 48 hours after dosing and were recovered by 28 days. No myofiber degeneration or necrosis was observed at 28 or 63 days in any group. In conclusion, a single intramuscular dose of C4 produced no acute or chronic systemic toxicity or inflammation in rats, suggesting that C4 may be toxicologically safe for clinical use in cancer brachytherapy.

Practical Small Vessel Disease Score Relates to Stroke, Dementia, and Death.

Background and Purpose- In the general population, we investigated the association of a recently developed cerebral small vessel disease (CSVD) sum score with stroke, dementia, and mortality. Methods- One thousand six hundred fifty-one stroke-free and nondemented participants (mean age, 73.3 years; 54.5% women) of the population-based Rotterdam Study underwent brain magnetic resonance imaging (1.5T) in 2005-2011 and were followed for stroke, dementia, and mortality until 2016-2017. The CSVD sum score was composed by counting the presence of 4 magnetic resonance imaging markers (white matter hyperintensities, lacunes, cerebral microbleeds, and perivascular spaces; range, 0-4). We determined the association of the CSVD score with risk of stroke, dementia, and mortality using Cox models, adjusting for age, sex, and other Framingham Stroke Risk Profile predictors. Additionally, we assessed mortality as a competing risk for stroke and dementia and calculated absolute risk estimates for all outcomes. Results- During a mean follow-up of 7.2 years, 66 participants developed stroke, 76 developed dementia, and 306 died. The Framingham Stroke Risk Profile-adjusted hazard ratios of 1 point higher sum score were 1.54 (95% CI, 1.16-2.03) for stroke, 1.25 (95% CI, 0.95-1.64) for dementia, and 1.15 (95% CI, 1.01-1.31) for mortality. No significant differences were seen for subdistribution hazard ratios for stroke and dementia. A higher CSVD score yielded higher absolute risk estimates for all outcomes, calculated during 10 years. Conclusions- The CSVD score is a practical measure of global vascular brain injury. A higher sum score on magnetic resonance imaging is associated with higher risk of suffering a stroke, developing dementia, and death.

Lower patient-reported function at 2 years is associated with elevated knee cartilage T1rho and T2 relaxation times at 5 years in young athletes after ACL reconstruction.

The purpose was to test the following hypotheses: (1) magnetic resonance imaging (MRI) markers of early knee cartilage degeneration would be present in the involved limb of young athletes after anterior cruciate ligament reconstruction (ACLR) and (2) poor knee function would be associated with MRI markers of cartilage degeneration. Twenty-five young athletes after primary, unilateral ACLR (mean age, 16.7years) were followed to 5-year post-return-to-sport (RTS) clearance, as a part of a larger, prospective cohort study in young athletes post-ACLR. At 2-year post-RTS, patient-reported knee function was evaluated using the Knee injury and Osteoarthritis Outcome Score (KOOS). At 5-year post-RTS, qualitative MRI sequences (3T) and quantitative T1rho and T2 maps segmented into six regions at the femur and tibia were performed for the involved and uninvolved knee cartilages. Relaxation times were compared between knees using Holm-corrected paired t tests. Linear regression was used to examine the association between KOOS scores at 2years and relaxation times at 5years. Elevated T1rho and T2 relaxation times were observed in the involved knee at the anterior medial femoral condyle compared to the uninvolved knee (p = 0.006, p = 0.024, respectively). Lower KOOS-Pain, KOOS-Symptoms, KOOS-ADL, and KOOS-Sport scores at 2-year post-RTS were associated with higher T1rho or T2 relaxation times in various regions of the involved knee at 5-year post-RTS (all p < 0.05). MRI markers of early cartilage degeneration were identified in the medial compartment of the involved knee in young athletes 5-year post-RTS after ACLR. Lower KOOS scores at 2-year post-RTS were associated with elevated knee cartilage T1rho and T2 relaxation times at 5-year post-RTS. Evaluating patient-reported function over time after ACLR appears to provide insight into future degenerative changes in the knee cartilage matrix.

