Alzheimer Disease: Asthana S

Ries ML, Carlsson CM, Rowley HA, Sager MA, Gleason CE, Asthana S, Johnson SC. · William S. Middleton Memorial Veterans Hospital Geriatric Research Education and Clinical Center, Madison, Wisconsin 53705, USA. · J Am Geriatr Soc. · Pubmed #18410325 links to  free full text

Abstract: Given the predicted increase in prevalence of Alzheimer's disease (AD) in the coming decades, early detection and intervention in persons with the predementia condition known as mild cognitive impairment (MCI) is of paramount importance. Recent years have seen remarkable advances in the application of neuroimaging and other biomarkers to the study of MCI. This article reviews the most recent developments in the use of magnetic resonance imaging (MRI) to characterize brain changes and to prognosticate clinical outcomes of patients with MCI. The review begins with description of methods and findings in structural MRI research, delineating findings regarding both gross atrophy and microstructural brain changes in MCI. Second, we describe the most recent findings regarding brain function in MCI, enumerating findings from functional MRI and brain perfusion studies. Third, we will make recommendations regarding the current clinical use of MRI in identification of MCI. As a conclusion, we will look to the future of neuroimaging as a tool in early AD detection.

Cholerton B, Gleason CE, Baker LD, Asthana S. · Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle/Tacoma, Washington, USA. · Drugs Aging. · Pubmed #12149049 No free full text.

Abstract: The ovarian hormone estrogen has long been used to treat the physical symptoms of menopause and to aid in the prevention of osteoporosis in postmenopausal women. Cumulative evidence from basic science and clinical research suggests that estrogen also plays a significant neuromodulatory and neuroprotective role. The numerous estrogenic effects in the brain include the modulation of synaptogenesis, increased cerebral blood flow, mediation of important neurotransmitters and hormones, protection against apoptosis, anti-inflammatory actions, and antioxidant properties. These multiple actions in the central nervous system support estrogen as a potential treatment for the cognitive decline associated with Alzheimer's disease (AD), the most common form of dementia. Evidence from epidemiological studies supports enhanced cognitive function in women with AD taking estrogen replacement therapy (ERT) as well as a reduced risk for developing AD in healthy women receiving ERT. Additional clinical evidence suggests that estrogen may modulate specific cognitive functions such as working memory and verbal learning and memory. However, results from more recent controlled trials have not consistently shown a beneficial effect of estrogen on the cognitive function of women with AD. Future research should focus on examining the influence of multiple potential mediators of ERT including the route of estrogen administration, form of estrogen (conjugated estrogens vs estradiol), duration of treatment, opposed versus unopposed estrogen and the use of estrogen analogues. Further, sensitive neuropsychological measures may provide more detailed information concerning the specific effects of estrogen on cognitive function. These important issues must be addressed in order to establish the role of estrogen for the prevention and treatment of AD in women.

Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, Chapman D, Schwartz MW, Plymate S, Craft S. · Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle 98108, USA. · Neurology. · Pubmed #12821730 No free full text.

Abstract: BACKGROUND: Abnormal insulin metabolism may contribute to the clinical symptoms and pathophysiology of AD. In vitro studies show that insulin enhances the release of beta-amyloid protein (Abeta) or inhibits its degradation, either of which might increase amyloid burden. METHODS: On separate mornings, 16 healthy older adults (10 women, 6 men; mean age 68.7 years, SD 8.6 years) each underwent two infusions consisting of either saline (placebo) or insulin (1.0 mU x kg(-1) x min(-1)) plus dextrose to maintain euglycemia. After 120 minutes of infusion, blood, CSF, and cognitive measures were acquired. RESULTS: As expected, insulin infusion produced an increase in CSF insulin concentration. Insulin infusion also led to an increase in CSF Abeta42 levels, most notably in older subjects. As has been observed previously, insulin infusion facilitated declarative memory, but such facilitation was attenuated in the subjects with the greatest increase in CSF Abeta42 levels. CONCLUSIONS: These findings are consistent with recent in vitro studies of insulin effects on Abeta and support the notion that insulin may modulate Abeta42 levels acutely in humans.

Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, Wait C, Petrova A, Latendresse S, Watson GS, Newcomer JW, Schellenberg GD, Krohn AJ. · Geriatric Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108, USA. · Psychoneuroendocrinology. · Pubmed #12812866 No free full text.

