The First Examination of Diagnostic Performance of Automated Measurement of the Callosal Angle in 1856 Elderly Patients and Volunteers Indicates That 12.4% of Exams Met the Criteria for Possible Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: Many patients with dementia may have comorbid or misdiagnosed normal pressure hydrocephalus, a treatable neurologic disorder. The callosal angle is a validated biomarker for normal pressure hydrocephalus with 93% diagnostic accuracy. Our purpose was to develop and evaluate an algorithm for automatically computing callosal angles from MR images of the brain. MATERIALS AND METHODS: This article reports the results of analyzing callosal angles from 1856 subjects with 5264 MR images from the Open Access Series of Imaging Studies and the Alzheimer's Disease Neuroimaging Initiative databases. Measurement variability was examined between 2 neuroradiologists (n = 50) and between manual and automatic measurements (n = 281); from differences in simulated head orientation; and from real-world changes in patients with multiple examinations (n = 906). We evaluated the effectiveness of the automatic callosal angle to differentiate normal pressure hydrocephalus from Alzheimer disease in a simulated cohort. RESULTS: The algorithm identified that 12.4% of subjects from these carefully screened cohorts had callosal angles of <90°, a published threshold for possible normal pressure hydrocephalus. The intraclass correlation coefficient was 0.97 for agreement between neuroradiologists and 0.90 for agreement between manual and automatic measurement. The method was robust to different head orientations. The median coefficient of variation for repeat examinations was 4.2% (Q1 = 3.1%, Q3 = 5.8%). The simulated classification of normal pressure hydrocephalus versus Alzheimer using the automatic callosal angle had an accuracy, sensitivity, and specificity of 0.87 each. CONCLUSIONS: In even the most pristine research databases, analyses of the callosal angle indicate that some patients may have normal pressure hydrocephalus. The automatic callosal angle measurement can rapidly and objectively screen for normal pressure hydrocephalus in patients who would otherwise be misdiagnosed.

Urine dicarboxylic acids change in pre-symptomatic Alzheimer's disease and reflect loss of energy capacity and hippocampal volume.

Non-invasive biomarkers will enable widespread screening and early diagnosis of Alzheimer's disease (AD). We hypothesized that the considerable loss of brain tissue in AD will result in detection of brain lipid components in urine, and that these will change in concert with CSF and brain biomarkers of AD. We examined urine dicarboxylic acids (DCA) of carbon length 3-10 to reflect products of oxidative damage and energy generation or balance that may account for changes in brain function in AD. Mean C4-C5 DCAs were lower and mean C7-C10 DCAs were higher in the urine from AD compared to cognitively healthy (CH) individuals. Moreover, mean C4-C5 DCAs were lower and mean C7-C9 were higher in urine from CH individuals with abnormal compared to normal CSF amyloid and Tau levels; i.e., the apparent urine changes in AD also appeared to be present in CH individuals that have CSF risk factors of early AD pathology. In examining the relationship between urine DCAs and AD biomarkers, we found short chain DCAs positively correlated with CSF Aß42, while C7-C10 DCAs negatively correlated with CSF Aß42 and positively correlated with CSF Tau levels. Furthermore, we found a negative correlation of C7-C10 DCAs with hippocampal volume (p < 0.01), which was not found in the occipital volume. Urine measures of DCAs have an 82% ability to predict cognitively healthy participants with normal CSF amyloid/Tau. These data suggest that urine measures of increased lipoxidation and dysfunctional energy balance reflect early AD pathology from brain and CSF biomarkers. Measures of urine DCAs may contribute to personalized healthcare by indicating AD pathology and may be utilized to explore population wellness or monitor the efficacy of therapies in clinical trials.

Natural history and clinical detection of undiagnosed coeliac disease in a North American community.

BACKGROUND: Coeliac disease is a substantially underdiagnosed disorder, with clinical testing currently guided by case finding. AIM: To determine the presence of indications for diagnostic testing and frequency of clinical testing in undiagnosed coeliac disease. METHODS: This was a case-control study of adults without prior diagnosis of coeliac disease. Undiagnosed cases were identified through sequential serology, and unaffected age- and gender-matched controls were selected. Medical records were systematically reviewed for indications for and evidence of clinical testing. RESULTS: Of 47 557 adults, 408 cases of undiagnosed coeliac disease were identified. 408 serology negative matched controls were selected. Eight-matched pairs were excluded, leading to 800 included individuals (61% female; median age 44.2 years). The odds of any indication for clinical testing were similar among undiagnosed coeliac disease and controls (odds ratio (OR) 1.18; 95% CI: 0.85-1.63, P = 0.32). Most individual indications were not associated with serologic status. Exceptions to this include hypothyroidism, which was more likely in cases of undiagnosed coeliac disease, and dyspepsia and chronic diarrhoea, which were less likely. Cases of undiagnosed coeliac disease were more likely to develop osteoporosis (P = 0.005), dermatitis herpetiformis (P = 0.006), chronic fatigue (P = 0.033), thyroiditis (P = 0.003), autoimmune diseases (P = 0.008), and have a family member diagnosed with coeliac disease (P = 0.001). CONCLUSION: This study strongly suggests that current case finding is not effective in detecting undiagnosed coeliac disease. Individuals with undiagnosed coeliac disease were more likely than controls to develop indications for testing overtime. A more effective method for detection of coeliac disease is needed.

Undetectable negative tissue transglutaminase IgA antibodies predict mucosal healing in treated coeliac disease patients.

