Effects of chronic cannabidiol in a mouse model of naturally occurring neuroinflammation, neurodegeneration, and spontaneous seizures
(2022) Scientific Reports, 12 (1), art. no. 11286, .
Dearborn, J.T.a , Nelvagal, H.R.b , Rensing, N.R.c , Takahashi, K.b , Hughes, S.M.d , Wishart, T.M.e , Cooper, J.D.b , Wong, M.c , Sands, M.S.a f
Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1−/−) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1−/− mice compared to normal animals. Cln1−/− mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency. © 2022, The Author(s).
Soft, bioresorbable coolers for reversible conduction block of peripheral nerves
(2022) Science, 377 (6601), pp. 109-115.
Reeder, J.T.a b c , Xie, Z.d e , Yang, Q.c f , Seo, M.-H.b c g , Yan, Y.h , Deng, Y.i , Jinkins, K.R.c , Krishnan, S.R.b c , Liu, C.c j , McKay, S.j , Patnaude, E.j , Johnson, A.j , Zhao, Z.d e , Kim, M.J.k , Xu, Y.l , Huang, I.b c , Avila, R.f , Felicelli, C.m , Ray, E.n , Guo, X.d e , Ray, W.Z.h n , Huang, Y.b c f o , MacEwan, M.R.h n , Rogers, J.A.b c f j p q r
Implantable devices capable of targeted and reversible blocking of peripheral nerve activity may provide alternatives to opioids for treating pain. Local cooling represents an attractive means for on-demand elimination of pain signals, but traditional technologies are limited by rigid, bulky form factors; imprecise cooling; and requirements for extraction surgeries. Here, we introduce soft, bioresorbable, microfluidic devices that enable delivery of focused, minimally invasive cooling power at arbitrary depths in living tissues with real-time temperature feedback control. Construction with water-soluble, biocompatible materials leads to dissolution and bioresorption as a mechanism to eliminate unnecessary device load and risk to the patient without additional surgeries. Multiweek in vivo trials demonstrate the ability to rapidly and precisely cool peripheral nerves to provide local, on-demand analgesia in rat models for neuropathic pain. © 2022 American Association for the Advancement of Science. All rights reserved.
A randomized feasibility study evaluating temozolomide circadian medicine in patients with glioma
(2022) Neuro-Oncology Practice, 9 (3), pp. 193-200. Cited 1 time.
Damato, A.R.a c , Katumba, R.G.N.d , Luo, J.a b , Atluri, H.d , Talcott, G.R.d , Govindan, A.d h , Slat, E.A.g , Weilbaecher, K.N.d , Tao, Y.a b , Huang, J.d , Butt, O.H.d , Ansstas, G.d , Johanns, T.M.d , Chheda, M.G.d , Herzog, E.D.c f , Rubin, J.B.e f , Campian, J.L.d
Background: Gliomas are the most common primary brain tumor in adults. Current treatments involve surgery, radiation, and temozolomide (TMZ) chemotherapy; however, prognosis remains poor and new approaches are required. Circadian medicine aims to maximize treatment efficacy and/or minimize toxicity by timed delivery of medications in accordance with the daily rhythms of the patient. We published a retrospective study showing greater anti-tumor efficacy for the morning, relative to the evening, administration of TMZ in patients with glioblastoma. We conducted this prospective randomized trial to determine the feasibility, and potential clinical impact, of TMZ chronotherapy in patients with gliomas (NCT02781792). Methods: Adult patients with gliomas (WHO grade II-IV) were enrolled prior to initiation of monthly TMZ therapy and were randomized to receive TMZ either in the morning (AM) before 10 am or in the evening (PM) after 8 pm. Pill diaries were recorded to measure compliance and FACT-Br quality of life (QoL) surveys were completed throughout treatment. Study compliance, adverse events (AE), and overall survival were compared between the two arms. Results: A total of 35 evaluable patients, including 21 with GBM, were analyzed (18 AM patients and 17 PM patients). Compliance data demonstrated the feasibility of timed TMZ dosing. There were no significant differences in AEs, QoL, or survival between the arms. Conclusions: Chronotherapy with TMZ is feasible. A larger study is needed to validate the effect of chronotherapy on clinical efficacy. © 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved.
Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer’s disease
(2022) Alzheimer’s and Dementia, .
Liu, L.a , Lauro, B.M.a , He, A.a , Lee, H.a , Bhattarai, S.b , Wolfe, M.S.b , Bennett, D.A.c , Karch, C.M.d e , Young-Pearse, T.a , Selkoe, D.J.a , Dominantly Inherited Alzheimer Network (DIAN)f
Introduction: Identifying CSF-based biomarkers for the β-amyloidosis that initiates Alzheimer’s disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. Methods: We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity and brain Aβ accumulation. Results: We show that Aβ 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD. Discussion: We conclude that the Aβ 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aβ42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD. © 2022 the Alzheimer’s Association
Investing in Late-Life Brain Capital
(2022) Innovation in Aging, 6 (3), art. no. igac016, .
Dawson, W.D.a b c , Smith, E.b d , Booi, L.b e , Mosse, M.d , Lavretsky, H.f , Reynolds, C.F.g , Cummings, J.h , Brannally, P.i , Hynes, W.d , Lenze, E.J.j , Manes, F.k l , Ayadi, R.m , Frank, L.n , Chapman, S.B.o , Robertson, I.H.b o , Rubenstein, L.p , Jraissati, J.q , Ibáñez, A.b r , Fillit, H.s t , Jeste, D.V.u v , Rao, A.w x , Berk, M.y z , Storch, E.A.aa , Santuccione Chadha, A.ab ac , Eyre, H.A.y ad
Within many societies and cultures around the world, older adults are too often undervalued and underappreciated. This exacerbates many key challenges that older adults may face. It also undermines the many positive aspects of late life that are of tremendous value at both an individual and societal level. We propose a new approach to elevate health and well-being in late life by optimizing late-life Brain Capital. This form of capital prioritizes brain skills and brain health in a brain economy, which the challenges and opportunities of the 21st-century demands. This approach incorporates investing in late-life Brain Capital, developing initiatives focused on building late-life Brain Capital. © 2022 The Author(s) 2022.
Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer’s disease
(2021) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 13 (1), art. no. e12197, .
Keret, O.a , Staffaroni, A.M.b , Ringman, J.M.c , Cobigo, Y.b , Goh, S.-Y.M.b , Wolf, A.b , Allen, I.E.a d , Salloway, S.e , Chhatwal, J.f , Brickman, A.M.g , Reyes-Dumeyer, D.g , Bateman, R.J.h i j k l , Benzinger, T.L.S.h j , Morris, J.C.h i j k l , Ances, B.M.h i j k l , Joseph-Mathurin, N.h i j k l , Perrin, R.J.h i j k l , Gordon, B.A.h i j k l , Levin, J.m n , Vöglein, J.m n , Jucker, M.o p , la Fougère, C.o q , Martins, R.N.r s t u v , Sohrabi, H.R.r s t u v , Taddei, K.s u , Villemagne, V.L.w , Schofield, P.R.x y , Brooks, W.S.x z , Fulham, M.aa , Masters, C.L.ab , Ghetti, B.ac , Saykin, A.J.ad ae , Jack, C.R.af , Graff-Radford, N.R.ag , Weiner, M.ah ai aj ak al , Cash, D.M.am an , Allegri, R.F.ao , Chrem, P.ao , Yi, S.ap , Miller, B.L.a b , Rabinovici, G.D.a , Rosen, H.J.a b , Dominantly Inherited Alzheimer Networkaq
Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer’s disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score’s predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%–98.2%]) and improved prediction beyond established methods based on familial age of onset. Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials. © 2021 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer’s Association