Abstract: In previous studies, adults with Alzheimer's disease (AD) showed memory enhancement when plasma insulin levels were raised to 85 microU/ml, whereas normal adults' memory was unchanged. Degree of memory enhancement was also related to apolipoprotein E (apoE) genotype status for AD patients. Response differences between normal and AD groups could reflect dose-response differences for insulin. To examine this question, 22 adults with AD and 15 normal adults received five doses of insulin on separate days in counterbalanced order, resulting in five plasma insulin levels (10, 25, 35, 85 and 135 microU/ml), while plasma glucose levels of ~100 mg/dl were maintained. Cognitive performance and plasma APP levels were measured after 120 min of infusion. Relative to baseline, AD patients who were not apoE- epsilon 4 homozygotes had improved memory at higher insulin levels of 35 and 85 microuU/ml, whereas normal adults and AD patients who were epsilon 4 homozygotes showed improved memory at insulin levels of 25 microU/ml. Normal adults' memory was also improved at insulin levels of 85 microU/ml. Plasma APP was lowered for adults with AD without the epsilon 4 allele at higher levels (85 microU/ml) than for normal adults and epsilon 4 homozygotes, who showed decreased APP at the 35 microU/ml level. AD patients with a single epsilon 4 allele showed a different pattern of insulin effects on APP than did other subjects. In general, few effects of insulin were seen at the highest dose for any subject group. These results support a role for insulin in normal memory and APP modulation that follows a curvilinear response pattern, and suggest that AD patients who are not epsilon 4 homozygotes have reduced sensitivity to insulin that may interfere with such modulation.

Baker LD, Sambamurti K, Craft S, Cherrier M, Raskind MA, Stanczyk FZ, Plymate SR, Asthana S. · Geriatric Research, Education, and Clinical Center, the VA Puget Sound Health Care System, Seattle/Tacoma, WA, USA. · Am J Geriatr Psychiatry. · Pubmed #12611754 No free full text.

Abstract: OBJECTIVE: One mechanism to support the potentially beneficial effects of estrogen in the brain for postmenopausal women potentially involves the hormone's ability to favorably alter the processing of amyloid-precursor protein (APP), believed to play an important role in the pathobiology of Alzheimer disease (AD). The authors evaluated the effects of estrogen administration on plasma concentration of one by-product of APP processing, Abeta40, for postmenopausal women with AD. METHODS: In a placebo-controlled, double blind, parallel-group design study, 20 women were randomized to receive either 0.10 mg/day of transdermal 17beta-estradiol or a placebo for 8 weeks and were retrospectively evaluated as to whether basal levels of Abeta40 were affected by pre-study use of hormone replacement therapy (HRT). Blood samples were collected and cognitive tests were administered at baseline; at Weeks 3, 5, and 8 during treatment; and again 8 weeks after treatment termination. RESULTS: For the group as a whole, plasma Abeta40 was not reliably reduced in response to short-term estradiol administration. For HRT-naïve subjects, baseline Abeta40 concentrations were higher than those of previous HRT users, and controlled estradiol administration significantly reduced plasma Abeta40 by the end of the 8-week treatment period. CONCLUSIONS: These results provide preliminary clinical evidence to support an effect of estradiol on Abeta-processing for AD women who are HRT-naïve. This finding suggests that the hormone may serve as an Abeta-lowering agent for HRT-naïve AD women, which may, in turn, have ultimate ramifications for the progression of AD pathology.

Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind MA, Plymate SR. · Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle/Tacoma, Tacoma, WA 98493, USA. · Neurology. · Pubmed #11524467 No free full text.

Abstract: OBJECTIVE: To characterize the cognitive and neuroendocrine response to treatment with a high dose of estrogen for postmenopausal women with AD. METHODS: Twenty postmenopausal women with AD were randomized to receive either 0.10 mg/day of 17 beta-estradiol by skin patch or a placebo patch for 8 weeks. Subjects were evaluated at baseline, at weeks 3, 5, and 8 during treatment, and again 8 weeks after treatment termination. During each visit, cognition was assessed with a battery of neuropsychological tests, and blood samples were collected to measure plasma estradiol as well as several other neuroendocrine markers of interest. RESULTS: Significant effects of estrogen treatment were observed on attention (Stroop Color Word Interference Test), verbal memory (Buschke Selective Reminding Test), and visual memory (Figure Copy/Memory). In addition, women treated with estrogen demonstrated improved performance on a test of semantic memory (Boston Naming Test) compared with subjects who received a placebo. Estrogen appeared to have a suppressive effect on the insulin-like growth factor (IGF) system such that plasma concentration of IGF binding protein-3 was significantly reduced and plasma levels of estradiol and IGF-I were negatively correlated during estrogen treatment. CONCLUSIONS: Administration of a higher dose of estrogen may enhance attention and memory for postmenopausal women with AD. Although these findings provide further clinical evidence to support a cognitive benefit of estrogen for women with AD, studies evaluating the effect of estradiol administration, in particular, using larger sample sizes and for longer treatment durations are warranted before the therapeutic potential of estrogen replacement for women with AD can be firmly established.

