Age-Related Decline in Brain Resources Modulates Genetic Effects on Cognitive Functioning

Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words

Aging and functional reorganization of striatum- and Medial-Temporal Lobe-dependent memory systems

Bisherige Forschung hat zwischen zwei Gedächtnissystemen unterschieden: dem sog. deklarativen Gedächtnis (DG), welches sich durch die Fähigkeit vergangene Lebensereignisse bewusst zu erinnern auszeichnet und mit dem lobus temporalis medialis (MTL) in Verbindung steht, und dem prozeduralen Gedächtnis (PG), welches erlernte Fertigkeiten beinhaltet und mit dem Corpus striatum assoziiert ist. Weitere Studien haben ergeben, dass Alterung von neurologischen Schäden in beiden Systemen, erhöhter Aktivität im MTL und einer relativ geringeren Beeinträchtigung des PG begleitet ist. Hyperaktivität im MTL wurde dabei sowohl mit verbesserten als auch verschlechterten Gedächtnisleistungen in Verbindung gebracht. Die hier vorgelegte Dissertation befasst sich mit dem Einfluss von Alterung auf die Beziehungen zwischen o. g. Hirnnetzwerken und prozeduralen bzw. deklarativen Gedächtnisfähigkeiten. Studie I zeigte, dass Altersunterschiede in einer prozeduralen Gedächtnisaufgabe graduell im Verlaufe des Trainings entstehen und vmtl. mit negativen Einflüssen von Alterung auf den Übergang von PG zu DG in Zusammenhang stehen. Zwei striatal-dopaminerge genetische Polymorphismen, rs907094 auf DARPP-32 und VNTR auf DAT, wirkten sich dabei auf das DG älterer aber nicht jüngerer Erwachsener aus. In Studie II wurden Beeinträchtigungen im neuronalen Vorhersagefehler, einem neuronales Lernsignal im Striatum, in älteren Probanden gefunden. Studie III konnte teilweise intaktes PG in einer räumlichen Gedächtnisaufgabe demonstrieren, wobei der Polymorphismus rs17070145 auf WWC1, der sich auf Lanzeitpotenzierung im MTL auswirkt, diese Altersunterschiede modulierte. In Studie IV wurden neuronale Repräsentationen und Komputationen während einer räumlichen Gedächtnisaufgabe untersucht. Während jüngere Probanden in dieser Studie Anzeichen von MTL-basiertem DG zeigten, zeigten ältere Teilnehmer Evidenz von PG. Die neuronalen Signaturen älterer Erwachsener wurden jedoch am stärksten im MTL beobachtet.Previous research has distinguished between a declarative memory system that stores flexible representations and is subserved by the medial-temporal lobe (MTL) and a procedural memory system that expresses past experiences through skills and is based mainly on the striatum. Investigations into age-related changes in these memory systems indicated a complex pattern of neural degradation in both systems, elevated MTL activity as well as partially spared procedural memory functions in older adults. A literature review further suggests that MTL overactivity can be caused by factors which are either beneficial or detrimental for memory. The present dissertation investigated the effects of human aging on the relations of brain functions to declarative and procedural memory. In Study I, age differences in a procedural memory task gradually emerged over the course of training and were linked to negative effects of aging on the transition from procedural to declarative memory. In addition, this study showed that striatal dopaminergic genetic polymorphisms, rs907094 on DARPP-32 and VNTR on DAT, affected declarative knowledge in older but not younger adults. Study II indicated that prediction error signals in the human brain, a neural computation associated with striatal learning functions, were partially impaired in older adults. Study III demonstrated partially intact procedural memory in older adults in a spatial memory task, whereby age differences were modulated by a polymorphism influencing long-term potentiation in the MTL (rs17070145 on WWC1). Finally, Study IV showed hat that neural representations and computations subserving spatial memory qualitatively differed between younger and older adults. The performance and neural activation of younger adults showed unique properties of MTL-dependent declarative memory. Older adults, in contrast, showed behavioral and neural indications of procedural memory but the localization of the neural signatures peaked in the MTL

Individual Differences and Episodic Memory: Examining Behaviour, Genetics, and Brain Activity.

Dual-process models propose that two processes support recognition memory; familiarity, a general sense that something has been previously encountered; and recollection, the retrieval of details concerning the context in which a previous encounter occurred. Event-related potential (ERP) studies of recognition memory have identified a set of old/new effects that are thought to reflect these processes: the 300-500ms bilateral-frontal effect, thought to reflect familiarity and the 500-800ms left-parietal effect, thought to reflect recollection. Whilst the exact functional role of these effects remains unclear, they are widely viewed as reliable indices of retrieval. The ERP literature reviewed in this thesis suggests that the characteristics of these recognition effects vary with task specific details and individual participant differences, suggesting that the recognition effects purported to index retrieval may be conditional on both task and participant. This thesis examined the influence of individual differences on behavioural measures of recognition and the neural correlates of recognition memory, focusing on factors of stimulus material, task performance and participant genotype. Clear evidence of stimulus differences were found, with pictures eliciting more anteriorly distributed effects than words, and a late onsetting frontopolar old/new effect that was unique for voices. Furthermore, the pattern of ERP activity associated with successful recognition of faces appeared to vary as a function of general face recognition ability, with participants poorer at remembering faces exhibiting a 300-500ms old/new effect not present for those good at remembering faces. The data also suggested that activity over right-frontal electrodes, evident in some previous studies, may be participant specific and could reflect additional retrieval support processes. Contrary to expectations, behavioural task performance was not found to significantly modulate the ‘typical’ recognition memory effects. However, a number of genetic polymorphisms were found to significantly influence both behavioural scores and the pattern of ERP activity associated with recognition memory. These results therefore suggest that inherent participant differences influence the neural correlates of recognition memory, in a way that variations in task performance do not. Overall, the results from this thesis therefore suggest that the ‘typical’ bilateral-frontal and left-parietal effects thought to index retrieval are not universal. Furthermore the results suggest that the specific processes engaged during retrieval (as indexed by variations in ERP activity) may be dependent on specific task requirements, stimulus material and the genetic makeup of the individual

