Faculty Bibliography

OBJECTIVE:This study examined Dot Counting Test (DCT) performance among patient populations with no/minimal impairment and mild impairment in an attempt to cross-validate a more parsimonious interpretative strategy and to derive optimal E-Score cutoffs. METHOD: = 183) settings. Patients were separated by validity status (valid/invalid), and subsequently two comparison groups were formed from each sample's valid group. Namely, Group 1 included patients with no to minimal cognitive impairment, and Group 2 included those with mild neurocognitive disorder. Analysis of variance tested for differences between rounded and unrounded DCT E-Scores across both comparison groups and the invalid group. Receiver operating characteristic curve analyses identified optimal validity cut-scores for each sample and stratified by comparison groups. RESULTS:In the VA sample, cut scores of ≥13 (rounded) and ≥12.58 (unrounded) differentiated Group 1 from the invalid performers (87% sensitivity/88% specificity), and cut scores of ≥17 (rounded; 58% sensitivity/90% specificity) and ≥16.49 (unrounded; 61% sensitivity/90% specificity) differentiated Group 2 from the invalid group. Similarly, in the AMC group, a cut score of ≥13 (rounded and unrounded; 75% sensitivity/90% specificity) differentiated Group 1 from the invalid group, whereas cut scores of ≥18 (rounded; 43% sensitivity/94% specificity) and ≥16.94 (unrounded; 46% sensitivity/90% specificity) differentiated Group 2 from the invalid performers. CONCLUSIONS:Different cut scores were indicated based on degree of cognitive impairment, and provide proof-of-concept for a more parsimonious interpretative paradigm than using individual cut scores derived for specific diagnostic groups.

BACKGROUND:Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS:Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS:Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS:Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

Proteomic studies of human Alzheimer's disease brain tissue have potential to identify protein changes that drive disease, and to identify new drug targets. Here, we analyse 38 published Alzheimer's disease proteomic studies, generating a map of protein changes in human brain tissue across thirteen brain regions, three disease stages (preclinical Alzheimer's disease, mild cognitive impairment, advanced Alzheimer's disease), and proteins enriched in amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. Our dataset is compiled into a searchable database (NeuroPro). We found 848 proteins were consistently altered in 5 or more studies. Comparison of protein changes in early-stage and advanced Alzheimer's disease revealed proteins associated with synapse, vesicle, and lysosomal pathways show change early in disease, but widespread changes in mitochondrial associated protein expression change are only seen in advanced Alzheimer's disease. Protein changes were similar for brain regions considered vulnerable and regions considered resistant. This resource provides insight into Alzheimer's disease brain protein changes and highlights proteins of interest for further study.

This study cross-validated the dot counting test (DCT) as a performance validity test (PVT) in an adult attention-deficit/hyperactivity disorder (ADHD) clinical population and examined the effect of ADHD subtype and psychiatric comorbidity on accuracy for detecting invalidity. DCT performance was assessed among 210 consecutive adult ADHD referrals who underwent neuropsychological evaluation and were classified into valid (n = 175) or invalid (n = 35) groups based on seven independent criterion PVTs. The invalid group had significantly worse DCT performance than the valid group using both the standard and unrounded scoring procedure (

Wolfram syndrome is a neurodegenerative disorder caused by pathogenic variants in the genes WFS1 or CISD2. Clinically, the classic phenotype is composed of optic atrophy, diabetes mellitus type 1, diabetes insipidus, and deafness. Wolfram syndrome, however, is phenotypically heterogenous with variable clinical manifestations and age of onset. We describe four cases of genetically confirmed Wolfram syndrome with variable presentations, including acute-on-chronic vision loss, dyschromatopsia, and tonic pupils. All patients had optic atrophy, only three had diabetes, and none exhibited the classic Wolfram phenotype. MRI revealed a varying degree of the classical features associated with the syndrome, including optic nerve, cerebellar, and brainstem atrophy. The cohort's genotype and presentation supported the reported phenotype-genotype correlations for Wolfram, where missense variants lead to milder, later-onset presentation of the Wolfram syndrome spectrum. When early onset optic atrophy and/or diabetes mellitus are present in a patient, a diagnosis of Wolfram syndrome should be considered, as early diagnosis is crucial for the appropriate referrals and management of the associated conditions. Nevertheless, the condition should also be considered in otherwise unexplained, later-onset optic atrophy, given the phenotypic spectrum.