Craft S, Asthana S, Schellenberg G, Cherrier M, Baker LD, Newcomer J, Plymate S, Latendresse S, Petrova A, Raskind M, Peskind E, Lofgreen C, Grimwood K. · Geriatric Research, Education, and Clinical Center, Veteran Affairs Puget Sound Health Care System, University of Washington School of Medicine, Seattle, Wash., · Neuroendocrinology. · Pubmed #10461029 No free full text.

Abstract: Higher fasting plasma insulin levels and reduced CSF-to-plasma insulin ratios, suggestive of insulin resistance, have been observed in patients with Alzheimer's disease (AD) who do not possess an apolipoprotein E (APOE)-epsilon4 allele. We examined the relationship of APOE and gender to peripheral insulin action and hyperinsulinemic memory facilitation in patients with AD using a sensitive measure of insulin-mediated glucose disposal. Participants were 32 patients with AD (9 without an epsilon4 allele, 23 with an epsilon4 allele) and 25 healthy age-matched adults (16 without an epsilon4 allele, 9 with an epsilon4 allele). AD subjects without an epsilon4 allele had significantly lower insulin-mediated glucose disposal rates than AD patients with an epsilon4 allele (p < 0.03), or than normal adults without an epsilon4 allele (p < 0.02). Female AD subjects showed lower insulin-mediated glucose disposal rates than did male AD subjects (p < 0.02). No significant interaction was observed between APOE group and gender, suggesting that these effects are independent. AD subjects without an epsilon4 allele also showed significant memory facilitation in the hyperinsulinemic condition (p < 0.04), whereas the AD-epsilon4 group did not. Also in the hyperinsulinemic condition, AD patients without an epsilon4 allele had lower insulin levels than patients with an epsilon4 allele (p < 0.02), and women with AD had lower insulin levels than did men with AD despite similar insulin infusion rates and body mass (p < 0.004). No gender or genotype effects were observed in either condition for normal subjects. These results provide in vivo evidence of differences in insulin-mediated energy metabolism between epsilon4 and non-epsilon4 AD, and suggest that defective insulin action may be of particular pathophysiologic significance for patients without an epsilon-4 allele.

Asthana S, Craft S, Baker LD, Raskind MA, Birnbaum RS, Lofgreen CP, Veith RC, Plymate SR. · Geriatric Research, Education and Clinical Center (GRECC), VA Puget Sound Health Care System, American Lake Division, Tacoma, WA 98493, USA. · Psychoneuroendocrinology. · Pubmed #10399774 No free full text.

Abstract: Preliminary evidence from clinical studies indicates that treatment with estrogen augments cognitive function for women with Alzheimer's disease (AD). The neurobiology of estrogen, particularly its neuromodulatory and neuroprotective actions, provide a viable basis to support such cognition-enhancing effects. We conducted a placebo-controlled, double-blind, parallel-group design pilot clinical study to evaluate the cognitive and neuroendocrine response to estrogen administration for postmenopausal women with AD. Twelve women with probably AD of mild-moderate severity completed the study. During an eight week treatment period, six women received 0.05 mg/day dosage of 17 beta-estradiol via a skin patch and the remaining six wore a placebo skin patch. Subjects were randomized to equal distribution, and evaluated at baseline, at weeks 1, 3, 5, and 8 on treatment, and at weeks 9, 10, 11, and 13 off treatment. On each day of evaluation, cognition was assessed using a battery of neuropsychological tests, and blood samples were collected to measure plasma concentrations of estradiol and estrone. In addition, several neuroendocrine markers were measured in plasma to evaluate the relationship between estrogen-induced cognitive effects and fluctuations in the catecholaminergic and insulin-like growth factor systems. Significant effects of estrogen treatment were observed on attention (i.e. Stroop: number of self-corrections in the Interference condition, F[1,8] = 8.22, P < 0.03) and verbal memory (i.e., Buschke: delayed cued recall, F[3,30] = 4.31, P < 0.02). The salutary effects of estrogen on cognition were observed after the first week of treatment, and started to diminish when treatment was terminated. For women treated with estrogen, enhancement in verbal memory was positively correlated with plasma levels of estradiol (r = 0.96, P < 0.02) and negatively correlated with concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) in plasma (r = -0.92, P < 0.03). Furthermore, a trend in the data was evident to suggest a negative relationship between plasma levels of insulin-like growth factor-1 (IGF-1) and verbal memory (r = -0.86, P = 0.06). Estrogen administration suppressed peripheral markers of the IGF system, as evidenced by a negative correlation between plasma concentration of estradiol and IGF-1 (r = -0.93, P < 0.03), and a trend for a similar relationship between plasma levels of estradiol and IGFBP-3 (r = -0.86, P = 0.06). With respect to the catecholamines assayed, norepinephrine was positively correlated with verbal memory (r = 0.95, P < 0.02) for women who were treated with estrogen. Furthermore, there was a trend to suggest a negative relationship between plasma epinephrine levels and the number of errors committed on a test of attention (r = -0.84, P = 0.07). In the placebo group, no significant effects of estrogen replacement were evident either on measures of cognition or on any of the neuroendocrine markers. The results of this study suggest that estrogen replacement may enhance cognition for postmenopausal women with AD. Furthermore, several markers of neuroendocrine activity may serve to index the magnitude of estrogen-induced facilitation on cognition. In addition, research findings from the present study will provide important information for the design of larger prospective clinical studies that are essential to definitively establish the therapeutic role of estrogen replacement for postmenopausal women with AD.

Asthana S, Raffaele KC, Greig NH, Schapiro MB, Blackman MR, Soncrant TT. · Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10372954 No free full text.

Abstract: We have reported that physostigmine, a reversible cholinesterase inhibitor, enhances verbal memory in patients with Alzheimer disease (AD). To elucidate the mechanism of cognition enhancement, plasma hormones were measured during high-dose acute and low-dose chronic steady-state intravenous infusions of physostigmine in nine subjects with AD. High-dose hormone responses were measured during and for 24 h after the infusion of physostigmine 1-1.5 mg over 45-60 min. Chronic responses were measured during continuous intravenous infusions of physostigmine at doses (0.5-25 mg/day) that escalated over 2 weeks, and then during 1 week infusion of the dose that optimized cognition (2-12 mg/day) or placebo administered in a randomized, double-blind, cross-over design. A replicable improvement in verbal memory was found in five subjects. High-dose physostigmine infusion that produced noxious side effects resulted in significant elevation above baseline in plasma levels of adrenocorticotrophic hormone (ACTH) (p = 0.0001), cortisol (p = 0.0001), and beta-endorphin (p = 0.0001). Chronic physostigmine administration, in the absence of adverse effects, produced no significant elevation in ACTH (p = 0.08), cortisol (p = 0.70), or beta-endorphin (p = 0.82). These results indicate that high-dose physostigmine activates the hypothalamic-pituitary-adrenal (HPA) axis, likely representing a "stress response." In contrast, cognition-enhancing doses do not produce a peripheral corticosteroid response. Thus, physostigmine-induced memory improvement is independent of the activation of the HPA axis.

Xu G, McLaren DG, Ries ML, Fitzgerald ME, Bendlin BB, Rowley HA, Sager MA, Atwood C, Asthana S, Johnson SC. · Geriatric Research Education and Clinical Center, William S Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. · Brain. · Pubmed #18829694 No free full text.

Abstract: First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimer's disease.

La Rue A, Hermann B, Jones JE, Johnson S, Asthana S, Sager MA. · Wisconsin Alzheimer's Institute, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. <> · Alzheimers Dement. · Pubmed #18631980 links to  free full text

Abstract: BACKGROUND: An exaggerated recency effect (ie, disproportionate recall of last-presented items) has been consistently observed in the word list learning of patients with Alzheimer's disease (AD). Our study sought to determine whether there were similar alterations in serial position learning among asymptomatic persons at risk for AD as a result of parental family history. METHODS: Subjects included 623 asymptomatic middle-aged children of patients with AD (median, 53 years) and 157 control participants whose parents survived to at least age 70 without AD or other memory disorders. All participants were administered the Rey Auditory Verbal Learning Test, which requires learning and recall of 15 unrelated nouns. RESULTS: There was no significant difference in total words recalled between the AD children and control groups. However, compared with controls, AD children exhibited a significantly greater tendency to recall words from the end (recency) versus beginning (primacy) of the list. Serial position effects were unrelated to apolipoprotein allele epsilon 4 or depressive symptoms. CONCLUSIONS: Asymptomatic persons at risk for AD by virtue of family history do not show a difference in total words recalled compared with controls, but they exhibit a distinctly different serial position curve, suggesting greater reliance on immediate as opposed to episodic memory. This is the same serial position pattern observed in mild AD, seen here in reduced severity. Longitudinal follow-up is planned to determine whether changes in serial position patterns are a meaningful marker for preclinical detection of AD.

