WashU weekly Neuroscience publications: July 14, 2024

Clinical application of plasma P-tau217 to assess eligibility for amyloid-lowering immunotherapy in memory clinic patients with early Alzheimer’s disease
(2024) Alzheimer’s Research and Therapy, 16 (1), art. no. 154, . 

Howe, M.D.^a b , Britton, K.J.^c , Joyce, H.E.^a , Menard, W.^a , Emrani, S.^d , Kunicki, Z.J.^b , Faust, M.A.^a , Dawson, B.C.^a , Riddle, M.C.^a b , Huey, E.D.^a b , Janelidze, S.^e , Hansson, O.^e f , Salloway, S.P.^a b

^a Butler Hospital Memory & amp; Aging Program, 345 Blackstone Boulevard, Providence, RI 02906, United States
^b Department of Psychiatry and Human Behavior, Brown University, Providence, RI, United States
^c Washington University in St. Louis, St. Louis, MO, United States
^d University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^e Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden
^f Memory Clinic, Skåne University Hospital, Malmö, Sweden

Abstract
Background: With the approval of disease-modifying treatments (DMTs) for early Alzheimer’s disease (AD), there is an increased need for efficient and non-invasive detection methods for cerebral amyloid-β (Aβ) pathology. Current methods, including positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis, are costly and invasive methods that may limit access to new treatments. Plasma tau phosphorylated at threonine-217 (P-tau217) presents a promising alternative, yet optimal cutoffs for treatment eligibility with DMTs like aducanumab require further investigation. This study evaluates the efficacy of one- and two-cutoff strategies for determining DMT eligibility at the Butler Hospital Memory & Aging Program (MAP). Methods: In this retrospective, cross-sectional diagnostic cohort study, we first developed P-tau217 cutoffs using site-specific and BioFINDER-2 training data, which were then tested in potential DMT candidates from Butler MAP (total n = 150). ROC analysis was used to calculate the area under the curve (AUC) and accuracy of P-tau217 interpretation strategies, using Aβ-PET/CSF testing as the standard of truth. Results: Potential DMT candidates at Butler MAP (n = 50), primarily diagnosed with mild cognitive impairment (n = 29 [58%]) or mild dementia (21 [42%]), were predominantly Aβ-positive (38 [76%]), and half (25 [50%]) were subsequently treated with aducanumab. Elevated P-tau217 predicted cerebral Aβ positivity in potential DMT candidates (AUC = 0.97 [0.92–1]), with diagnostic accuracy ranging from 0.88 (0.76–0.95, p = 0.028) to 0.96 (0.86–1, p <.001). When using site-specific cutoffs, a subset of DMT candidates (10%) exhibited borderline P-tau217 (between 0.273 and 0.399 pg/mL) that would have potentially required confirmatory testing. Conclusions: This study, which included participants treated with aducanumab, confirms the utility of one- and two-cutoff strategies for interpreting plasma P-tau217 in assessing DMT eligibility. Using P-tau217 could potentially replace more invasive diagnostic methods, and all aducanumab-treated participants would have been deemed eligible based on P-tau217. However, false positives remain a concern, particularly when applying externally derived cutoffs that exhibited lower specificity which could have led to inappropriate treatment of Aβ-negative participants. Future research should focus on prospective validation of P-tau217 cutoffs to enhance their generalizability and inform standardized treatment decision-making across diverse populations. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2024.

Author Keywords
Alzheimer’s disease;  Blood biomarkers;  Clinical research;  Dementia;  Immunotherapy

Funding details
Eisai
Biogen
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Lunds UniversitetLU
Cure Alzheimer’s FundCAF
2P01AG051449-06, R01AG079241
Alzheimer’s AssociationAASG-23–1061717
Alzheimer’s AssociationAA
2022-Projekt0080
National Institute on AgingNIAR01AG083740
National Institute on AgingNIA
Knut och Alice Wallenbergs Stiftelse2022–0231
Knut och Alice Wallenbergs Stiftelse
2022–00775, ERAPERMED2021-184
University Hospital FoundationUHF2020-O000028
University Hospital FoundationUHF
AlzheimerfondenAF-980907
Alzheimerfonden
1412/22
2022–1259
HjärnfondenFO2021-0293
Hjärnfonden

Document Type: Article
Publication Stage: Final
Source: Scopus

Low-intensity pulsed ultrasound stimulation (LIPUS) modulates microglial activation following intracortical microelectrode implantation
(2024) Nature Communications, 15 (1), art. no. 5512, . 

Li, F.^a b c , Gallego, J.^a b , Tirko, N.N.^d , Greaser, J.^e , Bashe, D.^f , Patel, R.^g , Shaker, E.^a , Van Valkenburg, G.E.^a , Alsubhi, A.S.^e , Wellman, S.^h , Singh, V.^a , Padilla, C.G.^a b , Gheres, K.W.^e , Broussard, J.I.^e , Bagwell, R.^e , Mulvihill, M.^e , Kozai, T.D.Y.^{a b i j k}

^a Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
^b Center for Neural Basis of Cognition, Pittsburgh, PA, United States
^c Computational Modeling and Simulation PhD Program, University of Pittsburgh, Pittsburgh, PA, United States
^d Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, United States
^e Actuated Medical, Bellefonte, PA, United States
^f Washington University in St. Louis, St. Louis, MO, United States
^g Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States
^h Columbia University, New York, NY, United States
ⁱ Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States
^j McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^k NeuroTech Center, University of Pittsburgh Brain Institute, Pittsburgh, PA, United States

Abstract
Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes. © The Author(s) 2024.

Funding details
R01NS105691, R01NS129632, R21EB028055, R44MH131514, R01NS115707, R01NS094396
1943906

Document Type: Article
Publication Stage: Final
Source: Scopus

A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease
(2024) Alzheimer’s Research and Therapy, 16 (1), art. no. 151, . 

Galasko, D.^a , Farlow, M.R.^b , Lucey, B.P.^c , Honig, L.S.^d , Elbert, D.^e , Bateman, R.^c , Momper, J.^a , Thomas, R.G.^a , Rissman, R.A.^a , Pa, J.^a , Aslanyan, V.^f , Balasubramanian, A.^a , West, T.^g , Maccecchini, M.^h , Feldman, H.H.^a

^a Department of Neurosciences, UC San Diego, 9444 Medical Center Drive, Suite 1-100, La Jolla, San Diego, CA 9209, United States
^b Indiana University, Indianapolis, IN, United States
^c Washington University, St Louis, MO, United States
^d Columbia University, New York, NY, United States
^e University of Washington, Seattle, WA, United States
^f University of Southern California, Los Angeles, CA, United States
^g C2N Diagnostics, St Louis, MO, United States
^h Annovis Bio, Malvern, PA, United States

Abstract
Background: Amyloid beta protein (Aβ) is a treatment target in Alzheimer’s Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. Methods: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21–23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. Results: From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups. Conclusions: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. Trial registration: NCT02925650 on clinicaltrials.gov (registered on 10-24-2016). © The Author(s) 2024.

Author Keywords
Alzheimer’s disease;  Amyloid beta protein;  APP;  Clinical trial;  Pharmacodynamics

Funding details
Indiana UniversityIU
Columbia University
Johns Hopkins HospitalJHH

Document Type: Article
Publication Stage: Final
Source: Scopus

Rate of abnormalities in quantitative MR neuroimaging of persons with chronic traumatic brain injury
(2024) BMC Neurology, 24 (1), art. no. 235, . 