Haemoglobin, magnetic resonance imaging markers and cognition: a subsample of population-based study

BackgroundLow haemoglobin is highly prevalent among the elderly and has been associated with dementia. However, the mechanisms underlying this association with cognitive dysfunction, either through cerebrovascular disease or neurodegeneration, remain poorly understood. We aimed to examine the association of decreased haemoglobin levels with markers of cerebral small vessel disease (CSVD), neurodegeneration and cognitive impairment in an elderly Asian population.MethodsA total of 796 Chinese, Malay and Indian participants aged 60 years and older from the Epidemiology of Dementia in Singapore study were included in this study. After providing information on demographics, anthropometry and cardiovascular risk factors, participants underwent 3-T brain magnetic resonance imaging (MRI) to measure markers of CSVD, including cerebral microbleeds, cortical cerebral microinfarcts, lacunes, enlarged perivascular spaces and white matter hyperintensities, as well as neurodegenerative markers, including cortical thickness and subcortical structure volumes quantified using FreeSurfer. Cognition was assessed using a detailed neuropsychological assessment. Logistic and linear regression models were constructed, adjusting for age, gender, education, race, body mass index, smoking, hypertension, hyperlipidaemia, diabetes, glomerular filtration rate and other MRI markers, to test the association between haemoglobin levels and the MRI markers and cognition.ResultsDecreased haemoglobin levels were associated with cerebral microbleeds, specifically lobar microbleeds (OR, 1.21; 95% CI, 1.04–1.40; p = 0.015). Decreased haemoglobin levels were also associated with occipital cortical thinning (mean difference, − 0.011; 95% CI, − 0.019, − 0.004; p = 0.003) and smaller accumbens volume (mean difference, − 0.01; 95% CI, − 0.02, 0.00; p = 0.005). A significant association was also observed between decreased haemoglobin levels and poorer global cognitive performance (mean difference, − 0.04; 95% CI, − 0.09, 0.00; p = 0.048). In cognitive domain analysis, associations were again observed between decreased haemoglobin levels and worse performance on attention (mean difference, − 0.05; 95% CI, − 0.10, − 0.01; p = 0.028) and language (mean difference, − 0.06; 95% CI, − 0.12, 0.00; p = 0.048) domains; however, these associations did not survive multiple comparison.ConclusionsDecreased haemoglobin levels were associated with lobar microbleeds, neurodegenerative markers and cognitive dysfunction. Future studies should ascertain whether iron, folate or vitamin B12 supplementation is able to ameliorate the onset and progression of cognitive impairment and dementia associated with low haemoglobin.

The structural MRI markers and cognitive decline in prodromal Alzheimer's disease: a 2-year longitudinal study.

Being clinically diagnosed with a mild cognitive impairment (MCI) due to Alzheimer's disease (AD) is widely studied. Yet, the clinical and structural neuroimaging characteristics for prodromal AD, which are defined as A+T+MCI based on the AT (N) system are still highly desirable. This study evaluates the differences of the cognitive assessments and structural magnetic resonance imaging (MRI) between the early MCI (EMCI) and late MCI (LMCI) participants based on the AT (N) system. The potential clinical value of the structural MRI as a predictor of cognitive decline during follow-up in prodromal AD is further investigated. A total of 406 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were chosen and dichotomized into EMCI and LMCI groups according to the Second Edition (Logical Memory II) Wechsler Memory Scale. Multiple markers' data was collected, including age, sex, years of education, ApoE4 status, cerebrospinal fluid (CSF) biomarkers, standardized uptake values ratios (SUVR) means of florbetapir-PET-AV45, cognitive measures, and structural MRI. We chose 197 A+T+MCI participants (prodromal AD) with positive biomarkers of Aβ plaques (labeled "A") and fibrillar tau (labeled "T"). We diagnosed Aβ plaques positive by the SUVR means of florbetapir-PET-AV45 (cut-off >1.1) and fibrillar tau positive by CSF phosphorylated-tau at threonine 181 (p-tau) (cut-off >23 pg/mL). The differences of cognitive assessments and regions of interest (ROIs) defined on the MRI template between EMCI and LMCI were compared. Furthermore, the potential clinical utility of the MRI as the predictor of cognitive decline in prodromal AD was evaluated by investigating the relationship between baseline MRI markers and cognition decline at the follow-up period, through a linear regression model. The LMCI participants had a significantly more amyloid burden and CSF levels of total t-tau than the EMCI participants. The LMCI participants scored a lower result than the EMCI group in the global cognition scales and subscales which included tests for memory, delayed recall memory, executive function, language, attention and visuospatial skills. The cognition levels declined faster in the LMCI participants during the 12- and 24-month follow-up. There were significant differences in ROIs on the structural MRI between the two groups, including a bilateral entorhinal, a bilateral hippocampus, a bilateral amygdala, a bilateral lateral ventricle and cingulate, a corpus callosum, and a left temporal. The thickness average of the left entorhinal, the left middle temporal, the left superior temporal, and the right isthmus cingulate was a main contributor to the decreased global cognition levels. The thickness average of the left superior temporal and bilateral entorhinal played a key role in the memory domain decline. The thickness average of the left middle temporal, and the right isthmus cingulate was significantly associated with an executive function decline. Based on the AT (N) system, surely, both the EMCI and LMCI diagnoses presented significant differences in multiple cognition domains. Signature ROIs from the structural MRI tests had correlated a cognitive decline, and could act as one potential predictive marker.

