Classification of Skull Shape Deformities Related to Craniosynostosis on 3D Photogrammetry.

Implementation of the Utrecht Cranial Shape Quantificator (UCSQ) classification method on 3D photogrammetry in patients with different types of craniosynostosis is the aim of the present study. Five children (age <1 year) of every group of the common craniosynostoses (scaphocephaly, brachycephaly, trigonocephaly, right-sided and left-sided anterior plagiocephaly) were randomly included. The program 3-Matic (v13.0) was used to import and analyze the included 3dMD photos. Three external landmarks were placed. Using the landmarks, a base plane was created, as well as a plane 4 cm superior to the base plane. Using UCSQ, we created sinusoid curves of the patients, the resulting curves were analyzed and values were extracted for calculations. Results per patient were run through a diagnostic flowchart in order to determine correctness of the flowchart when using 3D photogrammetry. Each of the patients (n=25) of the different craniosynostosis subgroups is diagnosed correctly based on the different steps in the flowchart. This study proposes and implements a diagnostic approach of craniosynostosis based on 3D photogrammetry. By using a diagnostic flowchart based on specific characteristics for every type of craniosynostosis related to specific skull deformities, diagnosis can be established. All variables are expressed in number and are therefore objective.

UCSQ Method Applied on 3D Photogrammetry: Non-Invasive Objective Differentiation Between Synostotic and Positional Plagiocephaly.

OBJECTIVE: Objective differentiation between unilateral coronal synostosis (UCS) and positional posterior plagiocephaly (PPP) based on 3D photogrammetry according to Utrecht Cranial Shape Quantificator (UCSQ). DESIGN: Retrospective study. SETTING: Primary craniofacial center. PATIENTS, PARTICIPANTS: Thirty-two unoperated patients (17 UCS; 15 PPP) (age < 1 year). INTERVENTIONS: Extraction of variables from sinusoid curves derived using UCSQ: asymmetry ratio forehead and occiput peak, ratio of gradient forehead and occiput peak, location forehead and occiput peak. MAIN OUTCOME MEASURE(S): Variables, derived using 3D photogrammetry, were analyzed for differentiation between UCS and PPP. RESULTS: Frontal peak was shifted to the right side of the head in left-sided UCS (mean x-value 207 [192-220]), and right-sided PPP (mean x-value 210 [200-216]), and to the left in right-sided UCS (mean x-value 161 [156-166]), and left-sided PPP (mean x-value 150 [144-154]). Occipital peak was significantly shifted to the right side of the head in left-sided PPP (mean x-value 338 [336-340]) and to the left in right-sided PPP (mean x-value 23 [14-32]). Mean x-value of occipital peak was 9 (354-30) in left- and 2 (350-12) in right-sided UCS. Calculated ratio of gradient of the frontal peak is, in combination with the calculated asymmetry ratio of the frontal peak, a distinctive finding. CONCLUSIONS: UCSQ objectively captures shape of synostotic and positional plagiocephaly using 3D photogrammetry, we therefore developed a suitable method to objectively differentiate UCS from PPP using radiation-free methods.

Diabetes and hypertension are related to amyloid-beta burden in the population-based Rotterdam Study.

Higher vascular disease burden increases the likelihood of developing dementia, including Alzheimer's disease. Better understanding the association between vascular risk factors and Alzheimer's disease pathology at the predementia stage is critical for developing effective strategies to delay cognitive decline. In this work, we estimated the impact of six vascular risk factors on the presence and severity of in vivo measured brain amyloid-beta (Aß) plaques in participants from the population-based Rotterdam Study. Vascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, physical inactivity and smoking) were assessed 13 (2004-2008) and 7 years (2009-2014) prior to 18F-florbetaben PET (2018-2021) in 635 dementia-free participants. Vascular risk factors were associated with binary amyloid PET status or continuous PET readouts (standard uptake value ratios, SUVrs) using logistic and linear regression models, respectively, adjusted for age, sex, education, APOE4 risk allele count and time between vascular risk and PET assessment. Participants' mean age at time of amyloid PET was 69 years (range: 60-90), 325 (51.2%) were women and 190 (29.9%) carried at least one APOE4 risk allele. The adjusted prevalence estimates of an amyloid-positive PET status markedly increased with age [12.8% (95% CI 11.6; 14) in 60-69 years versus 35% (36; 40.8) in 80-89 years age groups] and APOE4 allele count [9.7% (8.8; 10.6) in non-carriers versus 38.4% (36; 40.8) to 60.4% (54; 66.8) in carriers of one or two risk allele(s)]. Diabetes 7 years prior to PET assessment was associated with a higher risk of a positive amyloid status [odds ratio (95% CI) = 3.68 (1.76; 7.61), P < 0.001] and higher standard uptake value ratios, indicating more severe Aß pathology [standardized beta = 0.40 (0.17; 0.64), P = 0.001]. Hypertension was associated with higher SUVr values in APOE4 carriers (mean SUVr difference of 0.09), but not in non-carriers (mean SUVr difference 0.02; P = 0.005). In contrast, hypercholesterolaemia was related to lower SUVr values in APOE4 carriers (mean SUVr difference -0.06), but not in non-carriers (mean SUVr difference 0.02). Obesity, physical inactivity and smoking were not related to amyloid PET measures. The current findings suggest a contribution of diabetes, hypertension and hypercholesterolaemia to the pathophysiology of Alzheimer's disease in a general population of older non-demented adults. As these conditions respond well to lifestyle modification and drug treatment, further research should focus on the preventative effect of early risk management on the development of Alzheimer's disease neuropathology.

