Sultan Darvesh

Diagnosis of Alzheimer's disease (AD) requires symptoms of dementia and accumulation of amyloid-β (Aβ) and tau in the brain. Molecular imaging of Aβ or tau in AD, though informative, is complicated by the finding that similar changes are found in brains of ~ 30% of cognitively normal older individuals. Butyrylcholinesterase (BChE), normally present in low levels in the cerebral cortex, is found in high levels associated with Aβ plaques in AD. When associated with plaques, the biochemical properties of BChE are altered. The aim of the present study was to determine if the BChE ligand, [¹⁸F]1-methyl-4-piperidinyl p-fluorobenzoate ([¹⁸F]BMP), can image BChE-associated plaques in the 5XFAD mouse model of AD and distinguish it from its wild-type (WT) counterpart. [¹⁸F]BMP was synthesized and evaluated in wild-type (WT), 5XFAD and BChE knock-out (BChE-KO) mouse models for in vivo dynamic PET imaging of BChE. Time-activity curves were generated and [¹⁸F]BMP clearance parameters were determined. Brain, liver and urine homogenates were evaluated for [¹⁸F]BMP and its metabolites. Ex vivo autoradiography mapped the distribution of [¹⁸F]BMP brain retention. In vivo PET imaging following injection of [¹⁸F]BMP demonstrated significantly greater brain retention of activity in 5XFAD mice compared to WT, while BChE-KO mice appeared similar to WT levels. Metabolite analysis confirmed [¹⁸F]BMP was metabolized in the periphery but survived in sufficient quantity to enter the brain. Ex vivo autoradiography showed [¹⁸F]BMP retention in the 5XFAD brain where BChE-associated plaques were prominent. These results demonstrate that PET imaging of BChE-associated plaques is feasible, offering an avenue to evaluate the role(s) of BChE in AD pathogenesis and progression to complement the existing AD biomarker framework.

In comatose patients at risk of death by neurologic criteria (DNC), spinal-mediated movements (SMM) and movements of unclear neuroanatomic origin (MUO) are

Purpose Diagnosis of Alzheimer’s disease (AD) requires symptoms of dementia and accumulation of amyloid-β (Aβ) and tau in the brain. Molecular imaging of Aβ or tau in AD, though informative, is complicated by the finding that similar changes are found in brains of ~ 30% of cognitively normal older individuals. Butyrylcholinesterase (BChE), normally present in low levels in the cerebral cortex, is found in high levels associated with Aβ plaques in AD. When associated with this pathological structure, the biochemical properties of BChE are altered. The aim of the present study was to determine if [ ¹⁸ F]1-Methyl-4-piperidinyl p-fluorobenzoate ([ ¹⁸ F]BMP) can image BChE associated with Aβ in 5XFAD mouse model of AD and distinguish it from its wild-type (WT) counterpart. Procedures [ ¹⁸ F]BMP was synthesized and evaluated in wild-type (WT), 5XFAD and BChE knock-out (BChE-KO) mouse models for in vivo dynamic PET imaging of BChE. Time-activity curves were generated and [ ¹⁸ F]BMP clearance parameters were determined. Brain, liver and urine homogenates were evaluated for [ ¹⁸ F]BMP and its metabolites. Ex vivo autoradiography mapped the distribution of [ ¹⁸ F]BMP brain retention. Results In vivo PET imaging following injection of [ ¹⁸ F]BMP demonstrated significantly greater brain retention of activity in the 5XFAD mouse model compared to WT, while BChE-KO mice mirrored WT levels. Metabolite analysis confirmed [ ¹⁸ F]BMP was metabolized in the periphery but survived in sufficient quantity to enter the brain. Ex vivo autoradiography showed [ ¹⁸ F]BMP retention in the 5XFAD mouse brain where BChE-associated Aβ plaques were prominent. Conclusions These results demonstrate that PET imaging of BChE-associated Aβ plaques is feasible, offering an avenue to evaluate role(s) of BChE in AD pathogenesis, progression and complement the existing AD biomarker framework.

