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ASSOCIATIONS BETWEEN GLUCOSE LEVELS AND NEUROPATHOLOGICAL ENDPOINTS AMONG PEOPLE NEVER TREATED FOR DIABETES: THE ADULT CHANGES IN THOUGHT STUDY

      Project Description: We sought to determine associations between average glucose levels and neuropathological endpoints from a community-based prospective cohort study. The sample was consented decedents with death preceding 10/1/2013 (n=529) excluding those with withdrawn consent (2), no chart review data (19), no continuous Group Health enrollment for 5 years preceding death (25), insufficient laboratory measures to calculate exposure (87), history of treated diabetes (77), or with extremely outlying glucose values (1), leaving n=318. We used clinical HbA1c and glucose measures in a hierarchical Bayesian model to estimate average glucose levels in the five years preceding death. Autopsy protocols included evaluations of the outcomes shown in Table 2. We performed modified Poisson regression analyses to determine associations between average glucose levels and each neuropathological outcome. Our primary models adjusted for study cohort, age at death, sex, and education. In sensitivity analyses we also adjusted for medical comorbidities derived from systematic medical record data abstraction and for APOE genotype. Models also incorporated inverse probability weighting to account for selection to the autopsy cohort, with the bootstrap applied to account for additional uncertainty introduced by estimation of the weights used in the outcome models. We stratified average glucose exposures into <100 mg/dL, 100-110 mg/dL, and >110 mg/dL. Demographic and clinical characteristics are summarized in Table 1, and neuropathological findings are summarized in Table 2. The most interesting unweighted regression findings were for hippocampal sclerosis. Compared to people with average glucose levels < 100 mg/dL, people with average glucose levels 100-110 mg/dL had a relative risk (RR) (95% confidence interval, CI) of 0.50 (0.16-1.51), while people with average glucose levels >110 mg/dL had a RR (95% CI) of 2.24 (0.99-5.06, omnibus p=0.01). Findings were similar in models further adjusting for medical comorbidity and APOE genotype. Point estimates were similar models accounting for selection into the autopsy cohort, but sparse data led to broad confidence intervals when using bootstrapping to account for uncertainty in model-estimated weights. There may be a relationship between average glucose levels and neuropathological processes.
      Table 1Demographic characteristics of the included participants stratified by glucose exposures


