Faculty Bibliography

OBJECTIVES/OBJECTIVE:Tension-type headache (TTH) is the most prevalent primary headache disorder. We assessed the cross-sectional impact of TTH on health related quality of life (HRQoL) in a general population. We also examined the association of HRQoL scores with headache frequency, disability, medication overuse, poor self-rated health, psychiatric comorbidity, and pain sensitivity in individuals with TTH. METHODS:A sample of 547 subjects completed a headache diagnostic interview, the SF-12 to calculate physical (PCS) and mental (MCS) health component scores, depression (major depression inventory [MDI]) and neuroticism (Eysenck Personality Questionnaire) measures. We defined the following headache diagnosis categories: pure TTH, pure migraine, and coexistent headache (TTH + migraine). Cases were further classified into chronic (≥15) or episodic (<15 headache days/month). RESULTS:Using generalized linear models (GLM) adjusted for age, sex and education, both PCS-12 and MCS-12 scores varied in groups distinguished by migraine and TTH status; scores were lower for individuals with coexistent headache (TTH + migraine; n=83), followed by pure TTH (n=97) and pure migraine (n=43) compared to the no headache group (n=324) (p≤0.001). In analyses considering chronicity, PCS-12 scores were lower in chronic coexistent headache followed by pure chronic TTH (CTTH), episodic migraine +/- episodic TTH (ETTH) and pure ETTH than in the no headache group (p≤0.001). MCS-12 scores were lower in pure CTTH, followed by chronic coexistent headache, episodic migraine +/- ETTH and pure ETTH compared to the no headache group (p≤0.001). Multiple regression models showed that in TTH, lower PCS-12 scores were associated with age (p=0.04), female sex (p=0.02), and poor self-rated health (p≤0.001). Lower MCS-12 scores in TTH were associated with depression (p≤0.001). CONCLUSIONS:In a population sample, TTH, and to higher degree CTTH, are associated with decreased HRQoL.

RATIONALE AND OBJECTIVES/OBJECTIVE:Periventricular and deep white matter hyperintensities (WMHs) in the elderly have been reported with distinctive roles in the progression of cognitive decline and dementia. However, the definition of these two subregions of WMHs is arbitrary and varies across studies. Here, we evaluate three partition methods for WMH subregions, including two widely used conventional methods (CV & D10) and one novel method based on bilateral distance (BD). MATERIALS AND METHODS/METHODS:The three partition methods were assessed on the MRI scans of 60 subjects, with 20 normal control, 20 mild cognitive impairment, and 20 Alzheimer's disease (AD). Resulting WMH subregional volumes were (1) compared among different partition methods and subject groups, and (2) tested for clinical associations with cognition and dementia. Inter-rater, intrarater, and interscan reproducibility of WMHs volumes were tested on 12 randomly selected subjects from the 60. RESULTS:For all three partition methods, increased periventricular WMHs were found for AD subjects over normal control. For BD and D10, but not CV method, increased Periventricular WMHs were found for AD subjects over mild cognitive impairment. Significant correlations were found between PVWMHs and Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating scores. Furthermore, PVWMHs under BD partition showed higher correlations than D10 and CV. High intrarater and interscan reproducibility (ICCA = 0.998 and 0.992 correspondingly) and substantial inter-rater reproducibility (ICCA = 0.886) were detected. CONCLUSION/CONCLUSIONS:Different WMH partition methods showed comparable diagnostic abilities. The proposed BD method showed advantages in quantifying PVWMH over conventional CV and D10 methods, in terms of higher consistency, larger contrast, and higher diagnosis accuracy. Furthermore, the PVWMH under BD partition showed stronger clinical correlations than conventional methods.