Importance: Accurate and timely confirmation of death by neurologic criteria (DNC) is essential for clinical decision-making and organ-donation processes, yet currently available ancillary tests have suboptimal diagnostic performance or limited validation.Objectives: To determine the diagnostic accuracy, interrater reliability, and safety of brain computed tomography (CT) perfusion and CT angiography as ancillary investigations for DNC.Design, Setting, and Participants: Between April 25, 2017, and March 10, 2021, a prospective, multicenter, blinded diagnostic accuracy cohort study was conducted in 15 adult intensive care units across Canada. Consecutive, critically ill adults (aged ≥18 years) with a Glasgow Coma Scale score of 3 and no confounding factors who were at high risk of DNC were included. Data collection and analysis were performed from April 2021 to July 2024.Exposure: Contrast-enhanced brain CT perfusion with CT angiography reconstructions performed within 2 hours of a blinded, standardized clinical DNC examination.Main Outcomes and Measures: The primary outcomes were the sensitivity and specificity of qualitative and quantitative brainstem CT perfusion for DNC determination, assessed by 2 independent neuroradiologists blinded to clinical findings; the prespecified validation threshold was greater than 98%. Secondary outcomes were the diagnostic accuracy of whole-brain CT perfusion and CT angiography, interrater reliability (Cohen κ), and adverse events associated with imaging.Results: A total of 282 patients (mean [SD] age, 57.8 [15.4] years; 133 [47%] female) completed the study protocol and were included in the primary analysis; 204 (72%) of these were ultimately declared deceased by standardized clinical criteria. Qualitative brainstem CT perfusion showed a sensitivity of 98.5% (95% CI, 95.8%-99.7%) and a specificity of 74.4% (95% CI, 63.2%-83.6%); quantitative brainstem CT perfusion was not diagnostically accurate. Qualitative whole-brain CT perfusion yielded a sensitivity of 93.6% (95% CI, 89.3%-96.6%) and a specificity of 92.3% (95% CI, 84.0%-97.1%). CT angiography sensitivity ranged from 75.5% (95% CI, 69.0%-81.2%) to 87.3% (95% CI, 81.9%-91.5%), and its specificity ranged from 89.7% (95% CI, 80.8%-95.5%) to 91.0% (95% CI, 82.4%-96.3%). Interrater reliability was excellent for all ancillary tests (κ ranged from 0.81 [95% CI, 0.73-0.89] to 0.84 [95% CI, 0.78-0.91]). Fourteen patients (5%) experienced minor, self-limited adverse events; no serious adverse events occurred.Conclusions and Relevance: The observed sensitivity and specificity measures for CT perfusion and CT angiography as an ancillary test for DNC did not meet the prespecified validation threshold of greater than 98%. Clinical examination remains the cornerstone of DNC, and ancillary imaging should be interpreted cautiously within a comprehensive clinical assessment.

Cellular senescence is a hallmark of aging and the age-related condition, Alzheimer’s disease (AD). How senescence contributes to cholinergic and neuropathologic changes in AD remains uncertain. Furthermore, little is known about the relationship between senescence and cholinesterases (ChEs). Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are important in neurotransmission, cell cycle regulation, and AD amyloid-β (Aβ) pathology. Senolytic agents have shown therapeutic promise in AD models. Therefore, we evaluated in vitro and in silico activity of senolytics, dasatinib (1), nintedanib (2), fisetin (3), quercetin (4), GW2580 (5), and nootropic, meclofenoxate hydrochloride (6), toward AChE and BChE. As ChEs associated with AD pathology have altered biochemical properties, we also evaluated agents 1-6 in AD brain tissues. Enzyme kinetics showed agents 1, 3, 4, and 6 inhibited both ChEs, while 2 and 5 inhibited only AChE. Histochemistry showed inhibition of Aβ plaque-associated ChEs (1 and 2: both ChEs; 5: BChE; 6: AChE), but not normal neural-associated ChEs. Modeling studies showed 1-6 interacted with the same five binding locations of both ChEs, some of which may be allosteric sites. These agents may exert their beneficial effects, in part, by inhibiting ChEs associated with AD pathology and provide new avenues for development of next-generation inhibitors targeting pathology-associated ChEs.

The French composer, Maurice Ravel, at the peak of his career, showed signs of a progressive disorder that affected his ability to function with verbal and musical language, as noted by the neurologist Théophile Alajouanine. The worsening of the disease led to a craniotomy, performed in 1937, which failed to reveal the cause of his illness, and he died shortly thereafter. A lack of post-mortem neuropathological evidence precluded a definitive diagnosis of the illness, which remained enigmatic. Speculations about the precise diagnosis of Ravel's neurological disease have been largely based on Alajouanine's observations, which included aphasia and amusia, mostly expressive, and ideomotor apraxia, while musical judgement, taste, and memory remained relatively intact, implying different neuroanatomical substrates. A possible subform of frontotemporal lobar degeneration complex was the diagnostic suggestion of many authors. His untimely death deprived the world of this remarkable musician, and the music that remained trapped in his mind.

Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (M^pro) and papain-like protease (PL^pro), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 M^pro and PL^pro protease activity in vitro was identified. In silico docking studies also predicted binding of the phenothiazine to the active sites of M^pro and PL^pro from distantly related alphacoronavirus, HCoV-229E (229E) and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cell culture infection models. It was further demonstrated that the compound inhibited 229E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses.