Tarik Karakaya

Different Patterns of White Matter Degeneration Using Multiple Diffusion Indices and Volumetric Data in Mild Cognitive Impairment and Alzheimer Patients

Alzheimeŕs disease (AD) represents the most prevalent neurodegenerative disorder that causes cognitive decline in old age. In its early stages, AD is associated with microstructural abnormalities in white matter (WM). In the current study, multiple indices of diffusion tensor imaging (DTI) and brain volumetric measurements were employed to comprehensively investigate the landscape of AD pathology. The sample comprised 58 individuals including cognitively normal subjects (controls), amnestic mild cognitive impairment (MCI) and AD patients. Relative to controls, both MCI and AD subjects showed widespread changes of anisotropic fraction (FA) in the corpus callosum, cingulate and uncinate fasciculus. Mean diffusivity and radial changes were also observed in AD patients in comparison with controls. After controlling for the gray matter atrophy the number of regions of significantly lower FA in AD patients relative to controls was decreased; nonetheless, unique areas of microstructural damage remained, e.g., the corpus callosum and uncinate fasciculus. Despite sample size limitations, the current results suggest that a combination of secondary and primary degeneration occurrs in MCI and AD, although the secondary degeneration appears to have a more critical role during the stages of disease involving dementia.

Differential effects of the ApoE4 genotype on brain structure and function.

The apolipoprotein E ε4 allele is a well established genetic risk factor for sporadic Alzheimers disease. It is associated with structural and functional brain changes in healthy young, middle-aged and elderly subjects. In the current study, we assessed the impact of the ApoE genotype on brain macro- and microstructure, cognitive functioning and brain activity in fifty healthy young subjects (25 ApoE ε4 (ε4+) carriers and 25 non-carriers (ε4-), mean age 26.4±4.6years). We used diffusion tensor imaging (DTI) and voxel based morphometry (VBM) to assess brain structure, an extensive neuropsychological battery to test cognitive functioning and event-related functional magnetic resonance imaging (fMRI) to capture brain activity during episodic memory encoding and retrieval. ApoE ε4 carriers differed from non-carriers in fMRI activations but not in cognitive performance nor in brain micro- and macrostructure. These results suggest functional alterations in the episodic memory network that are modulated by the ε4 allele and might precede clinical or structural neurodegeneration.

Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer´s Disease

Mild cognitive impairment (MCI) is a syndrome which, depending on various neurobiological, psychological and social factors, carries a high risk of developing into dementia. As far as diagnostic uncertainty and the heterogeneous underlying pathophysiological mechanisms are concerned, only limited therapeutic options are currently available. Clinical trials involving a wide range of substances have failed to show efficacy on primary and secondary outcome parameters. Most results reflect not only a lack of effectiveness of drug therapy but also methodological constraints in true prodromal Alzheimer´s disease (AD) based on clinical criteria. Biomarkers may help to identify MCI as a prodromal phase of dementia, so it is important to use them to improve specificity of case selection in future studies. For MCI as a prodromal syndrome of AD, clinical trials with disease modifying drugs that target underlying pathological mechanisms such as amyloid-beta accumulation and neurofibrillary tangle formation may help develop effective treatment options in the future. Alternative pharmacological approaches are currently being evaluated in ongoing phase 1 and phase 2 studies. Nevertheless, a lack of approved pharmacotherapeutic options has led to specific interventions that focus on patient education and life-style related factors receiving increasing attention.

Treatment options for tauopathies.

