Predictors of cognitive impairment in pseudotumor cerebri.

AIMS OF THE STUDY: We aimed to define the cognitive burden of the largest pseudotumor cerebri syndrome (PTCS) population to date, compare objective to subjective cognitive dysfunction, and determine clinical predictors of cognitive dysfunction amongst an array of previously unstudied factors. CLINICAL RATIONALE: Patients with PTCS commonly report cognitive dysfunction, a factor associated with poor quality of life. It is not definitively known whether cognitive impairment is present in these patients, and what features of the syndrome predict impairment. MATERIALS AND METHODS: We administered a cognitive battery consisting of the National Adult Reading Test, Mini-Mental Status Exam, Digit Span, Boston Naming Test, Rey Auditory Verbal Learning Test, Clock Drawing, Trail Making Test, Controlled Oral Word Association, and Category Fluency. Cognitive impairment was defined as mild-single domain with one test score, and mild-multiple domain with two scores, more than two standard deviations below the mean for age-, gender-, and education-adjusted norms. RESULTS: One-hundred and one prospectively recruited PTCS patients were enrolled. The objective testing showed 30 patients had mild-single domain impairment, and 25 had mild-multi domain impairment. More patients without objective cognitive impairment had transverse venous sinus stenosis, but otherwise the groups did not differ. Two measures of headache severity, the Headache Impact Test and pain on the Numeric Rating Scale, were negatively associated with the composite cognitive score, as was ocular pain, vision-related disability, and mental health. Opening pressure and visual function were not associated with objective cognitive impairment. We found no association between subjective and objective cognitive impairment. CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients with PTCS may be cognitively impaired, and this correlates with measures of headache burden. Studies evaluating cognitive impairment before and after remission of the headache disorder would have to be performed to investigate this relationship further. Patients with self-perception of cognitive burden are no more likely to be cognitively impaired.

Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/ßA3/A1-crystallin via V-ATPase-MTORC1 signaling.

In phagocytic cells, including the retinal pigment epithelium (RPE), acidic compartments of the endolysosomal system are regulators of both phagocytosis and autophagy, thereby helping to maintain cellular homeostasis. The acidification of the endolysosomal system is modulated by a proton pump, the V-ATPase, but the mechanisms that direct the activity of the V-ATPase remain elusive. We found that in RPE cells, CRYBA1/ßA3/A1-crystallin, a lens protein also expressed in RPE, is localized to lysosomes, where it regulates endolysosomal acidification by modulating the V-ATPase, thereby controlling both phagocytosis and autophagy. We demonstrated that CRYBA1 coimmunoprecipitates with the ATP6V0A1/V0-ATPase a1 subunit. Interestingly, in mice when Cryba1 (the gene encoding both the ßA3- and ßA1-crystallin forms) is knocked out specifically in RPE, V-ATPase activity is decreased and lysosomal pH is elevated, while cathepsin D (CTSD) activity is decreased. Fundus photographs of these Cryba1 conditional knockout (cKO) mice showed scattered lesions by 4 months of age that increased in older mice, with accumulation of lipid-droplets as determined by immunohistochemistry. Transmission electron microscopy (TEM) of cryba1 cKO mice revealed vacuole-like structures with partially degraded cellular organelles, undigested photoreceptor outer segments and accumulation of autophagosomes. Further, following autophagy induction both in vivo and in vitro, phospho-AKT and phospho-RPTOR/Raptor decrease, while pMTOR increases in RPE cells, inhibiting autophagy and AKT-MTORC1 signaling. Impaired lysosomal clearance in the RPE of the cryba1 cKO mice also resulted in abnormalities in retinal function that increased with age, as demonstrated by electroretinography. Our findings suggest that loss of CRYBA1 causes lysosomal dysregulation leading to the impairment of both autophagy and phagocytosis.