Cerebral cortex maldevelopment in syndromic craniosynostosis.

AIM: To assess the relationship of surface area of the cerebral cortex to intracranial volume (ICV) in syndromic craniosynostosis. METHOD: Records of 140 patients (64 males, 76 females; mean age 8y 6mo [SD 5y 6mo], range 1y 2mo-24y 2mo) with syndromic craniosynostosis were reviewed to include clinical and imaging data. Two hundred and three total magnetic resonance imaging (MRI) scans were evaluated in this study (148 patients with fibroblast growth factor receptor [FGFR], 19 patients with TWIST1, and 36 controls). MRIs were processed via FreeSurfer pipeline to determine total ICV and cortical surface area (CSA). Scaling coefficients were calculated from log-transformed data via mixed regression to account for multiple measurements, sex, syndrome, and age. Educational outcomes were reported by syndrome. RESULTS: Mean ICV was greater in patients with FGFR (1519cm3 , SD 269cm3 , p=0.016) than in patients with TWIST1 (1304cm3 , SD 145cm3 ) or controls (1405cm3 , SD 158cm3 ). CSA was related to ICV by a scaling law with an exponent of 0.68 (95% confidence interval [CI] 0.61-0.76) in patients with FGFR compared to 0.81 (95% CI 0.50-1.12) in patients with TWIST1 and 0.77 (95% CI 0.61-0.93) in controls. Lobar analysis revealed reduced scaling in the parietal (0.50, 95% CI 0.42-0.59) and occipital (0.67, 95% CI 0.54-0.80) lobes of patients with FGFR compared with controls. Modified learning environments were needed more often in patients with FGFR. INTERPRETATION: Despite adequate ICV in FGFR-mediated craniosynostosis, CSA development is reduced, indicating maldevelopment, particularly in parietal and occipital lobes. Modified education is also more common in patients with FGFR.

Low plasma ergothioneine levels are associated with neurodegeneration and cerebrovascular disease in dementia.

Ergothioneine (ET) is a dietary amino-thione with strong antioxidant and cytoprotective properties and has possible therapeutic potential for neurodegenerative and vascular diseases. Decreased blood concentrations of ET have been found in patients with mild cognitive impairment, but its status in neurodegenerative and vascular dementias is currently unclear. To address this, a cross-sectional study was conducted on 496 participants, consisting of 88 with no cognitive impairment (NCI), 201 with cognitive impairment, no dementia (CIND) as well as 207 with dementia, of whom 160 have Alzheimer's Disease (AD) and 47 have vascular dementia. All subjects underwent blood-draw, neuropsychological assessments, as well as neuroimaging assessments of cerebrovascular diseases (CeVD) and brain atrophy. Plasma ET as well as its metabolite l-hercynine were measured using high sensitivity liquid chromatography tandem-mass spectrometry (LC-MS/MS). Plasma ET concentrations were lowest in dementia (p < 0.001 vs. NCI and CIND), with intermediate levels in CIND (p < 0.001 vs. NCI). A significant increase in l-hercynine to ET ratio was also observed in dementia (p < 0.01 vs. NCI). In multivariate models adjusted for demographic and vascular risk factors, lower levels of ET were significantly associated with dementia both with or without CeVD, while ET associations with CIND were significant only in the presence of CeVD. Furthermore, lower ET levels were also associated with white matter hyperintensities and brain atrophy markers (reduced global cortical thickness and hippocampal volumes). The incremental decreases in ET levels along the CIND-dementia clinical continuum suggest that low levels of ET are associated with disease severity and could be a potential biomarker for cognitive impairment. Deficiency of ET may contribute towards neurodegeneration- and CeVD-associated cognitive impairments, possibly via the exacerbation of oxidative stress in these conditions.

Plasma P-tau181 to Aß42 ratio is associated with brain amyloid burden and hippocampal atrophy in an Asian cohort of Alzheimer's disease patients with concomitant cerebrovascular disease.

INTRODUCTION: There is increasing evidence that phosphorylated tau (P-tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non-White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown. METHODS: Single molecule array (Simoa) measurements of plasma P-tau181, total tau, amyloid beta (Aß)40 and Aß42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aß+), hippocampal atrophy, and CeVD in a Singapore-based cohort of non-cognitively impaired (NCI; n = 43), cognitively impaired no dementia (CIND; n = 91), AD (n = 44), and vascular dementia (VaD; n = 22) subjects. RESULTS: P-tau181/Aß42 ratio showed the highest area under the curve (AUC) for Aß+ (AUC = 0.889) and for discriminating between AD Aß+ and VaD Aß- subjects (AUC = 0.903). In addition, P-tau181/Aß42 ratio was associated with hippocampal atrophy. None of the biomarkers was associated with CeVD. DISCUSSION: Plasma P-tau181/Aß42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.

Clinical Relevance of Cortical Cerebral Microinfarcts on 1.5T Magnetic Resonance Imaging in the Late-Adult Population.

BACKGROUND AND PURPOSE: Cortical cerebral microinfarcts (CMIs) have been linked with dementia and impaired cognition in cross-sectional studies. However, the clinical relevance of CMIs in a large population-based setting is lacking. We examine the association of cortical CMIs detected on 1.5T magnetic resonance imaging with cardiovascular risk factors, cerebrovascular disease, and brain tissue volumes. We further explore the association between cortical CMIs with cognitive decline and risk of stroke, dementia, and mortality in the general population. METHODS: Two thousand one hundred fifty-six participants (age: 75.7±5.9 years, women: 55.6%) with clinical history and baseline magnetic resonance imaging (January 2009-December 2013) were included from the Rotterdam Study. Cortical CMIs were graded based on a previously validated method. Markers of cerebrovascular disease and brain tissue volumes were assessed on magnetic resonance imaging. Cognition was assessed using a detailed neuropsychological test at baseline and at 5 years of follow-up. Data on incident stroke, dementia, and mortality were included until January 2016. RESULTS: Two hundred twenty-seven individuals (10.5%) had ≥1 cortical CMIs. The major risk factors of cortical CMIs were male sex, current smoking, history of heart disease, and stroke. Furthermore, presence of cortical CMIs was associated with infarcts and smaller brain volume. Persons with cortical CMIs showed cognitive decline in Stroop tests (color-naming and interference subtasks; ß for color-naming, 0.18 [95% CI, 0.04-0.33], P interaction ≤0.001 and ß for interference subtask, 1.74, [95% CI, 0.66-2.82], P interaction ≤0.001). During a mean follow-up of 5.2 years, 73 (4.3%) individuals developed incident stroke, 95 (5.1%) incident dementia, and 399 (19.2%) died. People with cortical CMIs were at an increased risk of stroke (hazard ratio, 1.18 [95% CI, 1.09-1.28]) and mortality (hazard ratio, 1.09 [95% CI, 1.00-1.19]). CONCLUSIONS: Cortical CMIs are highly prevalent in a population-based setting and are associated with cardiovascular disease, cognitive decline, and increased risk of stroke and mortality. Future investigations will have to show whether cortical CMIs are a useful biomarker to intervene upon to reduce the burden of stroke.

Cortical Thickness in Crouzon-Pfeiffer Syndrome: Findings in Relation to Primary Cranial Vault Expansion.

BACKGROUND: Episodes of intracranial hypertension are associated with reductions in cerebral cortical thickness (CT) in syndromic craniosynostosis. Here we focus on Crouzon-Pfeiffer syndrome patients to measure CT and evaluate associations with type of primary cranial vault expansion and synostosis pattern. METHODS: Records from 34 Crouzon-Pfeiffer patients were reviewed along with MRI data on CT and intracranial volume to examine associations. Patients were grouped according to initial cranial vault expansion (frontal/occipital). Data were analyzed by multiple linear regression controlled for age and brain volume to determine an association between global/lobar CT and vault expansion type. Synostosis pattern effect sizes on global/lobar CT were calculated as secondary outcomes. RESULTS: Occipital expansion patients demonstrated 0.02 mm thicker cortex globally (P = 0.81) with regional findings, including: thicker cortex in frontal (0.02 mm, P = 0.77), parietal (0.06 mm, P = 0.44) and occipital (0.04 mm, P = 0.54) regions; and thinner cortex in temporal (-0.03 mm, P = 0.69), cingulate (-0.04 mm, P = 0.785), and, insula (-0.09 mm, P = 0.51) regions. Greatest effect sizes were observed between left lambdoid synostosis and the right cingulate (d = -1.00) and right lambdoid synostosis and the left cingulate (d = -1.23). Left and right coronal synostosis yielded effect sizes of d = -0.56 and d = -0.42 on respective frontal lobes. CONCLUSIONS: Both frontal and occipital primary cranial vault expansions correlate to similar regional CT in Crouzon-Pfeiffer patients. Lambdoid synostosis appears to be associated with cortical thinning, particularly in the cingulate gyri.

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

BACKGROUND: Low 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. METHODS: A 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. RESULTS: Decreased 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. CONCLUSIONS: Decreased 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.

Small cortical infarcts: prevalence, determinants, and cognitive correlates in the general population.

BACKGROUND: Cortical brain infarcts are defined as infarcts involving cortical gray matter, but may differ considerably in size. It is unknown whether small cortical infarcts have a similar clinical phenotype as larger counterparts. We investigated prevalence, determinants, and cognitive correlates of small cortical infarcts in the general population and compared these with large cortical infarcts and lacunar infarcts. METHODS: Four thousand nine hundred five nondemented individuals (age 63·95 ± 10·99) from a population-based study were included. Infarcts were rated on magnetic resonance imaging and participants were classified according to mean infarct diameter into small (≤15 mm in largest diameter) or large (>15 mm) cortical infarcts, lacunar infarcts, or a combination of subtypes. Spatial distribution maps were created for manually labeled small and large infarcts. Participants underwent cognitive testing. Analyses were performed using multinomial regression and analysis of covariance. RESULTS: Three hundred eighty-one (7·8%) persons had any infarct on magnetic resonance imaging, among whom 54 with small (1·1%) and 77 (1·6%) with large cortical infarcts. Small cortical infarcts were mainly localized in external watershed areas, whereas large cortical infarcts were localized primarily in large arterial territories. Age (odds ratio = 1·06; 95% confidence interval = 1·02, 1·09), male gender (1·98; 1·01, 3·92), and smoking (2·55; 1·06, 6·14) were determinants of small cortical infarcts. Participants with these infarcts had worse scores in delayed memory, processing speed, and attention tests than persons without infarcts, even after adjustment for cardiovascular risk factors. CONCLUSIONS: In the elderly, small cortical infarcts appear as frequent as large infarcts but in different localization. Our results suggest that small cortical infarcts share cardiovascular risk factors and cognitive correlates with large cortical, but also with lacunar infarcts.

Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging.

BACKGROUND: Increasing evidence suggests a role of atherosclerosis in the pathogenesis of cognitive impairment and dementia. Calcification volume measured with computed tomography (CT) is a valid marker of atherosclerosis. This study investigates associations of atherosclerosis (measured using CT) at four locations with cognition and brain changes on magnetic resonance imaging (MRI). METHODS: To quantify calcification volume, 2414 nondemented people from the Rotterdam Study underwent CT of the coronary arteries, aortic arch, extracranial carotid arteries, and intracranial carotid arteries. To assess global cognition and performance on memory, executive function, information processing speed, and motor speed, they also underwent neuropsychological tests. In a random subgroup of 844 participants, brain MRI was performed. Automated segmentation and quantification of brain MRI scans yielded brain tissue volumes in milliliters. Diffusion tensor imaging was used to measure the microstructural integrity of the white matter. Relationships of atherosclerotic calcification with cognition, brain tissue volumes, and diffusion tensor imaging measures were assessed with linear regression models and adjusted for relevant confounders. RESULTS: With larger calcification volumes, lower cognitive scores were observed. When calcification volumes were larger, total brain volumes were also smaller. Specifically, larger coronary artery calcification volumes related to smaller gray matter volumes, and extracranial and intracranial carotid calcification volumes related to smaller white matter volumes. Larger calcification volume in all vessel beds was accompanied by worse microstructural integrity of the white matter. CONCLUSIONS: Larger calcification volume is associated with worse cognitive performance. It also relates to smaller brain tissue volumes and worse white matter microstructural integrity, revealing possible mechanisms through which atherosclerosis may lead to poorer cognition.

Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy.

A limited number of studies have associated adjuvant chemotherapy with structural brain changes. These studies had small sample sizes and were conducted shortly after cessation of chemotherapy. Results of these studies indicate local gray matter volume decrease and an increase in white matter lesions. Up till now, it is unclear if non-CNS chemotherapy is associated with long-term structural brain changes. We compared focal and total brain volume (TBV) of a large set of non-CNS directed chemotherapy-exposed breast cancer survivors, on average 21 years post-treatment, to that of a population-based sample of women without a history of cancer. Structural MRI (1.5T) was performed in 184 chemotherapy-exposed breast cancer patients, mean age 64.0 (SD = 6.5) years, who had been diagnosed with cancer on average 21.1 (SD = 4.4) years before, and 368 age-matched cancer-free reference subjects from a population-based cohort study. Outcome measures were: TBV and total gray and white matter volume, and hippocampal volume. In addition, voxel based morphometry was performed to analyze differences in focal gray matter. The chemotherapy-exposed breast cancer survivors had significantly smaller TBV (-3.5 ml, P = 0.019) and gray matter volume (-2.9 ml, P = 0.003) than the reference subjects. No significant differences were observed in white matter volume, hippocampal volume, or local gray matter volume. This study shows that adjuvant chemotherapy for breast cancer is associated with long-term reductions in TBV and overall gray matter volume in the absence of focal reductions. The observed smaller gray matter volume in chemotherapy-exposed survivors was comparable to the effect of almost 4 years of age on gray matter volume reduction. These volume differences might be associated with the slightly worse cognitive performance that we observed previously in this group of breast cancer survivors.

Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study.

BACKGROUND AND PURPOSE: Cerebral white matter lesions and lacunar infarcts are small vessel disease-related lesions, which are associated with cognitive decline and dementia. We aimed to assess the relationship between risk factors, effect modifiers, and progression of these lesions. Furthermore, we studied the cognitive consequences of lesion progression. METHODS: Six hundred sixty-eight people, aged 60 to 90 years, underwent repeated MRI scanning and neuropsychological testing within 3-year follow-up. We rated incident lacunar infarcts and change in periventricular and subcortical white matter lesion severity with a semiquantitative scale. We assessed the relationships between age, sex, baseline lesion load, risk factors, lesion progression, and change in cognitive function by multivariate regression analyses and additional stratified analyses. RESULTS: Baseline lesion load, higher age, high blood pressure, and current smoking were independently associated with progression of white matter lesions. Women had more marked progression of subcortical white matter lesions and incident lacunar infarcts compared with men. Carotid atherosclerosis was associated with incident lacunar infarcts. Higher blood pressure did not contribute to lesion progression in people with already severe lesions at baseline nor in the very old. Lesion progression was associated with a paralleled decline in general cognitive function and in particular with a decreased information processing speed. CONCLUSIONS: Higher age, female sex, cigarette smoking, elevated blood pressure, and baseline lesion load were associated with small vessel disease progression. Age and baseline lesion load influenced the risk relations with blood pressure. Progression of small vessel disease was related to a paralleled decline in cognitive function.

Brain tissue volumes in the general elderly population. The Rotterdam Scan Study.

We investigated how volumes of cerebrospinal fluid (CSF), grey matter (GM) and white matter (WM) varied with age, sex, small vessel disease and cardiovascular risk factors in the Rotterdam Scan Study. Participants (n=490; 60-90 years) were non-demented and 51.0% had hypertension, 4.9% had diabetes mellitus, 17.8% were current smoker and 54.0% were former smoker. We segmented brain MR-images into GM, normal WM, white matter lesion (WML) and CSF. Brain infarcts were rated visually. Volumes were expressed as percentage of intra-cranial volume. With increasing age, volumes of total brain, normal WM and total WM decreased; that of GM remained unchanged; and that of WML increased, in both men and women. Excluding persons with infarcts did not alter these results. Persons with larger load of small vessel disease had smaller brain volume, especially normal WM volume. Diastolic blood pressure, diabetes mellitus and current smoking were also related to smaller brain volume. In the elderly, higher age, small vessel disease and cardiovascular risk factors are associated with smaller brain volume, especially WM volume.