Structural and functional cerebral changes in patients with schizophrenia and genetic risk-allele carriers

Schizophrenia is one of the most frequent psychiatric disorders and is associated with a substantial part of worldwide disease burdon1. The clinical symptoms of patients with schizophrenia can be separated into positive symptoms such as halluciations and delusions as well as negative symptoms such as cognitive impairments, apathy, blunted affect and social withdrawal2. It has been suggested that understanding the underlying pathophysiological processes that give rise to these symptoms is a crucial step for the development of efficient treatment for schizophrenia3. In the presented work two aspects of the clinical symptomatology of schizophrenia are analyzed with respect to their potential neurobiological correlate. Following the dopamine-hypothesis, patients with schizophrenia exhibit an increase in dopaminergic neurotransmission in the striatum which might be related to the experience of positive symptoms4,5. In the first publication evidence for this dopamine-hypothesis from in-vivo neuroimaging studies was investigated in a comprehensive meta-analysis. Results are in the line with the dopamine-hypothesis and point to an increase of striatal presynaptic dopamine synthesis in schizophrenia: - Howes OD*, Kambeitz J*, Kim E, Stahl D, Slifstein M, Abi-Dargham A*, Kapur S* (2012): The nature of dopamine dysfunction in schizophrenia and what this means for treatment. Arch Gen Psychiatry 69: 776–786. * these authors contributed equally ISI Web of Knowledge: Archives of General Psychiatry (now: JAMA Psychiatry) impact factor 2012: 13.77 5-year impact factor 2012: 14.47 Ranked 3rd of all psychiatry journals The negative symptoms of schizophrenia such as cognitive impairments have frequently been associated with changes of cerebral gray matter in numerous brain regions including the hippocampus6–9. In the second publication, effects of a potential risk-gene on the hippocampus are analyzed. Results indicate reduced hippocampal structure and function in carriers of the met-allele of the BDNF polymorphism val(66)met: - Kambeitz JP*, Bhattacharyya S*, Kambeitz-Ilankovic LM, Valli I, Collier DA, McGuire P (2012): Effect of BDNF val(66)met polymorphism on declarative memory and its neural substrate: a meta-analysis. Neurosci Biobehav Rev 36: 2165–2177. * these authors contributed equally ISI Web of Knowledge: Neuroscience and Biobehavioral Reviews impact factor 2012: 9.44 5-year impact factor 2012: 9.92 Ranked 12th of all neurosciences journal

Monoaminergic and Neurotrophic Gene Variation Associated with Fronto-Limbic Circuitry affect Mood and Cognitive Recovery Post-TBI

Following traumatic brain injury (TBI), ~80% of individuals will experience cognitive deficits, and ~50% will experience post-TBI depression (PTD). Identifying individual risk patterns for these complications is important for preventive treatment and early intervention. In uninjured populations, individuals with depression have distinct accompanying cognitive deficits. Importantly, dysregulation of fronto-limbic regions may, in part, explain the co-occurrence of both depressive and cognitive symptoms. The work presented investigates biological factors that influence survival after severe TBI, and among survivors, the presence and severity of PTD and/or cognitive deficits. The scientific framework under which this work was completed proposes targeted interactions between monoaminergic and neurotrophic gene variation that may lead to cognitive deficits and depressive symptoms. In addition to cognition, serotonergic (5-HT) and dopaminergic (DA) signaling both contribute to depressed mood and anhedonia, suggesting genetic variation in their signaling pathways may modulate PTD risk. Brain-derived neurotrophic factor (BDNF), a ubiquitous neurotrophin involved in neuronal survival and synaptic plasticity, is implicated in depression and cognitive dysfunction, and BDNF interacts with 5-HT/DA signaling in mood and cognitive processes. The work presented examines monoaminergic-neurotrophic biomarkers for predicting PTD risk and cognitive deficits. Serum and cerebrospinal fluid (CSF) BDNF levels, and fronto-limbic atrophy, were examined as possible biomarkers of PTD and cognitive deficits. A battery of targeted genes were examined for their proposed roles in survival, depression, cognition, and/or modulation of fronto-limbic connectivity. The data show variation within monoaminergic genes was associated with PTD incidence (serotonin transporter, 5-HTTLPR) and cognitive deficits post-TBI (dopamine D2 receptor, DRD2 and COMT). When investigating BDNF associations with PTD, we discovered that variation in BDNF interacts with MONOAMINERGIC AND NEUROTROPHIC GENE VARIATION ASSOCIATED WITH FRONTO-LIMBIC CIRCUITRY AFFECT MOOD AND COGNITIVE RECOVERY POST-TBI Michelle D. Failla, PhD University of Pittsburgh, 2014 v age to influence TBI survival, and acute BDNF levels were consistent biomarkers for TBI survival. Among TBI survivors, acute BDNF levels were associated with chronic cognitive performance and depressive symptoms severity, suggesting early neurotrophic support may facilitate chronic recovery. Investigating fronto-limbic regional brain volumes identified significant relationships to PTD and suggested non-uniform fronto-limbic atrophy patterns that may explain PTD susceptibility. Overall, this work supports that monoaminergic-neurotrophin genetic variability affects individual risk for PTD and related cognitive deficits, possibly through relationships with fronto-limbic circuitry