Background:AD is associated with memory impairments and neurodegeneration in the hippocampus. Oth... more Background:AD is associated with memory impairments and neurodegeneration in the hippocampus. Others showed that normal elders with early AD evidenced by increased brain amyloid b (Ab), had impaired functional connectivity with posterior cingulated cortex or precuneus [J Neurosci. 2009 (40):12686-94; Biol Psychiatry. 2010 67(6):584-7]. Our goal was to test the hypothesis that early AD, evidenced by increased brain amyloid b (Ab), is associated with reduction of hippocampal volume and alternation of functional connectivity of the hippocampus-centeredmemory network, in the absence of neuropsychological change.Methods: Cognitive normal elderly (N1⁄424, aged 60 89 years) had brain Ab assessedwith florbetapir F 18 PET by visual ratings and standard uptake value ratio (SUVr). Nine participants were A b + and 15 were negative A b -. Whole brain resting-state fMRI was acquired and registered to a template T1 image. Correlation coefficient with a seed region in combined bilateral hippocampal head was calculated with every voxel in the forebrain gray matter. Hippocampal and cortical volumes were measured with Freesurfer and hippocampal subfield volumes in the body were measured with ASHS.Results: There were no effects of Ab on standard neuropsychological tests, a memory-related pattern separation test, or cortical gray matter volumes. In comparison with A b subjects, A b + subjects had reduced volumes in right CA3 of the hippocampal body (256 5 vs. 316 7 mm 3), left hippocampal head (14956 190 vs. 1757 6 209 mm 3), and entire hippocampus (7312 6 631 vs. 7912 6 705 mm 3). In comparison with the A b group, functional connectivity with the hippocampus seed in the A b + group increased in left thalamus but decreased in left middle frontal gyrus and left precentral gyrus (p<0.01 after correction, Figure 1). The connectivity between the hippocampus seed and the left thalamus cluster significantly correlated with SUVr even when covarying for either age or hippocampal volume (r1⁄40.50, p<0.05) and marginally significant for the other two clusters. Conclusions: Our finding of changes in structure and functional connectivity of the hippocampus in early AD demonstrates disruption of the hippocampus-centered memory network prior to neuropsychological changes. These neuroimaging findings may be used for early detection and to identify subjects for AD prevention trials.
Background Functional decline in Alzheimer’s disease (AD) is typically measured using single-time... more Background Functional decline in Alzheimer’s disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. Methods This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. ...
Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, an... more Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, and conducting clinical research. Biomarkers hold promise for targeted therapeutic approaches, selection of participants in clinical trials, and direct physiological efficacy readouts. However, the anchoring of biomarker research to clinical symptomatology is often based on short and insensitive cognitive screening. This gives the impression that cognitive symptoms occur relatively late and that their progression in the early stages of the disease is slow. A thorough cognitive assessment is a powerful tool and has a key role in the accurate and early diagnosis of dementia. It is very different from the cognitive testing usually seen in biomarker research and drug development. Yet the distinction between these approaches is unclear to many. This paper highlights the misconceptions around cognitive research in dementia and suggests a way forward to facilitate biomarker and drug development through the improved utility of cognitive assessment tools.
The ‘Remote Assessment of Disease and Relapse – Alzheimer’s Disease’ (RADAR‐AD) study is assessin... more The ‘Remote Assessment of Disease and Relapse – Alzheimer’s Disease’ (RADAR‐AD) study is assessing functional decline in Alzheimer’s disease (AD) using remote monitoring techniques (RMT’s). Compared to traditional pen‐and‐paper clinical assessments, RMT’s can continuously and objectively monitor function during activities of daily living (ADL), which are arguably more sensitive to the earliest stages of AD. The aim of this abstract is to compare the results of the augmented reality task ‘Altoida’, that recreates an ADL requiring spatial navigation and memory, implemented as a tablet application, between 1) healthy controls, preclinical AD and prodromal AD, and with 2) standard clinical tests for cognitive and functional decline.
The Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR‐AD) study is assessing ... more The Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR‐AD) study is assessing functional decline in Alzheimer’s Disease (AD) using remote monitoring techniques (RMT’s). RMT’s allow for continuous and objective monitoring of function, potentially improving the sensitivity of assessment in AD. Gait is an important functional domain to maintain independent living. Yet, relatively little is known on gait impairments in the pre‐symptomatic stages of AD. Therefore, the aim of this study is to compare outcomes of in‐clinic gait assessments, using high frequency inertial measurement units, between healthy controls, preclinical AD patients, and cognitively impaired AD patients.
short-term worsening and 50 showed short-term improvement (mean time to first change1⁄4 170 days ... more short-term worsening and 50 showed short-term improvement (mean time to first change1⁄4 170 days 6 std 108 days). Of the 73 patients with standardized cognitive tests scores , 25 showed short-term worsening (34%) and 48 showed short-term improvement, (mean time to first change1⁄4 106 days (6 std 92 days). F irst change scores were significantly correlated. In all measurements, short-term improvements led to significant increases in the probability of worsening (p<0.01). In all measures, short-term worsening to any degree was associated with long-term worsening. Initial improvement results were similar -e.g. initial symptomatic improvement resulted in 90% still improved at 1 year, and 67% at 2 years. In contrast to worsening, the greater the degree of improvement, the higher the chance of remaining improved. Conclusions: Regarding treatment with cholinesterase inhibitors, clinically important improvement early in the course of treatment forecasted longer term improvement, especially when improvements were large. Any degree of worsening was associated with persistently poor long-term outcomes. The twoyear time course suggests that this might extend to potentially diseasemodifying compounds.
