Katharina Henke

Antibodies against β-Amyloid Slow Cognitive Decline in Alzheimer's Disease

To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimers disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimers disease.

A model for memory systems based on processing modes rather than consciousness

Prominent models of human long-term memory distinguish between memory systems on the basis of whether learning and retrieval occur consciously or unconsciously. Episodic memory formation requires the rapid encoding of associations between different aspects of an event which, according to these models, depends on the hippocampus and on consciousness. However, recent evidence indicates that the hippocampus mediates rapid associative learning with and without consciousness in humans and animals, for long-term and short-term retention. Consciousness seems to be a poor criterion for differentiating between declarative (or explicit) and nondeclarative (or implicit) types of memory. A new model is therefore required in which memory systems are distinguished based on the processing operations involved rather than by consciousness.

Human hippocampus establishes associations in memory

Studies of amnesia have demonstrated that the hippocampus is necessary for long‐term memory, but its precise role in memory is unknown. We designed a positron emission tomography experiment with tailored encoding and retrieval tasks that permitted the isolation of different mnemonic functions theorized to be mediated by the hippocampus. These functions included encoding single items, establishing interitem associations, novelty detection, and retrieving recently formed associations. Of these, we found hippocampal and parahippocampal activation only during associative learning. Our results indicate that the hippocampal formation may be particularly involved in the establishment of associations among components of an episode in memory. Hippocampus 7:249–256, 1997. © 1997 Wiley‐Liss, Inc.

Glucocorticoid-induced impairment of declarative memory retrieval is associated with reduced blood flow in the medial temporal lobe

Previous work indicates that stress levels of circulating glucocorticoids can impair retrieval of declarative memory in human subjects. Several studies have reported that declarative memory retrieval relies on the medial temporal lobe. The present study used \mathrm{H}^{15}_{2}O‐positron emission tomography to investigate whether acutely elevated glucocorticoid levels affect regional cerebral blood flow in the medial temporal lobe, as well as in other brain regions, during declarative memory retrieval in healthy male human subjects. When measured over four different declarative memory retrieval tasks, a single, stress‐level dose of cortisone (25 mg) administered orally 1 h before retention testing, induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, the left visual cortex and the cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval. Cortisone administration also significantly impaired cued recall of word pairs learned 24 h earlier, while drug effects on performance in the other tasks (verbal recognition, semantic generation and categorization) were not significant. The present results provide further evidence that acutely elevated glucocorticoid levels can impair declarative memory retrieval processes and suggest that such impairments may be related to a disturbance of medial temporal lobe function.

A functional genetic variation of the 5-HT2a receptor affects human memory

Human memory capacity is highly variable across individuals and is influenced by both genetic and environmental factors. A roughly 50% heritability estimate indicates that naturally occurring genetic variations have an important impact on this cognitive ability. Therefore, we investigated a functional variation of a memory-related serotonin receptor in 349 healthy young volunteers, and found 21% poorer memory performance in subjects with the rare variant.

Implicit associative learning engages the hippocampus and interacts with explicit associative learning.

The hippocampus is crucial for conscious, explicit memory, but whether it is also involved in nonconscious, implicit memory is uncertain. We investigated with functional magnetic resonance imaging whether implicit learning engages the hippocampus and interacts with subsequent explicit learning. The presentation of subliminal faces-written profession pairs for implicit learning was followed by the explicit learning of supraliminal pairs composed of the same faces combined with written professions semantically incongruous to those presented subliminally (experiment 1), semantically congruous professions (experiment 2), or identical professions (experiment 3). We found that implicit face-profession learning interacted with explicit face-profession learning in all experiments, impairing the explicit retrieval of the associations. Hippocampal activity increased during the subliminal presentation of face-profession pairs versus face-nonword pairs and correlated with the later impairment of explicit retrieval. These findings suggest that implicit semantic associative learning engages the hippocampus and influences explicit memory.

