Elissa L. Ash

The LRRK2 G2019S mutation as the cause of Parkinson’s disease in Ashkenazi Jews

Mutations in the leucine rich repeat kinase 2 gene (LRRK2) are recognized as the most common cause of genetic Parkinsonism to date. The G2019S mutation has been implicated as an important determinant of Parkinson’s disease (PD) in both Ashkenazi Jewish and North African Arab populations with carrier frequency of 29.7% among familial and 6% in sporadic Ashkenazi Jewish PD cases. PD patients with the G2019S mutation display similar clinical characteristics to patients with sporadic PD. While the function of the LRRK2 protein has yet to be fully determined, its distribution coincides with brain areas most affected by PD. The G2019S mutation is believed to be responsible for up-regulation of LRRK2 kinase activity, which may ultimately play a role in neuronal loss. The utility of LRRK2 G2019S screening in family members of Ashkenazi PD patients is discussed. LRRK2 G2019S mutation carriers without PD may be an ideal population for the study of possible neuroprotective strategies as they become available, and for furthering the understanding of the pathogenesis and long-term clinical outcomes of the disease.

How Attention Modulates Encoding of Dynamic Stimuli

When encoding a real-life, continuous stimulus, the same neural circuits support processing and integration of prior as well as new incoming information. This ongoing interplay is modulated by attention, and is evident in regions such as the prefrontal cortex section of the task positive network (TPN), and in the posterior cingulate cortex (PCC), a hub of the default mode network (DMN). Yet the exact nature of such modulation is still unclear. To investigate this issue, we utilized an fMRI task that employed movies as the encoded stimuli and manipulated attentional load via an easy or hard secondary task that was performed simultaneously with encoding. Results showed increased intersubject correlation (inter-SC) levels when encoding movies in a condition of high, as compared to low attentional load. This was evident in bilateral ventrolateral and dorsomedial prefrontal cortices and the dorsal PCC (dPCC). These regions became more attuned to the combination of the movie and the secondary task as the attentional demand of the latter increased. Activation analyses revealed that at higher load the prefrontal TPN regions were more activated, whereas the dPCC was more deactivated. Attentional load also influenced connectivity within and between the networks. At high load the dPCC was anti-correlated to the prefrontal regions, which were more functionally coherent amongst themselves. Finally and critically, greater inter-SC in the dPCC at high load during encoding predicted lower memory strength when that information was retrieved. This association between inter-SC levels and memory strength suggest that as attentional demands increased, the dPCC was more attuned to the secondary task at the expense of the encoded stimulus, thus weakening memory for the encoded stimulus. Together, our findings show that attentional load modulated the function of core TPN and DMN regions. Furthermore, the observed relationship between memory strength and the modulation of the dPCC points to this region as a key area involved in the manipulation of attentional load on memory function.

Schema benefit vs. proactive interference: Contradicting behavioral outcomes and coexisting neural patterns

Prior knowledge can either assist or hinder the ability to learn new information. These contradicting behavioral outcomes, referred to as schema benefit and proactive interference respectively, have been studied separately. Here we examined whether the known neural correlates of each process coexist, and how they are influenced by attentional loading and aging. To this end we used an fMRI task that affected both processes simultaneously by presenting pairs of related short movies in succession. The first movie of each pair provided context for the second movie, which could evoke schema benefit and/or proactive interference. Inclusion of an easy or hard secondary task performed during encoding of the movies, as well as testing both younger (22-35y) and older (65-79y) adults, allowed examining the effect of attentional load and older age on the neural patterns associated with context. Analyses focused on three predefined regions and examined how their inter-subject correlation (inter-SC) and functional connectivity (FC) with the hippocampi changed between the first and second movie. The results in the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) matched and expanded previous findings: higher inter-SC and lower FC were observed during the second compared to the first movie; yet the differentiation between the first and second movies in these regions was attenuated under high attentional load, pointing to dependency on attentional resources. Instead, at high load there was a significant context effect in the FC of the left ventrolateral prefrontal cortex (vlPFC), and greater FC in the second movie was related to greater proactive interference. Further, older adults showed context effect in the PCC and vlPFC. Intriguingly, older adults with inter-SC mPFC patterns similar to younger adults exhibited schema benefit in our task, while those with inter-SC PCC patterns similar to younger adults showed proactive interference in an independent task. The brain-behavior relationships corroborate the functional significance of these regions and indicate that the mPFC mainly contributes to schema benefit, while the left vlPFC and PCC contribute to proactive interference. Importantly, our findings show that the functions of the regions are retained throughout the lifespan and may predict the predominant behavioral outcome.