Rahmani, F.^a , Batson, R.D.^b , Zimmerman, A.^c , Reddigari, S.^c , Bigler, E.D.^d , Lanning, S.C.^e , Ilasa, E.^e , Grafman, J.H.^f , Lu, H.^g , Lin, A.P.^h , Raji, C.A.^a i

^a Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^b Endocrine & amp; Brain Injury Research Alliance, Neurevolution Medicine, PLLC, NUNM Helfgott Research Institute, Portland, OR, United States
^c BrainSpec, Inc, Boston, MA, United States
^d Department of Neurology, Department of Psychiatry, University of Utah, Salt Lake City, UT, United States
^e Swedish Radia, Seattle, WA, United States
^f Departments of Physical Medicine & amp; Rehabilitation, Neurology, Cognitive Neurology and Alzheimer’s Center, Department of Psychiatry, Feinberg School of Medicine, Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, IL, United States
^g Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^h Center for Clinical Spectroscopy, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
ⁱ Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Background: Mild traumatic brain injury (mTBI) can result in lasting brain damage that is often too subtle to detect by qualitative visual inspection on conventional MR imaging. Although a number of FDA-cleared MR neuroimaging tools have demonstrated changes associated with mTBI, they are still under-utilized in clinical practice. Methods: We investigated a group of 65 individuals with predominantly mTBI (60 mTBI, 48 due to motor-vehicle collision, mean age 47 ± 13 years, 27 men and 38 women) with MR neuroimaging performed in a median of 37 months post-injury. We evaluated abnormalities in brain volumetry including analysis of left-right asymmetry by quantitative volumetric analysis, cerebral perfusion by pseudo-continuous arterial spin labeling (PCASL), white matter microstructure by diffusion tensor imaging (DTI), and neurometabolites via magnetic resonance spectroscopy (MRS). Results: All participants demonstrated atrophy in at least one lobar structure or increased lateral ventricular volume. The globus pallidi and cerebellar grey matter were most likely to demonstrate atrophy and asymmetry. Perfusion imaging revealed significant reductions of cerebral blood flow in both occipital and right frontoparietal regions. Diffusion abnormalities were relatively less common though a subset analysis of participants with higher resolution DTI demonstrated additional abnormalities. All participants showed abnormal levels on at least one brain metabolite, most commonly in choline and N-acetylaspartate. Conclusion: We demonstrate the presence of coup-contrecoup perfusion injury patterns, widespread atrophy, regional brain volume asymmetry, and metabolic aberrations as sensitive markers of chronic mTBI sequelae. Our findings expand the historic focus on quantitative imaging of mTBI with DTI by highlighting the complementary importance of volumetry, arterial spin labeling perfusion and magnetic resonance spectroscopy neurometabolite analyses in the evaluation of chronic mTBI. © The Author(s) 2024.

Author Keywords
Diffusion Tensor Imaging;  Magnetic resonance spectroscopy;  Pseudocontinuous arterial spin labeling;  Traumatic brain Injury

Funding details
R01AG079241, RF1AG072637, R01AG072637, NS106711, P41 EB031771, R01AG070883

Document Type: Article
Publication Stage: Final
Source: Scopus

Baseline levels and longitudinal changes in plasma Aβ42/40 among Black and white individuals
(2024) Nature Communications, 15 (1), art. no. 5539, . 

Xiong, C.^a b , Luo, J.^c d , Wolk, D.A.^e , Shaw, L.M.^e f , Roberson, E.D.^g , Murchison, C.F.^g , Henson, R.L.^b , Benzinger, T.L.S.^b h , Bui, Q.^a , Agboola, F.^a , Grant, E.^a , Gremminger, E.N.^a , Moulder, K.L.^b , Geldmacher, D.S.^g , Clay, O.J.^g i , Babulal, G.^b , Cruchaga, C.^b , Holtzman, D.M.^b , Bateman, R.J.^b , Morris, J.C.^b , Schindler, S.E.^b

^a Division of Biostatistics, Washington University, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Siteman Cancer Center Biostatistics and Qualitative Research Shared Resource, Washington University School of Medicine, St. Louis, MO, United States
^e Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
^g Alzheimer’s Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
^h Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
ⁱ Department of Psychology, University of Alabama at Birmingham, Birmingham, AL, United States

Abstract
Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C2N Diagnostics’ PrecivityAD test for Aβ42 and Aβ40. Compared to white individuals, Black individuals had higher average plasma Aβ42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aβ40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aβ42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups. © The Author(s) 2024.

Funding details
Cure Alzheimer’s FundCAF
National Institutes of HealthNIHR44 AG059489, R01 AG067505, P30 AG066444, P01 AG003991, R01 AG070941, P30 AG072979, P01 AG026276, P20 AG068024
National Institutes of HealthNIH
CA2016636
Alzheimer’s Drug Discovery FoundationADDFGC-201711-2013978
Alzheimer’s Drug Discovery FoundationADDF

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluating the psychometric structure of the Hamilton Rating Scale for Depression pre- and post-treatment in antidepressant randomised trials: Secondary analysis of 6843 individual participants from 20 trials
(2024) Psychiatry Research, 339, art. no. 116057, . 

Byrne, D.^a , Doyle, F.^a , Brannick, S.^b , Carney, R.M.^c , Cuijpers, P.^d , Dima, A.L.^e , Freedland, K.^c , Guerin, S.^f , Hevey, D.^g , Kathuria, B.^h , Wallace, E.^i j , Boland, F.^a

^a Division of Population Health Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
^b Clinical Director, Aware, Dublin, Ireland
^c Department of Psychiatry, Washington University School of Medicine, St Louis, United States
^d Department of Clinical, Neuro and Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^e Health Psychology and Health Services, Sant Joan de Déu Research Institute, Barcelona, Spain
^f School of Psychology, University College Dublin, Dublin, Ireland
^g School of Psychology, Trinity College Dublin, Dublin, Ireland
^h Digital Transformation, Medical Affairs, Novartis Ireland Ltd., Dublin, Ireland
ⁱ Department of General Practice, University College Cork, Cork, Ireland
^j Department of General Practice, RCSI University of Medicine and Health Sciences, Dublin, Ireland

Abstract
Background: The 17-item Hamilton Rating Scale for Depression (HRSD-17) is the most popular depression measure in antidepressant clinical trials. Prior evidence indicates poor replicability and inconsistent factorial structure. This has not been studied in pooled randomised trial data, nor has a psychometrically optimal model been developed. Aims: To examine the psychometric properties of the HRSD-17 for pre-treatment and post-treatment clinical trial data in a large pooled database of antidepressant randomised controlled trial participants, and to determine an optimal abbreviated version. Method: Data for 6843 participants were obtained from the data repository Vivli.org and randomly split into groups for exploratory (n = 3421) and confirmatory (n = 3422) factor analysis. Invariance methods were used to assess potential sex differences. Results: The HRSD-17 was psychometrically sub-optimal and non-invariant for all models. High item variances and low variance explained suggested redundancy in each model. EFA failed at baseline and produced four item models for outcome groups (five for placebo-outcome), which were metric but not scalar invariant. Conclusions: In antidepressant trial data, the HRSD-17 was psychometrically inadequate and scores were not sex invariant. Neither full nor abbreviated HRSD models are suitable for use in clinical trial settings and the HRSD’s status as the gold standard should be reconsidered. © 2024

Author Keywords
Antidepressants;  Clinical trial;  Depression;  Factor analysis;  Invariance;  Psychometrics;  RCT

Funding details
Irish Research Council

Document Type: Article
Publication Stage: Final
Source: Scopus

Ophthalmoparesis as an unusual manifestation of anti-3‑hydroxy-3-methyl-glutaryl-coenzyme A reductase antibody-associated myopathies
(2024) Neuromuscular Disorders, 42, pp. 1-4. 

