- Email: [email protected]
Influence of APOE genotype and pet brain imaging on preclinical prediction of Alzheimer disease
s74
RATES OF ATROPHY IN EARLY 1330] INCREASED CAL AD: STUDIES WITH REGISTRATION OF
AND PRECLINISERIAL MRI.
Ilnaging and pathological Etudies have eqtahlished that progressive cerebral atrophy in characteristic of Alrheimer’s disease and that the medial temporal lobe is involved early in the disease. What is less clear however is: the point at which rates of atrophy first start to accelerate and; exactly how rates and pattern of atrophy change as the disease progresses. In order to examine these questions we conducted a longitudinal prospective study of individuals at risk of familial AD. A matched control group and an early sporadic AD group were similarly studied. Registration and subtraction of wial brain MRI was used to quantify rates of atrophy. Rate!, of global atrophy mcrea\ed prerymptomatically in individuals who progressed to dementia and were Ggnificantly (p
undergoing repeated PET studies during two years we observed that 26 percent of the MCI patvats converted to Alrheimer-s disease and that the deficits in glucose metabolism predicted clinical outcome i 93 percent of the cases. The cortical metabolic disturbances were quite Ggniticant m MCI patients. Detection of neuroreceptor impairments including the nicotinic receptors will probably be an earlier marker for disease processes than glucow metabolism or cerebral blood flow. The deficits in nicotinic receptors of the temporal cortex significantly correlate with the cogntive function of the patient. Functional activation studies provide valuable insight into brain function related to cognitive function especially when both receptor dynamics and blood flow changes are studied. Different regional activation pattern are observed between MCI and AD patients. Functional brain studies performed during attentional task provide us with a further insight into the early dynamic disturbances in brain function and cognitive impairment in AD patients. Possible correlation\ with neuropatologioal markers such as tau and $-amyloid m CSF i?, explored. The effect of long-term treatment with cholinesterase inhibitors is evaluated with regard to improvement in brain activation pattern in brain. Especially the importance of the prefrontal regions for conscious retrieval in AD patients and how new treatment \trategie\ can influcrnce the brain procrwng efficiency of the AD patient\ i\ presently under investigatmna.
CLINICAL AND PATHOLOGIC FEATURES OF EARLY PRE-CLINICAL ALZHEIMER’S DISEASE (AD) David
p3iJ
INFLUENCE OF APOE GENOTYPE AND PET BRAIN IMAGING ON PRECLINICAL PREDICTION OF ALZHEIMER DISEASE
The major known genetic risk for AlLheimer disease (AD), apolipoprotein E-4 (APOE-4), I\ associated with lowered cerebml glucose metabolivn in bmin regions showing AD neuropathological damage. To detrrmme cognitive and metahohc decline patterns according to genetic risk, we investigated cerebral metabolic rates using positron emission tomography (PET) m middle-aged and older person with normal memory performance. Method.\. We collected PET, magnetic resonance imaging (MRI), neuropsychological, and APOE data on 54 non-demented subjects (27 with APOE-4, 27 without APOE-4) and 1I patients with AD at baseline, and 20 of the non-demented subjects (IO with APOE-4, 10 without APOE-4) two years later (mean. SD for follow-up wab 27.9, 1.7 months). Re.ur/tr. Baseline PET measures of the non-demented wbject\ (region of interest and \tatisticul parametric mapping analy\ec with co-registered MRI) indicated significantly lower metabolism in nondemented bubJects with a single copy of the APOE- allele compared to those without APOh-4 m the inferior parietal, lateral temporal, and posterior cmgulate rrgmn\. The AD group had the lowest metabolic rates in these region\. Inferior parietal, medial and lateral temporal, and posterior cingulate hypometabolism predicted cognitive decline after two years of follow-up in non-demented subjects with the APOE- allele. PET scans performed after two years showed the greatest magnitude and extent of metabolic decline in the inferior parietal and lateral temporal cortices. After correction for multiple comparisons, these metabolic changes remained significant for the APOE- group, wherein every subject had observable metabolic decline in these regions. Conchaion. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a meam for preclinical AD detection that will e%iat in response monitormg dunng experimental treatments. Moreover, thi\ strategy should allow investigators to ue relatively small sample sire\ when testing antidementia treatmentr aimed at preventing cognitive decline and delaying dementia onset in older persons wth age-related memory complaints. Objective.
FUNCTIONAL IMAGING 13321BRAIN ALZHEIMER’S DISEASE
IN EARLY AND PRECLINICAL
With the present conservative approach of the clinical criteria for Alzheimer~~s disease the diagnosis is very often given when the clinical symptoms of the disease is quite clear. Future drug treatment in the early course of the d&ease will prompt the need for an early probably presymptomatic diagnosis. The data so far obtain rugge$t that identification of early functional changes in brain by imaging techniques such as positron emission tomography (PET) can be obtained at a presymptomatic stage of the disease. How early in the course of the disease can functional impairments reflecting pathophysiological processes be detected in the bran? Early presymptomatic metabolism disturbances have been obaened in longitudinal studies of Alzheimer families with chromo\omal aberratmn$. In a recent study of mild cognitive whjecth (MCI)
A. Bennett,
Rush-Presbyterian-St.
Luke’s
Medical
Center,
Chicqo,
AND
IL
We compared rates of change in cognitive function in 159 persons with mild cognitive impairment (MCI) to 464 persons with no cognitive impairment (NCI) and to 63 persons with early AD in the Religious Orders Study, a longitudinal clinicalpathologic study of aging and AD. A global score based on the average z-scores of 20 individual cognitive tests was wed to summarize level of and change in cognitwe function using repeated meawre~ random effects models; an episodic memory subglobal was made based on 7 tests. For persons with MCI, the global score declined 0.42 standard units per year, compared to I, IO for there with AD and 0.13 for those with NCI; there was significant heterogeneity and the correlation between initial level and rate of change was only r=.l7. By contrast, the memory score declined 0.28 standard umts per year for those with MCI, compared to 0.72 for those with AD and 0.04 for those with NCI; the correlation between initial level and rate of change war ry.54. Post-mortem data was available from X5 persons: 27 with MCI, 37 with NCI. and 2 I with AD. A global measure of AD pathology was created using the average L-scoreb for neuritic plaques (NP), diffuse plaques (DP). and neurofibrillary tangle\ (NW) from three neocort~cal regions. AD pathology mcreased linearly across the three groupa (test for trend using ANOVA) and accounted for 23X ot the varunce. These data wggest that both the course of cogmtive decline and severity of AD pathology in persona with MCI is intermediate to that of NC1 and AD. and that performance on te5ts of episodic memory may be a better predictor of future declmc than global cognitive function.
Symposium: Disease
piJ
Long-Term
NON-PHARMACOLOGIC
Management
APPROACHES
of Alzheimer’s
TO BEHAVIOR
Non-pharmacological rtrategie\ are first-line approaches for the non-cognitive behavioral manifestations of dementia. Behavioral treatments are most effective as an adjunct to pharmacotherapy, when pharmacotherapy is contraindicated or when behaviors occur primarily in response to environmental or interpersonal triggers. The focus is on changing the human, physical and social environment and activity routine to provide reassurance, appropriate stimulation and retreat. Interventions may include problem solving, enriched cues, memory aides, alternative therapies, guided social interaction, adapted work, exercise, communication btrategiea, caregwer \kdls training and supportive psychotherapy. Additional behavioral strategies include various forms of sensory stimulation (music, art‘;, pets), psychoxzcial interventions and modification to the living environments for persons with dementia. Although little Clas\ I evidence of efficacy i\ available to support thew intervention% increasing usage, consumer interest and clinical reports of reduced disruptive behavior\ warrant further \tudy.
RATES OF ATROPHY IN EARLY 1330] INCREASED CAL AD: STUDIES WITH REGISTRATION OF
AND PRECLINISERIAL MRI.
Ilnaging and pathological Etudies have eqtahlished that progressive cerebral atrophy in characteristic of Alrheimer’s disease and that the medial temporal lobe is involved early in the disease. What is less clear however is: the point at which rates of atrophy first start to accelerate and; exactly how rates and pattern of atrophy change as the disease progresses. In order to examine these questions we conducted a longitudinal prospective study of individuals at risk of familial AD. A matched control group and an early sporadic AD group were similarly studied. Registration and subtraction of wial brain MRI was used to quantify rates of atrophy. Rate!, of global atrophy mcrea\ed prerymptomatically in individuals who progressed to dementia and were Ggnificantly (p
undergoing repeated PET studies during two years we observed that 26 percent of the MCI patvats converted to Alrheimer-s disease and that the deficits in glucose metabolism predicted clinical outcome i 93 percent of the cases. The cortical metabolic disturbances were quite Ggniticant m MCI patients. Detection of neuroreceptor impairments including the nicotinic receptors will probably be an earlier marker for disease processes than glucow metabolism or cerebral blood flow. The deficits in nicotinic receptors of the temporal cortex significantly correlate with the cogntive function of the patient. Functional activation studies provide valuable insight into brain function related to cognitive function especially when both receptor dynamics and blood flow changes are studied. Different regional activation pattern are observed between MCI and AD patients. Functional brain studies performed during attentional task provide us with a further insight into the early dynamic disturbances in brain function and cognitive impairment in AD patients. Possible correlation\ with neuropatologioal markers such as tau and $-amyloid m CSF i?, explored. The effect of long-term treatment with cholinesterase inhibitors is evaluated with regard to improvement in brain activation pattern in brain. Especially the importance of the prefrontal regions for conscious retrieval in AD patients and how new treatment \trategie\ can influcrnce the brain procrwng efficiency of the AD patient\ i\ presently under investigatmna.
