Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson diseaseMilber JM, Noorigian JV, Morley JF, Petrovitch H, White L, Ross GW, Duda JE
Objective: To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD). Methods: We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed. Results: Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD. Conclusions: These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.
Neurology. 2012 Dec 11;79(24):2307-14. doi: 10.1212. PMID: 23152586
Modeling regional vulnerability to Alzheimer pathologyRoyall DR, Palmer RF, Petrovitch H, Ross GW, Masaki K, White LR
Latent growth curve (LGC) models estimate change over time in a cohort's serially obtained measurements. We have applied LGC techniques to a spatial distribution of Alzheimer's disease (AD) pathology using autopsy data from 435 participants in the Honolulu-Asia Aging Study. Neurofibrillary tangle (NFT) and neuritic plaques (NP) were distributed across differently ordered sets of anatomical regions. The gradient of spatial change in neuritic plaque (dNP), was significantly associated with that of neurofibrillary tangle (dNFT), but weakly and inversely (r = -0.12; p < 0.001). Both dNFT and dNP correlated significantly and inversely with Braak stage. Sixty-one percent of the variance in Braak stage was explained by dNFT independent of covariates. Only dNFT was significantly associated with longitudinal change in cognition. Only dNP was associated with apolipoprotein (APOE) e4 burden. This is the first application of LGC models to spatially-ordered data. The result is a quantification of the interindividual variation in the interregional vulnerability to Alzheimer's disease lesions.
Neurobiol Aging. 2012 Aug;33(8):1556-63. doi: 10.1016/j.neurobiolaging.2011.05.028. Epub 2011 Jul 30. PMID: 21803455
AD brain pathology: vascular origins? Results from the HAAS autopsy studyLauner LJ, Petrovitch H, Ross GW, Markesbery W, White LR
An increasing number of studies suggest a vascular contribution to Alzheimer's disease (AD). One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration (amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles) were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment.
Neurobiol Aging. 2008 Oct;29(10):1587-90. Epub 2007 Apr 26. PMID: 17466414
Sex hormones and neuropathology in elderly men: the HAASStrozyk D, White LR, Petrovitch H, Geerlings MI, Remaley AT, Launer LJ
Experimental studies suggest 17- estradiol (E2) and testosterone (T) may have neuroprotective properties that are associated with Alzheimer’s and vascular pathology. However, there are limited studies correlating steroid hormones with autopsy findings in humans. In this community-based autopsy study of elderly men (n = 232) participating in the Honolulu Asia Aging Study, we found a significant decrease of neurofibrillary tangles in the highest tertile of free serum estradiol [IRR = 0.43 (0.3–0.7)] after controlling for age at blood draw, interval from blood draw until death, ApoE allele, and socio-demographic health factors. Higher Free-T levels were associated with a twofold increased risk for micro infarcts [IRR = 2.2; 95% CI (1.2–4.1)]. There was no association between sex hormones and amyloid plaques or cerebral amyloid angiopathy. This community-based autopsy study suggests that peripheral levels of sex hormones are associated with neurofibrillary tangles and micro-infarcts, but not with other neuropathologic markers of brain disease in elderly men.
Neurobiol Aging. 2007 Jan;28(1):62-8. Epub 2006 Feb 28. PMID: 16500732