Putko, B.^a , Pestronk, A.^b , Van Stavern, G.P.^c , Phan, C.L.^d , Beecher, G.^d , Liewluck, T.^a

^a Department of Neurology, Mayo Clinic-Rochester, Rochester, MN, United States
^b Department of Neurology, Washington University, St. Louis, MO, United States
^c Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States
^d Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada

Abstract
We describe two anti-3‑hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody-positive patients with treatment-responsive ophthalmoparesis. Patient 1 was a 53-year-old male with progressive proximal limb weakness, dysphagia, ptosis, and diplopia over 6 weeks and creatine kinase (CK) of 3,512 units/L. Patient 2 was a 55-year-old female with progressive proximal weakness, dysarthria, ptosis, diplopia, and dyspnea over 2 weeks with CK of 31,998 units/L. Both patients had normal thyroid studies and repetitive nerve stimulation, myopathic electromyography with fibrillation potentials, magnetic resonance imaging demonstrating abnormal enhancement of extraocular muscles, muscle biopsy showing necrotic myofibers, and positive anti-HMGCR antibodies. Patient 1 also had weakly positive anti-PM/Scl antibodies. Immunomodulatory therapies led to resolution of oculobulbar weakness and normalization of CK levels in both patients, while limb weakness resolved completely in patient 1 and partially in patient 2. These cases expand the phenotypic spectrum of anti-HMGCR antibody-associated myopathies to include subacute ophthalmoparesis with limb-girdle weakness and markedly elevated CK. © 2024

Document Type: Article
Publication Stage: Final
Source: Scopus

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
(2024) American Journal of Human Genetics, 111 (7), pp. 1316-1329. 

Manzoni, C.^a , Kia, D.A.^b , Ferrari, R.^b , Leonenko, G.^c , Costa, B.^b , Saba, V.^d , Jabbari, E.^b , Tan, M.M.^b e , Albani, D.^f , Alvarez, V.^g h , Alvarez, I.^i j , Andreassen, O.A.^k l , Angiolillo, A.^m , Arighi, A.ⁿ , Baker, M.^o , Benussi, L.^p , Bessi, V.^q , Binetti, G.^r , Blackburn, D.J.^s , Boada, M.^t u , Boeve, B.F.^v , Borrego-Ecija, S.^w , Borroni, B.^x , Bråthen, G.^y z , Brooks, W.S.^aa , Bruni, A.C.^ab , Caroppo, P.^ac , Bandres-Ciga, S.^ad , Clarimon, J.^ae , Colao, R.^ab , Cruchaga, C.^af ag , Danek, A.^ah , de Boer, S.C.^ai aj ak , de Rojas, I.^t u , di Costanzo, A.^m , Dickson, D.W.^o , Diehl-Schmid, J.^al am , Dobson-Stone, C.^ak an , Dols-Icardo, O.^u ae , Donizetti, A.^ao , Dopper, E.^ap , Durante, E.^aq , Ferrari, C.^q , Forloni, G.^f , Frangipane, F.^ab , Fratiglioni, L.^ar as , Kramberger, M.G.^at au , Galimberti, D.^n av , Gallucci, M.^aw , García-González, P.^t u , Ghidoni, R.^p , Giaccone, G.^ac , Graff, C.^ar ax , Graff-Radford, N.R.^ay , Grafman, J.^az , Halliday, G.M.^ak an , Hernandez, D.G.^ba , Hjermind, L.E.^bb , Hodges, J.R.^ak , Holloway, G.^bc , Huey, E.D.^bd , Illán-Gala, I.^u ae , Josephs, K.A.^v , Knopman, D.S.^v , Kristiansen, M.^be bf bg , Kwok, J.B.^ak an , Leber, I.^bh bi , Leonard, H.L.^ad bj bk , Libri, I.^x , Lleo, A.^u ae , Mackenzie, I.R.^bl bm , Madhan, G.K.^be bf bg , Maletta, R.^ab , Marquié, M.^t u , Maver, A.^bn , Menendez-Gonzalez, M.^g h bo , Milan, G.^bp , Miller, B.L.^bq br bs , Morris, C.M.^bt , Morris, H.R.^b , Nacmias, B.^q bu , Newton, J.^bc , Nielsen, J.E.^bb , Nilsson, C.^bv , Novelli, V.^bw , Padovani, A.^x , Pal, S.^bc , Pasquier, F.^bx by bz , Pastor, P.^ca cb , Perneczky, R.^{cc cd ce cf cg} , Peterlin, B.^bn , Petersen, R.C.^v , Piguet, O.^ak ch , Pijnenburg, Y.A.^ai aj , Puca, A.A.^ci cj , Rademakers, R.^o ck cl , Rainero, I.^cm cn , Reus, L.M.^ai aj co , Richardson, A.M.^cp , Riemenschneider, M.^cq , Rogaeva, E.^cr , Rogelj, B.^cs ct , Rollinson, S.^cu , Rosen, H.^cv , Rossi, G.^ac , Rowe, J.B.^cw , Rubino, E.^cm cn , Ruiz, A.^t u , Salvi, E.^cx cy , Sanchez-Valle, R.^w , Sando, S.B.^y z , Santillo, A.F.^cz , Saxon, J.A.^cp , Schlachetzki, J.C.^da , Scholz, S.W.^db dc , Seelaar, H.^ap , Seeley, W.W.^cv , Serpente, M.ⁿ , Sorbi, S.^q bu , Sordon, S.^cq , St George-Hyslop, P.^cr dd , Thompson, J.C.^cp cu , Van Broeckhoven, C.^cl de , Van Deerlin, V.M.^df , Van der Lee, S.J.^ai aj dg , Van Swieten, J.^ap , Tagliavini, F.^ac , van der Zee, J.^cl de , Veronesi, A.^aq , Vitale, E.^dh di , Waldo, M.L.^dj , Yokoyama, J.S.^{bq br bs dk} , Nalls, M.A.^ad bj , Momeni, P.^dl , Singleton, A.B.^ad ba , Hardy, J.^{dm dn do dp} , Escott-Price, V.^c

