%0 Journal Article %J J Alzheimers Dis %D 2021 %T Near-Infrared Optical Spectroscopy In Vivo Distinguishes Subjects with Alzheimer's Disease from Age-Matched Controls. %A Greco, Frank A %A McKee, Ann C %A Kowall, Neil W %A Hanlon, Eugene B %X

BACKGROUND: Medical imaging methods such as PET and MRI aid clinical assessment of Alzheimer's disease (AD). Less expensive, less technically demanding, and more widely deployable technologies are needed to expand objective screening for diagnosis, treatment, and research. We previously reported brain tissue near-infrared optical spectroscopy (NIR) in vitro indicating the potential to meet this need.

OBJECTIVE: To determine whether completely non-invasive, clinical, NIR in vivo can distinguish AD patients from age-matched controls and to show the potential of NIR as a clinical screen and monitor of therapeutic efficacy.

METHODS: NIR spectra were acquired in vivo. Three groups were studied: autopsy-confirmed AD, control and mild cognitive impairment (MCI). A feature selection approach using the first derivative of the intensity normalized spectra was used to discover spectral regions that best distinguished "AD-alone" (i.e., without other significant neuropathology) from controls. The approach was then applied to other autopsy-confirmed AD cases and to clinically diagnosed MCI cases.

RESULTS: Two regions about 860 and 895 nm completely separate AD patients from controls and differentiate MCI subjects according to the degree of impairment. The 895 nm feature is more important in separating MCI subjects from controls (ratio-of-weights: 1.3); the 860 nm feature is more important for distinguishing MCI from AD (ratio-of-weights: 8.2).

CONCLUSION: These results form a proof of the concept that near-infrared spectroscopy can detect and classify diseased and normal human brain in vivo. A clinical trial is needed to determine whether the two features can track disease progression and monitor potential therapeutic interventions.

%B J Alzheimers Dis %V 82 %P 791-802 %8 2021 Jul 20 %G eng %N 2 %R 10.3233/JAD-201021 %0 Journal Article %J J Alzheimers Dis %D 2020 %T Revised Framingham Stroke Risk Profile: Association with Cognitive Status and MRI-Derived Volumetric Measures. %A Pelcher, Isabelle %A Puzo, Christian %A Tripodis, Yorghos %A Aparicio, Hugo J %A Steinberg, Eric G %A Phelps, Alyssa %A Martin, Brett %A Palmisano, Joseph N %A Vassey, Elizabeth %A Lindbergh, Cutter %A McKee, Ann C %A Stein, Thor D %A Killiany, Ronald J %A Au, Rhoda %A Kowall, Neil W %A Stern, Robert A %A Mez, Jesse %A Alosco, Michael L %X

BACKGROUND: The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk.

OBJECTIVE: This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS).

METHODS: Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n = 1,196). Models controlled for age, sex, education, racial identity, APOEɛ4 status, and estimated intracranial volume for MRI models.

RESULTS: The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β= 0.02, p = 0.028) and worse performance on: Trail Making Test A (β= 0.05, p <  0.001) and B (β= 0.057, p <  0.001), and Digit Symbol (β= -0.058, p <  0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV.

CONCLUSION: These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.

%B J Alzheimers Dis %V 78 %P 1393-1408 %8 2020 Dec 08 %G eng %N 4 %R 10.3233/JAD-200803 %0 Journal Article %J J Alzheimers Dis %D 2018 %T A Clinicopathological Investigation of White Matter Hyperintensities and Alzheimer's Disease Neuropathology. %A Alosco, Michael L %A Sugarman, Michael A %A Besser, Lilah M %A Tripodis, Yorghos %A Martin, Brett %A Palmisano, Joseph N %A Kowall, Neil W %A Au, Rhoda %A Mez, Jesse %A DeCarli, Charles %A Stein, Thor D %A McKee, Ann C %A Killiany, Ronald J %A Stern, Robert A %X

BACKGROUND: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility.

OBJECTIVE: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP.

METHODS: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy.

RESULTS: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04).

CONCLUSIONS: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

%B J Alzheimers Dis %V 63 %P 1347-1360 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29843242?dopt=Abstract %R 10.3233/JAD-180017 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Modeling the Relationships Among Late-Life Body Mass Index, Cerebrovascular Disease, and Alzheimer's Disease Neuropathology in an Autopsy Sample of 1,421 Subjects from the National Alzheimer's Coordinating Center Data Set. %A Alosco, Michael L %A Duskin, Jonathan %A Besser, Lilah M %A Martin, Brett %A Chaisson, Christine E %A Gunstad, John %A Kowall, Neil W %A McKee, Ann C %A Stern, Robert A %A Tripodis, Yorghos %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Autopsy %K Body Mass Index %K Cerebrovascular Disorders %K Datasets as Topic %K Female %K Humans %K Male %K National Institute on Aging (U.S.) %K Neuropathology %K Neuropsychological Tests %K Retrospective Studies %K United States %X

The relationship between late-life body mass index (BMI) and Alzheimer's disease (AD) is poorly understood due to the lack of research in samples with autopsy-confirmed AD neuropathology (ADNP). The role of cerebrovascular disease (CVD) in the interplay between late-life BMI and ADNP is unclear. We conducted a retrospective longitudinal investigation and used joint modeling of linear mixed effects to investigate causal relationships among repeated antemortem BMI measurements, CVD (quantified neuropathologically), and ADNP in an autopsy sample of subjects across the AD clinical continuum. The sample included 1,421 subjects from the National Alzheimer's Coordinating Center's Uniform Data Set and Neuropathology Data Set with diagnoses of normal cognition (NC; n = 234), mild cognitive impairment (MCI; n = 201), or AD dementia (n = 986). ADNP was defined as moderate to frequent neuritic plaques and Braak stageIII-VI. Ischemic Injury Scale (IIS) operationalized CVD. Joint modeling examined relationships among BMI, IIS, and ADNP in the overall sample and stratified by initial visit Clinical Dementia Rating score. Subject-specific random intercept for BMI was the predictor for ADNP due to minimal BMI change (p = 0.3028). Analyses controlling for demographic variables and APOE ɛ4 showed lower late-life BMI predicted increased odds of ADNP in the overall sample (p < 0.001), and in subjects with CDR of 0 (p = 0.0021) and 0.5 (p = 0.0012), but not ≥1.0 (p = 0.2012). Although higher IIS predicted greater odds of ADNP (p < 0.0001), BMI did not predict IIS (p = 0.2814). The current findings confirm lower late-life BMI confers increased odds for ADNP. Lower late-life BMI may be a preclinical indicator of underlying ADNP.

%B J Alzheimers Dis %V 57 %P 953-968 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304301?dopt=Abstract %R 10.3233/JAD-161205 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Interaction Between Midlife Blood Glucose and APOE Genotype Predicts Later Alzheimer's Disease Pathology. %A Bangen, Katherine J %A Himali, Jayandra J %A Beiser, Alexa S %A Nation, Daniel A %A Libon, David J %A Fox, Caroline S %A Seshadri, Sudha %A Wolf, Philip A %A McKee, Ann C %A Au, Rhoda %A Delano-Wood, Lisa %X

Elevated blood glucose and the apolipoprotein (APOE) ɛ4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer's disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment.

%B J Alzheimers Dis %V 53 %P 1553-62 %8 2016 Jul 06 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/27392855?dopt=Abstract %R 10.3233/JAD-160163