Correlates of functional capacity among centenarians.

This study investigated correlates of functional capacity among participants of the Georgia Centenarian Study. Six domains (demographics and health, positive and negative affect, personality, social and economic support, life events and coping, distal influences) were related to functional capacity for 234 centenarians and near centenarians (i.e., 98 years and older). Data were provided by proxy informants. Domain-specific multiple regression analyses suggested that younger centenarians, those living in the community and rated to be in better health were more likely to have higher functional capacity scores. Higher scores in positive affect, conscientiousness, social provisions, religious coping, and engaged lifestyle were also associated with higher levels of functional capacity. The results suggest that functional capacity levels continue to be associated with age after 100 years of life and that positive affect levels and past lifestyle activities as reported by proxies are salient factors of adaptation in very late life.

Age group differences in positive and negative affect among oldest-old adults: findings from the Georgia Centenarian Study.

OBJECTIVES: The developmental adaptation model (Martin & Martin, 2002) provides insights into how current experiences and resources (proximal variables) and past experiences (distal variables) are correlated with outcomes (e.g., well-being) in later life. Applying this model, the current study examined proximal and distal variables associated with positive and negative affect in oldest-old adults, investigating age differences. METHODS: Data from 306 octogenarians and centenarians who participated in Phase III of the Georgia Centenarian Study were used. Proximal variables included physical functioning, cognitive functioning, self-rated health, number of chronic conditions, social resources, and perceived economic status; distal variables included education, social productive activities, management of personal assets, and other learning experiences. Analysis of variance and block-wise regression analyses were conducted. RESULTS: Octogenarians showed significantly higher levels of positive emotion than centenarians. Cognitive functioning was significantly associated with positive affect, and number of health problems was significantly associated with negative affect after controlling for gender, ethnicity, residence, and marital status. Furthermore, four significant interaction effects suggested that positive affect significantly depended on the levels of cognitive and physical functioning among centenarians, whereas positive affect was dependent on the levels of physical health problems and learning experiences among octogenarians. CONCLUSION: Findings of this study addressed the importance of current and past experiences and resources in subjective well-being among oldest-old adults as a life-long process. Mechanisms connecting aging processes at the end of a long life to subjective well-being should be explored in future studies.

Cognitive performance in centenarians and the oldest old: norms from the Georgia Centenarian Study.

We present normative data from a large population-based sample of centenarians for several brief, global neurocognitive tasks amenable for frail elders. Comparative data from octogenarians are included. A total of 244 centenarians and 80 octogenarians from Phase III of the Georgia Centenarian Study were administered the Mini-Mental Status Examination, Severe Impairment Battery, and Behavioral Dyscontrol Scale. Centenarians (age 98-107) were stratified into three age cohorts (98-99, 100-101, 102-107), octogenarians into two 5- year cohorts (80-84, 85-89). Highly significant differences were observed between groups on all measures, with greater variation and dispersion in performance among centenarians, as well as stronger associations between age and performance. Descriptive statistics and normative ranges (unweighted and population-weighted) are provided by age cohort. Additional statistics are provided by education level. While most previous centenarian studies have used convenience samples, ours is population-based and likely more valid for comparison in applied settings. Results suggest centenarians look different than do even the oldest age range of most normative aging datasets (e.g., 85-90). Results support using global measures of neurocognition to describe cognitive status in the oldest old, and we provide normative comparisons to do so.

Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease.

Previous studies demonstrate increased levels of 4-hydroxynonenal (HNE) and acrolein in vulnerable brain regions of subjects with mild cognitive impairment and late-stage Alzheimer disease (LAD). Recently preclinical AD (PCAD) subjects, who demonstrate normal antemortem neuropsychological test scores but abundant AD pathology at autopsy, have become the focus of increased study. Levels of extractable HNE and acrolein were quantified by gas chromatography-mass spectrometry with negative chemical ionization, and protein-bound HNE and acrolein were quantified by dot-blot immunohistochemistry in the hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyri (SMTG), and cerebellum (CER) of 10 PCAD and 10 age-matched normal control (NC) subjects. Results of the analyses show a significant (P<0.05) increase in levels of extractable acrolein in the HPG of PCAD subjects compared to age-matched NC subjects and a significant decrease in extractable acrolein in PCAD CER. Significant increases in protein-bound HNE in HPG and a significant decrease in CER of PCAD subjects compared to NC subjects were observed. No significant alterations were observed in either extractable or protein-bound HNE or acrolein in the SMTG of PCAD subjects. Additionally, no significant differences in levels of protein carbonyls were observed in the HPG, SMTG, or CER of PCAD subjects compared to NC subjects.