Opinion statementTo date, there are no approved and established pharmacologic treatment options for tauopathies, a very heterogenous group of neuropsychiatric diseases often leading to dementia and clinically diagnosed as atypical Parkinson syndromes. Among these so-called Parkinson plus syndromes are progressive supranuclear palsy (PSP), also referred to as Steele-Richardson-Olszewski syndrome; frontotemporal dementia (FTD); and corticobasal degeneration (CBD). Available treatment strategies are based mainly on small clinical trials, miscellaneous case reports, or small case-controlled studies. The results of these studies and conclusions about the efficacy of the medication used are often contradictory. Approved therapeutic agents for Alzheimer´s dementia, such as acetylcholinesterase inhibitors and memantine, have been used off-label to treat cognitive and behavioral symptoms in tauopathies, but the outcome has not been consistent. Therapeutic agents for the symptomatic treatment of Parkinson’s disease (levodopa or dopamine agonists) are used for motor symptoms in tauopathies. For behavioral or psychopathological symptoms, treatment with antidepressants—especially selective serotonin reuptake inhibitors—could be helpful. Antipsychotics are often not well tolerated because of their adverse effects, which are pronounced in tauopathies; these drugs should be given very carefully because of an increased risk of cerebrovascular events. In addition to pharmacologic options, physical, occupational, or speech therapy can be applied to improve functional abilities. Each pharmacologic or nonpharmacologic intervention should be fitted to the specific symptoms of the individual patient, and decisions about the type and duration of treatment should be based on its efficacy for the individual and the patient’s tolerance. Currently, no effective treatment is available that targets the cause of these diseases. Current research focuses on targeting tau protein pathology, including pathologic aggregation or phosphorylation; these approaches seem to be very promising.

Association of microstructural white matter abnormalities with cognitive dysfunction in geriatric patients with major depression.

Major depression disorder (MDD) is one of the most common causes of disability in people over 60years of age. Previous studies have linked affective and cognitive symptoms of MDD to white matter (WM) disruption in limbic-cortical circuits. However, the relationship between clinical cognitive deficits and loss of integrity in particular WM tracts is poorly understood. Fractional anisotropy (FA) as a measure of WM integrity was investigated in 17 elderly MDD subjects in comparison with 18 age-matched controls using tract-based spatial statistics (TBSS) and correlated with clinical and cognitive parameters. MDD patients revealed significantly reduced FA in the right posterior cingulate cluster (PCC) compared with controls. FA in the right PCC (but not in the left PCC) showed a significant positive correlation with performance in a verbal naming task, and showed a non-significant trend toward a correlation with verbal fluency and episodic memory performance. In control subjects, no correlations were found between cognitive tasks and FA values either in the right or left PCC. Results provide additional evidence supporting the neuronal disconnection hypothesis in MDD and suggest that cognitive deficits are related to the loss of integrity in WM tracts associated with the disorder.

Verbal episodic memory deficits in remitted bipolar patients: A combined behavioural and fMRI study

BACKGROUND Episodic memory deficits affect the majority of patients with bipolar disorder (BD). AIMS The study investigates episodic memory performance through different approaches, including behavioural measures, physiological parameters, and the underlying functional activation patterns with functional neuroimaging (fMRI). METHODS 26 Remitted BD patients and a matched group of healthy controls underwent a verbal episodic memory test together with monitored autonomic response, psychopathological ratings and functional magnetic resonance imaging (fMRI) during the verbal episodic memory test. RESULTS Compared to healthy controls, BD patients performed significantly worse during the episodic memory task. The results further indicate that verbal episodic memory deficits in BD are associated with abnormal functional activity patterns in frontal, occipital and limbic regions, and an increase in stress parameters. LIMITATIONS We aimed to minimise sample heterogeneity by setting clear criteria for remission, based on the scores of a depression (BDI II) and mania scale (BRMAS) and on the DSM IV criteria. However, our patients were not symptom-free and scored higher on BDI II scores than the control group. CONCLUSIONS The results are of interest for the treatment of cognitive symptoms in BD patients, as persistent cognitive impairment may hamper full rehabilitation.

Recognition memory is associated with altered resting- state functional connectivity in people at genetic risk for Alzheimer's disease

The apolipoprotein E ε4 (ApoE ε4) allele not only represents the strongest single genetic risk factor for sporadic Alzheimers disease, but also imposes independent effects on brain function in healthy individuals where it has been shown to promote subtle memory deficits and altered intrinsic functional brain network connectivity. Based on previous work showing a potential relevance of the default mode network (DMN) functional connectivity for episodic memory function, we hypothesized that the ApoE ε4 genotype would affect memory performance via modulation of the DMN. We assessed 63 healthy individuals (50–80 years old), of which 20 carried the ε4 allele. All participants underwent resting‐state functional magnetic resonance imaging (fMRI), high‐resolution 3D anatomical MRI imaging and neuropsychological assessment. Functional connectivity analysis of resting‐state activity was performed with a predefined seed region located in the left posterior cingulate cortex (PCC), a core region of the DMN. ApoE ε4 carriers performed significantly poorer than non‐carriers in wordlist recognition and cued recall. Furthermore, ε4 carriers showed increased connectivity relative to ε4 non‐carriers between the PCC seed region and left‐hemispheric middle temporal gyrus (MTG). There was a positive correlation between recognition memory scores and resting‐state connectivity in the left MTG in ε4 carriers. These results can be interpreted as compensatory mechanisms strengthening the cross‐links between DMN core areas and cortical areas involved in memory processing.

Age-Related Effects of the Apolipoprotein E Gene on Brain Function

The apolipoprotein E (ApoE) ɛ4 allele is a well-established genetic risk factor for sporadic Alzheimers disease. Some evidence suggests a negative role of the ApoE ɛ4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age. We investigated age-related effects of the ApoE gene on brain function by assessing cognitive performance, as well as functional activation patterns during retrieval of Face-Name pairs in a group of young (n = 50; age 26.4±4.6 years, 25 ɛ4 carriers) and old (n = 40; age 66.1±7.0 years, 20 ɛ4 carriers) participants. A cross-sectional factorial design was used to examine the effects of age, ApoE genotype, and their interaction on both cognitive performance and the blood oxygenation level dependent (BOLD) brain response during retrieval of Face-Name pairs. While there were no genotype-related differences in cognitive performance, we found a significant interaction of age and ApoE genotype on task-related activation bilaterally in anterior cingulate gyrus and superior frontal gyrus, as well as left and right insula. Old age was associated with increased activity in ɛ4 carriers. The increased BOLD response in old ɛ4 carriers during retrieval could indicate a neurocognitive disadvantage associated with the ɛ4 allele with increasing age. Furthermore, recruitment of neuronal resources resulted in enhanced memory performance in young ɛ4 carriers, pointing to a better neurofunctional capacity associated with the ApoE4 genotype in young age.

Consolidation time affects performance and neural activity during visual working memory

We tested the effects of variation of stimulus onset asynchrony (SOA) on visual working memory (WM) performance across different load levels and the underlying brain activation patterns using functional magnetic resonance imaging (fMRI) in 48 healthy participants. Participants were instructed to memorise arrays of coloured squares and had to perform a match/non-match judgement on a probe stimulus after a jittered delay. We presented visual pattern masks at four SOAs after the offset of the memory array (100 ms, 200 ms, 400 ms, and 800 ms). Memory performance decreased with increased load and shortened SOA. Brain activation data showed significant effects of load (during encoding and retrieval), SOA (retrieval) and an interaction of load by SOA (encoding), mainly in frontal and parietal areas. There was also a direct relationship between successfully stored items and activation in the right inferior parietal lobule and the left middle frontal gyrus. The neurobehavioral results suggest that the frontal regions, together with the inferior parietal lobe, are associated with successful WM performance, especially under the most challenging conditions of high load and short SOAs.

Effects of age and apolipoprotein E genotype on memory function: An fMRI study

variance via linear regression (adjusted for age, gender, total intracranial volume, and CDR) were performed to study cross-sectional group differences.Results: The PS1 group showed significantly lower whole-brain volume than APP carriers, and a trend for lower cortical GM and thalamic volumes. By contrast, the APP carriers had significantly lower hippocampus to cortical GM ratio than PS1. Compared to non-carriers, the PS1 group had significantly lower whole-brain and thalamic volumes. Both carrier groups showed trends towards lower caudate volumes, but only the APP carriers towards lower putamen volumes than non-carriers. Figure 1 shows the groupaverage volumes and these results. Conclusions: The results suggest that there may be differences in regional atrophy patterns between PS1 and APP. The number of APP carriers included was relatively low, and it will be important to corroborate these findings with on-going recruitment to DIAN and with longitudinal studies. These observations will have important implications for upcoming FAD treatment trials and their choice of outcome measures.