^a UCL School of Pharmacy, London, United Kingdom
^b Department of Clinical and Movement, Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom
^c Division of Psychological Medicine and Clinical Neurosciences, UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom
^d Medical and Genomic Statistics Unit, Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
^e Department of Neurology, Oslo University Hospital, Oslo, Norway
^f Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy
^g Hospital Universitario Central de Asturias, Oviedo, Spain
^h Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain
ⁱ Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain
^j Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain
^k NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
^l Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
^m Centre for Research and Training in Medicine of Aging, Department of Medicine and Health Science “V. Tiberio, ” University of Molise, Campobasso, Italy
ⁿ Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
^o Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, United States
^p Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
^q Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy
^r MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
^s University of Sheffield, Sheffield, United Kingdom
^t Research Center and Memory Clinic. Ace Alzheimer Center Barcelona – Universitat Internacional de Catalunya, Barcelona, Spain
^u CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
^v Department of Neurology, Mayo Clinic Rochester, Rochester, MN, United States
^w Alzheimer’s Disease and Other Cognitive Disorders Unit, Service of Neurology. Hospital Clínic de Barcelona, Fundació Clínic Barcelona-IDIBAPS, Barcelona, Spain
^x Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
^y Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim, Trondheim, Norway
^z Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
^aa Neuroscience Research Australia, Randwick Clinical Campus, UNSW Medicine and Health, University of New South Wales, Sydney, Australia
^ab Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
^ac Unit of Neurology (V) and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
^ad Center for Alzheimer’s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^ae Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
^af Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^ag NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
^ah Neurologische Klinik, LMU Klinikum, Munich, Germany
^ai Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
^aj Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
^ak Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
^al Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
^am kbo-Inn-Salzach-Klinikum, Wasserburg, Germany
^an School of Medical Sciences, University of Sydney, Sydney, NSW, Australia
^ao Department of Biology, University of Naples Federico II, Naples, Italy
^ap Department of Neurology & Alzheimer Center, Erasmus University Medical Center, Rotterdam, Netherlands
^aq Immunohematology and Transfusional Medicine Service, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy
^ar Karolinska Institutet, Department NVS, KI-Alzheimer Disease Research Center, Stockholm, Sweden
^as Theme Inflammation and Aging, Karolinska Universtiy Hospital, Stockholm, Sweden
^at Department of Neurology, University Medical Center, Medical faculty, Ljubljana University of Ljubljana, Ljubljana, Slovenia
^au Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), Division of Clinical Geriatrics, Huddinge, Sweden
^av Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
^aw Cognitive Impairment Center, Local Health Authority n.2 Marca Trevigiana, Treviso, Italy
^ax Unit for hereditary dementia, Karolinska Universtiy Hospital-Solna, Stockholm, Sweden
^ay Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, United States
^az Shirley Ryan AbilityLab, Chicago, IL, United States
^ba Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
^bb Neurogenetics Clinic & Research Lab, Danish Dementia Research Centre, Copenhagen University Hospital, Copenhagen, Denmark
^bc Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, United Kingdom
^bd Bio Med Psychiatry & Human Behavior, Brown University, Providence, RI, United States
^be UCL Genomics, London, United Kingdom
^bf UCL Great Ormond Street Institute of Child Health, London, United Kingdom
^bg Zayed Centre for Research into Rare Disease in Children, London, United Kingdom
^bh Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau – ICM, Paris, France
^bi AP-HP Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Neurology, Institute of Memory and Alzheimer’s Disease, Paris, France
^bj Data Tecnica International LLC, Washington, DC, United States
^bk DZNE Tübingen, Tübingen, Germany
^bl Department of Pathology, University of British Columbia, Vancouver, Canada
^bm Department of Pathology, Vancouver Coastal Health, Vancouver, Canada
^bn Clinical institute of Genomic Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia
^bo Universidad de Oviedo, Medicine Department, Oviedo, Spain
^bp Geriatric Center “Frullone” ASL NA1, Naples, Italy
^bq Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
^br Global Brain Health Institute, University of California, San Francisco, San Francisco, CA, United States
^bs Trinity College Dublin, Dublin, Ireland
^bt Newcastle Brain Tissue Resource, Newcastle University, Edwardson Building, Nuns Moor Road, Newcastle upon Tyne, United Kingdom
^bu IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
^bv Department of Clinical Sciences, Neurology, Lund University, Lund/Malmö, Sweden
^bw Centro Cardiologico Monzino IRCCS, Milan, Italy
^bx University of Lille, Lille, France
^by CHU Lille, Lille, France
^bz Inserm, Labex DISTALZ, LiCEND, Lille, France
^ca Unit of Neurodegenerative Diseases, Department of Neurology, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
^cb The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
^cc Department of Psychiatry and Psychotherapy, LMU Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany
^cd German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
^ce Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^cf Ageing Epidemiology (AGE) Research Unit, School of Public Health, Imperial College London, London, United Kingdom
^cg Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
^ch School of Psychology, University of Sydney, Sydney, NSW, Australia
^ci Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana,” University of Salerno, Fisciano, Italy
^cj Cardiovascular Research Unit, IRCCS MultiMedica, Milan, Italy
^ck VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
^cl Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
^cm Department of Neuroscience, “Rita Levi Montalcini,” University of Torino, Torino, Italy
^cn Center for Alzheimer’s Disease and Related Dementias, Department of Neuroscience and Mental Health, A.O.UCittà della Salute e della Scienza di Torino, Torino, Italy
^co Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States
^cp Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Trust, Manchester Academic Health Sciences Unit, University of Manchester, Manchester, United Kingdom
^cq Department of Psychiatry, Saarland University, Homburg, Germany
^cr Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Toronto, ON, Canada
^cs Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
^ct Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
^cu Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
^cv Department of Neurology, University of California, San Francisco, San Francisco, CA, United States
^cw University of Cambridge Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom
^cx Unit of Neuroalgologia (III), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
^cy Data science center, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
^cz Department of Clinical Sciences, Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund/Malmö, Sweden
^da Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, United States
^db Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
^dc Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, United States
^dd Department of Neurology, Columbia University, New York, NY, United States
^de Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
^df Perelman School of Medicine at the University of Pennsylvania, Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, PA, United States
^dg Section Genomics of Neurodegenerative Diseases and Aging, Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
^dh Institute of Biochemistry and Cell Biology, National Research Council (CNR), Naples, Italy
^di School of Integrative Science and Technology Department of Biology Kean University, Union, NJ, United States
^dj Clinical Sciences Helsingborg, Department of Clinical Sciences, Lund University, Lund, Sweden
^dk Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
^dl Rona Holdings, Cupertino, CA, United States
^dm UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
^dn Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, United Kingdom
^do NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom
^dp Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, Hong Kong

Abstract
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex. © 2024 The Author(s)

Funding details
Kyowa Kirin
International Parkinson and Movement Disorder SocietyMDS
Medical Research CouncilMRC
PSP AssociationPSPA
National Institutes of HealthNIH
Roche
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s Society284
Alzheimer’s Society

Document Type: Article
Publication Stage: Final
Source: Scopus

Attenuating midline thalamus bursting to mitigate absence epilepsy
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (28), pp. e2403763121. 

Dong, P.^a , Bakhurin, K.^b , Li, Y.^c , Mikati, M.A.^d e , Cui, J.^f , Grill, W.M.^c d g , Yin, H.H.^b d , Yang, H.^a d

^a Department of Biochemistry, Duke University Medical Center, Durham, United Kingdom
^b Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, United Kingdom
^c Department of Biomedical Engineering, Duke University, Durham, NC 27708, United Kingdom
^d Department of Neurobiology, Duke University Medical Center, Durham, United Kingdom
^e Department of Pediatrics, Duke University Medical Center, Durham, United Kingdom
^f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^g Department of Neurosurgery, Duke University Medical Center, Durham, United Kingdom

Abstract
Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing next generation therapeutics to treat absence epilepsy.

Author Keywords
absence seizure;  BK channelopathy;  epilepsy;  midline thalamus;  thalamus

Document Type: Article
Publication Stage: Final
Source: Scopus

Cell-Specific Single Viral Vector CRISPR/Cas9 Editing and Genetically Encoded Tool Delivery in the Central and Peripheral Nervous Systems
(2024) eNeuro, 11 (7), art. no. ENEURO.0438-23.2024, . 