Haasl RJ, Ahmadi MR, Meethal SV, Gleason CE, Johnson SC, Asthana S, Bowen RL, Atwood CS. · Section of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. · BMC Med Genet. · Pubmed #18439297 links to  free full text

Abstract: ABSTRACT: Genetic and biochemical studies support the apolipoprotein E (APOE) epsilon4 allele as a major risk factor for late-onset Alzheimer's disease (AD), though ~50% of AD patients do not carry the allele. APOE transports cholesterol for luteinizing hormone (LH)-regulated steroidogenesis, and both LH and neurosteroids have been implicated in the etiology of AD. Since polymorphisms of LH beta-subunit (LHB) and its receptor (LHCGR) have not been tested for their association with AD, we scored AD and age-matched control samples for APOE genotype and 14 polymorphisms of LHB and LHCGR. Thirteen gene-gene interactions between the loci of LHB, LHCGR, and APOE were associated with AD. The most strongly supported of these interactions was between an LHCGR intronic polymorphism (rs4073366; lhcgr2) and APOE in males, which was detected using all three interaction analyses: linkage disequilibrium, multi-dimensionality reduction, and logistic regression. While the APOE epsilon4 allele carried significant risk of AD in males [p = 0.007, odds ratio (OR) = 3.08(95%confidence interval: 1.37, 6.91)], epsilon4-positive males carrying 1 or 2 C-alleles at lhcgr2 exhibited significantly decreased risk of AD [OR = 0.06(0.01, 0.38); p = 0.003]. This suggests that the lhcgr2 C-allele or a closely linked locus greatly reduces the risk of AD in males carrying an APOE epsilon4 allele. The reversal of risk embodied in this interaction powerfully supports the importance of considering the role gene-gene interactions play in the etiology of complex biological diseases and demonstrates the importance of using multiple analytic methods to detect well-supported gene-gene interactions.

Carlsson CM, Gleason CE, Hess TM, Moreland KA, Blazel HM, Koscik RL, Schreiber NT, Johnson SC, Atwood CS, Puglielli L, Hermann BP, McBride PE, Stein JH, Sager MA, Asthana S. · Department of Medicine, Section of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. · J Alzheimers Dis. · Pubmed #18376061 No free full text.

Abstract: BACKGROUND: Statins reduce amyloid-beta (Abeta) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Abeta metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. METHODS: In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Abeta42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. RESULTS: Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Abeta42 (p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. CONCLUSION: In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Abeta42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Abeta metabolism, but also other preclinical processes related to the development of AD.

Trivedi MA, Schmitz TW, Ries ML, Hess TM, Fitzgerald ME, Atwood CS, Rowley HA, Asthana S, Sager MA, Johnson SC. · Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. · Neuropsychologia. · Pubmed #18241895 links to  free full text

Abstract: In the present study, we used fMRI to examine the influence of age on two other known risk factors for Alzheimer's disease (AD), APOE genotype and parental history of AD (FH status), during episodic encoding (ENC) and metacognitive self-appraisal (SA) paradigms. These paradigms have previously been shown to evoke activity from brain regions that are implicated in AD. First we examined the effect of age across the adult lifespan (age 18-84 years) on cerebral activity in a large sample (n=231) of cognitively healthy individuals. Next we examined a subset (n=155) on whom APOE status and FH status were known. For ENC, we found that increasing age was associated with reduced activity in the ventral temporal lobes and hippocampus. Our analysis of risk factors suggested that FH and age exerted independent effects, but APOE interacted with age such that APOE e4 carriers exhibit age-related increases in activity in the hippocampus. For the metacognitive SA task, increasing age was found to be associated with reduced activity in the medial prefrontal cortex, and increased activity in the mesial temporal lobe, posterior orbital cortex and striatum. Neither AD risk factor significantly modified age-related changes in brain activity during SA. These results suggest that FH and aging are exerting independent effects in both tasks while APOE affected the relationship with age in the hippocampus in one of the two tasks given.

Ertekin-Taner N, Younkin LH, Yager DM, Parfitt F, Baker MC, Asthana S, Hutton ML, Younkin SG, Graff-Radford NR. · Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224, USA. · Neurology. · Pubmed #17914065 No free full text.