      Characteristic
      Average glucose <100 mg/dL (n=102)Average glucose

      100-110 mg/dL (n=110)
      Average glucose >110 mg/dL (n=106)
      N or median% or IQRN or median% or IQRN or median% or IQR
      Demographic characteristics
       Age at death88.584.2-92.288.083.3-92.188.082.5-92.6
       Female5554%6256%5552%
       At least some college7069%7467%6965%
      Clinical characteristics
       Cerebrovascular disease
      Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      6059%5247%5047%
       Coronary artery disease
      Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      6160%6559%6258%
       Hypertension
      Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      5352%7266%7874%
      Average blood pressures over 5 years
       Systolic blood pressure135128-144134124-142132125-143
       Diastolic blood pressure7268-767167-767167-75
       Atrial fibrillation
      Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      4645%4743%4542%
       Lifetime smoking history5352%6458%5855%
       Regular exercise over 5 years34
      Exercise data were not available for 11 people with average glucose <100 mg/dL (11%), 11 people with average glucose 100-110 mg/dL (11%), and 12 people with average glucose >110 mg/dL (11%).
      37%39
      Exercise data were not available for 11 people with average glucose <100 mg/dL (11%), 11 people with average glucose 100-110 mg/dL (11%), and 12 people with average glucose >110 mg/dL (11%).
      40%34
      Exercise data were not available for 11 people with average glucose <100 mg/dL (11%), 11 people with average glucose 100-110 mg/dL (11%), and 12 people with average glucose >110 mg/dL (11%).
      36%
       BMI
      Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      24.222.1-26.524.122.2-27.525.622.6-28.0
      Genetic characteristics
       1 or more APOE ε4 alleles30
      APOE genotype data were not available for 8 people with average glucose < 100 mg/dL (8%), 11 people with average glucose 100-110 mg/dL (10%), and 12 people with average glucose >110 mg/dL (11%).
      32%27
      APOE genotype data were not available for 8 people with average glucose < 100 mg/dL (8%), 11 people with average glucose 100-110 mg/dL (10%), and 12 people with average glucose >110 mg/dL (11%).
      27%21
      APOE genotype data were not available for 8 people with average glucose < 100 mg/dL (8%), 11 people with average glucose 100-110 mg/dL (10%), and 12 people with average glucose >110 mg/dL (11%).
      22%
      Dementia status
       Dementia
      Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      35
      Dementia status not evaluated within 2 years of death for 7 people with average glucose <100 mg/dL (7%), 6 people with average glucose 100-110 mg/dL (6%), and 10 people with average glucose >110 mg/dL (9%).
      34%41
      Dementia status not evaluated within 2 years of death for 7 people with average glucose <100 mg/dL (7%), 6 people with average glucose 100-110 mg/dL (6%), and 10 people with average glucose >110 mg/dL (9%).
      37%39
      Dementia status not evaluated within 2 years of death for 7 people with average glucose <100 mg/dL (7%), 6 people with average glucose 100-110 mg/dL (6%), and 10 people with average glucose >110 mg/dL (9%).
      37%
      Probable or Possible AD
      Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      30
      Dementia status not evaluated within 2 years of death for 7 people with average glucose <100 mg/dL (7%), 6 people with average glucose 100-110 mg/dL (6%), and 10 people with average glucose >110 mg/dL (9%).
      29%31
      Dementia status not evaluated within 2 years of death for 7 people with average glucose <100 mg/dL (7%), 6 people with average glucose 100-110 mg/dL (6%), and 10 people with average glucose >110 mg/dL (9%).
      28%31
      Dementia status not evaluated within 2 years of death for 7 people with average glucose <100 mg/dL (7%), 6 people with average glucose 100-110 mg/dL (6%), and 10 people with average glucose >110 mg/dL (9%).
      29%
      a Exercise data were not available for 11 people with average glucose <100 mg/dL (11%), 11 people with average glucose 100-110 mg/dL (11%), and 12 people with average glucose >110 mg/dL (11%).
      b APOE genotype data were not available for 8 people with average glucose < 100 mg/dL (8%), 11 people with average glucose 100-110 mg/dL (10%), and 12 people with average glucose >110 mg/dL (11%).
      c Dementia status not evaluated within 2 years of death for 7 people with average glucose <100 mg/dL (7%), 6 people with average glucose 100-110 mg/dL (6%), and 10 people with average glucose >110 mg/dL (9%).
      d Cerebrovascular disease was defined as … Coronary artery disease was defined as … Hypertension was defined as … Blood pressures were recorded from medical records up to three times per year; results reflect average values over the five years preceding death. Atrial fibrillation was defined on the basis of ICD-9 codes as previously published. Smoking history was defined on the basis of self-reported smoking history at ACT study visits. BMI (body mass index) was defined as kg/m2 based on the last study visit prior to death. Dementia evaluation was based on neurological and neuropsychological data considered at a consensus conference for participants with Cognitive Abilities Screening Instrument (CASI) scores below 85. Dementia diagnoses reflect Diagnostic and Statistical Manual – 4th edition (DSM-IV) criteria. Probable or Possible AD (Alzheimer’s disease) reflect National Institutes of Neurological, Communicative Disorders, and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Other abbreviations: mg/dL: milligrams per deciliter. IQR: Inter-quartile range.
      Table 2Neuropathological findings stratified by glucose exposures
      Average glucose