Moffa, J.C.^a b , Bland, I.N.^a , Tooley, J.R.^a c , Kalyanaraman, V.^a , Heitmeier, M.^a , Creed, M.C.^a d , Copits, B.A.^a

^a Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Washington University Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Washington University, Division of Biological and Behavioral Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Departments of Neuroscience, Psychiatry, and Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
CRISPR/Cas9 gene editing represents an exciting avenue to study genes of unknown function and can be combined with genetically encoded tools such as fluorescent proteins, channelrhodopsins, DREADDs, and various biosensors to more deeply probe the function of these genes in different cell types. However, current strategies to also manipulate or visualize edited cells are challenging due to the large size of Cas9 proteins and the limited packaging capacity of adeno-associated viruses (AAVs).Toovercometheseconstraints,wedeveloped an alternative gene editing strategy using a single AAV vector and mouse lines that express Cre-dependent Cas9 to achieve efficient cell-type specific editing across the nervous system. Expressing Cre-dependent Cas9 from a genomic locus affords space to package guide RNAs for gene editing together with Cre-dependent, genetically encoded tools to manipulate, map, or monitor neurons using a single virus. We validated this strategy with three common tools in neuroscience: ChRonos, a channelrhodopsin, for studying synaptic transmission using optogenetics, GCaMP8f for recording Ca2+ transients using photometry, and mCherry for tracing axonal projections. We tested these tools in multiple brain regions and cell types, including GABAergic neurons in the nucleus accumbens, glutamatergic neurons projecting from the ventral pallidum to the lateral habenula, dopaminergic neurons in the ventral tegmental area, and proprioceptive neurons in the periphery. This flexible approach could help identify and test the function of novel genes affecting synaptic transmission, circuit activity, or morphology with a single viral injection. © 2024 Moffa et al.

Author Keywords
CRISPR/Cas9;  gene editing;  imaging;  optogenetics;  photometry;  tool

Funding details
Washington University in St. LouisWUSTL
McDonnell Center for Systems Neuroscience
DA058755
DA049924, R01s NS130046
U24 NS124025
SCR_023243

Document Type: Article
Publication Stage: Final
Source: Scopus

The role of occipital condyle and atlas anomalies on occipital cervical fusion outcomes in Chiari malformation type I with syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium
(2024) Journal of Neurosurgery: Pediatrics, 34 (1), pp. 66-74. 

Yahanda, A.T.^a , Koueik, J.^c , Ackerman, L.L.^d , Adelson, P.D.^e , Albert, G.W.^f , Aldana, P.R.^g , Alden, T.D.^h , Anderson, R.C.E.ⁱ , Bauer, D.F.^j , Bethel-Anderson, T.^a , Bierbrauer, K.^k , Brockmeyer, D.L.^l , Chern, J.J.^m , Couture, D.E.ⁿ , Daniels, D.J.^o , Dlouhy, B.J.^p , Durham, S.R.^q , Ellenbogen, R.G.^r , Eskandari, R.^s , Fuchs, H.E.^t , Grant, G.A.^t , Graupman, P.C.^u , Greene, S.^v , Greenfield, J.P.^w , Gross, N.L.^x , Guillaume, D.J.^y , Hankinson, T.C.^z , Heuer, G.G.^aa , Iantosca, M.^ab , Iskandar, B.J.^c , Jackson, E.M.^ac , Jallo, G.I.^ad , Johnston, J.M.^ae , Kaufman, B.A.^af , Keating, R.F.^ag , Khan, N.R.^ah , Krieger, M.D.^q , Leonard, J.R.^ai , Maher, C.O.^aj , Mangano, F.T.^k , Martin, J.^ak , McComb, J.G.^q , McEvoy, S.D.^a , Meehan, T.^a , Menezes, A.H.^p , Muhlbauer, M.S.^ah , O’Neill, B.R.^z , Olavarria, G.^al , Ragheb, J.^am , Selden, N.R.^an , Shah, M.N.^ao , Shannon, C.N.^ap , Shimony, J.S.^b , Smyth, M.D.^ad , Stone, S.S.D.^aq , Strahle, J.M.^a , Tamber, M.S.^ar , Torner, J.C.^p , Tuite, G.F.^ad , Tyler-Kabara, E.C.^as , Wait, S.D.^at , Wellons, J.C.^ao , Whitehead, W.E.^j , Park, T.S.^a , Limbrick, D.D.^a , Ahmed, R.^c

^a Departments of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Departments of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurological Surgery, University of Wisconsin at Madison, Wisconsin, United States
^d Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
^e Department of Neurosurgery, West Virginia University School, Morgantown, WV, United States
^f Division of Neurosurgery, Arkansas Children’s Hospital, Little Rock, AR, United States
^g Division of Pediatric Neurosurgery, University of Florida College of Medicine, Jacksonville, FL, United States
^h Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Illinois, United States
ⁱ Neurosurgeons of New Jersey, Ridgewood, NJ, United States
^j Division of Pediatric Neurosurgery, Texas Children’s Hospital, Houston, TX, United States
^k Division of Pediatric Neurosurgery, Cincinnati Children’s Medical Center, Cincinnati, OH, United States
^l Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, UT, United States
^m Division of Pediatric Neurosurgery, Children’s Healthcare of Atlanta University, Atlanta, GA, United States
ⁿ Department of Neurological Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, United States
^o Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
^p Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
^q Division of Pediatric Neurosurgery, Children’s Hospital of Los Angeles, USC Keck School of Medicine, Los Angeles, CA, United States
^r Division of Pediatric Neurosurgery, Seattle Children’s Hospital, Seattle, WA, United States
^s Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, United States
^t Department of Neurosurgery, Duke University School of Medicine, Durham, NC, United States
^u Division of Pediatric Neurosurgery, Gillette Children’s Hospital, St. Paul, MN, United States
^v Divsion of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^w Department of Neurological Surgery, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY, United States
^x Warren Clinic Pediatric Neurosurgery, Saint Francis Health System, Tulsa, OK, United States
^y Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
^z Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, United States
^aa Division of Pediatric Neurosurgery, Children’s Hospital of PhiladelphiaPA, United States
^ab Division of Pediatric Neurosurgery, Penn State Health Children’s Hospital, Hershey, PA, United States
^ac Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^ad Division of Neurosurgery, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
^ae Department of Neurosurgery, University of Alabama at BirminghamAL, United States
^af Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI, United States
^ag Department of Neurosurgery, Children’s National Medical Center, Washington, DC, United States
^ah Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN, United States
^ai Division of Pediatric Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
^aj Department of Neurosurgery, Stanford University, Palo Alto, CA, United States
^ak Department of Neurosurgery, Connecticut Children’s Hospital, Hartford, CT, United States
^al Division of Pediatric Neurosurgery, Arnold Palmer Hospital for Children, Orlando, FL, United States
^am Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, United States
^an Department of Neurological Surgery, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, OR, United States
^ao Division of Pediatric Neurosurgery, McGovern Medical School, Houston, TX, United States
^ap American Society for Reproductive Medicine, Birmingham, AL, United States
^aq Division of Pediatric Neurosurgery, Boston Children’s Hospital, Boston, MA, United States
^ar Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada
^as Department of Neurosurgery, Dell Medical School, Austin, TX, United States
^at Carolina Neurosurgery and Spine Associates, Charlotte, NC, United States

Abstract
OBJECTIVE Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF). METHODS The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio. RESULTS Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle–C2 sagittal vertical alignment (C–C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95). CONCLUSIONS The authors’ results indicate that the occipital condyle–atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology. © 2024 American Association of Neurological Surgeons. All rights reserved.

Author Keywords
atlas assimilation;  Chiari malformation;  condylar hypoplasia;  congenital;  occipitocervical fusion;  syringomyelia

Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Center for Advancing Translational SciencesNCATS
University of WashingtonUW
National Institutes of HealthNIHUL1 TR002345
National Institutes of HealthNIH
U54 HD087011

Document Type: Article
Publication Stage: Final
Source: Scopus

Ventricular catheter tissue obstruction and shunt malfunction in 9 hydrocephalus etiologies
(2024) Journal of Neurosurgery: Pediatrics, 34 (1), pp. 84-93. 

Garcia-Bonilla, M.^a b i , Hariharan, P.^c , Gluski, J.^d , Ruiz-Cardozo, M.A.^j , Otun, A.^a , Morales, D.M.^a , Marupudi, N.I.^e , Whitehead, W.E.^f , Jea, A.^g , Rocque, B.G.^h , McAllister, J.P., II^a , Limbrick, D.D., Jr.^a b , Harris, C.A.^d

^a Department of Neurosurgery, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States
^c Departments of Biomedical Engineering, Wayne State University, Detroit, MI, United States
^d Departments of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, United States
^e Department of Neurosurgery, Children’s Hospital of Michigan, Detroit, MI, United States
^f Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^g Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
^h Division of Pediatric Neurosurgery, Department of Neurosurgery, University of Alabama, Birmingham, AL, United States
ⁱ Virginia Commonwealth University, Richmond, VA, United States

Abstract
OBJECTIVE Hydrocephalus is a neurological disorder with an incidence of 80–125 per 100,000 births in the United States. The most common treatment, ventricular shunting, has a failure rate of up to 85% within 10 years of placement. The authors aimed to analyze the association between ventricular catheter (VC) tissue obstructions and shunt malfunction for each hydrocephalus etiology. METHODS Patient information was collected from 5 hospitals and entered into a REDCap (Research Electronic Data Capture) database by hydrocephalus etiology. The hardware samples were fixed, and each VC tip drainage hole was classified by tissue obstruction after macroscopic analysis. Shunt malfunction data, including shunt revision rate, time to failure, and age at surgery, were correlated with the degree of tissue obstruction in VCs for each etiology. RESULTS Posthemorrhagic hydrocephalus was the most common etiology (48.9% of total cases). Proximal catheter obstruction was the most frequent cause of hardware removal (90.4%). Myelomeningocele (44% ± 29%), other congenital etiologies (48% ± 40%), hydrocephalus with brain tumors (45% ± 35%), and posthemorrhagic hydrocephalus (41% ± 35%) showed tissue aggregates in more than 40% of the VC holes. A total of 76.8% of samples removed because of symptoms of obstruction showed cellular or tissue aggregates. No conclusive etiological associations were detected when correlating the percentage of holes with tissue for each VC and age at surgery, shunt revision rates, or time between shunt implantation and removal. CONCLUSIONS The proximal VC obstruction was accompanied by tissue aggregates in 76.8% of cases. However, the presence of tissue in the VC did not seem to be associated with hydrocephalus etiology. ©AANS 2024.

Author Keywords
KEYWORDS hydrocephalus etiology;  obstructive failure;  shunt malfunction

Funding details
National Institute of Neurological Disorders and StrokeNINDS
Baylor College of Medicine
Children’s Hospital of MichiganCHM
R01NS094570

Document Type: Article
Publication Stage: Final
Source: Scopus

Evolutionary divergence of plasticity in brain morphology between ecologically divergent habitats of Trinidadian guppies
(2024) Evolution, 78 (7), pp. 1261-1274. 

Axelrod, C.J.^a b , Yang, Y.^b c , Grant, E.^b , Fleming, J.^b , Stone, I.^b , Carlson, B.A.^b , Gordon, S.P.^a b

^a Department of Ecology and Evolution, Cornell University, Ithaca, NY, United States
^b Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Integrative Biology, University of South Florida, Tampa, FL, United States

Abstract
Phenotypic plasticity is critical for organismal performance and can evolve in response to natural selection. Brain morphology is often developmentally plastic, affecting animal performance in a variety of contexts. However, the degree to which the plasticity of brain morphology evolves has rarely been explored. Here, we use Trinidadian guppies (Poecilia reticulata), which are known for their repeated adaptation to high-predation (HP) and low-predation (LP) environments, to examine the evolution and plasticity of brain morphology. We exposed second-generation offspring of individuals from HP and LP sites to 2 different treatments: predation cues and conspecific social environment. Results show that LP guppies had greater plasticity in brain morphology compared to their ancestral HP population, suggesting that plasticity can evolve in response to environmentally divergent habitats. We also show sexual dimorphism in the plasticity of brain morphology, highlighting the importance of considering sex-specific variation in adaptive diversification. Overall, these results may suggest the evolution of brain morphology plasticity as an important mechanism that allows for ecological diversification and adaptation to divergent habitats. © 2024 The Author(s). Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE). All rights reserved.

Author Keywords
brain morphology;  local adaptation;  phenotypic plasticity;  rapid evolution;  sexual dimorphism;  Trinidadian guppy

Funding details
Cornell UniversityCU
Washington University in St. LouisWUSTL
National Science FoundationNSFIOS-1755071, 2203122
National Science FoundationNSF

Document Type: Article
Publication Stage: Final
Source: Scopus

Prolonged hourly neurological examinations are associated with increased delirium and no discernible benefit in mild/moderate geriatric traumatic brain injury
(2024) Journal of Trauma and Acute Care Surgery, 97 (1), pp. 105-111. 

Fonseca, R.A.^a , Canas, M.^a , Diaz, L.^a , Aldana, J.A.^a , Afzal, H.^a , De Filippis, A.^b , Toro, D.D.^a , Day, A.^a , McCarthy, J.^a , Stansfield, K.^a , Bochicchio, G.V.^a , Niziolek, G.^a , Kranker, L.M.^a , Rosengart, M.R.^a , Hoofnagle, M.^a , Leonard, J.^a

^a The Department of Acute and Critical Care Surgery, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States

Abstract
BACKGROUND: Serial neurological examinations (NEs) are routinely recommended in the intensive care unit (ICU) within the first 24 hours following a traumatic brain injury (TBI). There are currently no widely accepted guidelines for the frequency of NEs. Disruptions to the sleep-wake cycles increase the delirium rate. We aimed to evaluate whether there is a correlation between prolonged hourly (Q1)-NE and development of delirium and to determine if this practice reduces the likelihood of missing the detection of a process requiring emergent intervention. METHODS: A retrospective analysis of patients with mild/moderate TBI, admitted to the ICU with serial NEs, was performed. Cohorts were stratified by the duration of exposure to Q1-NE, into prolonged (≥24 hours) and nonprolonged (<24 hours). Our primary outcomes of interest were delirium, evaluated using the Confusion Assessment Method; radiological progression from baseline images; neurological deterioration (focal neurological deficit, abnormal pupillary examination, or Glasgow Coma Scale score decrease >2); and neurosurgical procedures. RESULTS: A total of 522 patients were included. No significant differences were found in demographics. Patients in the prolonged Q1-NE group (26.1%) had higher Injury Severity Score with similar head Abbreviated Injury Score, significantly higher delirium rate (59% vs. 35%, p < 0.001), and a longer hospital/ICU length of stay when compared with the nonprolonged Q1-NE group. No neurosurgical interventions were found to be performed emergently as a result of findings on NEs. Multivariate analysis demonstrated that prolonged Q1-NE was the only independent risk factor associated with a 2.5-fold increase in delirium rate. The number needed to harm for prolonged Q1-NE was 4. CONCLUSION: Geriatric patients with mild/moderate TBI exposed to Q1-NE for periods longer than 24 hours had nearly a threefold increase in ICU delirium rate. One of five patients exposed to prolonged Q1-NE is harmed by the development of delirium. No patients were found to directly benefit as a result of more frequent NEs. (J Trauma Acute Care Surg. 2024;97: 105–111. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.) © 2024 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
CAM-ICU;  delirium;  Neurochecks;  TBI

Document Type: Article
Publication Stage: Final
Source: Scopus

Direct measurements of neurosteroid binding to specific sites on GABAA receptors
(2024) British Journal of Pharmacology, . 