C-Reactive Protein, Plasma Amyloid-β Levels, and Their Interaction With Magnetic Resonance Imaging Markers

Background and Purpose- Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers. Methods- We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1-38, Aβ1-40, and Aβ1-42 were assessed using ELISA. Results- Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00-0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19-2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00-1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00-1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1-42, a strong association was observed between CRP and lacunar ( P interaction, 0.004), enlarged perivascular spaces ( P interaction, 0.002), and microbleed counts ( P interaction, <0.001). Similarly, among persons in higher tertile of Aβ1-38, a strong association was observed between CRP and microbleed counts ( P interaction, 0.004). Conclusions- Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.

Neuroimaging Determinants of Poststroke Cognitive Performance.

Background and Purpose- We aimed to define the neuroimaging determinants of poststroke cognitive performance and their relative contributions among a spectrum of magnetic resonance imaging markers, including lesion burden and strategic locations. Methods- We prospectively included patients with stroke from the GRECogVASC study (Groupe de Réflexion pour l'Évaluation Cognitive Vasculaire) who underwent 3-T magnetic resonance imaging and a comprehensive standardized battery of neuropsychological tests 6 months after the index event. An optimized global cognitive score and neuroimaging markers, including stroke characteristics, cerebral atrophy markers, and small vessel diseases markers, were assessed. Location of strategic strokes was determined using a specifically designed method taking into account stroke size and cerebral atrophy. A stepwise multivariable linear regression model was used to identify magnetic resonance imaging determinants of cognitive performance. Results- Data were available for 356 patients (mean age: 63.67±10.6 years; 326 [91.6%] of the patients had experienced an ischemic stroke). Six months poststroke, 50.8% of patients presented with a neurocognitive disorder. Strategic strokes (right corticospinal tract, left antero-middle thalamus, left arcuate fasciculus, left middle frontal gyrus, and left postero-inferior cerebellum; R2=0.225; P=0.0001), medial temporal lobe atrophy ( R2=0.077; P=0.0001), total brain tissue volume ( R2=0.028; P=0.004), and stroke volume ( R2=0.013; P=0.005) were independent determinants of cognitive performance. Strategic strokes accounted for the largest proportion of the variance in the cognitive score (22.5%). The white matter hyperintensity burden, brain microbleeds, and dilated perivascular spaces were not independent determinants. Conclusions- Optimized global cognitive score and combined approach of both quantitative measures related to structure loss and qualitative measures related to the presence of strategic lesion are required to improve the determination of structure-function relationship of cognitive performance after stroke.

Secondary prevention of Alzheimer\u2019s dementia: neuroimaging contributions

BackgroundIn Alzheimer’s disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations.Main bodyAmyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. 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.ConclusionWe propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI.

Identification of Cortical and Subcortical Correlates of Cognitive Performance in Multiple Sclerosis Using Voxel-Based Morphometry.

