Cortical Thickness In Patients Research Articles

A preliminary study of the influence of age of onset and childhood trauma on cortical thickness in major depressive disorder.

Background. Major depressive disorder (MDD) neural underpinnings may differ based on onset age and childhood trauma. We assessed cortical thickness in patients who differed in age of MDD onset and examined trauma history influence. Methods. Adults with MDD (N = 36) and controls (HC; N = 18) underwent magnetic resonance imaging. Twenty patients had MDD onset <24 years of age (pediatric onset) and 16 had onset >25 years of age (adult onset). The MDD group was also subdivided into those with (N = 12) and without (N = 19) physical and/or sexual abuse as assessed by the Childhood Trauma Questionnaire (CTQ). Cortical thickness was analyzed with FreeSurfer software. Results. Thicker frontal pole and a tendency for thinner transverse temporal cortices existed in MDD. The former was driven by the pediatric onset group and abuse history (independently), particularly in the right frontal pole. Inverse correlations existed between CTQ scores and frontal pole cortex thickness. A similar inverse relation existed with left inferior and right superior parietal cortex thickness. The superior temporal cortex tended to be thinner in pediatric versus adult onset groups with childhood abuse. Conclusions. This preliminary work suggests neural differences between pediatric and adult MDD onset. Trauma history also contributes to cytoarchitectural modulation. Thickened frontal pole cortices as a compensatory mechanism in MDD warrant evaluation.

Disconnection Mechanism and Regional Cortical Atrophy Contribute to Impaired Processing of Facial Expressions and Theory of Mind in Multiple Sclerosis: A Structural MRI Study

Successful socialization requires the ability of understanding of others’ mental states. This ability called as mentalization (Theory of Mind) may become deficient and contribute to everyday life difficulties in multiple sclerosis. We aimed to explore the impact of brain pathology on mentalization performance in multiple sclerosis. Mentalization performance of 49 patients with multiple sclerosis was compared to 24 age- and gender matched healthy controls. T1- and T2-weighted three-dimensional brain MRI images were acquired at 3Tesla from patients with multiple sclerosis and 18 gender- and age matched healthy controls. We assessed overall brain cortical thickness in patients with multiple sclerosis and the scanned healthy controls, and measured the total and regional T1 and T2 white matter lesion volumes in patients with multiple sclerosis. Performances in tests of recognition of mental states and emotions from facial expressions and eye gazes correlated with both total T1-lesion load and regional T1-lesion load of association fiber tracts interconnecting cortical regions related to visual and emotion processing (genu and splenium of corpus callosum, right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, uncinate fasciculus). Both of these tests showed correlations with specific cortical areas involved in emotion recognition from facial expressions (right and left fusiform face area, frontal eye filed), processing of emotions (right entorhinal cortex) and socially relevant information (left temporal pole). Thus, both disconnection mechanism due to white matter lesions and cortical thinning of specific brain areas may result in cognitive deficit in multiple sclerosis affecting emotion and mental state processing from facial expressions and contributing to everyday and social life difficulties of these patients.

Sex-Related Differences of Cortical Thickness in Patients with Chronic Abdominal Pain

Background & AimsRegional reductions in gray matter (GM) have been reported in several chronic somatic and visceral pain conditions, including irritable bowel syndrome (IBS) and chronic pancreatitis. Reported GM reductions include insular and anterior cingulate cortices, even though subregions are generally not specified. The majority of published studies suffer from limited sample size, heterogeneity of populations, and lack of analyses for sex differences. We aimed to characterize regional changes in cortical thickness (CT) in a large number of well phenotyped IBS patients, taking into account the role of sex related differences.MethodsCortical GM thickness was determined in 266 subjects (90 IBS [70 predominantly premenopausal female] and 176 healthy controls (HC) [155 predominantly premenopausal female]) using the Laboratory of Neuro Imaging (LONI) Pipeline. A combined region of interest (ROI) and whole brain approach was used to detect any sub-regional and vertex-level differences after removing effects of age and total GM volume. Correlation analyses were performed on behavioral data.ResultsWhile IBS as a group did not show significant differences in CT compared to HCs, sex related differences were observed both within the IBS and the HC groups. When female IBS patients were compared to female HCs, whole brain analysis showed significant CT increase in somatosensory and primary motor cortex, as well as CT decrease in bilateral subgenual anterior cingulate cortex (sgACC). The ROI analysis showed significant regional CT decrease in bilateral subregions of insular cortex, while CT decrease in cingulate was limited to left sgACC, accounting for the effect of age and GM volume. Several measures of IBS symptom severity showed significant correlation with CT changes in female IBS patients.ConclusionsSignificant, sex related differences in CT are present in both HCs and in IBS patients. The biphasic neuroplastic changes in female IBS patients are related to symptom severity.

