Alzheimer’s disease (AD) is characterized by progressive cognitive and functional decline. Individuals diagnosed with AD often suffer from a range of behavioral disturbances, often referred to as neuropsychiatric symptoms (NPS). The term describes heterogeneous behavioral or mood disturbances, such as aggression, agitation, anxiety, apathy, depression, psychosis, and sleep disruption. NPS are near universal among patients at all stages and etiologies of dementia, are generally multi-determined, may wax and wane, and complicate caring for patients with dementia (Porsteinsson and Antonsdottir, Reference Porsteinsson and Antonsdottir2017).
Extensive and reciprocal neuronal connections exist between the epicenters of emotions and cognition. This interface is convoluted as the exact mechanism of the interconnect between NPS and cognitive impairment remains obscure. Proposed mechanisms include four possible pathways: (1) etiologic pathway: where a NPS is causing pathophysiologic changes in brain tissue that is causally linked to the development of AD pathology; (2) common neuropathological pathway: NPS may be a direct non-cognitive manifestation of the Alzheimer’s neurodegenerative disease because it affects key brain areas underlying behavior, emotion, and perception; (3) psychological reaction: a person experiencing cognitive decline may develop depression, anxiety, or similar NPS because of the awareness of gradual loss of cognitive and functional abilities; and (4) interaction: a synergistic interaction between NPS and a biological factor leads to AD/mild cognitive impairment (MCI). These four mechanisms (and other possible mechanisms) are not mutually exclusive and may act in some sort of combinations (Porsteinsson and Antonsdottir, Reference Porsteinsson and Antonsdottir2015).
More precise neuroimaging and neurochemistry methods are leading to a clearer understanding of the relationship between the underlying AD brain disease and its clinical manifestations in the form of NPS. Furthermore, there is an increasing recognition of the overlap of neural circuits across multiple NPS that may mediate the AD pathology with behavioral manifestations of NPS (Rosenberg et al., Reference Rosenberg, Nowrangi and Lyketsos2015). The contribution of individual regions or activity patterns within this system is likely to be different across symptoms, which may explain the unique clinical manifestation of individual NPS domains. A thorough characterization of the shared neural circuit with the consideration of the disproportional contribution of individual regions or activity patterns to different NPS may provide a link between NPS and AD pathology. Assessment of circuit function might also play a role as a biomarker to assess or predict treatment response (Wang et al., Reference Wang2019).
The inability to address many important research questions despite a significant increase in funding suggests a systemic problem in the production of clinical research. Part of the solution may lie in point-of-care (POC) trials where eligible participants are identified at health care encounters, so the study population reflects the range and distribution of patients seen in clinical practice. In contrast to conventional randomized clinical trials, POC trials do not need to have study staff at each participating site to collect and enter study data into a research clinical database. Instead, the outcome data and patient characteristics are obtained from existing medical records. It introduces a new relationship between clinical care and research to address the current difficulty in which “there are too many research questions, too few investigators, and too little funding” in clinical research. Although the data of POC trials may not be as complete and clean as in clinical trials, there is an ongoing effort to improve electronic medical records (EMR) systems to facilitate their utilization for clinical research (Shih et al., Reference Shih, Turakhia and Lai2015).