      <100 mg/dL
      Average glucose

      100-110 mg/dL
      Average glucose

      >110 mg/dL
      N=102(n=110)(n=106)
      N%N%N%
      Neuritic plaques
      Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      4342%5449%5047%
      Neurofibrillary tangles
      Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      2424%3229%2826%
      Amyloid angiopathy
      Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      ,
      Amyloid angiopathy data were missing for 1 person with average glucose <100 mg/dL (1%), for 1 person with average glucose 100-110 mg/dL (1%), and for 1 person with average glucose >110 mg/dL (1%).
      2828%3128%2726%
      Cerebral microinfarcts
      Cerebral microinfarcts were missing for 2 people with average glucose <100 mg/dL (2%), for 1 person with average glucose 100-110 mg/dL (1%), and for 1 person with average glucose > 110 mg/dL.
      ≥3 vs 0-21212%1211%1413%
      ≥2 vs 0-12525%2826%3029%
      Any vs. none4242%5348%5149%
      Cystic infarcts
      Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      ,
      Cystic infarct data were missing for 3 people with average glucose <100 mg/dL (3%), for 1 person with average glucose 100-110 mg/dL (1%), and for 4 people with average glucose >110 mg/dL (4%).
      3030%2927%2726%
      Atherosclerosis
      Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      ,
      Atherosclerosis data were missing for 3 people with average glucose <100 mg/dL (3%), for 4 people with average glucose 100-110 mg/dL (4%), and for 5 people with average glucose >110 mg/dL (5%).
      5960%6258%6261%
      Lewy bodies
      Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      Frontal or temporal cortex
      Frontal or temporal cortex Lewy body data were missing for 0 people with average glucose <100 mg/dL, for 1 person with average glucose 100-110 mg/dL (1%), and for 1 person with average glucose >110 mg/dL (1%).
      55%66%55%
      Substantia nigra or locus ceruleus
      Substantia nigra or locus ceruleus Lewy body data were missing for 0 people with average glucose <100 mg/dL or 100-110 mg/dL, and for 1 person (1%) with average glucose >110 mg/dL.
      1313%1413%1312%
      Amygdal
      Amygdala Lewy body data were missing for 9 people with average glucose <100 mg/dL (9%), for 8 people with average glucose 100-110 mg/dL (8%), and for 5 people with average glucose >110 mg/dL (5%).
      1415%1717%1212%
      Hippocampal sclerosis
      Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      ,
      Hippocampal sclerosis data were missing for 4 people with average glucose <100 mg/dL (3%), for 4 people with average glucose 100-110 mg/dL (4%), and for 2 people with average glucose >110 mg/dL (2%).
      77%44%1817%
      a Neuritic plaques were characterized as intermediate or frequent vs. none or sparse. Neurofibrillary tangles were characterized as Braak and Braak stage V or VI vs. stage 0-IV. Amyloid angiopathy was characterized as any vs. none. Cystic infarcts were characterized as any vs. none. Atherosclerosis was characterized as moderate or severe vs. none or mild. Lewy bodies were characterized as present vs. absent in each of the regions specified. Hippocampal sclerosis was characterized as present vs. absent.
      b Amyloid angiopathy data were missing for 1 person with average glucose <100 mg/dL (1%), for 1 person with average glucose 100-110 mg/dL (1%), and for 1 person with average glucose >110 mg/dL (1%).
      c Cerebral microinfarcts were missing for 2 people with average glucose <100 mg/dL (2%), for 1 person with average glucose 100-110 mg/dL (1%), and for 1 person with average glucose > 110 mg/dL.
      d Cystic infarct data were missing for 3 people with average glucose <100 mg/dL (3%), for 1 person with average glucose 100-110 mg/dL (1%), and for 4 people with average glucose >110 mg/dL (4%).
      e Atherosclerosis data were missing for 3 people with average glucose <100 mg/dL (3%), for 4 people with average glucose 100-110 mg/dL (4%), and for 5 people with average glucose >110 mg/dL (5%).
      f Frontal or temporal cortex Lewy body data were missing for 0 people with average glucose <100 mg/dL, for 1 person with average glucose 100-110 mg/dL (1%), and for 1 person with average glucose >110 mg/dL (1%).
      g Substantia nigra or locus ceruleus Lewy body data were missing for 0 people with average glucose <100 mg/dL or 100-110 mg/dL, and for 1 person (1%) with average glucose >110 mg/dL.
      h Amygdala Lewy body data were missing for 9 people with average glucose <100 mg/dL (9%), for 8 people with average glucose 100-110 mg/dL (8%), and for 5 people with average glucose >110 mg/dL (5%).
      i Hippocampal sclerosis data were missing for 4 people with average glucose <100 mg/dL (3%), for 4 people with average glucose 100-110 mg/dL (4%), and for 2 people with average glucose >110 mg/dL (2%).