Comparison of cortical thickness in patients with early‐stage versus late‐stage amnestic mild cognitive impairment

Disappointing outcomes from clinical trials involving amyloid-modifying therapies for Alzheimer's disease (AD) have prompted more focus on the concept of early-stage (E) amnestic mild cognitive impairment (E-aMCI). However, limited evidence suggests that E-aMCI may represent aMCI at a very early stage of AD. Furthermore, the nature of the progression of E-aMCI to late-stage aMCI (L-aMCI) remains unclear. Therefore, the aim of the present study was to characterize patterns of cortical thinning in both E-aMCI and L-aMCI patients. Cortical thicknesses were measured in 190 patients with aMCI and 147 subjects with normal cognition. In accordance with memory test scores involving delayed recall items, aMCI patients were divided into two subgroups, containing 73 E-aMCI subjects with milder memory impairment [scores between -1.5 standard deviation (SD) and -1.0 SD compared with age- and education-matched norms] and 117 L-aMCI subjects with more severe memory impairment (scores lower than -1.5 SD). Compared with controls, the E-aMCI group exhibited cortical thinning in the left medial temporal and insular regions, whereas the L-aMCI group showed cortical thinning in widespread regions, including the bilateral dorsolateral prefrontal, anterior and medial temporal, and temporo-parietal association cortices, and the precuneus. When the two aMCI groups were directly compared, the L-aMCI group showed greater cortical thinning in the right superior prefrontal, medial temporal, posterior cingulate and lateral parietal cortices. Our findings suggest that E-aMCI might represent an early symptomatic stage of AD. Furthermore, L-aMCI might resemble AD more closely than E-aMCI, in terms of the topography of cortical thinning.

Associations of white matter integrity and cortical thickness in patients with schizophrenia and healthy controls.

Typical brain development includes coordinated changes in both white matter (WM) integrity and cortical thickness (CT). These processes have been shown to be disrupted in schizophrenia, which is characterized by abnormalities in WM microstructure and by reduced CT. The aim of this study was to identify patterns of association between WM markers and cortex-wide CT in healthy controls (HCs) and patients with schizophrenia (SCZ). Using diffusion tensor imaging and structural magnetic resonance imaging data of the Mind Clinical Imaging Consortium study (130 HC and 111 SCZ), we tested for associations between (a) fractional anisotropy in selected manually labeled WM pathways (corpus callosum, anterior thalamic radiation, and superior longitudinal fasciculus) and CT, and (b) the number of lesion-like WM regions ("potholes") and CT. In HC, but not SCZ, we found highly significant negative associations between WM integrity and CT in several pathways, including frontal, temporal, and occipital brain regions. Conversely, in SCZ the number of WM potholes correlated with reduced CT in the left lateral temporal gyrus, left fusiform, and left lateral occipital brain area. Taken together, we found differential patterns of association between WM integrity and CT in HC and SCZ. Although the pattern in HC can be explained from a developmental perspective, the reduced gray matter CT in SCZ patients might be the result of focal but spatially heterogeneous disruptions of WM integrity.

