Semantic memory activation in individuals at risk for developing Alzheimer disease.

OBJECTIVE: To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE epsilon4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names. METHODS: Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no epsilon4 allele (control [CON]); 2) family history, no epsilon4 allele (FH); and 3) family history and epsilon4 allele (FH+epsilon4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). RESULTS: Cognitively intact older adults with AD risk factors (FH and FH+epsilon4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+epsilon4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. CONCLUSIONS: Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.

Semantic memory activation in amnestic mild cognitive impairment.

Cognitively intact older individuals at risk for developing Alzheimer's disease frequently show increased functional magnetic resonance imaging (fMRI) brain activation presumably associated with compensatory recruitment, whereas mild cognitive impairment (MCI) patients tend not to show increased activation presumably due to reduced neural reserve. Previous studies, however, have typically used episodic memory activation tasks, placing MCI participants at a performance disadvantage relative to healthy elders. In this event-related fMRI study, we employed a low effort, high accuracy semantic memory task to determine if increased activation of memory circuits is preserved in amnestic MCI when task performance is controlled. Fifty-seven participants, aged 65-85 years, comprised three groups (n = 19 each): amnestic MCI patients; cognitively intact older participants at risk for developing Alzheimer's disease based on having at least one ApoE epsilon4 allele and a positive family history of Alzheimer's disease (At Risk); and cognitively intact participants without Alzheimer's disease risk factors (Control). fMRI was conducted on a 3T MR scanner while participants performed a famous name discrimination task. Participants also underwent neuropsychological testing outside the scanner; whole brain and hippocampal atrophy were assessed from anatomical MRI scans. The three groups did not differ on demographic variables or on fame discrimination performance (>87% correct for all groups). As expected, the amnestic MCI participants demonstrated reduced episodic memory performance. Spatial extent of activation (Fame--Unfamiliar subtraction) differentiated the three groups (Control = 0 ml, At Risk = 9.7 ml, MCI = 34.7 ml). The MCI and At Risk groups showed significantly greater per cent signal change than Control participants in 8 of 14 functionally defined regions, including the medial temporal lobe, temporoparietal junction, and posterior cingulate/precuneus. MCI participants also showed greater activation than Controls in two frontal regions. At Risk, but not MCI, participants showed increased activity in the left hippocampal complex; MCI participants, however, evidenced increased activity in this region when hippocampal atrophy was controlled. When performance is equated, MCI patients demonstrate functional compensation in brain regions subserving semantic memory systems that generally equals or exceeds that observed in cognitively intact individuals at risk for Alzheimer's disease. This hyperactivation profile in MCI is even observed in the left hippocampal complex, but only when the extent of hippocampal atrophy is taken into consideration.

Intact physiological response to arousal with impaired emotional recognition in alexithymia.

BACKGROUND: The purpose of the present study was to clarify the relationship between the recognition of emotion and physiological response to emotion (i.e. arousal) in alexithymia. METHODS: This study investigated differences in physiological arousal state, as measured by continuous heart rate, electrodermal activity (EDA) and self-reported emotional intensity before and after exposure to an emotionally arousing or neutral videotape among 41 high- or low-alexithymic young adult participants. RESULTS: Across subjects, emotionally negative stimuli produced increased physiological arousal. However, high-alexithymic participants exposed to the arousing videotape did not report increased subjective emotional intensity, as did low-alexithymic participants. In addition, the baseline EDA of high-alexithymic participants was significantly higher than that of the low-alexithymic participants. CONCLUSIONS: Results support the prediction that alexithymia leads to a decoupling between subjective and physiological arousal when exposed to emotionally negative stimuli. This decoupling may increase alexithymic individuals' risks for stress-related illness.

Chronic propranolol induces deficits in retention but not acquisition performance in the water maze in mice.

Agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, reports suggest that beta-adrenergic receptor antagonists, such as propranolol, have conflicting behavioral effects with acute vs chronic dosing. This study was designed to evaluate the effects of chronic propranolol on retention for a spatial learning task. Adult male ICR mice were given daily injections of propranolol (2, 4, 8, or 12 mg/kg ip) or 0. 9% NaCl for 15 days prior to, and during, trials in a Morris water maze. Mice received five massed acquisition (escape) trials in each of three daily sessions, followed by a single 60-s probe trial on the fourth day. The location of the submerged platform was constant for each animal over acquisition trials, but varied across animals; starting position varied across trials. A 5 (dose) x 3 (trial blocks) mixed factorial ANOVA for escape time yielded a significant trial blocks effect only (p <.001), showing performance improving over sessions. Time spent in the target quadrant on the probe trial was shorter under all doses of propranolol when compared to vehicle group (all p <.001), indicating poorer retention of prior platform location. This effect, however, was not dose-related. Swim speed was not significantly affected by propranolol. These data demonstrate that chronic dosing with propranolol can impair retention of spatial learning, which cannot be attributed to reduced arousal or motor function.

Chronic administration of propranolol impairs inhibitory avoidance retention in mice.

Adrenergic systems are importantly involved in memory storage processes. As such, agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, the anxiety literature cautions that beta-adrenergic receptor antagonists, such as propranolol, may have different behavioral effects with acute vs chronic dosing. The effects of chronic propranolol specifically on memory modulation are unknown. This study was designed to evaluate the effects of chronic propranolol on retention for an aversive task, in which there is endogenous adrenergic activation. Adult male ICR mice were given daily injections of one of four doses of propranolol (2, 4, 8, and 12 mg/kg) or 0.9% NaCl vehicle for 15 days prior to, and continuing during, behavioral tests of exploration and retention. Exploratory behavior, as an index of anxiety level, was measured in a conventional elevated plus-maze, whereas retention of an aversive experience was measured in a step-through inhibitory avoidance apparatus. Sensitivity to aversive footshock was also evaluated. Compared to controls, propranolol-treated mice showed a dose-dependent decrease in retention for the inhibitory avoidance task, but no effect on anxiety on the plus-maze or on footshock sensitivity. Taken together with results from previous studies, it is apparent that propranolol can have different behavioral effects when administered acutely vs chronically, and its chronic effects significantly impair memory storage processes. Since these drugs are typically used chronically, and often in older adults, they could contribute to functional memory impairments.

Psychiatric complications of dementia: impact on caregivers.

This study was designed to determine the relationship between psychiatric features of dementia and their impact on caregivers. 35 patient-caregiver pairs were evaluated at two university-affiliated dementia clinics, using standard instruments to rate patient psychiatric features and caregiver burden and depression. There were highly significant correlations between patient agitation and both caregiver burden (r = 0.59, p = 0.0002) and depression (r = 61, p = 0.0001). These associations remained significant after adjusting for multiple demographic and dementia variables. There was no significant association between patient delusions, hallucinations, or depression and caregiver burden or depression. Agitation, particularly physical aggression, may impact caregivers even more than does the cognitive status of the demented patient.

The progression of beta-amyloid deposition in the frontal cortex of the aged canine.

Brains from 41 aged canines (> or = 10 years of age) were examined immunohistochemically to characterize the laminar distribution and age-related progression of beta-amyloid (A beta) in frontal cortex. We classified the A beta patterns into four distinct types. Type I was characterized by small, faint deposits of A beta in deep cortical layers. Type II consisted of diffuse deposits of A beta mainly in layers V and VI. Type III had both dense plaques in superficial layers, and diffuse deposits in deep layers. Finally, Type IV had solely dense plaques throughout all layers of cortex. We compared the A beta distribution pattern between the Old canines (10-15 years, n = 22) and the Very Old canines (> 15 years, n = 19). The Old group primarily had negative staining, or Type I and Type II patterns of amyloid deposition (73%). Conversely, the Very Old group had predominantly Types II, III and IV deposits (89.5%), a difference that was significant (P < 0.05). We suggest that A beta deposition in canine frontal cortex is a progressive age-related process beginning with diffuse deposits in the deep cortical layers followed by the development of deposits in outer layers. In support of this hypothesis, the deeper layer diffuse plaques in the Very Old group of dogs also contain the largest proportion of beta-amyloid with an isomerized aspartic acid residue at position 7, indicating that these deposits had been present for some time. We also observed fiber-like A beta immunoreactivity within regions of diffuse A beta deposits. These fibers appeared to be degenerating neurites, which were negative for hyperphosphorylated tau. Therefore, these fibers may represent a very early form of neuritic change that precede tau hyperphosphorylation or develop by an alternative pathway.

