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The incorporation of target engagement, efficacy, and imaging abnormalities biomarkers on preclinical (animal) drug development brings the promise of accelerating drug development. In this chapter, we will highlight innovative methodological considerations that will bring greater predictive power relative to the traditional approaches in the preclinical stage of drug discovery. First, we discuss various animal models used in Alzheimer’s disease research and important aspects to consider when choosing the appropriate model to test a novel therapeutic intervention. Second, compared to the traditional histological methods, utilizing in vivo biomarkers in preclinical assessment allows quantifying disease pathophysiology with complex longitudinal designs. We discuss the feasibility and implications of longitudinal study designs and how the same in vivo biomarkers used in human clinical trials can be implemented to evaluate the preclinical development stages. Lastly, we discuss why the incorporation of methods from human clinical trials can advance the preclinical phases of drug discovery.
A 65-year-old accountant presented to the consultation to investigate whether her memory lapses are the first manifestations of Fahr’s disease. She noticed, during the last few years, a progressive difficulty in accomplishing her tasks at work. She felt tired and described that it takes her more time to prepare her reports as compared to a few years ago. She needs to read her drafts several times in order to ensure her work is complete and accurate. She also described more dependence on her personal notes to remember her tasks such as lists for shopping. During meetings and conversations at work, she described difficulties recalling people’s names. She has started to search for words during conversations. Although inconvenient, the impact of these difficulties on her work remains minimal, and she continues to take good care of her home affairs. Her husband denies that the patient is underperforming at home. She described no difficulties completing her domestic, financial, and personal obligations.
A 62-year-old male (Patient 1) was admitted to the Capital Medical University Hospital, in Beijing, China, because of a 3-month history of progressive cognitive impairment and abnormal behaviors including performing motor gestures and talking to himself incoherently. During the first evaluation, it was reported that the patient had insomnia as an early clinical manifestation accompanied by intense dreams and sleep talking. During the 14 days of hospitalization, the patient showed intractable insomnia, progressive cognitive deterioration, mental confusion, visual and auditory hallucinations, and paranoia. Twelve months after the onset of the symptoms, the patient returned to the hospital awake but unresponsive and died due to breathing difficulties.
A 75-year-old, right-handed man accompanied by his wife presented at initial consultation, with a history of mild difficulties with short-term recall for the past 2 years. Although he wrote down the time and place of upcoming appointments accurately, he repeatedly sought reassurance from his wife about them. He kept rechecking where things had been deposited. There was some hesitation for words during conversations.
Mrs. M is a 79-year-old active and independent lady who lives with her 88-year-old husband. She has been serving as his caregiver since his AD dementia diagnosis. Both cohabit with each other in the same house for more than 30 years. She has been responsible for maintaining their home, preparing meals, and has taken care of their financial affairs for many years. Mrs. M was invited to participate in a 3-year longitudinal study, as a cognitively healthy person, involving magnetic resonance imaging (MRI) and positron emission tomography (PET) scans for amyloid plaques, neurofibrillary tangles, and glucose metabolism.
To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants.
COMPASS-ND includes persons with Alzheimer’s disease (AD; n = 150), Parkinson’s disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c.
Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%–40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent.
COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.
Covering the spectrum of cognitive decline in aging using illustrative cases, from mild impairment to dementia, this set of case studies offers a wide-ranging guide for trainees and clinicians. This second volume includes updated research diagnostic criteria and details of new imaging technology, including novel biomarkers such as PET amyloid and tau, to inform readers in clinical practice. Each case includes a clinical history, examination findings and special investigations, followed by diagnosis and discussion, to encourage clinical reasoning, integrative thinking, and problem-solving skills. To reinforce diagnostic skills, the cases include careful analysis of individual presenting patterns and up-to-date information on diagnostic classification and tools. The reader will be able to distinguish patients who need reassurance, closer follow-up or immediate referral to specialized services. With an international authorship, this book is for trainees and clinicians in neurology, psychiatry and neuropsychology.
In Canada, standard dementia workup consists of clinical, neurological, and cognitive evaluation, as well as structural brain imaging. For atypical dementia presentations, additional FDG-PET brain imaging is recommended. Cerebrospinal fluid (CSF) biomarkers have recently been proposed as the gold standard for in vivo detection of Alzheimer’s disease (AD) pathophysiology (NIA-AA research framework, 2018). As clinical implementation of CSF assessment is still limited in Canada, the present study assessed its impact on diagnostic accuracy in atypical neurodegenerative disorders in the clinical practice.
This retrospective clinical chart review included patients with cognitive complaints who underwent lumbar puncture (LP) in addition to the standard diagnostic workup. CSF analysis determined the presence of biological AD based on reduced amyloid-β42-to-total-tau index (ATI) and increased phosphorylated-tau (p-tau) levels. CSF-based diagnoses were compared to standard workup and FDG-PET-based diagnoses.
A total of 28 patients with atypical dementia presentations were included in the present study after evaluation for cognitive complaints at a specialized dementia clinic between November 2017 and July 2019. CSF analysis changed or better specified the initial clinical diagnosis in 43.0% of cases (alternative diagnosis revealed in 25% and excluded in 18%). In patients with additional FDG-PET imaging (n = 23), FDG-PET and CSF-based diagnosis did not correspond in 35% of patients, even though FDG-PET appeared to increase diagnostic accuracy compared to the initial clinical diagnosis.
CSF biomarkers improved diagnostic accuracy in atypical cognitively-impaired patients beyond standard workup and FDG-PET imaging. These results support CSF analysis implementation for atypical dementias in Canada, in addition to the standard diagnostic workup.
The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.
The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.
The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.
Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.