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Possible Consequences of the Approval of a Disease-Modifying Therapy for Alzheimer Disease
Erik S. Musiek, MD, PhD; John C. Morris, MD
doi : 10.1001/jamaneurol.2020.4478
JAMA Neurol. 2021;78(2):141-142
On July 8, 2020, Biogen submitted an application to the US Food and Drug Administration (FDA) for approval of aducanumab for the treatment of Alzheimer disease (AD) dementia. Aducanumab, a monoclonal antibody targeting aggregated amyloid-?, showed in a phase 3 clinical trial (but apparently not in another phase 3 trial) success in clearing amyloid plaques from the brain and slowing the rate of cognitive decline in some patients with mild AD dementia.1 While the aducanumab clinical trial data are complicated and the path to approval far from clear, approval is certainly possible, and other promising antibodies (such as Biogen’s BAN-2401 and Genentech’s gantenerumab) are just steps behind. Thus, the long-awaited advent of disease-modifying therapy for AD may be soon upon us, representing a major advance in the battle against AD and a beacon of much-needed hope for patients. However, the potential seismic effect of a disease-modifying therapy for AD requires serious consideration because it could present significant challenges for AD clinical practice and research, some of which are considered here.
Rapid Progress Toward Reliable Blood Tests for Alzheimer Disease
Elisabeth H. Thijssen, MSc; Gil D. Rabinovici, MD
doi : 10.1001/jamaneurol.2020.4200
JAMA Neurol. 2021;78(2):143-145
One of the most important advances in Alzheimer disease (AD) clinical research in the past 2 decades has been the development of biomarkers that detect amyloid-? (A?) plaques and tau neurofibrillary tangles in vivo with cerebrospinal fluid (CSF) assays or positron emission tomography (PET). Coupled with imaging or fluid-based markers of brain structural and functional integrity, these biomarkers allow researchers to capture the 3 key features of AD: amyloid plaques, tau neurofibrillary tangles, and neurodegeneration in living people (Figure). One of the most important insights from biomarker studies in AD is the existence of a prolonged preclinical stage spanning 2 decades, during which plaques and tangles deposit in the brain without leading to cognitive symptoms or functional decline. Individuals with preclinical biomarker changes are at risk for cognitive decline and may thus be excellent candidates for early intervention with disease-modifying therapies.1 The “biomarker revolution” in AD has culminated in the National Institute on Aging–Alzheimer Association Research Framework, which reconceptualizes AD as a biologic entity that is defined entirely by amyloid, tau, and neurodegeneration [AT(N)] biomarkers irrespective of clinical symptoms or functional decline.2
Self-driven Prehospital Triage Decisions for Suspected Stroke—Another Step Closer
Kori S. Zachrison, MD, MSc; Pooja Khatri, MD, MSc
doi : 10.1001/jamaneurol.2020.4425
JAMA Neurol. 2021;78(2):146-148
Setting the course for prehospital triage of patients with suspected stroke is challenging. Few would disagree, and to be frank, this is rather old news. Yet the critical question remains unsolved: how do we optimally drive prehospital triage decisions for patients with suspected stroke? Central to this question is the challenge of identifying stroke specifically due to large vessel occlusion (LVO) in the prehospital setting. Furthermore, the “best choice” among the various prehospital LVO screening tools available has not been clear. Although several versions have been developed, many had not been validated in the prehospital setting to date, let alone externally validated with head-to-head, prospective comparisons. In this issue of JAMA Neurology, Nguyen and colleagues1 make a substantial contribution to our understanding of these scales and their relative strengths and feasibilities.
Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease
Shorena Janelidze, PhD; David Berron, PhD; Ruben Smith, MD, PhD; et al.
doi : 10.1001/jamaneurol.2020.4201
JAMA Neurol. 2021;78(2):149-156
Importance There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes.
Comparison of Prehospital Scales for Predicting Large Anterior Vessel Occlusion in the Ambulance Setting
T. Truc My Nguyen, MD; Ido R. van den Wijngaard, PhD; Jan Bosch, MSc; et al.
doi : 10.1001/jamaneurol.2020.4418
JAMA Neurol. 2021;78(2):157-164
Importance The efficacy of endovascular thrombectomy (EVT) for symptomatic large anterior vessel occlusion (sLAVO) sharply decreases with time. Because EVT is restricted to comprehensive stroke centers, prehospital triage of patients with acute stroke codes for sLAVO is crucial, and although several prediction scales are already in use, external validation, head-to-head comparison, and feasibility data are lacking.
Burden of Neurological Disorders Across the US From 1990-2017A Global Burden of Disease Study
GBD 2017 US Neurological Disorders Collaborators
doi : 10.1001/jamaneurol.2020.4152
JAMA Neurol. 2021;78(2):165-176
Importance Accurate and up-to-date estimates on incidence, prevalence, mortality, and disability-adjusted life-years (burden) of neurological disorders are the backbone of evidence-based health care planning and resource allocation for these disorders. It appears that no such estimates have been reported at the state level for the US.
Ticagrelor Added to Aspirin in Acute Ischemic Stroke or Transient Ischemic Attack in Prevention of Disabling StrokeA Randomized Clinical Trial
Pierre Amarenco, MD; Hans Denison, MD, PhD; Scott R. Evans, PhD
doi : 10.1001/jamaneurol.2020.4396
JAMA Neurol. 2021;78(2):177-185
Importance Reduction of subsequent disabling stroke is the main goal of preventive treatment in the acute setting after transient ischemic attack (TIA) or minor ischemic stroke.
Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral SclerosisA Randomized Clinical Trial
Brian J. Wainger, MD, PhD; Eric A. Macklin, PhD; Steve Vucic, PhD
doi : 10.1001/jamaneurol.2020.4300
JAMA Neurol. 2021;78(2):186-196
Importance Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.
Association Between Ambient Air Pollution and Amyloid Positron Emission Tomography Positivity in Older Adults With Cognitive Impairment
Leonardo Iaccarino, PhD; Renaud La Joie, PhD; Orit H. Lesman-Segev, MD
doi : 10.1001/jamaneurol.2020.3962
JAMA Neurol. 2021;78(2):197-207
Importance Amyloid-? (A?) deposition is a feature of Alzheimer disease (AD) and may be promoted by exogenous factors, such as ambient air quality.
Surgical Decompression for Space-Occupying Hemispheric InfarctionA Systematic Review and Individual Patient Meta-analysis of Randomized Clinical Trials
Hendrik Reinink, MD; Eric Jüttler, MD; Werner Hacke, MD
doi : 10.1001/jamaneurol.2020.3745
JAMA Neurol. 2021;78(2):208-216
Importance In patients with space-occupying hemispheric infarction, surgical decompression reduces the risk of death and increases the chance of a favorable outcome. Uncertainties, however, still remain about the benefit of this treatment for specific patient groups.
Association of Initial ?-Amyloid Levels With Subsequent Flortaucipir Positron Emission Tomography Changes in Persons Without Cognitive Impairment
David S. Knopman, MD; Emily S. Lundt, MS; Terry M. Therneau, PhD
doi : 10.1001/jamaneurol.2020.3921
JAMA Neurol. 2021;78(2):217-228
Importance Tau accumulation in Alzheimer disease (AD) is closely associated with cognitive impairment. Quantitating tau accumulation by positron emission tomography (PET) will be a useful outcome measure for future clinical trials in the AD spectrum.
Association Between Apolipoprotein E ?2 vs ?4, Age, and ?-Amyloid in Adults Without Cognitive Impairment
Philip S. Insel, MS; Oskar Hansson, MD, PhD; Niklas Mattsson-Carlgren, MD, PhD
doi : 10.1001/jamaneurol.2020.3780
JAMA Neurol. 2021;78(2):229-235
Importance Although the most common recent approach in Alzheimer disease drug discovery is to directly target the ?-amyloid (A?) pathway, the high prevalence of apolipoprotein E ?4 (APOE ?4) in Alzheimer disease and the ease of identifying ?4 carriers make the APOE genotype and its corresponding protein (apoE) an appealing therapeutic target to slow A? accumulation.
Association of Reperfusion After Thrombolysis With Clinical Outcome Across the 4.5- to 9-Hours and Wake-up Stroke Time WindowA Meta-Analysis of the EXTEND and EPITHET Randomized Clinical Trials
Bruce C. V. Campbell, PhD; Henry Ma, PhD; Mark W. Parsons, PhD
doi : 10.1001/jamaneurol.2020.4123
JAMA Neurol. 2021;78(2):236-240
Importance Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain.
