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ABSTRACT: Macroscopically, Alzheimer’s disease (AD) is characterized by global atrophy that is more pronounced, at least, initially,
in medial temporal lobe structures and accompanied by ventricular enlargement. Rates of hippocampal atrophy (rHVLs) and ventricular
volume gain (rVVGs) have been proposed as possible measures to judge the efficacy of treatments designed to be disease modifying.
Our interest has focused on whether and when rHVL and rVVG differ between healthy subjects destined to develop AD and those
destined to remain healthy. In prior work, based on 4 MRI scans obtained in a 6year period, on 26 healthy subjects (mean
age = 58.8years), we found that rHVLs were linear and significantly differed among subjects, even those sharing identical
apolipoprotein E (APOE) genotypes and that higher rHVLs were associated with subsequent poorer memory performance. In this
study, the same scans were used to investigate rVVGs. rVVGs were also found to be linear with differences observed among subjects
independent of APOE genotype. However, in contrast to rHVLs and hippocampal volumes, rVVGs and baseline ventricular volumes
correlated with age, but not with memory performance on a selective reminding task. The findings are consistent with selective
atrophy of the hippocampus rather than global cortical atrophy as responsible for age-related declines in episodic memory
in healthy subjects in their 6th and 7th decades while higher rVVGs may be associated with other age-related cognitive impairments.
Brain Imaging and Behavior 04/2012; 3(4):370-378. · 1.66 Impact Factor
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ABSTRACT: How and when the known genetic risk allele, apolipoprotein E-epsilon4 (APOEepsilon4), confers risk to Alzheimer's disease has yet to be determined. We studied older adults and found that APOEepsilon4 carriers had greater neural activation in the medial frontal and parahippocampal gyrus during a memory task (cluster-corrected p < .01). When compared to a group of younger adults, interactive effects of age and APOEepsilon4 were found in the inferior frontal-anterior temporal region, one of the first areas to develop amyloid plaques in patients with Alzheimer's disease, and, in the posterior cingulate, one of the earliest areas to show decreased cerebral metabolism in Alzheimer's disease. Thus, abnormally high activation in fronto-temporal areas are present in both younger and older APOEepsilon4 carriers confronted with a working memory task when compared to non-APOEepsilon4 carriers. This effect, however, appears to diminish with age.
Brain Imaging and Behavior 06/2010; 4(2):177-88. · 1.66 Impact Factor
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ABSTRACT: Although it is established that apolipoprotein E (APOE) e4 allele increases the risk of Alzheimer's disease (AD), epidemiological studies indicate that genetic risk decreases late in life. This raises the question of whether the effects of APOE on cognition that are seen in midlife arise from a cognitive phenotype of APOE or from the presence of early AD in some APOE-e4 carriers. The authors addressed this question by comparing the cognitive consequences of variation in the APOE gene between individuals over the age of 80 (old-old) and middle-aged and young-old individuals. A spatially cued discrimination paradigm--previously shown to be sensitive to AD and to APOE genotype--required a speeded categorization of a target letter following cues that were valid, invalid, or neutral in predicting target location. Results revealed greater costs of invalid cues in the APOE-e4 carriers of middle-aged and young-old, but not old-old, groups. The dissipation of the APOE effect in old-old individuals at lower risk of AD suggests that visuospatial attention impairments seen as early as midlife in APOE-e4 carriers may be a preclinical marker of AD.
Neuropsychology 02/2009; 23(1):81-9. · 3.82 Impact Factor
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John H Krystal,
Cameron S Carter,
Daniel Geschwind,
Husseini K Manji,
John S March,
Eric J Nestler,
Jon-Kar Zubieta,
Dennis S Charney,
David Goldman,
Raquel E Gur, [......],
Larry J Siever, Trey Sunderland,
Laurence H Tecott,
Michael E Thase,
Richard D Todd,
Myrna M Weissman,
Rachel Yehuda,
Takeo Yoshikawa,
Elizabeth A Young,
R McCandless
Biological psychiatry 05/2008; 63(8):725-7. · 8.93 Impact Factor
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ABSTRACT: Patients with minimal cognitive impairment (MCI) or Alzheimer's disease (AD) have smaller hippocampal volumes (HV) and increased rates of HV loss (rHVL). A 6-year study was conducted to assess rHVL in healthy aging subjects (HC) in which four MRI scans, each 2 years apart, were obtained on 26 HC with a mean age of 58.8 years when entering the study. rHVLs were linear and significantly differed among subjects, even those sharing an identical apoliporotein E genotype, ranging from .027 to .191 cc/year (S.D. = .022 cc/year), and were not affected by age or sex. rHVL, but not HV, at time of subject entry, was found to predict performance on the delayed recall measure of the Selective Reminder Task obtained 6 years after subject entry into study. Although the molecular events underlying rHVL are unclear, the significance of rHVL in subjects in their sixth and seventh decades of life for predicting age-related cognitive trajectories and whether changes in rHVLs foreshadow the development of MCI are the subject of ongoing study.
Neurobiology of aging 11/2006; 27(10):1385-94. · 5.94 Impact Factor
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ABSTRACT: Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer's disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer's disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer's disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions.
Journal of Geriatric Psychiatry and Neurology 10/2006; 19(3):172-9. · 3.07 Impact Factor
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ABSTRACT: The apolipoprotein E-epsilon4 allele (APOE-epsilon4) confers greater susceptibility to age-related memory disorders. Abnormalities in the cholinergic system are likely contributors to these disorders with both age and APOE-epsilon4 genotype modifying behavioral and physiological responses to drugs that alter cholinergic pathway function. Recently, we reported a greater in vivo distribution volume of the F-18 labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[18F]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([18F]FP-TZTP), in aging healthy subjects with an APOE-epsilon4 allele. To examine the effects of aging and the APOE-epsilon4 allele on the response of the muscarinic component of cholinergic pathway to pharmacologic augmentation, two [18F]FP-TZTP PET scans were conducted in 19 subjects varying in age from 22 to 74 years, the first served as baseline for the second scan that was performed while the subjects were either infused with saline (n = 6) or with the acetylcholinesterase inhibitor physostigmine (6 with an APOE-epsilon4 allele and 7 without an APOE-epsilon4 allele). Using a multiple regression analysis, both AGE (beta = 0.621 +/- 0.135, B = 0.353 +/- 0.077, t(10) = 4.61, P < 0.001) and APOE-epsilon4 genotype (beta = 0.742, B = 14.8 +/- 2.69, t(10) = 5.51, P < 0.0003) were found to be significant contributors to subject response to physostigmine. The adjusted R2 for the model as a whole was 0.786 (F(2,10) = 23.00, P < 0.0002) with both increasing age and the presence of the APOE-epsilon4 allele modifying the response to physostigmine in the direction of larger decreases in [18F]FP-TZTP distribution volumes in all brain regions examined. The findings, particularly the absence of an interaction between AGE and APOE-epsilon4 genotype, contribute to the growing body of evidence that suggests that the APOE-epsilon4 genotype is likely to contribute to brain structure and function prior to aging.
Synapse 07/2006; 60(1):86-92. · 2.94 Impact Factor
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ABSTRACT: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42 )and tau differ between patients with Alzheimer's Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated.
We assessed CSF beta-amyloid(1-42) and tau in 20 mild-to-moderate AD patients, 11 APOE epsilon4+ and 9 APOE epsilon4-, over a mean time of 3.8 years (range 1-11.1 years).
Over the period measured, CSF beta-amyloid(1-42) levels were lower in APOE epsilon4+ compared to APOE epsilon4- patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele.
While this is a limited clinical sample, the further decrease in CSF beta-amyloid(1-42 )(i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that beta-amyloid(1-42 )and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF beta-amyloid(1-42) and tau are used as measures of treatment response.
Dementia and Geriatric Cognitive Disorders 02/2006; 22(1):48-53. · 2.14 Impact Factor
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Katharina Buerger,
Stefan J Teipel,
Raymond Zinkowski, Trey Sunderland,
Niels Andreasen,
Kaj Blennow,
Michael Ewers,
John DeBernardis,
Yong Shen,
Daniel Kerkman,
Yansheng Du,
Harald Hampel
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ABSTRACT: We investigated the correlation between the apolipoprotein E varepsilon4 allele (apoE epsilon4) carrier status, a major risk factor of Alzheimer's disease (AD), and levels of tau protein phosphorylated at threonine 231 (P-tau(231P)) in cerebrospinal fluid (CSF) in predementia and clinical stages of AD and healthy controls (HC). Thirty-one subjects with mild cognitive impairment (MCI) who had converted to AD during follow-up were included, as well as 71 AD patients, and 29 HC subjects. In MCI, but not in AD and HC, CSF P-tau(231P) levels were significantly higher in apoE epsilon4 carriers compared to non-carriers (p<0.001). Controlling for disease duration, the apoE epsilon4 effect on P-tau(231P) remained significant. Our study indicates that the apoE epsilon4 carrier status should be considered when CSF P-tau(231P) is evaluated as biomarker candidate of AD in MCI subjects.
Neuroscience Letters 01/2006; 391(1-2):48-50. · 2.11 Impact Factor
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ABSTRACT: Previous literature shows that feature binding processes elicit fronto-hippocampal areas. The time course of this process, however, remains unknown. This is the first study that investigates feature binding using magnetoencephalography. Synthetic aperture magnetometry analysis was used to localize sources of increased power in the theta band during the encoding phases of a feature-binding task in the left and right medial frontal gyri (Brodmann's area 10) and left and right anterior cingulate gyri. Theta band synchronization was observed in many of these same areas, but also in other areas not noted to have increased theta band power suggesting a broad network of regions subserving the encoding phase of feature binding.
Neuroreport 12/2005; 16(16):1747-52. · 1.66 Impact Factor
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ABSTRACT: The effect of apolipoprotein E (APOE) genotype on longitudinal cognitive decline in midlife was investigated with attentional scaling. Healthy individuals (mean age 59.6 years) genotyped for APOE were tested at 3 12-month intervals on a cued visual search task. A random effects model revealed significant interaction in effect of precue size on search speed between APOE-epsilon4 gene dose and assessment, with longitudinal increases in noncarriers and heterozygotes but longitudinal decreases in homozygotes. Association of APOE-epsilon4 with cognitive decline in midlife is consistent with an Alzheimer's disease (AD) prodrome, albeit a decade or more before average age of AD diagnosis. However, cognitive decline in midlife associated with a gene modulating neuronal response to insult argues that the concept of an AD prodrome includes factors that allow as well as cause AD.
Neuropsychology 12/2005; 19(6):830-40. · 3.82 Impact Factor
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ABSTRACT: Biomarkers are hypothesized but not frequently used in research with the elderly because of a general paucity of supportive scientific data. However, there is an obvious need for greater diagnostic specificity and sensitivity across many diagnoses in the elderly, as well as good targets for therapeutic trials. The authors reviewed the available information in this field as part of a general review of geriatric research for the . Potential biomarkers with pathophysiologic significance have been studied in the field of Alzheimer disease research with some success, especially in the area of genetic markers (apolipoprotein E [APOE] epsilon4 allele), neuroimaging, and cerebrospinal fluid markers (beta-amyloid and tau). While some progress has been made in the search for adequate biomarkers in the elderly, in particular with Alzheimer disease, much more work is needed before these potential biomarkers can be reliably used in clinical practice.
Biological Psychiatry 09/2005; 58(4):272-6. · 8.28 Impact Factor
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Trey Sunderland
Biological Psychiatry 09/2005; 58(4):263-4. · 8.28 Impact Factor
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Dwight L Evans,
Dennis S Charney,
Lydia Lewis,
Robert N Golden,
Jack M Gorman,
K Ranga Rama Krishnan,
Charles B Nemeroff,
J Douglas Bremner,
Robert M Carney,
James C Coyne, [......],
Steven P Roose,
Julia Rowland,
Yvette Sheline,
David S Sheps,
Gregory Simon,
David Spiegel,
Albert Stunkard, Trey Sunderland,
Paul Tibbits,
William J Valvo
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ABSTRACT: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research.
Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors.
Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed.
A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.
Biological Psychiatry 09/2005; 58(3):175-89. · 8.28 Impact Factor
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The Journal of Clinical Psychiatry 06/2005; 66(5):658-9. · 5.80 Impact Factor
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ABSTRACT: Major Depressive Disorder (MDD) may be a risk factor for subsequent development of irreversible dementia; however, the influence of a premorbid history of MDD on the clinical course of patients diagnosed with probable Alzheimer disease (AD) has not been fully explored.
Forty-three AD patients with mild-to-moderate cognitive impairment were screened for a life-long history of MDD with the Clinical Assessment of Depression in Dementia Scale. Twenty-two subjects had a history of MDD before onset of cognitive impairment, but none was suffering from an MDD episode at time of cognitive assessment.
After controlling for age, education, duration of illness, gender, and medication status, subjects with a history of MDD had significantly lower scores, as a group, on cognitive performance tests, including the Mini-Mental State Exam, WAIS Full-Scale and Verbal Scale I.Q., and the Initiation/Perseveration subscale of the Mattis Dementia Rating Scale. These subjects also developed symptoms of dementia at a significantly earlier age than the subjects who had no premorbid history of MDD.
Although previous studies have shown that late-onset MDD may increase risk for subsequent dementia, the current results suggest that premorbid MDD is associated with more severe cognitive deficits during the actual course of dementia.
American Journal of Geriatric Psychiatry 05/2005; 13(4):312-8. · 3.64 Impact Factor
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ABSTRACT: The cognitive consequences of the apolipoprotein E-epsilon4 (APOE-epsilon4) allele were examined in middle age, before likely onset of symptoms of Alzheimer's disease. The authors identified 3 cognitive processes--visuospatial attention, spatial working memory, and the effect of visuospatial attention on working memory--and devised "behavioral assays" of the integrity of components of these processes. Redirecting visuospatial attention, retention of memory for location, and attentional modulation of memory of target location were affected by APOE genotype. Visuospatial attention showed additive effects of epsilon4 gene dose; each additional epsilon4 allele inherited further slowed disengagement from invalidly cued space. In contrast, working memory performance was affected only in epsilon4 homozygotes. Effect sizes for the APOE gene were moderate to large, ranging from 14% to 24%. Effects of APOE genotype on component processes of cognition in healthy, middle-aged adults is consistent with the emergence in adulthood of an APOE-epsilon4 cognitive phenotype.
Neuropsychology 04/2005; 19(2):199-211. · 3.82 Impact Factor
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ABSTRACT: Two groups of non-demented individuals, who differed on genetic risk for Alzheimer's disease (AD) based on their apolipoprotein E (APOE) genotype, were tested on a category fluency task. Twenty varepsilon4 carriers and twenty varepsilon4 non-carriers were tape recorded while saying animal names for ten minutes. Five measures were examined: total names generated; total clusters; mean cluster size; mean within-cluster retrieval time; and mean between-cluster retrieval time. Groups were matched on age and education and scored as normal on a battery of psychometric tests. The varepsilon4 carriers generated significantly fewer names and clusters, and took significantly longer to access clusters, when compared to the varepsilon4 non-carriers. No group differences were found for cluster size or within-cluster retrieval times. We previously reported [Rosen, V. M., Bergeson, J. L., Putnam, K., Harwell, A., Sunderland, T. (2002). Working memory and apolipoprotein E: What's the connection? Neuropsychologia 40, 2226-2233] that the varepsilon4 carriers in the present study scored significantly lower than the varepsilon4 non-carriers on a measure of working memory/attentional capacity [Operation Span Task, see Turner, M. L., Engle, R. W. (1989). Is working memory capacity task dependent? Journal of Memory and Language 28, 127-154]. In the present study, a significant negative relationship found between span performance and between-cluster retrieval times suggested that reduced attentional capacity may have negatively impacted semantic access for the varepsilon4 carriers. Finally, we found significant relationships between a Trail Making Test [Reitan, R. M. (1992). Trail Making Test, manual for administration and scoring. Tucson, AZ: Reitan Neuropsychology Laboratory] "switch" measure (Form B-Form A) and three of the five fluency measures. The findings suggested that the varepsilon4 carrier's reduced attentional capacity may have interfered with their covertly shifting attention among subcategories in the fluency task, resulting in fewer names and clusters generated and longer times to access clusters.
Neuropsychologia 02/2005; 43(4):647-58. · 3.64 Impact Factor
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Trey Sunderland,
Nadeem Mirza,
Karen T Putnam,
Gary Linker,
Deepa Bhupali,
Rob Durham,
Holly Soares,
Lida Kimmel,
David Friedman,
Judy Bergeson,
Gyorgy Csako,
James A Levy,
John J Bartko,
Robert M Cohen
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ABSTRACT: Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD.
We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing.
When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p < .01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p < .01).
The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.
Biological Psychiatry 11/2004; 56(9):670-6. · 8.28 Impact Factor
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ABSTRACT: Several approaches are described for the design of pharmacologic strategies for the manipulation of cognition. By a variety of criteria, it is concluded that antidepressants deserve a trial in some patients with cognitive dysfunction. Depression is an illness with prominent cognitive dysfunction that shares, to some extent, cognitive and biochemical impairments similar to those observed in cognitive dysfunction of organic etiology. Antidepressants appear to produce their beneficial effect on cognition in depression by inducing slow adaptive changes in catecholamine and indoleamine pathways, therein promoting alterations in the individual's central motivational state. Animal data supporting these ideas are reported. As reviewed, few satisfactory studies of antidepressants in cognitive dysfunction of organic etiology appear in the literature, perhaps as the result of the potent anticholinergic properties of the most popular antidepressant drugs.
Drug Development Research 10/2004; 4(5):517 - 532. · 1.19 Impact Factor