Constructional apraxia in Alzheimer's disease correlates with neuritic neuropathology in occipital cortex.

A variety of measures of neuropathology in Alzheimer's disease (AD) correlate with dementia severity. However, the role of beta-amyloid protein and abnormally phosphorylated tau protein in the decline of specific cognitive abilities is unknown. "Constructional praxis' (e.g., copying, constructing) is believed to require integrity of the parietal-occipital lobes. Unlike most other cognitive tasks, some AD patients are able to perform some constructional tasks even late in the disease course. Thus, it may be an ideal task to evaluate the relationship between various measures of AD neuropathology and cognitive performance. Fixed brain tissue was obtained from 16 AD patients who were cognitively assessed shortly before death. Parietal, frontal, entorhinal, and occipital cortices were examined by immunocytochemistry for beta-amyloid protein and abnormally phosphorylated tau protein at both early and later stages of neuropil thread and tangle formation. Constructional praxis in AD was strongly related to early-stage tau hyperphosphorylation in occipital cortex. Praxis ability was specific in that it was not significantly related to pathology in other areas and non-constructive tasks were not associated with occipital cortex pathology. In contrast, global dementia severity was related to beta-amyloid deposition in entorhinal, parietal, and frontal regions. These findings suggest that occipital cortex is critical for some constructional praxis tasks and that some regionally localizable tasks may be good indices of underlying pathology in corresponding brain regions.

Arousal-induced modulation of memory storage processes in humans.

We recently demonstrated in human subjects that muscle-tension-induced arousal can enhance later retention performance and that this effect is attenuated by beta-adrenergic receptor antagonists. In that study, each subject established a baseline for muscle tension by squeezing a hand dynamometer for 30 s with maximum force. This may have served to "prime" subsequent arousal produced by muscle tension. Two experiments were performed to address this issue. At the beginning of each experiment, young adult subjects were asked to squeeze the hand dynamometer at maximum effort either for 30 s (Prime) or for only 1 s (No prime). Then, during the task, arousal was induced by having each subject exert a moderate amount of tension (25 to 50% of baseline maximum). In the first experiment, subjects were shown four consecutive lists of 20 highly imageable nouns, given immediate recall tests of each, and then given a comprehensive recall and recognition test at the conclusion of the experiment. Moderate arousal was induced once for each list (at encoding, consolidation, or retrieval) or not at all for one list. The sequence of arousal induction was counterbalanced. Significant enhancement of delayed recall was seen in the 30-s group for those lists in which arousal was induced during the consolidation or retrieval period with no significant effects in the 1-s group. These results demonstrate that arousal can modulate memory consolidation when induced shortly after learning and that an initial priming event may affect the response to subsequent similar arousing events. In the second experiment, subjects read paragraphs, some of which contained highlighted words (working memory task); half of the subjects were given the 30-s procedure and half the 1-s procedure. Only those subjects in the 30-s group showed significant arousal-induced enhancement of delayed recognition of the highlighted words. Again, no significant effect on retention performance was seen in the group that squeezed the hand dynamometer for only 1 s during the priming period. Pulse data suggested that there may be somewhat greater heart-rate reactivity in the 30-s group. These findings suggest that memory modulation by arousal may be primed, or enhanced, by a relevant preliminary arousal event.

Apolipoprotein-E genotyping of diabetic dementia patients: is diabetes rare in Alzheimer's disease?