OBJECTIVE:Despite widespread use of the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF), it is surprisingly understudied among adults with attention-deficit/hyperactivity disorder (ADHD). This is significant as ADHD is a frequent referral for neuropsychological evaluation; however, the core symptom of attention difficulty is a nonspecific sequela of many psychological disorders. This study aimed to characterize MMPI-2-RF profiles among adults with ADHD and examine the effect of comorbid psychopathology. METHOD/METHODS:A large, demographically diverse sample of 413 consecutive adults referred for neuropsychological evaluation to assist with differential diagnosis of ADHD who completed the MMPI-2-RF was examined. Profiles of the 145 patients diagnosed with ADHD-only were compared to 192 with ADHD and a comorbid psychological disorder and a 55-patient non-ADHD psychiatric comparison group. Among the ADHD-only group, profiles also were compared based on ADHD-presentation type (Predominantly Inattentive vs. Combined presentation). RESULTS:The ADHD/psychopathology and psychiatric comparison groups scored higher than the ADHD-only group across nearly all scales with widespread clinical elevations. Conversely, the ADHD-only group displayed an isolated elevation on the Cognitive Complaints scale. Comparison between ADHD presentations revealed several small-moderate significant differences, the largest of which occurred on the Externalizing and Interpersonal scales. CONCLUSIONS:Adults with ADHD alone, and no other psychopathology have a unique MMPI-2-RF profile characterized by isolated elevation on the Cognitive Complaints scale. These results support use of the MMPI-2-RF in assessment of adults with ADHD as it can help distinguish ADHD alone from ADHD/comorbid psychopathology and identify relevant psychiatric comorbidities that may be contributing to patients' inattention complaints.

PURPOSE OF REVIEW/OBJECTIVE:We evaluate the evolving evidence of psychiatric comorbidities associated with episodic migraine. Utilizing recent research publications, we aim to assess traditional treatment option considerations and discuss recent and evolving non-pharmacologic treatment progress for episodic migraine and related psychiatric conditions. RECENT FINDINGS/RESULTS:Recent findings indicate that episodic migraine is strongly linked to comorbid depression, anxiety, posttraumatic stress disorder, and sleep disorders. Not only do patients with episodic migraine have higher rates of psychiatric comorbidity, but a higher number of headache days reported is also strongly linked to an increased risk of developing a psychiatric disorder, indicating there may be a link between frequency and psychiatric comorbidity and that patients with high-frequency episodic migraine should be assessed for psychiatric comorbidity. Few migraine preventive medications have examined the effect of the medication on both migraine and psychiatric comorbidity though we discuss what has been reported in the literature. Non-pharmacologic-based treatments including behavioral therapies and mind-body interventions previously developed for psychiatric conditions, e.g., mindfulness-based CBT (MBCT), acceptance and commitment therapy (ACT), and mindfulness-based stress reduction (MBSR) therapy, have promising results for patients diagnosed with episodic migraine and may therefore be useful in treating migraine and comorbid psychiatric conditions. Psychiatric comorbidity may affect the efficacy of the treatment of episodic migraine. Thus, we must assess for psychiatric comorbidities to inform better treatment plans for patients. Providing patients with episodic migraine with alternate modalities of treatment may help to improve patient-centered care and increase patients' sense of self-efficacy.

BACKGROUND AND PURPOSE:The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS:We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS:The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS:The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.

Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.