Nonconscious formation and reactivation of semantic associations by way of the medial temporal lobe

A successful strategy to memorize unrelated items is to associate them semantically. This learning method is typical for declarative memory and depends on the medial temporal lobe (MTL). Yet, only a small fraction of perceived items emerge into conscious awareness and receive the status of representations in declarative memory. This functional magnetic resonance imaging (fMRI) study tackled the mnemonic fate of unrelated item pairs processed without conscious awareness. Stimuli consisted of a face and a written profession (experimental condition) or of a face (control condition) exposed very briefly between pattern masks. Although the participants were unaware of the stimuli, activity in the hippocampus and perirhinal cortex was changed in the experimental versus the control condition; perirhinal activity changes correlated with the reaction time measure of the later nonconscious retrieval. For retrieval, the previously presented faces were shown again, this time for conscious inspection. The task was to guess the professional category of each face. This task was to induce a nonconscious retrieval of previously formed face-profession associations. Remarkably, activity in the hippocampus and perirhinal cortex was enhanced when subjects were confronted with faces from the experimental versus the control condition. The degree of hippocampal and perirhinal activation changes correlated with the reaction time measure of nonconscious retrieval. Together, our findings suggest that new semantic associations can be formed and retrieved by way of the medial temporal lobe without awareness of the associations or its components at encoding or any awareness that one is remembering at retrieval.

Memory-related hippocampal dysfunction in poly-drug ecstasy (3,4-methylenedioxymethamphetamine) users

Rationale3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is neurotoxic in animal studies and its use has been associated with cognitive impairments in humans.ObjectiveTo study hippocampal activation during the retrieval from episodic memory in polyvalent users of ecstasy.MethodsTwelve polyvalent ecstasy users and twelve matched controls were examined by means of functional magnetic resonance imaging (fMRI) while they retrieved face-profession associations from episodic memory.ResultsEcstasy users had a normal structural MRI scan without focal brain lesions or anatomical abnormalities. They exhibited equal retrieval accuracy during memory retrieval to that of the matched controls. Yet, their retrieval-related activity was lower and more spatially restricted in the left anterior hippocampus than that of the controls.ConclusionsThese results provide evidence for abnormal hippocampal functioning in MDMA users even at the presence of normal memory performance. This finding may be linked to MDMA-induced neurotoxicity and suggests that diminished hippocampal activation during memory retrieval might be a more sensitive or earlier index of MDMA-related neurotoxicity than neuropsychological performance.

Sensitivity-encoded (SENSE) echo planar fMRI at 3T in the medial temporal lobe

Parallel imaging techniques are useful for fMRI studies in light of the increasing susceptibility effects at high magnetic field strength. Yet, spatially varying noise amplification constitutes a challenge for the application of these techniques. The medial temporal lobe is particularly vulnerable to susceptibility effect with increasingly strong signal reduction. We present two fMRI studies comparing SENSE single-shot (ssh) echo planar imaging (EPI) at acceleration factors of 2.0, 2.4, 2.7, and 3.0 with conventional sshEPI at TE of 22 and 35 ms. Data were acquired during a learning task which activates the medial temporal lobe bilaterally. Susceptibility related image distortion was markedly reduced with increasing SENSE acceleration. Moreover, in the group results, statistical power increased in the whole brain with SENSE compared to conventional imaging and with a TE of 35 ms compared to 22 ms. Higher SENSE acceleration factors further improved image quality and increased statistical power in the occipital lobe and fusiform gyrus, but not in the medial temporal lobe. We therefore conclude that an sshEPI acquisition protocol with a moderate SENSE acceleration factor of R = 2.0 and TE 35 ms is suitable for the detection of medial temporal activation at 3T.

Memory Lost and Regained Following Bilateral Hippocampal Damage

We present a longitudinal neuropsychological study (31 examinations over a period of 18 months) of patient DF. DF demonstrated bilateral atrophy of the hippocampal formation and globus pallidus resulting from carbon monoxide poisoning. Eighteen months after the event, the volume of the hippocampal formation was reduced by 42 on the left side and 28 on the right. The patient initially presented with a severe global amnesia. Then, he showed a gradual, yet selective recovery of episodic memory function. Verbal free recall and spatial memory performance remained reduced, whereas immediate word recall and recognition memory, as well as picture learning and memory, improved to levels at the lower range of normal performance. Interestingly, nonspatial associative learning was never much impaired and recovered completely by the end of testing. These data are taken as evidence that the human hippocampal formation does not equally support different forms of episodic memory.