Objective: Cognitive impairment is an important feature in multiple sclerosis (MS) and has been associated to several Magnetic Resonance Imaging (MRI) markers, but especially brain atrophy. However, the relationship between specific neuropsychological tests examining several cognitive functions and brain volumes has been little explored. Furthermore, because MS frequently damage subcortical regions, it may be an interesting model to examine the role of subcortical areas in cognitive functioning. Our aim was to identify correlations between specific brain regions and performance in neuropsychological tests evaluating different cognitive functions in a large series of patients with MS.Methods: A total of 375 patients were evaluated with a comprehensive neuropsychological battery and with MRI. Voxel-based morphometry was conducted to analyse the correlation between cognitive performance and gray matter damage, using Statistical Parametric Mapping with the toolboxes VBM8 and Lesion Segmentation Tool.Results: The following correlations were found: Corsi block-tapping test with right insula; Trail Making Test with caudate nucleus, thalamus, and several cortical regions including the posterior cingulate and inferior frontal gyrus; Symbol Digit Modalities Test with caudate nucleus, thalamus, posterior cingulate, several frontal regions, insula, and cerebellum; Stroop Color and Word Test with caudate nucleus and putamen; Free and Cued Selective Reminding Test and Rey-Osterrieth Complex Figure with thalamus, precuneus, and parahippocampal gyrus; Boston Naming Test with thalamus, caudate nucleus, and hippocampus; semantic verbal fluency with thalamus and phonological verbal fluency with caudate nucleus; and Tower of London test with frontal lobe, caudate nucleus, and posterior cingulate.Conclusion: Our study provides valuable data on the cortical and subcortical basis of cognitive function in MS. Neuropsychological tests mainly assessing attention and executive function showed a stronger association with caudate volume, while tests primarily evaluating memory were more strongly correlated with the thalamus. Other relevant regions were the posterior cingulate/precuneus, which were associated with attentional tasks, and several frontal regions, which were found to be correlated with planning and higher order executive functioning. Furthermore, our study supports the brain vertical organization of cognitive functioning, with the participation of the cortex, thalamus, basal ganglia, and cerebellum.

Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury

Covert vascular brain injury (VBI) is highly prevalent in community-dwelling older persons, but its clinical and therapeutic implications are debated. To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia. We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death. Data were taken from prospective, longitudinal cohort studies including 50 or more adults. We performed inverse variance-weighted meta-analyses with random effects and z score-based meta-analyses for WMH burden. The significance threshold was P < .003 (17 independent tests). We complied with the Meta-analyses of Observational Studies in Epidemiology guidelines. Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death. Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12; P < .001), ischemic stroke (HR, 2.39; 95% CI, 1.65-3.47; P < .001), intracerebral hemorrhage (HR, 3.17; 95% CI, 1.54-6.52; P = .002), dementia (HR, 1.84; 95% CI, 1.40-2.43; P < .001), Alzheimer disease (HR, 1.50; 95% CI, 1.22-1.84; P < .001), and death (HR, 2.00; 95% CI, 1.69-2.36; P < .001). Presence of MRI-defined BIs was associated with higher risk of incident stroke (HR, 2.38; 95% CI, 1.87-3.04; P < .001), ischemic stroke (HR, 2.18; 95% CI, 1.67-2.85; P < .001), intracerebral hemorrhage (HR, 3.81; 95% CI, 1.75-8.27; P < .001), and death (HR, 1.64; 95% CI, 1.40-1.91; P < .001). Presence of CMBs was associated with increased risk of stroke (HR, 1.98; 95% CI, 1.55-2.53; P < .001), ischemic stroke (HR, 1.92; 95% CI, 1.40-2.63; P < .001), intracerebral hemorrhage (HR, 3.82; 95% CI, 2.15-6.80; P < .001), and death (HR, 1.53; 95% CI, 1.31-1.80; P < .001). Data on PVS were limited and insufficient to conduct meta-analyses but suggested an association of high PVS burden with increased risk of stroke, dementia, and death; this requires confirmation. We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit-risk ratio for available prevention strategies in individuals with covert VBI.

Longitudinal Progression Markers of Parkinson's Disease: Current View on Structural Imaging.