Background:AD is associated with memory impairments and neurodegeneration in the hippocampus. Oth... more Background:AD is associated with memory impairments and neurodegeneration in the hippocampus. Others showed that normal elders with early AD evidenced by increased brain amyloid b (Ab), had impaired functional connectivity with posterior cingulated cortex or precuneus [J Neurosci. 2009 (40):12686-94; Biol Psychiatry. 2010 67(6):584-7]. Our goal was to test the hypothesis that early AD, evidenced by increased brain amyloid b (Ab), is associated with reduction of hippocampal volume and alternation of functional connectivity of the hippocampus-centeredmemory network, in the absence of neuropsychological change.Methods: Cognitive normal elderly (N1⁄424, aged 60 89 years) had brain Ab assessedwith florbetapir F 18 PET by visual ratings and standard uptake value ratio (SUVr). Nine participants were A b + and 15 were negative A b -. Whole brain resting-state fMRI was acquired and registered to a template T1 image. Correlation coefficient with a seed region in combined bilateral hippocampal head was calculated with every voxel in the forebrain gray matter. Hippocampal and cortical volumes were measured with Freesurfer and hippocampal subfield volumes in the body were measured with ASHS.Results: There were no effects of Ab on standard neuropsychological tests, a memory-related pattern separation test, or cortical gray matter volumes. In comparison with A b subjects, A b + subjects had reduced volumes in right CA3 of the hippocampal body (256 5 vs. 316 7 mm 3), left hippocampal head (14956 190 vs. 1757 6 209 mm 3), and entire hippocampus (7312 6 631 vs. 7912 6 705 mm 3). In comparison with the A b group, functional connectivity with the hippocampus seed in the A b + group increased in left thalamus but decreased in left middle frontal gyrus and left precentral gyrus (p<0.01 after correction, Figure 1). The connectivity between the hippocampus seed and the left thalamus cluster significantly correlated with SUVr even when covarying for either age or hippocampal volume (r1⁄40.50, p<0.05) and marginally significant for the other two clusters. Conclusions: Our finding of changes in structure and functional connectivity of the hippocampus in early AD demonstrates disruption of the hippocampus-centered memory network prior to neuropsychological changes. These neuroimaging findings may be used for early detection and to identify subjects for AD prevention trials.
Background Functional decline in Alzheimer’s disease (AD) is typically measured using single-time... more Background Functional decline in Alzheimer’s disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. Methods This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. ...
Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, an... more Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, and conducting clinical research. Biomarkers hold promise for targeted therapeutic approaches, selection of participants in clinical trials, and direct physiological efficacy readouts. However, the anchoring of biomarker research to clinical symptomatology is often based on short and insensitive cognitive screening. This gives the impression that cognitive symptoms occur relatively late and that their progression in the early stages of the disease is slow. A thorough cognitive assessment is a powerful tool and has a key role in the accurate and early diagnosis of dementia. It is very different from the cognitive testing usually seen in biomarker research and drug development. Yet the distinction between these approaches is unclear to many. This paper highlights the misconceptions around cognitive research in dementia and suggests a way forward to facilitate biomarker and drug development through the improved utility of cognitive assessment tools.
The ‘Remote Assessment of Disease and Relapse – Alzheimer’s Disease’ (RADAR‐AD) study is assessin... more The ‘Remote Assessment of Disease and Relapse – Alzheimer’s Disease’ (RADAR‐AD) study is assessing functional decline in Alzheimer’s disease (AD) using remote monitoring techniques (RMT’s). Compared to traditional pen‐and‐paper clinical assessments, RMT’s can continuously and objectively monitor function during activities of daily living (ADL), which are arguably more sensitive to the earliest stages of AD. The aim of this abstract is to compare the results of the augmented reality task ‘Altoida’, that recreates an ADL requiring spatial navigation and memory, implemented as a tablet application, between 1) healthy controls, preclinical AD and prodromal AD, and with 2) standard clinical tests for cognitive and functional decline.
The Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR‐AD) study is assessing ... more The Remote Assessment of Disease and Relapse – Alzheimer’s Disease (RADAR‐AD) study is assessing functional decline in Alzheimer’s Disease (AD) using remote monitoring techniques (RMT’s). RMT’s allow for continuous and objective monitoring of function, potentially improving the sensitivity of assessment in AD. Gait is an important functional domain to maintain independent living. Yet, relatively little is known on gait impairments in the pre‐symptomatic stages of AD. Therefore, the aim of this study is to compare outcomes of in‐clinic gait assessments, using high frequency inertial measurement units, between healthy controls, preclinical AD patients, and cognitively impaired AD patients.
short-term worsening and 50 showed short-term improvement (mean time to first change1⁄4 170 days ... more short-term worsening and 50 showed short-term improvement (mean time to first change1⁄4 170 days 6 std 108 days). Of the 73 patients with standardized cognitive tests scores , 25 showed short-term worsening (34%) and 48 showed short-term improvement, (mean time to first change1⁄4 106 days (6 std 92 days). F irst change scores were significantly correlated. In all measurements, short-term improvements led to significant increases in the probability of worsening (p<0.01). In all measures, short-term worsening to any degree was associated with long-term worsening. Initial improvement results were similar -e.g. initial symptomatic improvement resulted in 90% still improved at 1 year, and 67% at 2 years. In contrast to worsening, the greater the degree of improvement, the higher the chance of remaining improved. Conclusions: Regarding treatment with cholinesterase inhibitors, clinically important improvement early in the course of treatment forecasted longer term improvement, especially when improvements were large. Any degree of worsening was associated with persistently poor long-term outcomes. The twoyear time course suggests that this might extend to potentially diseasemodifying compounds.
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Papers by Kristin Hannesdottir