BACKGROUND: Tissue transglutaminase (tTG) immunoglobulin A (IgA) testing is a sensitive adjunct to the diagnosis of coeliac disease. The threshold for positivity was developed for diagnosis, with negative results reported as below the reference value (<4 U/mL). AIM: To investigate if an undetectable (tTG IgA<1.2 U/mL) is more predictive of healing compared to patients with negative but detectable serology (1.2-3.9 U/mL). METHODS: We performed a retrospective study of 402 treated coeliac disease patients seen at the Mayo Clinic with negative tTG IgA values drawn within 1 month of duodenal biopsy between January 2009 and December 2015. The Corazza-Villanacci score was used to assess mucosal healing. The presence of gastrointestinal symptoms was also collected. Logistic regression was used to assess the relationship of clinical variables with a normal biopsy. RESULTS: Patients with undetectable titres more frequently had normal duodenal histology compared to patients with detectable tTG IgA levels (117/240 vs. 53/162; OR=1.96; 1.292, 2.961). Asymptomatic patients more frequently had normal duodenum as compared to symptomatic patients (88/163 vs. 82/239; OR=2.25; CI: 1.494, 3.377). Patients with undetectable serology and on a gluten-free diet for ≥2 years were more likely to have no villous atrophy compared to patients with detectable serology (148/192 vs. 55/88; OR=2.02; CI: 1.17, 3.49). CONCLUSION: In subjects recovering from coeliac disease with negative tTG IgA serology, an undetectable titre is associated with normal histology on follow-up biopsy.

Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01.

Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.

Evaluation of a practical visual MRI rating scale of brain white matter hyperintensities for clinicians based on largest lesion size regardless of location.

BACKGROUND AND PURPOSE: Age-related white matter hyperintensities have prognostic implications, but no accepted clinical standard exists for their assessment. We propose a simple objective visual rating system by using 3T brain MR imaging. MATERIALS AND METHODS: MR imaging from 559 participants was processed by using an automated method to determine WMH volumes and evaluated with a new visual rating scale based on the single largest WMH lesion diameter regardless of location. The reproducibility of the visual system was assessed. The association of WMH visual scores and automated volumes was then compared with cognitive scores from the Montreal Cognitive Assessment, which was available for 510 participants. RESULTS: Inter-reader reproducibility was good for subsamples with both high (n=52) and low (n=40) prevalence of large automated WMH volumes (agreement of 67% and 87.5%, κ=0.71 and 0.76, respectively). Correlation between increased WMH and cognitive deficit measurements was equal for our visual ratings and automated volumes (Spearman ρ=0.118 and 0.109; P values=0.008 and 0.014, respectively). The visual scale retained a significant association with MoCA score after adjusting for age, sex, and education (standardized ß=-0.087, P=.042). CONCLUSIONS: We propose a simple visual WMH scoring system suitable for use as a baseline evaluation in clinical practice.

MR imaging of hippocampal asymmetry at 3T in a multiethnic, population-based sample: results from the Dallas Heart Study.

BACKGROUND AND PURPOSE: Asymmetry of the hippocampus is regarded as an important clinical finding, but limited data on hippocampal asymmetry are available for the general population. Here we present hippocampal asymmetry data from the Dallas Heart Study determined by automated methods and its relationship to age, sex, and ethnicity. MATERIALS AND METHODS: 3D magnetization-prepared rapid acquisition of gradient echo MR imaging was performed in 2082 DHS-2 participants. The MR images were analyzed by using 2 standard automated brain-segmentation programs, FSL-FIRST and FreeSurfer. Individuals with imaging errors, self-reported stroke, or major structural abnormalities were excluded. Statistical analyses were performed to determine the significance of the findings across age, sex, and ethnicity. RESULTS: At the 90th percentile, FSL-FIRST demonstrated hippocampal asymmetry of 9.8% (95% CI, 9.3%-10.5%). The 90th percentile of hippocampal asymmetry, measured by the difference in right and left hippocampi volume and the larger hippocampus, was 17.9% (95% CI, 17.0%-19.1%). Hippocampal asymmetry increases with age (P=.0216), men have greater asymmetry than women as shown by FSL-FIRST (P=.0036), but ethnicity is not significantly correlated with asymmetry. To confirm these findings, we used FreeSurfer. FreeSurfer showed asymmetry of 4.4% (95% CI, 4.3%-4.7%) normalized to total volume and 8.5% (95% CI, 8.3%-9.0%) normalized by difference/larger hippocampus. FreeSurfer also showed that hippocampal asymmetry increases with age (P=.0024) and that men had greater asymmetry than women (P=.03). CONCLUSIONS: There is a significant degree of hippocampal asymmetry in the population. The data provided will aid in the research, diagnosis, and treatment of temporal lobe epilepsy and other neurologic disease.

Reminiscing psychotherapy with aging people.

Reminiscing is the process of remembering one's past, either verbally or internally. Time and the individual's selective processes influence what it remembered and how the memories are evoked. Although reminiscing starts around age 10 and persists throughout life, when aging people reflect on the past the behavior often is regarded as a sign of increasing mental deterioration. Some older people avoid reflecting on the past to prevent being labeled "senile." However, some clinical investigators have found reminiscing beneficial. In 1963 Butler wrote that the elderly psychiatric patients he observed engaged spontaneously in reminiscing and what he termed the "life review." He assumed the life review to be a normal, developmental phenomenon triggered by the person's realization of impending personal death. Potential benefits included resolution of old conflicts, personality reorganization, and restoration of meaning in the individual's life. Studying reminiscenses of aging persons who came from various settings, clinical investigators examined Butler's original ideas and noted other findings. Descriptions of the memories of older people without psychiatric illness demonstrate that some reminiscing is simple story-telling and glorification of the past in addition to life review. However, most investigators believed that remembering the past helped aging people personally and socially. Relationships between the content of memories and present conflicts were explored, and individual and group therapeutic approaches with aging people were designed to encourage reminiscing. Reminiscence provides unique opportunities for clients and therapists to have positive growth experiences.