Advances in neuroimaging techniques pave a rich avenue for in vivo progression biomarkers, which can objectively and noninvasively assess the long-term dynamic alterations in the brain of Parkinson's disease (PD) patients. This article reviews recent progress in structural magnetic resonance imaging (MRI) tools to track disease progression in PD, and discusses specific criteria a neuroimaging tool needs to meet to be a progression biomarker of PD and the potential applications of these techniques in PD based on current evidence. Recent longitudinal studies showed that quantitative structural MRI markers derived from T1-weighted, diffusion-weighted, neuromelanin-sensitive, and iron-sensitive imaging have the potential to track disease progression in PD. However, validation of these progression biomarkers is only beginning, and more work is required for multisite validation, the sample size for use in a clinical trial, and drug-responsiveness of most of these biomarkers. At present, the most clinical trial-ready biomarker is free-water diffusion imaging of the substantia nigra and seems well established to be used in disease-modifying studies in PD. A variety of structural imaging biomarkers are promising candidates to be progression biomarkers in PD. Further studies are needed to elucidate the sensitivity, reliability, sample size, and effect of confounding factors of these progression biomarkers.

Radiomic Features of Hippocampal Subregions in Alzheimer's Disease and Amnestic Mild Cognitive Impairment.

Alzheimer’s disease (AD) is characterized by progressive dementia, especially in episodic memory, and amnestic mild cognitive impairment (aMCI) is associated with a high risk of developing AD. Hippocampal atrophy/shape changes are believed to be the most robust magnetic resonance imaging (MRI) markers for AD and aMCI. Radiomics, a method of texture analysis, can quantitatively examine a large set of features and has previously been successfully applied to evaluate imaging biomarkers for AD. To test whether radiomic features in the hippocampus can be employed for early classification of AD and aMCI, 1692 features from the caudal and head parts of the bilateral hippocampus were extracted from 38 AD patients, 33 aMCI patients and 45 normal controls (NCs). One way analysis of variance (ANOVA) showed that 111 features exhibited statistically significant group differences (P < 0.01, Bonferroni corrected). Among these features, 98 were significantly correlated with Mini-Mental State Examination (MMSE) scores in AD and aMCI subjects (P < 0.01). The support vector machine (SVM) model demonstrated that radiomic features allowed us to distinguish AD from NC with an accuracy of 86.75% (specificity = 88.89% and sensitivity = 84.21%) and an area under curve (AUC) of 0.93. In conclusion, these findings provide evidence showing that radiomic features are beneficial in detecting early cognitive decline, and SVM classification analysis provides encouraging evidence for using hippocampal radiomic features as a potential biomarker for clinical applications in AD.

Circulating Vascular Growth Factors and Magnetic Resonance Imaging Markers of Small Vessel Disease and Atrophy in Middle-Aged Adults.

Background and Purpose- Little is known about associations between vascular growth factors and magnetic resonance imaging (MRI) markers in midlife. We investigated the association of serum VEGF (vascular endothelial growth factor), Ang2 (angiopoietin 2), sTie2 (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2), and HGF (hepatocyte growth factor) concentrations with MRI markers of brain aging in middle-aged adults. Methods- We evaluated 1853 participants (mean age, 46±9 years; 46% men) from the Framingham Heart Study. Serum growth factor concentrations were measured using standardized immunoassays. Outcomes included total brain, cortical and subcortical gray matter, white matter, cerebrospinal fluid, and white matter hyperintensity volumes derived from MRI; as well as fractional anisotropy in white matter tracts from diffusion tensor imaging. We related VEGF, Ang2, sTie2, and HGF to MRI measures using multivariable regression models adjusting for vascular risk factors. We tested for interactions with APOE (apolipoprotein E) genotype and CRP (C-reactive protein). Results were corrected for multiple comparisons. Results- Higher sTie2 was associated with smaller total brain (estimate by SD unit±SE=-0.08±0.02, P=0.002) and larger white matter hyperintensity (0.08±0.02, P=0.002) volumes. Furthermore, higher Ang2 (0.06±0.02, P=0.049) and HGF (0.09±0.02, P=0.001) were associated with larger cerebrospinal fluid volumes. Finally, higher Ang2 was associated with decreased fractional anisotropy, in APOE-ε4 carriers only. Conclusions- Vascular growth factors are associated with early MRI markers of small vessel disease and neurodegeneration in middle-aged adults.

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles