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2. Clinical trials and late‐stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014

Author

Schneider, LS, Mangialasche, F, Andreasen, N, Feldman, H, Giacobini, E, Jones, R, Mantua, V, Mecocci, P, Pani, L, Winblad, B, and Kivipelto, M

Subjects
Patient Safety, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Trials and Supportive Activities, Aging, Acquired Cognitive Impairment, Neurosciences, Brain Disorders, Clinical Research, Dementia, Neurodegenerative, Alzheimer's Disease, 5.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Alzheimer Disease, Biomarkers, Cholinesterase Inhibitors, Dopamine Agents, Drug Monitoring, Humans, Medication Therapy Management, Memantine, Memory Disorders, Nootropic Agents, Practice Guidelines as Topic, Randomized Controlled Trials as Topic, Alzheimer, clinical trial, dementia, drug development, treatment, Clinical Sciences, Cardiovascular System & Hematology
Abstract

The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30 years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or 'mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12 months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

Published
2014

7. Non-Invasive Transcutaneous Bioconductance in the Risk-Stratification of Indeterminate Pulmonary Lesions: IONIQ Science’s PL-210 Protocol in Evaluation of Continued Advances in the IONIQ Sciences Prolung System

Author

Goyal, A., primary, Tamayo, J., additional, Zink, R., additional, Kudulis, M., additional, Cerceo, J., additional, Miller, B., additional, Andreasen, N., additional, Goates, P., additional, Brimhall, O., additional, Garff, M., additional, and Yung, R.C.W., additional

Published
2022
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23. Intrathecal inflammation precedes development of Alzheimer's disease

Author

Tarkowski, E, Andreasen, N, and Tarkowski, A

Subjects
Influence, Physiological aspects, Cognitive disorders -- Influence -- Physiological aspects, Tumor necrosis factor -- Physiological aspects, Transforming growth factors -- Physiological aspects, Inflammation mediators -- Physiological aspects, Central nervous system diseases -- Physiological aspects, Alzheimer's disease -- Physiological aspects, Statistics (Data) -- Physiological aspects, Inflammation -- Mediators, Statistics -- Physiological aspects, Cognition disorders -- Influence -- Physiological aspects
Abstract

Objectives: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1β (IL1β), tumour necrosis factor a (TNFα), GM-CSF, of the anti-inflammatory cytokine TGFβ, of tau protein, a [...]

Published
2003

38. Remote Tongue Based Control of a Wheelchair Mounted Assistive Robotic Arm – a proof of concept study

Author

Lotte Andreasen N. S. Struijk, Strahinja Dosen, Asgereur Arna Palsdottir, and Mostafa Mohammadi

Subjects
Tetraplegia, 030506 rehabilitation, Computer science, Wheelchair mounted ARM, Interface (computing), 0206 medical engineering, 02 engineering and technology, medicine.disease, Sitting, 020601 biomedical engineering, Task (project management), law.invention, 03 medical and health sciences, Wheelchair, Remote control, Human–computer interaction, law, Proof of concept, medicine, 0305 other medical science, Robotic arm, Itongue
Abstract

Assistive robotic arms (ARM) have the potential tomake individuals with tetraplegia more independent by enablingthem to perform physical activities. Usually the ARMs are usedwithin reach of the user while the user is sitting in a poweredwheelchair. In this proof of concept study, we demonstrated forthe first time a tongue based method to provide an individualwith tetraplegia the ability to fetch remote objects such asbeverages while being bedridden. This is done through tonguebasedcontrol of a mobile and remote assistive roboticmanipulator (ARM) which was mounted on a poweredwheelchair. The tongue-computer interface was used by twosubjects to remotely navigate an ARM carrying wheelchairtowards a table and control the ARM to pick up a bottle of waterplaced on the table. The subjects were given approximately 40min to become familiar with the system and then they performedthe task 10 times. Subject 1 succeeded the task in 9 out of 10 trialsand subject 2 in 8 out of 10 trials. The trials lasted for 132±38 sand 195±64 s for subject 1 and 2, respectively. Thus, the systemhas the potential to further empower individuals with tetraplegiaby enabling them to remotely pick-up objects when e.g. lying inbed, making them more independent and reducing the need forcare. Future work will include further development of thesystem (better feedback, semi automation) as well asexperimental assessment with more subjects and tasks.

Published
2019
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40. Neurochemical aftermath of amateur boxing

Author

Zetterberg, H., Hietala, M. A., Jonsson, M., Andreasen, N., Styrud, E., Karlsson, I., Edman, A., Popa, C., Rasulzada, A., Wahlund, L. O., Mehta, P. D., Rosengren, L., Blennow, K., and Wallin, A.

Published
2006

44. Plasma A beta 42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study

Author

Perez-Grijalba, V, Arbizu, J, Romero, J, Prieto, E, Pesini, P, Sarasa, L, Guillen, F, Monleon, I, San-Jose, I, Martinez-Lage, P, Munuera, J, Hernandez, I, Buendia, M, Sotolongo-Grau, O, Alegret, M, Ruiz, A, Tarraga, L, Boada, M, Sarasa, M, Goni, M, Pujadas, F, Villarejo, A, Frank, A, Pena-Casanova, J, Fernandez, M, Pinol, G, Blesa, R, Gil, P, Pascual, LF, Aguilar, M, Frisoni, GB, Matias-Guiu, J, Andreasen, N, and Antunez, C

Subjects
Plasma, Mild cognitive impairment, Biomarker, Amyloid-beta, FDG-PET, Preclinical Alzheimer's disease, Amyloid-PET
Abstract

Background To facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer's disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (A beta) levels with the presence of pathological accumulation of A beta in the brain measured by amyloid-PET. Both plasma A beta 42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers. Methods We included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total A beta 40 and A beta 42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as A beta-PET positive or negative, and the ability of TP42/40 to detect A beta-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma A beta biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification. Results Eighteen (30.5%) subjects were A beta-PET positive. TP42/40 ratio alone identified A beta-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779-0.982). Discriminating performance of TP42/40 to detect A beta-PET-positive subjects yielded sensitivity and specificity values at Youden's cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of A beta-PET scans by 64%. Combination of both FDG-PET scores and plasma A beta biomarkers was found to be the most accurate A beta-PET predictor, with an AUC of 0.965 (95% CI = 0.913-0.100). Conclusions Plasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain A beta positivity in preclinical and prodromal stages of Alzheimer's disease.

Published
2019

48. Auditory and Visual Attention Assessed With PET

Author

OʼLeary, D. S., Andreasen, N. C., Hurtig, R. R., Torres, I. J., Flashman, L. A., Kesler, M. L., Arndt, S. V., Cizadlo, T. J., Ponto, L. L.B., Watkins, G. L., and Hichwa, R. D.

Published
1997

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