Family history and adaptation among centenarians and octogenarians.

BACKGROUND: The purpose of this study was to analyze various 'family history' variables (i.e. childhood health, financial situation while growing up, living with grandparents before age 17, and number of children) among participants of the Georgia Centenarian Study. OBJECTIVE: To determine whether family history variables predict critical outcome areas such as cognitive functioning, activities of daily living, mental health, and economic dependence. METHODS: A total of 318 older adults (236 centenarians and 82 octogenarians) were assessed with regard to their mental status, ADL (activities of daily living) functioning, depression, family history, loneliness, and perceived economic status. RESULTS: Analyses indicated that the number of children significantly predicted the ability to engage in activities of daily living and loneliness. In essence, the more children, the higher the activities of the daily living score and the lower the loneliness scores. In addition, childhood health significantly predicted loneliness. The poorer one's health in childhood, the higher the loneliness scores. CONCLUSION: The results of this study confirm the importance of distal family history variables on present-day functioning.

Predicting happiness among centenarians.

BACKGROUND: Happiness is believed to evolve from the comparison of current circumstances relative to past achievement. However, gerontological literature on happiness in extreme old age has been limited. OBJECTIVE: The purpose of this study was to determine how perceptions of health, social provisions, and economics link past satisfaction with life to current feelings of happiness among persons living to 100 years of age and beyond. METHODS: A total of 158 centenarians from the Georgia Centenarian Study were included to conduct the investigation. Items reflecting congruence and happiness from the Life Satisfaction Index were used to evaluate a model of happiness. Pathways between congruence, perceived economic security, subjective health, perceived social provisions, and happiness were analyzed using structural equation modeling. RESULTS: Congruence emerged as a key predictor of happiness. Furthermore, congruence predicted perceived economic security and subjective health, whereas perceived economic security had a strong influence on subjective health status. CONCLUSION: It appears that past satisfaction with life influences how centenarians frame subjective evaluations of health status and economic security. Furthermore, past satisfaction with life is directly associated with present happiness. This presents implications relative to understanding how perception of resources may enhance quality of life among persons who live exceptionally long lives.

Depression among centenarians and the oldest old: contributions of cognition and personality.

BACKGROUND: An estimated 20% of adults over the age of 55 experience clinical mental disorders such as depression and anxiety. For older adults, mental health concerns are often undetected, concomitant with physical challenges, and ultimately go untreated. These realities have significant implications for older adults' day-to-day functioning, particularly among the oldest old. OBJECTIVE: The present study examined the ability of cognition and personality in explaining depression within a sample of octogenarians and centenarians. METHODS: Participants were assessed during the most recent cross-sectional data collection of the Georgia Centenarian Study. The final eligible sample included 76 octogenarians (mean: 84.25 years, SD: 2.82; range: 81-90) and 158 centenarians and near centenarians (mean: 99.82 years, SD: 1.72; range: 98-109). RESULTS: Hierarchical regression analyses were conducted to examine the relation between key variables and depressive symptoms in the two age groups. Blocks entered into the analyses included: demographics (i.e. age group, residential status, sex, and ethnicity) and functioning, memory and problem-solving ability, and personality (i.e. extraversion and neuroticism). Models differed for octogenarians and centenarians. Decreased problem-solving ability was related to greater depressive symptoms among octogenarians. For centenarians, institutional residence and increased neurotic tendencies were related to greater depressive symptoms. CONCLUSION: Study findings demonstrate the need to examine a variety of factors which influence mental health in later life and to consider the unique contexts and differential experiences of octogenarians and centenarians.

Distal and proximal resource influences on economic dependency among the oldest old.

BACKGROUND: As exceptional survivors, centenarians may have characteristics that reduce their dependency on family and community support systems despite the expectation that their extreme age creates a burden on those systems. The Georgia Centenarian Study obtained information about assistance for income, medical care, and caregiving of all types for a sample of centenarians and octogenarians. Previous studies have not established which characteristics may contribute to economic dependency among the oldest old. OBJECTIVE: To identify distal and proximal resource influences on economic dependency, considering past lifestyle, proximal health, economic resources, personality, and coping behavior. METHODS: Analysis sample sizes ranged from 109 to 138 octogenarians and centenarians. Blockwise multiple regressions predicted whether they received income assistance, number of medical care events, number of caregiving types, and total caregiving hours. RESULTS: Past life style, gender, ethnicity, socioeconomic status, functional health, and coping were not related to economic dependency. With the exception of the number of types of care, centenarians were not more dependent than octogenarians. Cognitive ability had the strongest effects for medical care and caregiving services. 'Extraversion', 'ideas', 'neuroticism', and 'competence' personality factors had significant effects for caregiving types and total hours of care received. CONCLUSION: Monitoring and intervention to maintain cognitive ability are critical practices for autonomy and reduced economic dependency among the oldest old. Psychological resources are more important influences on social support than functional health and other proximal economic resources.

Social resources and longevity: findings from the Georgia centenarian study.

BACKGROUND: As the proportion of adults aged 85 and older increases, investigations of resources essential for adapting to the challenges of aging are required. OBJECTIVE: To comprehensively investigate the social resources of cognitively intact centenarians participating in the Georgia Centenarian Study and the association between these resources and residence status. METHODS: Two widely used measures of social resources were investigated among participants living in private homes, personal care facilities, and nursing homes. Logistic regression was used to determine significant predictors of nursing home residence. RESULTS: Differences in levels of social resources were found between centenarians and octogenarians, and among centenarians in different living situations. Analyses revealed differential findings between self- and proxy reports. Controlling for education, activities of daily living, and financial ability to meet needs, only one of the two social resources measures significantly reduced the odds of nursing home residence. CONCLUSION: The findings of this study add to the existing literature on one of the basic adaptive resources (social resources) for centenarians. Whether a more specific assessment of network contact is employed, or a more global assessment is used, differences in these constructs exist between centenarians and octogenarians, among centenarians in differing living conditions, and across types of informants. Researchers examining the different resources that may contribute to extraordinary longevity and positive adaptation may find it essential to differentiate between the oldest old and centenarians, and to account for differences based upon measure, reporter type, and centenarian residence status.

Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease.

The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimer's disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P=0.012), provoked hallucinations or delirium (P=0.042), or the presence of any of these noncognitive symptoms of DLB (P<0.0001). Letter fluency (P=0.007) was significantly lower and Wechsler Logical Memory I (P=0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD.

Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies.

BACKGROUND: Recent studies raised questions about the severity of cognitive impairment associated with dementia with Lewy bodies (DLB). However, there have been few analyses of large, multicenter data registries for clinical-pathologic correlation. METHODS: We evaluated data from the National Alzheimer's Coordinating Center registry (n = 5,813 cases meeting initial inclusion criteria) and the University of Kentucky Alzheimer's Disease Center autopsy series (n = 527) to compare quantitatively the severity of cognitive impairment associated with DLB pathology vs Alzheimer disease (AD) and AD+DLB pathologies. RESULTS: Mini-Mental State Examination (MMSE) scores showed that persons with pure DLB had cognitive impairment of relatively moderate severity (final MMSE score 15.6 +/- 8.7) compared to patients with pure AD and AD+DLB (final MMSE score 10.7 +/- 8.6 and 10.6 +/- 8.6). Persons with pure DLB pathology from both data sets had more years of formal education and were more likely to be male. Differences in final MMSE scores were significant (p < 0.01) between pure DLB and both AD+DLB and pure AD even after correction for education level, gender, and MMSE-death interval. Even in cases with extensive neocortical LBs, the degree of cognitive impairment was most strongly related to the amount of concomitant AD-type neurofibrillary pathology. CONCLUSIONS: Dementia with Lewy bodies can constitute a debilitating disease with associated psychiatric, motoric, and autonomic dysfunction. However, neocortical Lewy bodies are not a substrate for severe global cognitive impairment as assessed by the Mini-Mental State Examination. Instead, neocortical Lewy bodies appear to constitute or reflect an additive disease process, requiring Alzheimer disease or other concomitant brain diseases to induce severe global cognitive deterioration.

