Methazolamide

Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies.

Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration–approved against glaucoma and high‐altitude sickness.

Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro‐clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase‐VB (CA‐VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA‐VB silencing specifically reduces Aβ‐mediated endothelial apoptosis.

This work substantiates the potential application of CAIs in clinical trials for AD and CAA.

A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both eyes and cupped nerves. She had a family history of glaucoma in her father. She was started on latanoprost in both eyes and was referred for a glaucoma evaluation. On initial evaluation, her IOP was 25 mm Hg in the right eye and 26 mm Hg in the left eye. Central corneal thickness measured 592 µm in the right eye and 581 µm in the left eye. Her angles were open to gonioscopy without any peripheral anterior synechia. She had 1+ nuclear sclerosis with a corrected distance visual acuity (CDVA) of 20/25 in the right eye and 20/30− in the left eye and uncorrected near visual acuity of J1+ in each eye. Her nerves were 0.85 mm in the right eye and 0.75 mm in the left eye. Optical coherence tomography (OCT) showed retinal nerve fiber layer thinning and a dense superior arcuate scotoma into fixation in her right eye, and superior and inferior arcuate scotomas in her left eye (Figures 1 and 2 JOURNAL/jcrs/04.03/02158034-202307000-00019/figure1/v/2023-12-05T194319Z/r/image-tiff JOURNAL/jcrs/04.03/02158034-202307000-00019/figure2/v/2023-12-05T194319Z/r/image-tiff , Supplemental Figures 1 and 2, available at http://links.lww.com.libproxy1.nus.edu.sg/JRS/A882 and http://links.lww.com.libproxy1.nus.edu.sg/JRS/A883). She was successively trialed on fixed combination brimonidine–timolol, dorzolamide, and netarsudil, in addition to her latanoprost, but her IOP remained in the mid- to upper 20s in both eyes. The addition of acetazolamide lowered the pressure to 19 mm Hg in both eyes, but she tolerated it poorly. Methazolamide was also attempted with similar side effects.We elected to perform left eye cataract surgery combined with 360-degree viscocanaloplasty and insertion of a Hydrus microstent (Alcon Laboratories, Inc.). Surgery was uncomplicated with IOP of 16 mm Hg on postoperative day 1 with no glaucoma medications. However, by postoperative week 3, IOP returned to 27 mm Hg, and despite restarting latanoprost–netarsudil and finishing her steroid taper, IOP remained at 27 mm Hg by postoperative week 6. Brimonidine–timolol was added back to her left eye regimen and at postoperative week 8, IOP had elevated to 45 mm Hg. Maximizing her therapy with the addition of topical dorzolamide and oral methazolamide brought her IOP back down to 30 mm Hg. At that point, the decision was made to proceed with trabeculectomy of the left eye. The trabeculectomy was uneventful. However, postoperative attempts to augment filtration were rendered less successful by extremely thick Tenon layer. At her most recent follow-up the pressure in the left eye was mid-teens with brimonidine–timolol and dorzolamide.Her right eye IOP is in the upper 20s on maximum topical therapy. Knowing her postoperative course in the left eye, how would you manage the right eye? In addition to currently available options, would you consider a supraciliary shunt such as the MINIject (iSTAR) if such a device were U.S. Food and Drug Administration (FDA)-approved?