Abstract TMP38: Diminished Cortical Thickness and Increased Oxygen Extraction Fraction in Moyamoya Disease

PURPOSE: Chronic hemodynamic impairment may lead to reduced cortical thickness, perhaps related to metabolic down-regulation in cortical neurons. The purpose of this study was to determine whether hemodynamic impairment correlated with diminished cortical thickness in patients with idiopathic moyamoya phenomenon. METHODS: The study was a retrospective analysis of a prospective, blindly-adjudicated, multicenter patient cohort. Inclusion criteria required moyamoya phenomenon diagnosed by catheter angiography and presumed idiopathic basal arterial occlusive disease. Oxygen extraction fraction (OEF) was measured using positron emission tomography (PET). Hemodynamic impairment was determined by comparing the OEF of middle cerebral artery territories to cerebellar regions and to normal control subjects. MR imaging was obtained concurrently with PET, within several hours, and cortical thickness estimates were made with Freesurfer (http://surfer.nmr.mgh.harvard.edu). OEF measurements were then compared to cortical thickness measurements. RESULTS: Adequate MR studies were available for 40 subjects. Mean age was 44 years. Eleven were male. Thirty-one had bilateral disease. Three had increased OEF in both hemispheres and four had unilateral increased OEF. Three patients underwent revascularization surgery during follow-up. Robust linear regression of relative cortical thickness to relative OEF is shown below: the slope was -0.02693 (-0.03002, -0.02384), the intercept was 1.022 (1.019, 1.025) at 95% confidence. Pearson’s R-square was 0.9648. CONCLUSIONS: Chronic hemodynamic impairment may be associated with reduced cortical thickness. This may reflect reversible down-regulation or irreversible subclinical ischemic injury. Supported by NINDS RO1 NS051631, 1 UL1 RR024992-01, 1 TL1 RR024995-01 and 1 KL2 RR 024994-01 from the National Center for Research Resources (NCRR).

Cortical thickness alterations in social anxiety disorder

Social anxiety disorder (SAD) has been associated with aberrant processing of socio-emotional stimuli and failure to adaptively regulate emotion, corroborated by functional neuroimaging studies. However, only a few studies of structural brain abnormalities in SAD have been reported, and among these only one investigated cortical thickness. In the present study we used magnetic resonance imaging (MRI) in conjunction with an automated method to measure cortical thickness in patients with SAD (n=14) and healthy controls (n=12). Results showed significantly increased thickness of the left inferior temporal cortex in SAD patients relative to controls. Within the patient group, a negative association was found between social anxiety symptom severity and thickness of the right rostral anterior cingulate cortex. The observed alterations in brain structure may help explain previous findings of dysfunctional regulation and processing of emotion in SAD.

Cortical cerebral atrophy in patients with Parkinson’s disease: new trends in the diagnostics in vivo

The Parkinson’s disease (PD) pathology is not limited by degeneration of the nigrostriatal dopaminergic system, but includes also wide involvement of different regions of cerebral cortex. The aim of this study was the identification of differences in the brain cortical thickness in patients with early and advanced PD with the use of MRI morphometry. Sixty seven PD patients with Hoehn-Yahr 2 and 3 stages were examined. All patients underwent MRI with subsequent post-processing and receiving of cortical thickness parameters in different brain regions. Significant differences in the visual cortex, the cingulated and fusiform gyri and the frontopolar zone of a dominant hemisphere, and the Brodmann’s areas 1, 2, 3 and 4 of a non-dominant hemisphere were obtained. These data allow revealing relationships between non-motor manifestations of PD and degeneration of certain cortical regions of the brain.

ADHD comorbidity can matter when assessing cortical thickness abnormalities in patients with bipolar disorder

Attention-deficit hyperactivity disorder (ADHD) is prevalent in patients with bipolar disorder (BP), but very few studies consider this when interpreting magnetic resonance imaging findings. No studies, to our knowledge, have screened for or controlled for the presence of ADHD when examining cortical thickness in patients with BP. We used a 2 × 2 design to evaluate the joint effects of BP and ADHD on cortical thickness and uncover the importance of ADHD comorbidity in BP subjects. The study included 85 subjects: 31 healthy controls, 17 BP-only, 19 ADHD-only, and 18 BP/ADHD. All patients with BP were subtype I, euthymic, and not taking lithium. Groups did not differ significantly in age or gender distribution. We used cortical thickness measuring tools combined with cortical pattern matching methods to align sulcal/gyral anatomy across participants. Significance maps were used to check for both main effects of BP and ADHD and their interaction. Post-hoc comparisons assessed how the effects of BP on cortical thickness varied as a function of the presence or absence of ADHD. Interactions of BP and ADHD diagnoses were found in the left subgenual cingulate and right orbitofrontal cortex, demonstrating that the effect of BP on cortical thickness depends on ADHD status. Some brain abnormalities attributed to BP may result from the presence of ADHD. Diagnostic interactions were found in regions previously implicated in the pathophysiology of BP, making it vital to control for an ADHD comorbid diagnosis when attempting to isolate neural or genetic abnormalities specific to BP.