Chintala, S.M.^a , Tateiwa, H.^a b , Qian, M.^c , Xu, Y.^c , Amtashar, F.^a , Chen, Z.-W.^a d , Kirkpatrick, C.C.^e , Bracamontes, J.^a , Germann, A.L.^a , Akk, G.^a d , Covey, D.F.^a b d f , Evers, A.S.^a b d

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology and Intensive Care Medicine, Kochi Medical School, Kochi, Japan
^c Department of Developmental Biology (Pharmacology), Washington University School of Medicine, St. Louis, MO, United States
^d Taylor Family Institute for Innovative Psychiatric Research, St. Louis, MO, United States
^e Department of Chemistry, Saint Louis University, St. Louis, MO, United States
^f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background and Purpose: Neurosteroids are allosteric modulators of GABAA currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABAA receptor. Experimental Approach: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABAAR, a chimeric receptor containing transmembrane domains of the α1-GABAA receptor. Tryptophan mutagenesis was used to identify specific interactions. Key Results: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3β-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites. Conclusions and Implications: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABAAR were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites. © 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Author Keywords
Fӧrster resonance energy transfer;  GABAA receptors;  neuroactive steroids;  neurosteroids;  tryptophan quenching

Funding details
National Institutes of HealthNIHT32GM108539, R01HL067773, R01MH110550, P50 MH122379, R35GM149287, R35GM140947, R01GM108799, R01GM108580
National Institutes of HealthNIH

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

CSF proteomic profiles of neurodegeneration biomarkers in Alzheimer’s disease
(2024) Alzheimer’s and Dementia, . 

Delvenne, A.^a , Gobom, J.^b c , Schindler, S.E.^d e , Kate, M.T.^f g , Reus, L.M.^f , Dobricic, V.^h , Tijms, B.M.^f , Benzinger, T.L.S.ⁱ , Cruchaga, C.^j , Teunissen, C.E.^k , Ramakers, I.^a , Martinez-Lage, P.^l , Tainta, M.^l , Vandenberghe, R.^m n , Schaeverbeke, J.^m n , Engelborghs, S.^o p , Roeck, E.D.^o q , Popp, J.^r s , Peyratout, G.^r , Tsolaki, M.^t , Freund-Levi, Y.^u v w , Lovestone, S.^x , Streffer, J.^o y , Barkhof, F.^f z , Bertram, L.^h , Blennow, K.^b c aa ab , Zetterberg, H.^{b c ac ad ae af} , Visser, P.J.^a f ag , Vos, S.J.B.^a

^a Department of Psychiatry and Neuropsychology, Alzheimer Centrum Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
^b Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^c Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^f Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
^g Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
^h Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany
ⁱ Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^k Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam University Medical Centers (AUMC), Amsterdam Neuroscience, Amsterdam, Netherlands
^l Fundación CITA-Alzhéimer Fundazioa, Donostia, Spain
^m Neurology Service, University Hospitals Leuven, Leuven, Belgium
ⁿ Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium
^o Reference Center for Biological Markers of Dementia (BIODEM), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
^p Department of Neurology and Bru-BRAIN, Universitair Ziekenhuis Brussel and NEUR Research Group, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
^q Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium
^r Old Age Psychiatry, University Hospital Lausanne, Lausanne, Switzerland
^s Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatry University Hospital Zürich, Zürich, Switzerland
^t 1st Department of Neurology, AHEPA University Hospital, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Makedonia, Greece
^u Department of Neurobiology, Caring Sciences and Society (NVS), Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Huddinge, Sweden
^v Department of Psychiatry in Region Örebro County and School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
^w Department of Old Age Psychiatry, Psychology & Neuroscience, King’s College, London, United Kingdom
^x University of Oxford, United Kingdom (currently at Johnson and Johnson Medical Ltd., Oxford, United Kingdom
^y H. Lundbeck A/S, Valby, Denmark
^z Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London, London, United Kingdom
^aa Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
^ab Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China
^ac Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
^ad UK Dementia Research Institute at UCL, London, United Kingdom
^ae Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong
^af Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^ag Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Huddinge, Sweden

Abstract
INTRODUCTION: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer’s disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS: Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N− based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS: Only a few individuals were A+T+Ng−. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng− and A+T+NfL−, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV−, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. Highlights: In Alzheimer’s disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  biomarkers;  cerebrospinal fluid;  hippocampal volume;  neurodegeneration markers;  neurofilament light;  neurogranin;  pathophysiology;  proteomics

Funding details
Alzheimer’s AssociationAA
Alzheimer Nederland
Biogen
European CommissionEC
Seventh Framework ProgrammeFP7
ZonMw
Foundation for Barnes-Jewish HospitalFBJH
Cure Alzheimer’s FundCAF
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF
Siemens
Manchester Biomedical Research CentreBRC
Innovative Medicines InitiativeIMI
733050502
860197
320030_204886, 320030_141179
EU Joint Programme – Neurodegenerative Disease ResearchJPNDJPND2021‐00694
EU Joint Programme – Neurodegenerative Disease ResearchJPND
101034344
115952, 806999, IMI 2 JU
UK Dementia Research InstituteUK DRIUKDRI‐1003
UK Dementia Research InstituteUK DRI
National Institute on AgingNIAP30AG066444, P01AG003991, K23AG053426, P01AG026276
National Institute on AgingNIA
733050824736
2017‐PI01
71320, 101053962
115372
Stiftelsen för Gamla Tjänarinnor#FO2022‐0270
Stiftelsen för Gamla Tjänarinnor
SAO‐FRA 2021/0022
Alzheimer’s Drug Discovery FoundationADDF201809‐2016862
Alzheimer’s Drug Discovery FoundationADDF
7330505021
2022‐01018, 2019‐02397, 2023‐00356
QLRT‐2001‐2455, 37670

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

A µ-opioid receptor modulator that works cooperatively with naloxone
(2024) Nature, . Cited 1 time.

O’Brien, E.S.^a , Rangari, V.A.^b , El Daibani, A.^b , Eans, S.O.^c , Hammond, H.R.^c , White, E.^a , Wang, H.^a , Shiimura, Y.^a d , Krishna Kumar, K.^a , Jiang, Q.^b , Appourchaux, K.^b , Huang, W.^a , Zhang, C.^e , Kennedy, B.J.^f , Mathiesen, J.M.^g , Che, T.^b , McLaughlin, J.P.^c , Majumdar, S.^b , Kobilka, B.K.^a

^a Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, United States
^b Center for Clinical Pharmacology, University of Health Sciences and Pharmacy at St Louis and Washington University School of Medicine, St Louis, MO, United States
^c Department of Pharmacodynamics, University of Florida, Gainesville, FL, United States
^d Division of Molecular Genetics, Institute of Life Science, Kurume University, Fukuoka, Japan
^e Division of CryoEM and Bioimaging, SSRL, SLAC National Acceleration Laboratory, Menlo Park, CA, United States
^f Lotus Separations, Princeton University, Princeton, NJ, United States
^g Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

Abstract
The µ-opioid receptor (µOR) is a well-established target for analgesia1, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to ‘steer’ hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo. © The Author(s), under exclusive licence to Springer Nature Limited 2024.