CLINICAL AND PATHOLOGIC FEATURES OF EARLY PRE-CLINICAL ALZHEIMER’S DISEASE (AD) David
p3iJ
INFLUENCE OF APOE GENOTYPE AND PET BRAIN IMAGING ON PRECLINICAL PREDICTION OF ALZHEIMER DISEASE
The major known genetic risk for AlLheimer disease (AD), apolipoprotein E-4 (APOE-4), I\ associated with lowered cerebml glucose metabolivn in bmin regions showing AD neuropathological damage. To detrrmme cognitive and metahohc decline patterns according to genetic risk, we investigated cerebral metabolic rates using positron emission tomography (PET) m middle-aged and older person with normal memory performance. Method.\. We collected PET, magnetic resonance imaging (MRI), neuropsychological, and APOE data on 54 non-demented subjects (27 with APOE-4, 27 without APOE-4) and 1I patients with AD at baseline, and 20 of the non-demented subjects (IO with APOE-4, 10 without APOE-4) two years later (mean. SD for follow-up wab 27.9, 1.7 months). Re.ur/tr. Baseline PET measures of the non-demented wbject\ (region of interest and \tatisticul parametric mapping analy\ec with co-registered MRI) indicated significantly lower metabolism in nondemented bubJects with a single copy of the APOE- allele compared to those without APOh-4 m the inferior parietal, lateral temporal, and posterior cmgulate rrgmn\. The AD group had the lowest metabolic rates in these region\. Inferior parietal, medial and lateral temporal, and posterior cingulate hypometabolism predicted cognitive decline after two years of follow-up in non-demented subjects with the APOE- allele. PET scans performed after two years showed the greatest magnitude and extent of metabolic decline in the inferior parietal and lateral temporal cortices. After correction for multiple comparisons, these metabolic changes remained significant for the APOE- group, wherein every subject had observable metabolic decline in these regions. Conchaion. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a meam for preclinical AD detection that will e%iat in response monitormg dunng experimental treatments. Moreover, thi\ strategy should allow investigators to ue relatively small sample sire\ when testing antidementia treatmentr aimed at preventing cognitive decline and delaying dementia onset in older persons wth age-related memory complaints. Objective.
FUNCTIONAL IMAGING 13321BRAIN ALZHEIMER’S DISEASE
IN EARLY AND PRECLINICAL
With the present conservative approach of the clinical criteria for Alzheimer~~s disease the diagnosis is very often given when the clinical symptoms of the disease is quite clear. Future drug treatment in the early course of the d&ease will prompt the need for an early probably presymptomatic diagnosis. The data so far obtain rugge$t that identification of early functional changes in brain by imaging techniques such as positron emission tomography (PET) can be obtained at a presymptomatic stage of the disease. How early in the course of the disease can functional impairments reflecting pathophysiological processes be detected in the bran? Early presymptomatic metabolism disturbances have been obaened in longitudinal studies of Alzheimer families with chromo\omal aberratmn$. In a recent study of mild cognitive whjecth (MCI)
A. Bennett,
Rush-Presbyterian-St.
Luke’s
Medical
Center,
Chicqo,
AND
IL
We compared rates of change in cognitive function in 159 persons with mild cognitive impairment (MCI) to 464 persons with no cognitive impairment (NCI) and to 63 persons with early AD in the Religious Orders Study, a longitudinal clinicalpathologic study of aging and AD. A global score based on the average z-scores of 20 individual cognitive tests was wed to summarize level of and change in cognitwe function using repeated meawre~ random effects models; an episodic memory subglobal was made based on 7 tests. For persons with MCI, the global score declined 0.42 standard units per year, compared to I, IO for there with AD and 0.13 for those with NCI; there was significant heterogeneity and the correlation between initial level and rate of change was only r=.l7. By contrast, the memory score declined 0.28 standard umts per year for those with MCI, compared to 0.72 for those with AD and 0.04 for those with NCI; the correlation between initial level and rate of change war ry.54. Post-mortem data was available from X5 persons: 27 with MCI, 37 with NCI. and 2 I with AD. A global measure of AD pathology was created using the average L-scoreb for neuritic plaques (NP), diffuse plaques (DP). and neurofibrillary tangle\ (NW) from three neocort~cal regions. AD pathology mcreased linearly across the three groupa (test for trend using ANOVA) and accounted for 23X ot the varunce. These data wggest that both the course of cogmtive decline and severity of AD pathology in persona with MCI is intermediate to that of NC1 and AD. and that performance on te5ts of episodic memory may be a better predictor of future declmc than global cognitive function.
Symposium: Disease
piJ
Long-Term
NON-PHARMACOLOGIC
Management
APPROACHES
of Alzheimer’s
TO BEHAVIOR
Non-pharmacological rtrategie\ are first-line approaches for the non-cognitive behavioral manifestations of dementia. Behavioral treatments are most effective as an adjunct to pharmacotherapy, when pharmacotherapy is contraindicated or when behaviors occur primarily in response to environmental or interpersonal triggers. The focus is on changing the human, physical and social environment and activity routine to provide reassurance, appropriate stimulation and retreat. Interventions may include problem solving, enriched cues, memory aides, alternative therapies, guided social interaction, adapted work, exercise, communication btrategiea, caregwer \kdls training and supportive psychotherapy. Additional behavioral strategies include various forms of sensory stimulation (music, art‘;, pets), psychoxzcial interventions and modification to the living environments for persons with dementia. Although little Clas\ I evidence of efficacy i\ available to support thew intervention% increasing usage, consumer interest and clinical reports of reduced disruptive behavior\ warrant further \tudy.