Changes in cortical thickness in patients with chronic pancreatitis: A useful indicator of a reorganized pain system?

s / Pancreatology 12 (2012) 502–597 581 Conclusion: DCQD is protective against pancreatic injury in CER-AP and ARG-AP. Further work is required to determine the mechanism of action of DCQD.

Aberrant cortical gyrification in schizophrenia: a surface-based morphometry study

Schizophrenia is considered to be a disorder of cerebral connectivity associated with disturbances of cortical development. Disturbances in connectivity at an early period of cortical maturation can result in widespread defects in gyrification. Investigating the anatomic distribution of gyrification defects can provide important information about neurodevelopment in patients with schizophrenia. We undertook an automated surface-based morphometric assessment of gyrification on 3-dimensionally reconstructed cortical surfaces across multiple vertices that cover the entire cortex. We used a sample from our previous research of 57 patients (50 men) with schizophrenia and 41 controls (39 men) in whom we had tested a specific hypothesis regarding presence of both hypo and hypergyria in the prefrontal cortex using a frontal region-of-interest approach. Regions with significant reductions in gyrification (hypogyria) were seen predominantly in the left hemisphere, involving the insula and several regions of the multimodal association cortex. Although the prefrontal hypergyria documented earlier did not survive the statistical correction required for a whole brain search (cluster inclusion at p = 0.0001), significant hypergyric frontal clusters emerged when the threshold was lowered (cluster inclusion at p = 0.05). In the insula, a reduction in gyrification was related to reduced cortical thickness in patients with schizophrenia. We studied a sample of patients taking antipsychotic medications, which could have confounded the results. Our sample was predominantly male, limiting the generalizability of our findings. Our observations suggest that the disturbances in cortical gyrification seen in patients with schizophrenia might be related to a disrupted interaction between the paralimbic and the multimodal association cortex and thus might contribute to the pathogenesis of the illness.

Atypical fractures do not have a thicker cortex

An association between atypical fractures and general cortical thickness of the femoral shaft is often suggested in the literature. Our radiographic measurements of 59 atypical and 218 ordinary fractures now exclude a difference larger than 10 % in mean femoral cortical thickness (sum of lateral and medial) with 95 % confidence. An increased general cortical thickness in patients with fatigue fracture of the femoral shaft (atypical fractures) is commonly suggested. However, there are scarce data to support this. In a published nationwide Swedish study, we identified by radiographic review 59 women with an atypical fracture during 2008. The femoral cortical thickness index (thickness/femoral diameter) of these women was now compared with the 218 ordinary fractures that occurred in the same region of the femur in a case-control design. The cortical thickness index 5 cm below the lesser trochanter was the primary variable. Patients with atypical fractures were younger. Without correction for age, they had a thicker cortex (i.e., higher index). However, the difference in cortical thickness disappeared after age correction. The 95 % CI excludes a group mean difference exceeding 10 % of total mean thickness. Similarly, there was no significant difference in cortical thickness between patients with or without bisphosphonate treatment or between the ipsi- and contralateral femurs in patients with an atypical fracture. The concept of a generally increased cortical thickness in patients with atypical fractures should be reconsidered.

Exercise therapy, cardiorespiratory fitness and their effect on brain volumes: A randomised controlled trial in patients with schizophrenia and healthy controls

The objective of this study was to examine exercise effects on global brain volume, hippocampal volume, and cortical thickness in schizophrenia patients and healthy controls. Irrespective of diagnosis and intervention, associations between brain changes and cardiorespiratory fitness improvement were examined. Sixty-three schizophrenia patients and fifty-five healthy controls participated in this randomised controlled trial. Global brain volumes, hippocampal volume, and cortical thickness were estimated from 3-Tesla MRI scans. Cardiorespiratory fitness was assessed with a cardiopulmonary ergometer test. Subjects were assigned exercise therapy or occupational therapy (patients) and exercise therapy or life-as-usual (healthy controls) for six months 2h weekly. Exercise therapy effects were analysed for subjects who were compliant at least 50% of sessions offered. Significantly smaller baseline cerebral (grey) matter, and larger third ventricle volumes, and thinner cortex in most areas of the brain were found in patients versus controls. Exercise therapy did not affect global brain and hippocampal volume or cortical thickness in patients and controls. Cardiorespiratory fitness improvement was related to increased cerebral matter volume and lateral and third ventricle volume decrease in patients and to thickening in the left hemisphere in large areas of the frontal, temporal and cingulate cortex irrespective of diagnosis. One to 2h of exercise therapy did not elicit significant brain volume changes in patients or controls. However, cardiorespiratory fitness improvement attenuated brain volume changes in schizophrenia patients and increased thickness in large areas of the left cortex in both schizophrenia patients and healthy controls.

The Cortical Signature of Amyotrophic Lateral Sclerosis

The aim of this study was to explore the pattern of regional cortical thickness in patients with non-familial amyotrophic lateral sclerosis (ALS) and to investigate whether cortical thinning is associated with disease progression rate. Cortical thickness analysis was performed in 44 ALS patients and 26 healthy controls. Group differences in cortical thickness and the age-by-group effects were assessed using vertex-by-vertex and multivariate linear models. The discriminatory ability of MRI variables in distinguishing patients from controls was estimated using the Concordance Statistics (C-statistic) within logistic regression analyses. Correlations between cortical thickness measures and disease progression rate were tested using the Pearson coefficient. Relative to controls, ALS patients showed a bilateral cortical thinning of the primary motor, prefrontal and ventral frontal cortices, cingulate gyrus, insula, superior and inferior temporal and parietal regions, and medial and lateral occipital areas. There was a significant age-by-group effect in the sensorimotor cortices bilaterally, suggesting a stronger association between age and cortical thinning in ALS patients compared to controls. The mean cortical thickness of the sensorimotor cortices distinguished patients with ALS from controls (C-statistic ≥0.74). Cortical thinning of the left sensorimotor cortices was related to a faster clinical progression (r = −0.33, p = 0.03). Cortical thickness measurements allowed the detection and quantification of motor and extramotor involvement in patients with ALS. Cortical thinning of the precentral gyrus might offer a marker of upper motor neuron involvement and disease progression.

Effect of DISC1 SNPs on brain structure in healthy controls and patients with a history of psychosis

Disrupted-in-Schizophrenia-1 (DISC1) has been suggested as a susceptibility locus for a broad spectrum of psychiatric disorders. Risk variants have been associated with brain structural changes, which overlap alterations reported in schizophrenia and bipolar disorder patients. We used genome-wide genotyping data for a Norwegian sample of healthy controls (n = 171) and patients with a history of psychosis (n = 184), to investigate 61 SNPs in the DISC1 region for putative association with structural magnetic resonance imaging (sMRI) measures (hippocampal volume; mean cortical thickness; and total surface area, as well as cortical thickness and area divided into four lobar measures). SNP rs821589 was associated with mean temporal and total brain cortical thickness in controls (P(adjusted) = 0.009 and 0.02, respectively), but not in patients. SNPs rs11122319 and rs1417584 were associated with mean temporal cortical thickness in patients (P(adjusted) = 0.04 and 0.03, respectively), but not in controls, and both SNPs have previously been highly associated with DISC1 gene expression. There were significant genotype × case-control interactions. There was no significant association between SNPs and cortical area or hippocampal volume in controls, or with any of the structural measures in cases, after correction for multiple comparisons. In conclusion, DISC1 SNPs might impact brain structural variation, possibly differently in psychosis patients versus controls, but independent replication will be needed to confirm our findings.

Reduced gray to white matter tissue intensity contrast in schizophrenia.

BackgroundWhile numerous structural magnetic resonance imaging (MRI) studies revealed changes of brain volume or density, cortical thickness and fibre integrity in schizophrenia, the effect of tissue alterations on the contrast properties of neural structures has so far remained mostly unexplored.MethodsWhole brain high-resolution MRI at 3 Tesla was used to investigate tissue contrast and cortical thickness in patients with schizophrenia and healthy controls.ResultsPatients showed significantly decreased gray to white matter contrast in large portions throughout the cortical mantle with preponderance in inferior, middle, superior and medial temporal areas as well as in lateral and medial frontal regions. The extent of these intensity contrast changes exceeded the extent of cortical thinning. Further, contrast changes remained significant after controlling for cortical thickness measurements.ConclusionsOur findings clearly emphasize the presence of schizophrenia related brain tissue changes that alter the imaging properties of brain structures. Intensity contrast measurements might not only serve as a highly sensitive metric but also as a potential indicator of a distinct pathological process that might be independent from volume or thickness alterations.

Voxel-Based Morphometry (VBM) and Cortical Thickness in Motor Conversion Disorders (P03.124)

Objective: To determine if there are structural differences in gray-matter volumes between motor conversion disorder (MCD) patients compared to healthy volunteers (HV). Background MCD patients demonstrate medically-unexplained movements that appear similar to volitional movements, but are experienced as involuntary. The cortical correlates of self-agency remain unknown, although the temporoparietal junction has been proposed as the comparator region in the forward model of action. Previous studies have identified increased amygdala activity to arousing stimuli in MCD with greater functional connectivity to the supplementary motor area, but it is unknown if differences exist on a structural level. Design/Methods: We imaged 16 MCD patients and 16 HV, using T1-weighted 3D-MPRAGE sequences (1.5T MRI). Mood symptoms were measured with Beck depression (BDI) and anxiety (BAI) inventories. Gray-matter volumes and cortical thickness were evaluated with FSL and FreeSurfer with a region-of-interest-based approach. Results: Amygdala VBM showed no difference between patients and HV, nor was there correlation between amygdala size and BDI/BAI scores. We found a trend towards smaller hippocampi in patients which did not reach significance (LH, p=0.261, RH, p=0.052). Right hippocampal volumes were negatively correlated with BDI scores in patients (r= -0.55). There was increased cortical thickness in patients (t=2.0) in the left pars opercularis, right superior and inferior parietal areas, and decreased thickness in the left superior temporal, right pars opercularis, supramarginal and postcentral areas. Conclusions: Smaller hippocampal volumes are associated with mood disorders and negatively correlated with BDI scores in our study. Smaller hippocampi in MCD patients may be a correlate of stress as the hippocampus serves to regulate stress responses. We identified differences in regions involved in motor planning and control, which may contribute to symptomatology. Future studies with larger sample sizes are needed to assess if structural changes are a consistent finding in MCD and determine functional significance. Supported by: Funded by and conducted at the intramural National Institute of Neurological Disorders and Stroke, National Institutes of Health. Disclosure: Dr. Czarnecki has nothing to disclose. Dr. Kranick has nothing to disclose. Dr. Horovitz has nothing to disclose. Dr. Voon has nothing to disclose. Dr. Ostuni has nothing to disclose. Dr. Hallet has received personal compensation for activities with Neurotoxin Institute, Cambridge University Press, Springer Verlag, Taylor & Francis Group, Oxford University Press, John Wiley & Sons, AAN Enterprises, Lippincott, Williams &Wilkins, and Elsevier. Dr. Hallet has received (royalty or license fee or contractual rights) payments from the National Institutes of Health. Dr. Hallet has received research support from The National Institutes of Health.