OBJECTIVES: To determine whether diabetes is rare in Alzheimer disease (AD) relative to other types of dementia and whether diabetics with dementia have a low frequency of the Apolipoprotein-E E4 genotype. DESIGN: Observational survey study. SETTING: An Irvine, California, outpatient dementia assessment center. PARTICIPANTS: A total of 123 patients with AD, 51 with vascular dementia, 57 with "mixed" vascular dementia and AD, and 34 with "other" dementias (non-vascular non-AD). MEASUREMENTS: Demographic data; histories and evidence of diabetes, hypertension, heart disease, stroke; and Apolipoprotein-E genotype for 95 cases distributed across the groups. RESULTS: There were 15 diabetics in the sample (5.7%), all of whom had extensive vascular disease. Diabetes was rare in AD patients (0.8%) relative to vascular dementia (11.8%), mixed vascular/AD dementia (8.8%), and "other" dementia patients (8.8%). In addition, the E4 allele of apolipoprotein-E, associated with high risk for AD, was frequent in the AD group (71.4%), but in the diabetic group it was only as frequent as in the general population (38.5%). In the diabetics with E4, 60% (3/5) had mixed dementia. CONCLUSIONS: Diabetics with dementia rarely have AD except as a component of mixed dementia. Apo-E genotyping showed only average E4 allele frequency in diabetics compared with the high E4 frequency found in AD patients. However, mixed dementia in diabetics may be associated with the E4 allele, suggesting that close control of diabetes may be particularly important for those with E4 since they may be more likely than others to develop both diseases.

Acquisition and long-term retention of a fine motor skill in Alzheimer's disease.

This study investigated the acquisition and long-term retention of the rotary pursuit task under varying amounts of practice in 12 moderate-to-severely demented AD patients and 12 healthy older adults. Equal numbers of AD and control subjects were randomly assigned to either 40, 80, or 120 trials of training (40 trials/day) on the rotary pursuit task, followed by 15-trial retention tests 20 min, 2 days, 7 days, and 37 days following the end of practice. Performance improved significantly in both groups during the first 40 trials, while additional practice provided no ensuing positive or negative effects. Further, subjects in both groups showed minimal forgetting across the four retention tests. Therefore, the results demonstrated that AD patients can effectively learn and retain a motor skill for at least 1 month.

Low-dose propranolol reduces aggression and agitation resembling that associated with orbitofrontal dysfunction in elderly demented patients.

Although several reports suggest that intermediate to high doses of propranolol (80-160 and 200-600 mg/day) can effectively treat aggressive behavior in dementia, significant side effects can occur at these doses. To minimize these side effects, we treated and followed-up a series of 12 demented patients, whose caregivers sought medical help for their disruptive, aggressive behavior, with low-dose propranolol monotherapy (10-80 mg/day). Assessment measures obtained at baseline and during treatment by caregiver interview included ordinal ratings of aggression severity, the Cohen-Mansfield Agitation Inventory (CMAI), and the California Behavior Questionnaire (CBQ). The aggression ratings showed that low-dose propranolol effectively reduced aggression in eight of 12 patients (67%) within 2 weeks of treatment and remained effective for the duration of follow-up (1 to 14 months). Subscales of the CMAI showed responders to have significant reductions in physical and verbal aggression/agitation and in pacing/wandering. These results suggest that low-dose propranolol should be further studied for treating aggression or agitation in demented patients.

Beta-adrenergic receptor antagonist antihypertensive medications impair arousal-induced modulation of working memory in elderly humans.

It is well-established that administration of moderate doses of the adrenal catecholamines epinephrine or norepinephrine shortly after training results in the enhancement of later retention performance in laboratory animals. These substances, released endogenously as a result of arousal, are thought to modulate memory processes by stimulating peripheral receptors that send neural messages to the brain, thus altering the memory storage process. The applicability of this hypothesis to the modulation of memory processes in humans was tested in this experiment by using elderly subjects who were chronically taking beta-receptor antagonist medications to control hypertension. A moderate level of muscle-tension-induced arousal was produced by having subjects squeeze a hand dynamometer during the initial storage and recall of highlighted words in short 200-word paragraphs. Twenty young normal individuals, 22 normotensive elderly subjects, 21 elderly subjects taking either calcium-channel blockers or angiotensin-converting enzyme inhibitors to control hypertension, and 21 elderly subjects taking beta-blocker antihypertensive medications served as subjects. The young subjects, normal elderly subjects, and those taking non-beta-blocker medications all showed enhanced long-term recognition performance as a result of the arousal manipulation. However, those subjects chronically taking beta-receptor-antagonist medications showed no enhancement of memory.