Markus Donix

Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism

People with the apolipoprotein-Eepsilon4 (APOE-4) genetic risk for Alzheimers disease show morphologic differences in medial temporal lobe regions when compared to non-carriers of the allele. Using a high-resolution MRI and cortical unfolding approach, our aim was to determine the rate of cortical thinning among medial temporal lobe subregions over the course of 2 years. We hypothesized that APOE-4 genetic risk would contribute to longitudinal cortical thickness change in the subiculum and entorhinal cortex, regions preferentially susceptible to Alzheimers disease related pathology. Thirty-two cognitively intact subjects, mean age 61 years, 16 APOE-4 carriers, 16 non-carriers, underwent baseline and follow-up MRI scans. Over this relatively brief interval, we found significantly greater cortical thinning in the subiculum and entorhinal cortex of APOE-4 carriers when compared to non-carriers of the allele. Average cortical thinning across all medial temporal lobe subregions combined was also significantly greater for APOE-4 carriers. This finding is consistent with the hypothesis that carrying the APOE-4 allele renders subjects at a higher risk for developing Alzheimers disease.

Family History of Alzheimer's Disease and Hippocampal Structure in Healthy People

OBJECTIVE Structural brain changes appear years before the onset of Alzheimers disease, the leading cause of dementia late in life. Determining risk factors for such presymptomatic brain changes may assist in identifying candidates for future prevention treatment trials. In addition to the e4 allele of the apolipoprotein E gene (APOE-4), the major known genetic risk factor, a family history of Alzheimers disease also increases the risk to develop the disease, reflecting yet unidentified genetic and, perhaps, nongenetic risks. The authors investigated the influence of APOE-4 genotype and family history risks on cortical thickness in medial temporal lobe subregions among volunteers without cognitive impairment. METHOD High-resolution magnetic resonance imaging (MRI) and a cortical unfolding method were performed on 26 subjects (APOE-4 carriers: N=13; noncarriers: N=13) with at least one first-degree relative with Alzheimers disease and 25 subjects (APOE-4 carriers: N=12; noncarriers: N=13) without this risk factor. All subjects (mean age: 62.3 years [SD=10.7]; range=38-86 years) were cognitively healthy. RESULTS Family history of Alzheimers disease and APOE-4 status were associated with a thinner cortex in the entorhinal region, subiculum, and adjacent medial temporal lobe subfields. Although these associations were additive, family history of Alzheimers disease explained a greater proportion of the unique variance in cortical thickness than APOE-4 carrier status. CONCLUSIONS APOE-4 carrier status and family history of Alzheimers disease are independently associated with and contribute additively to hippocampal cortical thinning.

Altered neural network supporting declarative long-term memory in mild cognitive impairment

Autobiographical episodic memory represents a subsystem of declarative long-term memory and largely depends on combining information from multiple sources. The purpose of this study was to assess neural correlates of declarative long-term memory in patients with amnestic mild cognitive impairment (MCI) and controls using fMRI and a task requiring autobiographical and semantic memory retrieval. Comparison of the network supporting episodic autobiographical and semantic memory irrespective of remoteness (recent and remote) revealed significant activations in right parietal cortex and precuneus bilaterally in the patients. Autobiographical episodic versus semantic memory retrieval in the controls led to significant bilateral activations of the parietal-temporal junction, left temporal pole, anterior cingulate, retrosplenial cortex and cerebellum. In contrast, MCI patients activated left supplementary motor area, left premotor and superior temporal cortex. In MCI patients compared to controls a dysfunction of the retrosplenial cortex during memory retrieval was revealed by a lack of differential activation in relation to recency of memories and memory type. Our data suggest that MCI leads to a loss of specificity in the neural network supporting declarative long-term memory.

Serotonin 1A and 2A receptor densities, neurochemical and behavioural characteristics in two closely related mice strains after long-term isolation

Knowledge about individual differences in behavioural traits and their neurostructural and neurochemical correlates should improve therapeutic approaches of corresponding psychopathology. The presented investigations are aimed to reveal interrelationships between central nervous serotonergic [5-HT] receptor densities and neurochemical as well as behavioural traits in two mice strains. Male AB-Halle [ABH] and AB-Gatersleben [ABG] mice differing in aggression were investigated after 6 weeks of isolation housing. 5-HT1A and 5-HT2A receptors were analysed in different brain regions by in vitro autoradiography. HPLC determinations of aminergic transmission in the cortex, hippocampus, striatum as well as in the raphe-region and radioimmunoassay determination of serum corticosterone were done before (basal condition) and after behavioural tests (challenge condition). Receptor autoradiography revealed higher 5-HT1A receptor densities, especially in limbic regions, and lower 5-HT2A receptor densities in the basal ganglia of ABH mice. Furthermore, ABH mice characterized as behaviourally more active in the open field and plus maze as well as more reactive and aggressive during the social interaction test showed lower basal 5-hydroxyindolacetic acid [5-HIAA] concentrations in the hippocampus, cortex and raphe-region as well as a different activation pattern in serotonergic, dopaminergic and noradrenergic brain systems after challenge in comparison to ABG mice. Additionally lower corticosterone concentrations were found in ABH mice. Lower basal serotonergic and striatal dopaminergic, but higher basal cortical dopaminergic metabolism in contrast to enhanced challenge-induced central nervous serotonergic and cortical dopaminergic reactivities are discussed to be crucial for an enhanced reactive behavioural trait, which could secondarily result in aggression-related behaviours, where higher 5-HT1A receptor and lower 5-HT2A receptor densities may be essential.

APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer's disease.

Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimers disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimers disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimers disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimers disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.

High-resolution 7t fmri of human hippocampal subfields during associative learning

Examining the function of individual human hippocampal subfields remains challenging because of their small sizes and convoluted structures. Previous human fMRI studies at 3 T have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, CA3, and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study, we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution fMRI scanning at 7 T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.

Family History and APOE-4 Genetic Risk in Alzheimer’s Disease

Identifying risk factors for Alzheimer’s disease, such as carrying the APOE-4 allele, and understanding their contributions to disease pathophysiology or clinical presentation is critical for establishing and improving diagnostic and therapeutic strategies. A first-degree family history of Alzheimer’s disease represents a composite risk factor, which reflects the influence of known and unknown susceptibility genes and perhaps non-genetic risks. There is emerging evidence that investigating family history risk associated effects may contribute to advances in Alzheimer’s disease research and ultimately clinical practice.

Overgenerality of Autobiographical Memory in People with Amnestic Mild Cognitive Impairment and Early Alzheimer's Disease

Episodic autobiographical memory (ABM) is important for social functioning. Loss of specificity in ABM retrieval has been observed in people with mild to moderate Alzheimers disease (AD). Our aim was to extend these findings to subjects with amnestic mild cognitive impairment (aMCI) and very early AD. We performed a cued ABM task with both subject groups and healthy elderly controls. Although aMCI participants performed better than early AD subjects both showed reduced specificity of ABM retrieval when compared with controls. We conclude that qualitative memory retrieval deficits could contribute to social functioning impairment in people with aMCI and early AD, and highlight the complexity of symptoms already present in early stages of cognitive impairment.

Effects of Physical Activity Training in Patients with Alzheimer’s Dementia: Results of a Pilot RCT Study

Background There is evidence that physical activity (PA) is of cognitive benefit to the ageing brain, but little is known on the effect in patients with Alzheimer’s disease (AD). The present pilot study assessed the effect of a home-based PA training on clinical symptoms, functional abilities, and caregiver burden after 12 and 24 weeks. Methods In an RCT thirty patients (aged 72.4±4.3 years) with AD (MMSE: 20.6±6.5 points) and their family caregivers were allocated to a home-based 12-week PA intervention program or the usual care group. The program changed between passive, motor-assisted or active resistive leg training and changes in direction on a movement trainer in order to combine physical and cognitive stimuli. Results Analysis of activities of daily living in the patients (ADCS ADL total score) revealed a significant group × time interaction effect (95% CI of the difference between both groups at T2: 5.01–10.51). The control group experienced decreases in ADL performance at week 12 and 24 whereas patients in the intervention group remained stable. Analyses of executive function and language ability revealed considerable effects for semantic word fluency with a group × time interaction (95% CI of the difference between both groups at T2: 0.18–4.02). Patients in the intervention group improved during the intervention and returned to initial performance at week 12 whereas the controls revealed continuous worsening. Analyses of reaction time, hand-eye quickness and attention revealed improvement only in the intervention group. Caregiver burden remained stable in the intervention group but worsened in the control group. Conclusions This study suggests that PA in a home-based setting might be an effective and intrinsically attractive way to promote PA training in AD and modulate caregiver burden. The results demonstrate transfer benefits to ADL, cognitive and physical skill in patients with AD. Trial Registration ClinicalTrials.gov NCT02196545

Reduced hippocampal CA2, CA3, and dentate gyrus activity in asymptomatic people at genetic risk for Alzheimer's disease

Previous functional magnetic resonance imaging (MRI) studies in healthy subjects with the apolipoprotein Eepsilon4 (APOE-4) genetic risk for Alzheimers disease have shown increased activation during memory task performance in broadly distributed cortical regions. These findings have been hypothesized to reflect compensatory recruitment of intact brain regions that presumably result from subtle neural dysfunction reflecting incipient disease. In this study, we used high-resolution functional MRI in APOE-4 carriers and non-carriers to measure activity in hippocampal subregions (CA fields 1, 2, 3; dentate gyrus [DG], and subiculum) and adjacent medial temporal lobe (parahippocampal and entorhinal) subregions. We found reduced left CA2, CA3, and dentate gyrus (CA23DG) activity in cognitively intact APOE-4 carriers. These results suggest that reduced neural activity in hippocampal subregions may underlie the compensatory increase in extrahippocampal activity in people with a genetic risk for Alzheimers disease prior to the onset of cognitive deficits.