In an excellent and timely study published in this issue of International Psychogeriatrics, Nowrangi et al. report on a cross-sectional, retrospective study examining the interaction between structural brain volume measures derived from clinical 3T magnetic resonance imaging (MRI) scans and the occurrence of NPS in a heterogeneous cohort seen in an outpatient memory clinic at a tertiary teaching hospital (Nowrangi et al., Reference Nowrangi2020). The patients received a clinical workup for cognitive complaints, including dementia, which includes a comprehensive cognitive, neuropsychiatric, and functional evaluation. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant based, self-administered, brief assessment of 12 behavioral domains intended for clinical settings. The data were collected from the paper medical charts of patients that had usable clinical and neuroimaging data. Anatomical brain regions of interest were generated a priori based on a previous literature review, and regional volumes were measured in both hemispheres focusing on patients with 3 common and distressing NPS: agitation (5 regions), apathy (5 regions), and delusions (3 regions); with the idea that correlating NPS with a specific brain structure provides an approximation of the underlying mechanism. The clinical evaluations and diagnoses were done by physicians from different specialties but a limitation to the study is that there was not a standardized protocol for assessment, documentation, terminology, and diagnosis. Diagnostic terminology varied widely and was the impetus for avoiding specifying the etiology of the cognitive impairment but instead grouping the cohort based on Mini-Mental State Examination (MMSE) scores, attempting to create groups with mild, moderate, and severe impairment that approximate normal cognition, MCI, and dementia. Functional Activities Questionnaire scores approximately corresponded to the MMSE scores where the dementia group has the greatest amount of functional impairment and normal cognition the least, thus suggesting a successful subgrouping method. The cohort had mostly mild behavioral disturbance based on low NPI-Q scores. Despite these limitations, the most important finding of the study is that volumetric analysis of clinical quality, non-research protocol 3T MRI scans closely mirror results of research-quality protocol-based analysis when investigating the relationship of NPS with volumes of specific behaviorally relevant brain regions in individuals with cognitive impairment. In particular, the authors report consistent relationships between limbic lobe structures and prefrontal and frontal lobe structures and the specified behavioral domains of agitation, apathy, and delusions.
For future considerations, the authors suggest adopting a standardized assessment protocol in the clinic setting, using a blinded multi-rater consensus diagnosis, more granularity on the type, severity, and frequency of behavioral disturbances, as well as focusing on hypothesis testing to enhance statistical power. With the advent of EMR, automated clinical data extraction using artificial intelligence and machine learning capabilities for big data analytics may deliver even further advantages in the utilization of POC trials for clinical research.
You have
Access
Alzheimer’s disease (AD) is characterized by progressive cognitive and functional decline. Individuals diagnosed with AD often suffer from a range of behavioral disturbances, often referred to as neuropsychiatric symptoms (NPS). The term describes heterogeneous behavioral or mood disturbances, such as aggression, agitation, anxiety, apathy, depression, psychosis, and sleep disruption. NPS are near universal among patients at all stages and etiologies of dementia, are generally multi-determined, may wax and wane, and complicate caring for patients with dementia (Porsteinsson and Antonsdottir, Reference Porsteinsson and Antonsdottir2017).
Extensive and reciprocal neuronal connections exist between the epicenters of emotions and cognition. This interface is convoluted as the exact mechanism of the interconnect between NPS and cognitive impairment remains obscure. Proposed mechanisms include four possible pathways: (1) etiologic pathway: where a NPS is causing pathophysiologic changes in brain tissue that is causally linked to the development of AD pathology; (2) common neuropathological pathway: NPS may be a direct non-cognitive manifestation of the Alzheimer’s neurodegenerative disease because it affects key brain areas underlying behavior, emotion, and perception; (3) psychological reaction: a person experiencing cognitive decline may develop depression, anxiety, or similar NPS because of the awareness of gradual loss of cognitive and functional abilities; and (4) interaction: a synergistic interaction between NPS and a biological factor leads to AD/mild cognitive impairment (MCI). These four mechanisms (and other possible mechanisms) are not mutually exclusive and may act in some sort of combinations (Porsteinsson and Antonsdottir, Reference Porsteinsson and Antonsdottir2015).
More precise neuroimaging and neurochemistry methods are leading to a clearer understanding of the relationship between the underlying AD brain disease and its clinical manifestations in the form of NPS. Furthermore, there is an increasing recognition of the overlap of neural circuits across multiple NPS that may mediate the AD pathology with behavioral manifestations of NPS (Rosenberg et al., Reference Rosenberg, Nowrangi and Lyketsos2015). The contribution of individual regions or activity patterns within this system is likely to be different across symptoms, which may explain the unique clinical manifestation of individual NPS domains. A thorough characterization of the shared neural circuit with the consideration of the disproportional contribution of individual regions or activity patterns to different NPS may provide a link between NPS and AD pathology. Assessment of circuit function might also play a role as a biomarker to assess or predict treatment response (Wang et al., Reference Wang2019).