The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life.

BACKGROUND: It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic beta-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered. METHODS: Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups. RESULTS: A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups. CONCLUSIONS: 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

Improved predictive model for pre-symptomatic mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: Delineation of gray matter (GM) structures on brain MRI scans is termed segmentation. Accuracy of segmentation is a key factor in the valid comparison of GM density and volume between individuals and groups. Previously, it was demonstrated that a group of normal subjects who later developed mild cognitive impairment (MCI) had decreased GM volume in the medial temporal lobe compared to other normal subjects who remained normal an average 5.4 years after the scan. The objective of this study was to show whether accuracy of this predictive model was increased using an advanced segmentation technique. METHODS: Structural MRI was performed on 74 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 18 later developed MCI, and six of these 18 went on from MCI to an AD diagnosis. We independently delineated GM using both a standard segmentation technique and a local Gaussian active contour (LGAC) technique. We compared the contribution of extracted volumes from each technique to a model predicting subjects who will eventually develop MCI. RESULTS: Accuracy of the standard technique to distinguish pre-MCI from normal using imaging alone was 79% (sensitivity 78% and specificity 73%). Using LGAC, accuracy rose to 84% (sensitivity 78% and specificity 84%). DISCUSSION: Structural brain changes precede MCI in longitudinally followed normal subjects. The LGAC technique improves the accuracy of a predictive model incorporating these structural changes by improving GM segmentation and the specificity of the model.

Clinical features of mild cognitive impairment differ in the research and tertiary clinic settings.

OBJECTIVE: Comparative analysis of subjects with mild cognitive impairment (MCI) diagnosed in a primary research setting and those seen in a tertiary care memory disorders clinic. METHODS: Subjects who received a diagnosis of MCI between July 1, 2005, and December 31, 2006, in a longitudinal research study of normal cognition (n = 48) and patients diagnosed in a tertiary care referral clinic (n = 34) were evaluated using similar methodologies. Comparative analyses of detailed medical, neurological and neuropsychological data are presented. RESULTS: The diagnosis of MCI was not accepted by 13 of 48 subjects (27%) classified as MCI in the primary research setting. Nondegenerative, potentially treatable causes of cognitive decline were found in 3 of 34 subjects (9%) seen in the tertiary referral clinic and in 11 of 35 subjects (31%) identified as MCI in the primary research setting (p = 0.02, Fisher's exact test). MCI subjects identified in the primary research setting were older than those referred to the memory clinic (mean +/- SD, 79.7 +/- 7.0 vs. 71.5 +/- 9.0 years, p < 0.0001, t test) and had more years of education (16.0 +/- 3.2 vs. 13.6 +/- 4.2 years, p < 0.01, t test). MCI subjects in the primary research setting appeared to be in a milder stage of disease, characterized by higher Mini-Mental State Examination scores (28.2 +/- 1.8 vs. 25.7 +/- 1.8, p < 0.0001), and a tendency towards single domain involvement, predominantly memory (mean number of domains involved, 1.0 vs. 2.5, p < 0.0001). More advanced stages of MCI, seen in the tertiary referral population, had additional involvement of attention (p < 0.0001, Fisher's exact test) and visuospatial domains (p < 0.0002, Fisher's exact test). Semiquantitative grading of hippocampal and medial temporal lobe atrophy did not differ between groups (p = 0.81, Mann-Whitney U test). CONCLUSIONS: The diagnosis of MCI may be unwelcome in naïve persons. Remedial causes of MCI should be actively investigated. Demographic and clinical characteristics of MCI differ between research subjects and patients referred to a tertiary care clinic.

An aberrant protein complex in CSF as a biomarker of Alzheimer disease.

OBJECTIVE: To determine if an aberrant protein complex consisting of prostaglandin-d-synthase (PDS) and transthyretin (TTR) in CSF differentiates between subjects with Alzheimer disease (AD) and normal control (NC) subjects. METHODS: Western blot analysis and a unique sandwich ELISA were used to quantify levels of complexed PDS/TTR in ventricular CSF of subjects with autopsy-verified diagnoses and in lumbar CSF of living subjects with mild to moderate probable AD and age-matched NC subjects. Ventricular CSF was obtained from short postmortem interval autopsies of 7 NC subjects (4 men/3 women), 12 diseased control (DC) subjects (7 men/5 women), 4 subjects with mild cognitive impairment (MCI) (2 men/2 women), and 8 subjects with late-stage AD (LAD) (4 men/4 women). Lumbar CSF was obtained from 15 subjects with probable AD (5 men/10 women) and 14 age-matched NC subjects (10 men/4 women) and was analyzed in a double-blind fashion. RESULTS: A significant increase in complexed PDS/TTR in ventricular CSF was found in MCI and LAD subjects but not DC subjects compared with NC subjects. Double-blind analysis of complexed PDS/TTR in lumbar CSF showed a significant sixfold increase in levels of the PDS/TTR complex in living probable AD subjects compared with age-matched NC subjects and a 100% sensitivity and 93% specificity in the identification of subjects with AD. CONCLUSION: After further study of larger numbers of patients, quantifying prostaglandin-d-synthase/transthyretin complex in CSF may be useful in the diagnosis of Alzheimer disease, possibly in the early stages of the disease.

Brain structural alterations before mild cognitive impairment.

OBJECTIVE: To determine whether alterations of brain structure in normal aged individuals precede the development of mild cognitive impairment (MCI) or Alzheimer disease (AD). BACKGROUND: Persons with MCI and AD demonstrate cortical volume losses vs asymptomatic aged individuals, particularly in the hippocampus, amygdala, and entorhinal cortex. It is unknown whether these losses or other volumetric changes are present, and to what degree, in cognitively normal individuals before the clinical diagnosis of MCI. METHODS: Structural MRI was performed on a cross-section of 136 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 23 later developed MCI, and 9 of these 23 went on to an AD diagnosis. Extracted volumes from voxel-based morphometric analysis were combined with clinical data to compare the 23 subjects who eventually developed MCI to 113 subjects who remained cognitively normal over an average follow-up of 5.4 years. RESULTS: Initially normal subjects who eventually developed MCI demonstrated decreased gray matter volumes in the anteromedial temporal lobes bilaterally and left angular gyrus while still cognitively normal. CONCLUSION: Structural brain changes in anatomic areas involved in higher cognitive processes precede clinical signs and symptoms in longitudinally followed normal subjects destined to develop mild cognitive impairment.

Altered expression of zinc transporters-4 and -6 in mild cognitive impairment, early and late Alzheimer's disease brain.

Accumulating evidence suggests that a disruption of zinc (Zn) homeostasis may play a role in the pathogenesis of Alzheimer's disease. Although several Zn transporter proteins responsible for the regulation of Zn balance are present in the brain, there has been little study of these proteins in Alzheimer's disease. To determine if alterations of Zn transporter proteins exist, levels of Zn transporter-4, which functions to remove Zn from the cytoplasm to endosomal/lysosomal compartments, and Zn transporter-6, which allocates cytoplasmic Zn to the trans-Golgi network, were measured in the hippocampus/parahippocampal gyrus, superior and middle temporal gyrus, and cerebellum of subjects with mild cognitive impairment, early Alzheimer's disease, late stage Alzheimer's disease, and age-matched controls using Western blot analysis and protein specific antibodies. Our results show that Zn transporter-4 and Zn transporter-6 are significantly (P<0.05) increased in hippocampus/parahippocampal gyrus of early Alzheimer's disease and Alzheimer's disease subjects. Zn transporter-6 is also increased (P<0.1) in the superior and middle temporal gyrus of Alzheimer's disease brain.

Risk factors for transitions from normal to mild cognitive impairment and dementia.

