Joanna Szczepanik

Interactive Effects of Age and Hypertension on Volumes of Brain Structures

BACKGROUND AND PURPOSE Advanced age and hypertension have each been associated with changes in brain morphology and cognitive function. To investigate the interaction of age and hypertension with structural brain changes and neuropsychological performance in otherwise healthy patients with essential hypertension, we compared young-old (ages 56 to 69 years) and old-old (ages 70 to 84 years) hypertensive patients (n = 27) with 20 age-matched normotensive healthy control subjects, using quantitative volumetric MRI and a battery of neuropsychological tests. METHODS Quantitative regions of interest and segmentation analyses were applied to MRI scans of brain to measure volumes of different brain structures and of cerebrospinal fluid (CSF). Severity of white matter hyperintensities (WMHs) was qualitatively rated in the MRI scans. A battery of neuropsychological tests was administered to each subject. RESULTS The combined hypertensive group (young-old and old-old) had smaller volumes of thalamic nuclei and larger volumes of CSF in the cerebellum and temporal lobes and showed poorer performance in memory and language tests than did the control subjects. Main effects for age were significant in multiple brain regions of interest. The old-old hypertensive patients and age-matched control subjects demonstrated volume reductions in brain structures and increases in ventricular and peripheral CSF volumes compared with the younger subjects. There was a significant group x age-group interaction in temporal and occipital CSF, not related to WMH, with the old-old hypertensive patients having significantly larger CSF volumes in these regions than the young-old hypertensives and both healthy control groups. CONCLUSIONS Hypertension exacerbates the morphological changes accompanying advanced age. Temporal and occipital regions appear most vulnerable to brain atrophy due to the interactive effects of age and hypertension.

Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum

Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine’s actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [11C]raclopride‐PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [11C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D2/3 receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus‐plus‐constant‐infusion [11C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a ‘slot‐machine’ task. The ΔBP between conditions was assessed in striatal regions‐of‐interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BPND) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BPND reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males.

Relation of age and apolipoprotein E to cognitive function in Down syndrome adults

TO test the cognitive effects of aging and apolipoprotein E (APOE) in individuals at high risk for Alzheimers disease (AD), we assessed APOE genotypes and performance on a battery of neuropsychological tests in 41 non-demented, Down syndrome (DS) adults. Old DS subjects (ages 41–61 years) showed poorer memory and orientation scores than young DS adults (ages 22–38 years), but the groups did not differ in other measures after we controlled for intellectual function. Language ability was inversely related to APOE genotype, even after age was controlled for, with the presence of the ϵ2 allele corresponding to better language skills than ϵ4. Age-related cognitive changes in non-demented DS adults are consistent with the early effects of AD. The relationship between basic linguistic skills and APOE genotype supports this genetic factor in influencing the development of dementia and AD neuropathology in DS.

Time course of pharmacodynamic and pharmacokinetic effects of physostigmine assessed by functional brain imaging in humans

In imaging studies of brain functions using pharmacological probes, identification of the time point at which central effects of intravenously infused drugs become stable is crucial to separate the effects of experimental variables from the concomitant changes in drug effects over time. We evaluated the time courses of the pharmacokinetics and pharmacodynamics, including butyrylcholinesterase inhibition and central neural responses, of physostigmine in healthy young subjects. Ten positron emission tomography (PET) scans that alternated between a rest condition (eyes open, ears unplugged) and a working memory for faces (WM) task were acquired in healthy subjects. Subjects in the drug group received a saline infusion for the first two scans, providing a baseline measure, then received an infusion of physostigmine for all subsequent scans. Subjects in the control group received a placebo infusion of saline for all scans. Physostigmine plasma levels and percent butyrylcholinesterase inhibition increased over time (p < 0. 0001), and both became stable by 40 min. Physostigmine decreased reaction time (RT) (p = 0.0005), and this effect was detected after 20 min of infusion and stable thereafter. Physostigmine also decreased regional cerebral blood flow (rCBF) in right prefrontal cortex during task (p = 0.0002), and this effect was detected after 40 min of infusion and stable thereafter. No change in RT or rCBF was observed in the control group. These results indicate that a 40-min infusion of physostigmine was necessary to obtain stable central effects. More generally, we have demonstrated that experimental effects can vary with time, especially during the initial phases of a drug infusion, indicating that it is critical that these changes are controlled.

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.

DRD2/ANKK1 Taq1A polymorphism (rs1800497) has opposing effects on D2/3 receptor binding in healthy controls and patients with major depressive disorder.

The A1 allele of the DRD2/ANKK1 Taq1A polymorphism (rs1800497) is associated with reduced striatal D(2/3) receptor binding in healthy individuals (Con) as well as depression and addiction. However, the effect of rs1800497 on D(2/3) receptor binding in depressed patients as well as the SNPs effect on D(2/3) binding during reward-associated dopamine release is unknown. Twelve unmedicated patients with major depressive disorder (MDD) and 24 Con completed PET scans with [(11)C]raclopride, once without receiving monetary rewards (baseline) and once while winning money. In Con, the A1 allele was associated with reduced baseline binding potential (BP(ND)) in the middle caudate and ventral striatum. However, in MDD patients the A1 allele was associated with increased baseline BP(ND) in these regions. There were no significant associations between rs1800497 and change in BP(ND) during reward-associated dopamine release. Conceivably, the A1 allele predisposes to depression and addiction via its effect on the post-synaptic D(2) receptor.

Hippocampal atrophy in the healthy is initially linear and independent of age

Patients with minimal cognitive impairment (MCI) or Alzheimers 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.

Pretreatment Differences in BOLD Response to Emotional Faces Correlate with Antidepressant Response to Scopolamine

Background: Faster acting antidepressants and biomarkers that predict treatment response are needed to facilitate the development of more effective treatments for patients with major depressive disorders. Here, we evaluate implicitly and explicitly processed emotional faces using neuroimaging to identify potential biomarkers of treatment response to the antimuscarinic, scopolamine. Methods: Healthy participants (n=15) and unmedicated-depressed major depressive disorder patients (n=16) participated in a double-blind, placebo-controlled crossover infusion study using scopolamine (4 μg/kg). Before and following scopolamine, blood oxygen-level dependent signal was measured using functional MRI during a selective attention task. Two stimuli comprised of superimposed pictures of faces and houses were presented. Participants attended to one stimulus component and performed a matching task. Face emotion was modulated (happy/sad) creating implicit (attend-houses) and explicit (attend-faces) emotion processing conditions. The pretreatment difference in blood oxygen-level dependent response to happy and sad faces under implicit and explicit conditions (emotion processing biases) within a-priori regions of interest was correlated with subsequent treatment response in major depressive disorder. Results: Correlations were observed exclusively during implicit emotion processing in the regions of interest, which included the subgenual anterior cingulate (P<.02) and middle occipital cortices (P<.02). Conclusions: The magnitude and direction of differential blood oxygen-level– dependent response to implicitly processed emotional faces prior to treatment reflect the potential to respond to scopolamine. These findings replicate earlier results, highlighting the potential for pretreatment neural activity in the middle occipital cortices and subgenual anterior cingulate to inform us about the potential to respond clinically to scopolamine.

Amygdala response to explicit sad face stimuli at baseline predicts antidepressant treatment response to scopolamine in major depressive disorder

The muscarinic antagonist scopolamine produces rapid antidepressant effects in individuals with major depressive disorder (MDD). In healthy subjects, manipulation of acetyl-cholinergic transmission modulates attention in a stimulus-dependent manner. This study tested the hypothesis that baseline amygdalar activity in response to emotional stimuli correlates with antidepressant treatment response to scopolamine and could thus potentially predict treatment outcome. MDD patients and healthy controls performed an attention shifting task involving emotional faces while undergoing functional magnetic resonance imaging (fMRI). We found that blood oxygenation level dependent (BOLD) signal in the amygdala acquired while MDD patients processed sad face stimuli correlated positively with antidepressant response to scopolamine. Amygdalar response to sad faces in MDD patients who did not respond to scopolamine did not differ from that of healthy controls. This suggests that the pre-treatment task elicited amygdalar activity that may constitute a biomarker of antidepressant treatment response to scopolamine. Furthermore, in MDD patients who responded to scopolamine, we observed a post-scopolamine stimulus processing shift towards a pattern demonstrated by healthy controls, indicating a change in stimulus-dependent neural response potentially driven by attenuated cholinergic activity in the amygdala.

Cholinergic enhancement differentially modulates neural response to encoding during face identity and face location working memory tasks

Potentiation of cholinergic transmission influences stimulus processing by enhancing signal detection through suppression and/or filtering out of irrelevant information (bottom-up modulation) and with top-down task-oriented executive mechanisms based on the recruitment of prefrontal and parietal attentional systems. The cholinergic system also plays a critical role in working memory (WM) processes and preferentially modulates WM encoding, likely through stimulus-processing mechanisms. Previous research reported increased brain responses in visual extrastriate cortical regions during cholinergic enhancement in the encoding phase of WM, independently addressing object and spatial encoding. The current study used functional magnetic resonance imaging to determine the effects of cholinergic enhancement on encoding of key visual processing features. Subjects participated in two scanning sessions, one during an intravenous (i.v.) infusion of saline and the other during an infusion of the acetylcholinesterase inhibitor physostigmine. In each scan session, subjects alternated between a face identity recognition and a spatial location WM. Enhanced cholinergic function increased neural activity in the ventral stream during encoding of face identity and in the dorsal stream during encoding of face location. Conversely, a reduction in brain response was found for scrambled sensorimotor control images. The cholinergic effects on neural activity in the ventral stream during encoding of face identity were stronger than those observed in the dorsal stream during encoding of face location, likely as a consequence of the role of acetylcholine in establishing the inherently relevant nature of face identity. Despite the limited sample-size, the results suggest the stimulus-dependent role of cholinergic system in signal detection, as they show that cholinergic potentiation enhances neural activity in regions associated with early perceptual processing in a selective manner depending on the attended stimulus feature.