The inability to address many important research questions despite a significant increase in funding suggests a systemic problem in the production of clinical research. Part of the solution may lie in point-of-care (POC) trials where eligible participants are identified at health care encounters, so the study population reflects the range and distribution of patients seen in clinical practice. In contrast to conventional randomized clinical trials, POC trials do not need to have study staff at each participating site to collect and enter study data into a research clinical database. Instead, the outcome data and patient characteristics are obtained from existing medical records. It introduces a new relationship between clinical care and research to address the current difficulty in which “there are too many research questions, too few investigators, and too little funding” in clinical research. Although the data of POC trials may not be as complete and clean as in clinical trials, there is an ongoing effort to improve electronic medical records (EMR) systems to facilitate their utilization for clinical research (Shih et al., Reference Shih, Turakhia and Lai2015).
In an excellent and timely study published in this issue of International Psychogeriatrics, Nowrangi et al. report on a cross-sectional, retrospective study examining the interaction between structural brain volume measures derived from clinical 3T magnetic resonance imaging (MRI) scans and the occurrence of NPS in a heterogeneous cohort seen in an outpatient memory clinic at a tertiary teaching hospital (Nowrangi et al., Reference Nowrangi2020). The patients received a clinical workup for cognitive complaints, including dementia, which includes a comprehensive cognitive, neuropsychiatric, and functional evaluation. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant based, self-administered, brief assessment of 12 behavioral domains intended for clinical settings. The data were collected from the paper medical charts of patients that had usable clinical and neuroimaging data. Anatomical brain regions of interest were generated a priori based on a previous literature review, and regional volumes were measured in both hemispheres focusing on patients with 3 common and distressing NPS: agitation (5 regions), apathy (5 regions), and delusions (3 regions); with the idea that correlating NPS with a specific brain structure provides an approximation of the underlying mechanism. The clinical evaluations and diagnoses were done by physicians from different specialties but a limitation to the study is that there was not a standardized protocol for assessment, documentation, terminology, and diagnosis. Diagnostic terminology varied widely and was the impetus for avoiding specifying the etiology of the cognitive impairment but instead grouping the cohort based on Mini-Mental State Examination (MMSE) scores, attempting to create groups with mild, moderate, and severe impairment that approximate normal cognition, MCI, and dementia. Functional Activities Questionnaire scores approximately corresponded to the MMSE scores where the dementia group has the greatest amount of functional impairment and normal cognition the least, thus suggesting a successful subgrouping method. The cohort had mostly mild behavioral disturbance based on low NPI-Q scores. Despite these limitations, the most important finding of the study is that volumetric analysis of clinical quality, non-research protocol 3T MRI scans closely mirror results of research-quality protocol-based analysis when investigating the relationship of NPS with volumes of specific behaviorally relevant brain regions in individuals with cognitive impairment. In particular, the authors report consistent relationships between limbic lobe structures and prefrontal and frontal lobe structures and the specified behavioral domains of agitation, apathy, and delusions.
For future considerations, the authors suggest adopting a standardized assessment protocol in the clinic setting, using a blinded multi-rater consensus diagnosis, more granularity on the type, severity, and frequency of behavioral disturbances, as well as focusing on hypothesis testing to enhance statistical power. With the advent of EMR, automated clinical data extraction using artificial intelligence and machine learning capabilities for big data analytics may deliver even further advantages in the utilization of POC trials for clinical research.
Conflict of interest
Dr Porsteinsson reports personal fees from Acadia Pharmaceuticals, Avanir, Cadent Therapeutics, Eisai, Functional Neuromodulation, and Tetra Discovery Partners; grants to his institution from Avanir, Biogen, Biohaven, Eisai, Eli Lilly, Genentech/Roche, and Novartis; as well as funding from NIA, NIMH, and DOD. Dr Clark has nothing to disclose.