OBJECTIVE: To identify risk factors associated with transitions from cognitively normal to various forms of mild cognitive impairment (MCI) and then from MCI into early dementia with death as a competing state. METHODS: Cognitive assessments from 554 subjects participating in a longitudinal study at the University of Kentucky AD Center were used to classify individuals into one of three transient states at any visit: cognitively normal, amnestic MCI, or mixed MCI. Between visits subjects could die or become demented. A series of polytomous logistic models were used to model transitions among these states over time and to determine how the log odds of these transitions vary with age, education, sex, family history of dementia, and APOE status. RESULTS: Age affects all transitions among transient states as well as those to dementia or death. Presence of at least one apolipoprotein 4 allele affects transitions from cognitively normal into amnestic MCI or into dementia. At most 12 years of education affects transitions into mixed MCI. Transitions do not vary with sex or family history. CONCLUSION: Aside from age, the usual risk factors associated with conversion from cognitively normal into dementia are likely risk factors for transitions into mild cognitive impairment.

Alterations in zinc transporter protein-1 (ZnT-1) in the brain of subjects with mild cognitive impairment, early, and late-stage Alzheimer's disease.

Several studies show increased levels of zinc (Zn) in the Alzheimer's disease (AD) brain. More recently, alterations in synaptic Zn and Zn transporter proteins (ZnT) have been implicated in the accumulation of amyloid plaques in an animal model of AD. To determine if alterations in ZnT proteins are present in AD brain, we measured levels of ZnT-1, the protein responsible for export of Zn to the extracellular space in the amygdala (AMY), hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyrus (SMTG), inferior parietal lobule (IPL), and cerebellum (CER) of 19 AD and 14 age-matched control subjects. To determine if alterations of ZnT-1 occur early in the progression of AD, we analyzed protein levels in the HPG, SMTG and CER of 5 subjects with mild cognitive impairment (MCI), 5 subjects with early AD (EAD) and 4 appropriately age-matched controls. Western blot and dot-blot analysis showed statistically significant (p 0.05) elevations of ZnT-1 in AD AMY, HPG, and IPL and significantly depleted ZnT-1 in AD SMTG compared to age-matched control subjects. We also observed statistically significant elevations of ZnT-1 in the HPG of EAD subjects compared with controls. In contrast to late-stage AD subjects, ZnT-1 levels were significantly decreased in HPG of subjects with MCI and were significantly elevated in the SMTG of both MCI and EAD subjects compared with age-matched controls. Correlation analysis of ZnT-1 levels and senile plaque (SP) and neurofibrillary tangle (NFT) counts in the AMY and CA1 and subiculum of AD HPG showed a significant (p 0.05) positive correlation with SP counts and a trend towards a significant (p = 0.12) positive correlation with NFT counts in AMY. Overall, our results show alterations in one of the key proteins responsible for maintenance of Zn homeostasis early in the progression of AD suggesting that alterations in Zn balance could be involved in the pathogenesis of neuron degeneration and amyloid deposition in AD.

Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease.

Increasing evidence suggests that oxidative stress is associated with normal aging and several neurodegenerative diseases, including Alzheimer's disease (AD). Here we quantified multiple oxidized bases in nuclear and mitochondrial DNA of frontal, parietal, and temporal lobes and cerebellum from short postmortem interval AD brain and age-matched control subjects using gas chromatography/mass spectrometry with selective ion monitoring (GC/MS-SIM) and stable labeled internal standards. Nuclear and mitochondrial DNA were extracted from eight AD and eight age-matched control subjects. We found that levels of multiple oxidized bases in AD brain specimens were significantly (p < 0.05) higher in frontal, parietal, and temporal lobes compared to control subjects and that mitochondrial DNA had approximately 10-fold higher levels of oxidized bases than nuclear DNA. These data are consistent with higher levels of oxidative stress in mitochondria. Eight-hydroxyguanine, a widely studied biomarker of DNA damage, was approximately 10-fold higher than other oxidized base adducts in both AD and control subjects. DNA from temporal lobe showed the most oxidative damage, whereas cerebellum was only slightly affected in AD brains. These results suggest that oxidative damage to mitochondrial DNA may contribute to the neurodegeneration of AD.