Autologous Hematopoietic Stem Cell Transplant in Multiple SclerosisRecommendations of the National Multiple Sclerosis Society
Aaron E. Miller, MD; Tanuja Chitnis, MD; Bruce A. Cohen, MD
doi : 10.1001/jamaneurol.2020.4025
JAMA Neurol. 2021;78(2):241-246
Importance Autologous hematopoietic stem cell transplant (AHSCT) for multiple sclerosis has gained increasing interest in recent years. Despite the availability of many US Food and Drug Administration–approved disease-modifying therapies, some patients do not respond adequately and others may have very early aggressive disease that prompts consideration of alternative, highly effective, long-lasting therapy. The National Medical Advisory Committee of the National Multiple Sclerosis Society has reviewed recent literature on AHSCT for the purpose of making recommendations about its use based on current knowledge, as well as pointing out areas of controversy and issues requiring further research.
Combined Cranial Intraosseous and Cerebral Cavernous Malformations With Pathogenic CCM1 Germline Sequence Variations
Jian Ren, MD; Yukui Wei, MD; Tao Hong, MD
doi : 10.1001/jamaneurol.2020.4134
JAMA Neurol. 2021;78(2):247-248
A 46-year-old woman with a 2-year history of headache and nausea presented to the neurosurgery clinic. A physical examination revealed a palpable mass in the right frontal region. The neurologic evaluation had unremarkable results. Magnetic resonance imaging (MRI) of the head showed a right frontal extra-axial intraosseous mass. The lesion presented with atypical imaging features, with hypointensity on T1-weighted images, hyperintensity on T2-weighted images, and homogeneous enhancement on enhancing MRI (Figure 1A). The lesion was stable in size during the follow-up of 2 years and presented with nonaggressive features and a stippled appearance. The main differential diagnosis list includes an aneurysmal bone cyst, osteoma, osteosarcoma, fibrous dysplasia, giant cell tumor, osteolytic intraosseous meningioma, osteolytic metastases, and Paget disease. Susceptibility-weighted imaging revealed numerous lesions consistent with cerebral cavernous malformations (CCMs) involving the cerebral hemispheres bilaterally (Figure 1B). The multiple lesions detected by susceptibility-weighted imaging were not visible on T1-weighted or T2-weighted images. A spinal MRI was performed, and no vertebral lesions were detected. The patient declared that she had no family history of CCMs.
Creutzfeldt-Jakob Disease as a Novel Cause of Wing-Beating Tremor
Gary Álvarez Bravo, MD, MSc
doi : 10.1001/jamaneurol.2020.3899
JAMA Neurol. 2021;78(2):249-250
A 67-year-old man with an unremarkable personal history presented to the emergency department because of clumsiness accompanied by numbness in his left limbs and an unsteady gait for 6 hours. On neurological examination, he had left hypoesthesia, agraphestesia, and mild ataxia in his left limbs, plus a mild ataxic gait. Other items of the neurological examination had normal results.
A Middle-aged Woman With Severe Scoliosis and Encephalopathy
Gomathi Mohan, PhD; Geetha Bharathi, MD, MMedSc(HK), DCH(Sydney), PhD; Balachandar Vellingiri, MSc, MPhil, PhD
doi : 10.1001/jamaneurol.2020.4270
JAMA Neurol. 2021;78(2):251-252
A 42-year-old woman presented with clinical features of microcephaly, short stature, intellectual disability, severe degree of scoliosis, gait abnormality, and encephalopathy (Figure, A and B). She was born in 1973 at 38th week of gestation followed by a normal delivery (weight, 3.15 kg and head circumference, 42 cm) to nonconsanguineous parents. The head size was normal at birth, and no other abnormalities were seen during her infancy. At age 2 years, her parents noticed that she had delayed motor and language milestones. She experienced a progressive developmental delay such as reduction of head growth, loss of acquired communication, and loss of motor functions between ages 9 and 12 years. The severity of scoliosis increased with age, and she became a wheelchair user at age 18 years. She was referred to us at age 40 years with the characteristic features of growth deceleration (height, 142 cm; weight, 22 kg; body mass index, 11 [calculated as weight in kilograms divided by height in meters squared]), apraxia, left-sided hemiplegia, spasticity, sleep apnea, constipation, osteoporosis, hypoalgesia, and repetitive hand tapping (Video). Blood reports showed anemia (hemoglobin level of 9.1 g/dL; to convert to grams per liter, multiply by 10) and low levels of high-density lipoprotein cholesterol (47 mg/dL; to convert to millimoles per liter, multiply by 0.0259). There was no history of autistic behavior, vision or hearing impairments, or epilepsy. The electrocardiogram showed sinus rhythm with T wave inversion (V3-V6), and echocardiography showed mild cardiomegaly. The brain magnetic resonance imaging studies showed a diffuse reduction in the corpus callosum involving splenium and enlarged right ventricle, resulting in cerebral lateral ventricular asymmetry (Figure, C).