Funding details
American Diabetes AssociationADA
American Heart AssociationAHAR01DA036246
American Heart AssociationAHA

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Free Recall Outperforms Story Recall in Associations with Plasma Biomarkers in Preclinical Alzheimer Disease
(2024) Journal of Prevention of Alzheimer’s Disease, . 

Aschenbrenner, A.^a e , Hassenstab, J.J.^a , Schindler, S.E.^a , Janelidze, S.^b , Hansson, O.^b c , Morris, J.C.^a , Grober, E.^d

^a Department of Neurology, Washington University, St. Louis, United States
^b Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
^c Memory Clinic, Skåne University Hospital, Malmö, Sweden
^d Department of Neurology, Albert Einstein College of Medicine, New York, United States
^e 4488 Forest Park Ave, STE 301, St. Louis, MO 63108, United States

Abstract
Background: A decline in episodic memory is one of the earliest cognitive characteristics of Alzheimer disease and memory tests are heavily featured in cognitive composite endpoints that are used to demonstrate treatment efficacy. Assessments of episodic memory can take many forms including free recall, associate learning, and paragraph or story recall. Plasma biomarkers of Alzheimer disease are now widely available and will likely form the backbone of cohort enrichment strategies for future clinical trials. Thus, it is critical to evaluate which episodic memory measures are most sensitive to plasma markers of Alzheimer disease pathology. Objectives: To compare the associations of common episodic memory tests with plasma biomarkers of Alzheimer disease. Design: Longitudinal cohort study. Setting: Academic medical center in the midwestern United States. Participants: A total of 161 cognitively normal older adults with at least one plasma biomarker assessment and two or more annual clinical and cognitive assessments which included up to three different tests of episodic memory. Measurements: Episodic memory performance using free recall, paired associates recall or paragraph recall. Plasma Aβ42, Aβ40, ptau217, and neurofilament light chain were measured. Results: Free recall on the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT + IR) was substantially more sensitive to longitudinal cognitive change associated with abnormal baseline plasma Aβ42/Aβ40 and ptau217 compared to other measures of episodic memory. A cognitive composite that included only free recall showed larger decline associated with baseline Aβ42/Aβ40 when compared to those that included paragraph recall. Differences in decline across composites were minimal when considering baseline ptau217 or NfL. Conclusion: Episodic memory is a critical domain to assess in preclinical Alzheimer disease. Methods of assessing memory are not equal and longitudinal change in free recall substantially outperformed both paired associates and paragraph recall. Clinical trial results will depend critically on the episodic memory test(s) that are chosen for a composite endpoint and free recall from the FCSRT + IR is an optimal memory measure to include rather than paired associates or paragraph recall. © The Authors 2024.

Author Keywords
Alzheimer disease;  cognition;  composite scores;  Episodic memory;  plasma biomarkers

Funding details
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
Lunds UniversitetLU
GHR FoundationGHR
Cure Alzheimer’s FundCAF
European Research CouncilERCADG-101096455
European Research CouncilERC
University Hospital FoundationUHF2020-O000028
University Hospital FoundationUHF
1412/22
2022-00775, ERAPERMED2021-184
National Institute on AgingNIAR01AG083740, P30 AG066444, P01 AG003991, P01 AG026276
National Institute on AgingNIA
2022-1259
Alzheimer’s AssociationAAZEN24-1069572, SG-23-1061717
Alzheimer’s AssociationAA
HjärnfondenFO2021-0293
Hjärnfonden
Knut och Alice Wallenbergs Stiftelse2022-0231
Knut och Alice Wallenbergs Stiftelse
AlzheimerfondenAF-980907
Alzheimerfonden
2022-Projekt0080

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

The role of the Alzheimer’s Disease Neuroimaging Initiative in establishing the Dominantly Inherited Alzheimer Network
(2024) Alzheimer’s and Dementia, . 

Morris, J.C.^a b , Buckles, V.D.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
The Dominantly Inherited Alzheimer Network (DIAN) initially was funded by the National Institute on Aging (NIA) in 2008 and thus was able to adopt and incorporate the protocols developed by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that had been established by the NIA in 2004. The use of ADNI protocols for DIAN neuroimaging studies and assays of biological fluids for Alzheimer disease (AD) biomarkers permitted examination of the hypothesis that autosomal dominant AD (ADAD), studied by DIAN, and “sporadic” late-onset AD (LOAD), studied by ADNI, shared the same pathobiological construct. In a collaborative effort, the longitudinal DIAN and ADNI databases were compared and the findings supported the conclusion that ADAD and LOAD share a similar pathophysiology. The importance of the DIAN study thus is amplified by its relevance to LOAD, as characterized by the “parent” ADNI program. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer disease biomarkers;  autosomal dominant Alzheimer’s disease;  late onset Alzheimer’s disease

Funding details
P30 AG066444, P01AG003991, P01AG026276, U19AG032436
Alzheimer’s AssociationAADIAN_ADNI‐16‐434364
Alzheimer’s AssociationAA

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Assessing amyloid PET positivity and cognitive function in Down syndrome to guide clinical trials targeting amyloid
(2024) Alzheimer’s and Dementia, . 

Krasny, S.^a , Yan, C.^b , Hartley, S.L.^c , Handen, B.L.^d , Wisch, J.K.^b , Boehrwinkle, A.H.^b , Ances, B.M.^b , Rafii, M.S.^e , the ABC-DS consortium^f

^a Scripps Research Institute, La JollaCA, United States
^b Department of Neurology, Washington University, Saint Louis, MO, United States
^c Waisman Center, University of Wisconsin, Madison, WI, United States
^d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^e Alzheimer’s Therapeutic Research Institute, Keck School of Medicine of University of Southern California, San Diego, CA, United States

Abstract
INTRODUCTION: Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer’s disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs. METHODS: Cross-sectional data from the Alzheimer Biomarker Consortium–Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes. RESULTS: Four hundred nine DS adults (mean age = 44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age. DISCUSSION: These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics. HIGHLIGHTS: There is rapid increase in prevalence of amyloid beta (Aβ) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aβ PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aβ PET positivity and clinical symptom onset in DS. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
adults;  Alzheimer’s disease;  amyloid;  clinical trials;  cognitive;  dementia;  Down syndrome;  imaging;  positron emission tomography

Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
NIHR Cambridge Biomedical Research Centre
National Institute on AgingNIA
National Institutes of HealthNIHP30 AG062421, P50 AG008702, P50 AG005681, P50 AG005133, P30 AG066519, P50 AG16537, P30 AG062715
National Institutes of HealthNIH
U24 AG21886
National Center for Advancing Translational SciencesNCATSUL1 TR001414, UL1 TR001857, UL1 TR002373, UL1 TR001873, UL1 TR002345
National Center for Advancing Translational SciencesNCATS
P50 HD105353, U54 HD090256, U54 HD087011
National Institute of Child Health and Human DevelopmentNICHDU01 AG051406, U19 AG068054, U01 AG051412
National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Article in Press
Source: Scopus