Abstract: OBJECTIVE: Plasma A beta levels are elevated in early-onset Alzheimer disease (AD) caused by autosomal dominant mutations. Our objective was to determine whether similar genetic elevations exist in late-onset AD (LOAD). METHODS: We measured plasma A beta in first-degree relatives of patients with LOAD in a cross-sectional series and in extended LOAD families. We screened these subjects for pathogenic mutations in early-onset AD genes and determined their ApoE genotypes. RESULTS: Plasma A beta is significantly elevated in the LOAD first-degree relatives in comparison to unrelated controls and married-in spouses. These elevations are not due to ApoE epsilon 4 or pathogenic coding mutations in the known early-onset AD genes. CONCLUSIONS: The findings provide strong evidence for the existence of novel, as yet unknown genetic factors that affect late-onset Alzheimer disease by increasing A beta.

Johnson SC, Ries ML, Hess TM, Carlsson CM, Gleason CE, Alexander AL, Rowley HA, Asthana S, Sager MA. · Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA. · Arch Gen Psychiatry. · Pubmed #17909128 links to  free full text

Abstract: CONTEXT: Asymptomatic middle-aged adult children of patients with Alzheimer disease (AD) recently were found to exhibit functional magnetic resonance imaging (fMRI) deficits in the mesial temporal lobe during an encoding task. Whether this effect will be observed on other fMRI tasks is yet unknown. This study examines the neural substrates of self-appraisal (SA) in persons at risk for AD. Accurate appraisal of deficits is a problem for many patients with AD, and prior fMRI studies of healthy young adults indicate that brain areas vulnerable to AD such as the anterior mesial temporal lobe and posterior cingulate are involved during SA tasks. OBJECTIVE: To determine whether parental family history of AD (hereafter referred to as FH) or presence of the epsilon4 allele of the apolipoprotein E gene (APOE4) exerts independent effects on brain function during SA. DESIGN: Cross-sectional factorial design in which APOE4 status (present vs absent) was one factor and FH was the other. All participants received cognitive testing, genotyping, and an fMRI task that required subjective SA decisions regarding trait adjective words in comparison with semantic decisions about the same words. SETTING: An academic medical center with a research-dedicated 3.0-T MR imaging facility. PARTICIPANTS: Cognitively normal middle-aged adults (n = 110), 51 with an FH and 59 without an FH. MAIN OUTCOME MEASURE: Blood oxygen-dependent contrast measured using T2*-weighted echo-planar imaging. RESULTS: Parental family history of AD and APOE4 status interacted in the posterior cingulate and left superior and medial frontal regions. There were main effects of FH (FH negative > FH positive) in the left hippocampus and ventral posterior cingulate. There were no main effects of APOE genotype. CONCLUSIONS: Our results suggest that FH may affect brain function during subjective SA in regions commonly affected by AD. Although the participants in this study were asymptomatic and middle-aged, the findings suggest that there may be subtle alterations in brain function attributable to AD risk factors.

Johnson SC, Schmitz TW, Asthana S, Gluck MA, Myers C. · Geriatric Research Education and Clinical Center, Wm. S. Middleton VA Hospital, Madison, WI 53705, USA. · Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. · Pubmed #17851984 links to  free full text

Abstract: The ability to form associations between choice alternatives and their contingent outcomes is an important aspect of learning that may be sensitive to hippocampal dysfunction in memory disorders of aging such as amnestic mild cognitive impairment (MCIa), or early Alzheimer disease. In this preliminary study we examined brain activation using functional magnetic resonance imaging (fMRI) in 12 healthy elderly participants and nine patients with MCIa during an associative learning task. Using a high-field 3.0-Tesla MRI scanner, we examined the dynamic neural response during associative learning over trials. The slope of signal attenuation associated with learning was analyzed for differences between groups within an a priori defined hippocampal region. Results indicated dynamic signal attenuation associated with learning in the healthy elderly sample, but not in MCIa. The absence of an associative learning effect in the MCIa sample reaffirms an important link between the learning difficulties that are commonly encountered in MCIa and the mesial temporal region.

Johnson SC, Schmitz TW, Trivedi MA, Ries ML, Torgerson BM, Carlsson CM, Asthana S, Hermann BP, Sager MA. · University of Wisconsin-Madison, Wisconsin 53705, USA. · J Neurosci. · Pubmed #16738250 links to  free full text

Abstract: First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E epsilon4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Both putatively cause early brain changes before symptomatic disease, but the relative contribution of each to brain function is unknown. We examined 68 middle-aged participants with a parent diagnosed with AD [family history (+FH)] and 64 age- and education-matched controls without a first-degree family history of any dementia [no family history (-FH)]. All underwent cognitive testing, APOE genotyping, and a functional magnetic resonance imaging encoding task that required discrimination of novel items from previously learned items. A 2 x 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the -FH +epsilon4 group exhibited the greatest signal change, and the +FH +epsilon4 group exhibited the least. These findings indicate that FH of AD is an important predictor of hippocampal activation during encoding and that FH may modulate the effect of APOE4 in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function.

Kulstad JJ, Green PS, Cook DG, Watson GS, Reger MA, Baker LD, Plymate SR, Asthana S, Rhoads K, Mehta PD, Craft S. · Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA. · Neurology. · Pubmed #16717209 No free full text.

Abstract: BACKGROUND: Hyperinsulinemia and insulin resistance are risk factors for memory impairment and Alzheimer disease (AD). Insulin regulates levels of the amyloid beta-peptide (Abeta) in vitro in neuronal cultures and in vivo in the CSF of normal older adults. OBJECTIVE: To determine whether insulin affected plasma Abeta levels and whether such effects differed for patients with AD compared with normal older adults. METHODS: Fifty-nine patients with AD and 50 healthy older adults each received infusions of saline and of insulin (1.0 mU.kg(-1).min(-1)) with accompanying dextrose to maintain euglycemia. A subset of participants (19 AD, 12 normal) received two additional conditions, in which insulin was infused at a lower (0.33 mU.kg(-1).min(-1)) and higher (1.67 mU.kg(-1).min(-1)) rate. Plasma insulin and Abeta were measured after 120 minutes of infusion. RESULTS: Adults with AD had higher plasma insulin vs normal adults at the two higher infusion rates, despite receiving comparable amounts of insulin. For normal adults, insulin reduced plasma Abeta levels at the middle (1.0 mU.kg(-1).min(-1)) dose, with attenuated effects at lower and higher doses. In contrast, for patients with AD, insulin raised plasma Abeta levels at the two higher doses (1.0 and 1.67 mU.kg(-1).min(-1)). CONCLUSIONS: These results suggest that patients with Alzheimer disease (AD) have reduced insulin clearance and insulin-provoked plasma amyloid beta-peptide (Abeta) elevation. Abnormal regulation of peripheral Abeta by insulin may contribute to AD risk.

Trivedi MA, Schmitz TW, Ries ML, Torgerson BM, Sager MA, Hermann BP, Asthana S, Johnson SC. · Geriatric Research Education and Clinical Center, William S. Middleton Veteran's Affairs Hospital, Madison, WI, USA. · BMC Med. · Pubmed #16412236 links to  free full text

Abstract: BACKGROUND: The presence of the apolipoprotein E (APOE) epsilon4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the epsilon4 allele on hippocampal activation has not been firmly established. METHODS: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. RESULTS: We found that epsilon3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to epsilon3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in epsilon3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the epsilon3/3 homozygotes, but not in the epsilon3/4 heterozygotes. CONCLUSION: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE epsilon4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline.

Watson GS, Bernhardt T, Reger MA, Cholerton BA, Baker LD, Peskind ER, Asthana S, Plymate SR, Frölich L, Craft S. · Geriatric Research, Education, and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, and Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98108-1532, USA. · Neurobiol Aging. · Pubmed #16298239 No free full text.

Abstract: We assessed the effects of induced hyperinsulinemia on plasma and cerebrospinal fluid (CSF) levels of norepinephrine (NE) and on cognition for patients with Alzheimer's disease (AD) and normal older adults. For normal adults, insulin increased plasma and CSF NE levels; also, recall for paraphrased details of a story improved as CSF NE levels increased. Mental control was positively correlated with CSF levels of NE for patients. These findings demonstrate that raising peripheral insulin levels can modulate CNS NE levels and suggest that insulin-stimulated increases in NE may modulate cognitive functions.

Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S. · Geriatric Research, Education, and Clinical Center, Research and Development Service, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA. · Am J Geriatr Psychiatry. · Pubmed #16286438 No free full text.

Abstract: OBJECTIVE: Insulin resistance (impaired insulin action) has been associated with Alzheimer disease (AD) and memory impairment, independent of AD. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists improve insulin sensitivity and regulate in-vitro processing of the amyloid precursor protein (APP). Authors evaluated the effects of the PPAR-gamma agonist rosiglitazone on cognition and plasma levels of the APP derivative beta-amyloid (Abeta) in humans. METHODS: In a placebo-controlled, double-blind, parallel-group pilot study, 30 subjects with mild AD or amnestic mild cognitive impairment were randomized to a 6-month course of rosiglitazone (4 mg daily; N = 20) or placebo (N = 10). Primary endpoints were cognitive performance and plasma Abeta levels. RESULTS: Relative to the placebo group, subjects receiving rosiglitazone exhibited better delayed recall (at Months 4 and 6) and selective attention (Month 6). At Month 6, plasma Abeta levels were unchanged from baseline for subjects receiving rosiglitazone but declined for subjects receiving placebo, consistent with recent reports that plasma Abeta42 decreases with progression of AD. CONCLUSIONS: Findings provide preliminary support that rosiglitazone may offer a novel strategy for the treatment of cognitive decline associated with AD. Future confirmation in a larger study is needed to fully demonstrate rosiglitazone's therapeutic potential.

Johnson SC, Schmitz TW, Moritz CH, Meyerand ME, Rowley HA, Alexander AL, Hansen KW, Gleason CE, Carlsson CM, Ries ML, Asthana S, Chen K, Reiman EM, Alexander GE. · Geriatric Research Education and Clinical Center, Wm. S. Middleton VA Hospital, 2500 Overlook Terrace (11G), GRECC, Madison, WI 53705, USA. · Neurobiol Aging. · Pubmed #16226349 links to  free full text

Abstract: This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD.

Fishel MA, Watson GS, Montine TJ, Wang Q, Green PS, Kulstad JJ, Cook DG, Peskind ER, Baker LD, Goldgaber D, Nie W, Asthana S, Plymate SR, Schwartz MW, Craft S. · Department of Neurology, University of Washington, Seattle, WA 98108, USA. · Arch Neurol. · Pubmed #16216936 No free full text.

Abstract: BACKGROUND: Inflammation has been implicated as a pathogenetic factor in Alzheimer disease, possibly via effects on beta-amyloid (Abeta). Hyperinsulinemia induces inflammation and is a risk factor for Alzheimer disease. Thus, insulin abnormalities may contribute to Alzheimer disease pathophysiology through effects on the inflammatory network. OBJECTIVES: To determine the effects of induced hyperinsulinemia with euglycemia on Abeta, transthyretin, and inflammatory markers and modulators in plasma and cerebrospinal fluid (CSF). DESIGN: Randomized crossover trial. SETTING: Veterans Affairs hospital clinical research unit. PARTICIPANTS: Sixteen healthy adults ranging from 55 to 81 years of age (mean age, 68.2 years). INTERVENTIONS: On separate mornings, fasting participants received randomized infusions of saline or insulin (1.0 mU.kg(-1).min(-1)) with variable dextrose levels to maintain euglycemia, achieving plasma insulin levels typical of insulin resistance. Plasma and CSF were collected after an approximately 105-minute infusion. MAIN OUTCOME MEASURES: Plasma and CSF levels of interleukin 1alpha, interleukin 1beta, interleukin 6, tumor necrosis factor alpha, F2-isoprostane (CSF only), Abeta, norepinephrine, transthyretin, and apolipoprotein E. RESULTS: Insulin increased CSF levels of F2-isoprostane and cytokines (both P<.01), as well as plasma and CSF levels of Abeta42 (both P<.05). The changes in CSF levels of Abeta42 were predicted by increased F2-isoprostane and cytokine levels (both P<.01) and reduced transthyretin levels (P = .02). Increased inflammation was modulated by insulin-induced changes in CSF levels of norepinephrine and apolipoprotein E (both P<.05). CONCLUSION: Moderate hyperinsulinemia can elevate inflammatory markers and Abeta42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.

Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S. · Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA. · Neurology. · Pubmed #15985573 No free full text.

Abstract: OBJECTIVE: To determine the efficacy of testosterone (T) supplementation on cognition in a sample of men with Alzheimer disease (AD) or mild cognitive impairment (MCI). METHODS: Fifteen patients with AD and 17 patients with MCI aged 63 to 85 years completed a randomized, double-blind, placebo-controlled study. Nineteen participants received weekly intramuscular (IM) injections of 100 mg T enanthate and 13 participants received weekly injections of placebo (saline) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3, and week 6 of treatment and again after 6 weeks of washout. RESULTS: Peak serum total T levels were raised from baseline an average of 295% in the active treatment group. Improvements in spatial memory (p < 0.05) and constructional abilities (p < 0.05) and verbal memory were evident in the T group. No changes were noted for selective and divided attention or language. Prostate specific antigen did not significantly change during this brief treatment. CONCLUSION: Testosterone supplementation may benefit selective cognitive functions in men with Alzheimer disease and mild cognitive impairment.