A comment on “Contralateral cerebral hemodynamic changes after unilateral direct revascularization in patients with moyamoya disease”

A comment on “Contralateral cerebral hemodynamic changes after unilateral direct revascularization in patients with moyamoya disease”

Cortical Thickness in Fetal Alcohol Syndrome and Attention Deficit Disorder

Fetal alcohol syndrome represents the classic and most severe manifestation of epigenetic changes induced by exposure to alcohol during pregnancy. Often these patients develop attention deficit hyperactivity disorder. We analyzed cortical thickness in 20 children and adolescents with fetal alcohol syndrome and attention deficit hyperactivity disorder (group 1), in 20 patients without fetal alcohol syndrome (group 2), and in 20 control cases. The first group revealed total cortical thickness significantly superior to those of the other two groups. In per-lobe analyses of cortical thickness, group 1 demonstrated greater cortical thickness in the frontal, occipital, and right temporal and left frontal lobes compared with the second group, and in both temporal lobes and the right frontal lobe compared with the control group. This study demonstrated greater cortical thickness in patients with attention deficit hyperactivity disorder and heavy prenatal exposure to alcohol, probably as an expression of immature or abnormal brain development.

Letter to the Editor: The Effect of Long-term Alendronate Treatment on Cortical Thickness of the Proximal Femur

To the Editor: We read with interest the recent article by Unnanuntana et al. [8], who found no increase in proximal femoral cortical thickness in patients receiving prolonged alendronate therapy. Given the contrast to earlier observations by Lenart et al. [6], we raise the question of whether the technique of assessing proximal femoral cortical thickness and cortical thickness ratio on dual-energy x-ray absorptiometry are comparable to that of measuring off plain radiographs as performed by Lenart et al. [6]. Further, in light of the current findings reported by Unnanuntana et al., should a generalized increase in cortical thickness of the femoral diaphysis still be included as a minor criterion for atypical fractures, as previously proposed by Shane et al. and a task force for the American Society for Bone and Mineral Research [7]? The issue of cortical thickness after alendronate treatment has been a somewhat confusing entity in the recent orthopaedic literature [1, 5, 6, 8]. One study had documented an increased mean percentage of cortical thickness after alendronate treatment for 1 to 2 years [1]. Initially thought to be a beneficial effect of osteoclastic suppression, cortical thickening began to be viewed as a double-edged sword when lateral thickening was observed in atypical femur fractures [5]. Generalized increased cortical thickness in the proximal femur was first observed by Lenart et al. [6] in femurs with atypical fractures. This led to the notion that alendronate therapy may cause changes in cortical thickness around the subtrochanteric region of the femur, which may in turn predispose to atypical fractures. The recent study by Unnanuntana et al. [8] seems to show the contrary—that long-term alendronate therapy does not lead to increased cortical thickness. This raises the question of whether the increased cortical thickness observed in some patients with atypical femoral fractures is coincidental or causative. It is possible these patients already have increased cortical thickness before commencing alendronate therapy or that susceptible individuals have increased cortical thickness develop in response to alendronate therapy. However, increased normalized cortical thickness per se may not be pathologic and is to be expected in young, healthy individuals. Since atypical fractures first caught the attention of the medical community owing to their occurrence in otherwise healthy, postmenopausal women [2], many of whom had no documentation of osteoporosis observed on bone mineral density measurements [3], the observed increase in cortical thickness could represent radiographic evidence of good bone stock. Further, it is uncertain whether the original technique described by Lenart et al. [6] for measuring cortical thickness just below the fracture line is an appropriate indicator of general cortical thickening or part of the distal periosteal reaction. This latter supposition is consistent with our observations of only localized thickening in the lateral cortex and not generalized thickening in atypical femoral fractures [4]. Atypical fractures reportedly cluster in regions subject to maximal tensile loading in the femur [4] and the CT/MRI of contralateral cortical thickening reported by Kwek et al. [5] in patients with atypical fractures showed a localized region of resorptive cavities and bone marrow invasion into these lesions associated with thinning of the overlying cortex. Therefore, cortical thickening associated with atypical fractures appears to be a local phenomenon, possibly representing callus formation in response to microfractures in regions subject to abnormal stress. Cortical thickening in atypical fractures requires a more precise definition and analysis. The observed general cortical thickening is open to further discussion and research. Localized cortical thickening, however, heralds bone remodeling in response to stress and should be treated with caution [3].