Slowed processing on the alerting, orienting and executive control components of attention measured using the Attention Network Test-Interactions (ANT-I) have been widely reported in multiple sclerosis (MS). Despite the assumption that these components correspond to specific neuroanatomical networks in the brain, little is known about gray matter changes that occur in MS and their association with ANT-I performance. We investigated vertex-wise cortical thickness changes and deep gray matter volumetric changes in young MS participants (N = 21, age range: 18-35) with pediatric or young-adult onset and mild disease severity. ANT-I scores and cortical thickness were not significantly different between MS participants and healthy volunteers (N = 19, age range: 18-35), but thalamic volumes were significantly lower in MS. Slowed reaction times on the alerting component in MS correlated significantly with reduced volume of the right pallidum in MS. Slowed reaction times on executive control component correlated significantly with reduced thickness in the frontal, parietal and visual cortical areas and with reduced volume of the left putamen in MS. These findings demonstrate associations between gray matter changes and attentional performance even in the absence of widespread atrophy or slowed attentional processes.

OBJECTIVE:To determine whether a smartphone application (app) with an electronic headache diary and a progressive muscle relaxation (PMR) intervention is feasible and acceptable to people presenting to the Emergency Department (ED) with migraine. METHODS:This single arm prospective study assessed feasibility by actual use of the app and acceptability by satisfaction with the app. We report preliminary data on change in migraine disability and headache days. RESULTS:The 51 participants completed PMR sessions on a mean of 13 ± 19 (0,82) days for the 90-day study period, lasting a median of 11 min (IQR 6.5, 17) each. Median number of days of diary use was 34 (IQR 10, 77). Diaries were completed at least twice a week in half of study weeks (337/663). Participants were likely (≥4/5 on a 5-point Likert scale) to recommend both the app (85%) and PMR (91%). MIDAS scores significantly decreased by a mean of 38 points/participant (p < 0.0001). More frequent PMR use was associated with a higher odds of headache free days (p = 0.0148). CONCLUSION/CONCLUSIONS:Smartphone-based PMR introduced to patients who present to the ED for migraine is feasible and acceptable. More frequent users have more headache free days. Future work should focus on intervention engagement.

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1^fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.

Neuropsychiatric disturbances represent a common and uniquely challenging consequence of stroke. These disorders arise at the intersection of lesion-related brain dysfunction and psychological distress related to the event and its aftermath, making it difficult to identify what symptom is a direct physiological consequence of the stroke. Depression, anxiety, fatigue, apathy, emotionalism, and anger are the most common of these syndromes, and posttraumatic stress disorder related to the stroke event has become increasingly recognized as a relevant entity. Mania, obsessive-compulsive disorder, and psychosis are less commonly encountered but potentially highly debilitating conditions that may be underrecognized. Early identification and treatment may mitigate functional impairment and improve quality of life. Evidence-based guidelines from the general population are often relied upon to guide treatment. Further research is needed to understand and tailor treatment of these disorders in the poststroke population.

Cerebral cavernous malformations (CCMs) are vascular abnormalities that primarily occur in adulthood and cause cerebral hemorrhage, stroke, and seizures. CCMs are thought to be initiated by endothelial cell (EC) loss of any one of the three Ccm genes: CCM1 (KRIT1), CCM2 (OSM), or CCM3 (PDCD10). Here we report that mice with a brain EC-specific deletion of Pdcd10 (Pdcd10^BECKO) survive up to 6-12 months and develop bona fide CCM lesions in all regions of brain, allowing us to visualize the vascular dynamics of CCM lesions using transcranial two-photon microscopy. This approach reveals that CCMs initiate from protrusion at the level of capillary and post-capillary venules with gradual dissociation of pericytes. Microvascular beds in lesions are hyper-permeable, and these disorganized structures present endomucin-positive ECs and α-smooth muscle actin-positive pericytes. Caveolae in the endothelium of Pdcd10^BECKO lesions are drastically increased, enhancing Tie2 signaling in Ccm3-deficient ECs. Moreover, genetic deletion of caveolin-1 or pharmacological blockade of Tie2 signaling effectively normalizes microvascular structure and barrier function with attenuated EC-pericyte disassociation and CCM lesion formation in Pdcd10^BECKO mice. Our study establishes a chronic CCM model and uncovers a mechanism by which CCM3 mutation-induced caveolae-Tie2 signaling contributes to CCM pathogenesis.