Altered Topology in Information Processing of a Narrated Story in Older Adults with Mild Cognitive Impairment

The ability to store, integrate, and manipulate information declines with aging. These changes occur earlier, faster, and to a greater degree as a result of neurodegeneration. One of the most common and early characteristics of cognitive decline is difficulty with comprehension of information. The neural mechanisms underlying this breakdown of information processing are poorly understood. Using functional MRI and natural stimuli (e.g., stories), we mapped the neural mechanisms by which the human brain accumulates and processes information with increasing duration and complexity in participants with amnestic mild cognitive impairment (aMCI) and healthy older adults. To explore the mechanisms of information processing, we measured the reliability of brain responses elicited by listening to different versions of a narrated story created by segmenting the story into words, sentences, and paragraphs and then scrambling the segments. Comparing healthy older adults and participants with aMCI revealed that in both groups, all types of stimuli similarly recruited primary auditory areas. However, prominent differences between groups were found at the level of processing long and complex stimuli. In healthy older adults, parietal and frontal regions demonstrated highly synchronized responses in both the paragraph and full story conditions, as has been previously reported in young adults. Participants with aMCI, however, exhibited a robust functional shift of long time scale processing to the pre- and post-central sulci. Our results suggest that participants with aMCI experienced a functional shift of higher order auditory information processing, possibly reflecting a functional response to concurrent or impending neuronal or synaptic loss. This observation might assist in understanding mechanisms of cognitive decline in aMCI.

TMS as a Tool for Examining Cognitive Processing

Transcranial magnetic stimulation (TMS) is a non-invasive method where an externally placed, rapidly changing magnetic field causes induction of weak electric currents that lead to changes in neuronal polarization and activity. TMS is a modality that has emerged as a unique tool in the study of functional neuroscience for several reasons. TMS can be used to selectively activate or inhibit specific cortical structures, leading to transient perturbations in their function. Systematic study of these perturbations has been employed to determine the function of specific cortical structures and to investigate structure-function relationships. These studies extend to the functional mapping of brain structures as well as brain networks. While TMS was first validated in studies of motor cortex function, it has been applied to the study of cognition and cognitive processing. “Virtual lesions” can be transiently induced in areas of eloquent cortex that allow for the evaluation of their function in cognition and behavior and can be used to evaluate the modes and hierarchy of control of these functions. When TMS is delivered in a repetitive fashion, long-term alterations of cortical function are induced which can be used to study functional brain plasticity, and the changes in brain plasticity in different cognitive states, including aging and diseases involving cognition. Furthermore, repetitive TMS strategies have been developed as possible modulators of cognitive function, with potential to serve as cognitive enhancers in both healthy and disease states. In this review, specific attention is given to the use of TMS in the evaluation of neurophysiologic changes in Alzheimer’s disease (AD), as well as the potential role of TMS as a cognitive enhancing therapy in AD.

Two Ethnic Clusters with Huntington Disease in Israel: The Case of Mountain Jews and Karaites

Background: Worldwide prevalence estimates of Huntington disease (HD) vary widely, with no reliable information regarding the Jewish population in Israel. Methods: This specialized tertiary single-center cross-sectional study assessed clinical, cognitive, and demographic characteristics of 84 HD patients who were treated at the Movement Disorder Unit of the Tel Aviv Medical Center, Israel. Results: Our cohort was composed of one-third Ashkenazi Jews, 27% Mountain Jews (Caucasus Jews), 18% Sephardi Jews, and 21% Karaites, with both Mountain Jews and Karaites over-represented compared to their relevant proportion in the population of the state of Israel, which is less than 1%. No between-group differences were detected regarding the number of CAG (cytosine-adenine-guanine) repeats, age at onset, disease duration, years from symptom onset to diagnosis, gender, years of education, Unified Huntington Disease Rating Scale scores, or the Montreal Cognitive Assessment scores. Conclusion: We detected clustering of HD among the population treated at our Medical Center, which has the only specialized HD clinic in the country, with a high percentage of HD among 2 relatively small subpopulations of Jews: Mountain Jews and Karaites.

BRAIN PLASTICITY FOLLOWING PHYSICAL TRAINING IN INDIVIDUALS WITH MILD COGNITIVE IMPAIRMENT: NEUROIMAGING STUDY

TIA. Cognitive functions weremeasured using theMontreal Cognitive Assessment (MoCA). Multiple linear regression analysis was conducted to explore the associations between leisure activity participation with WMH and the moderating effects of leisure activities upon relationship between WMH and MoCA (with respective activity x WMH volume interaction). Analyses were further stratified by low (<6 years) or high education ( 6 years). Effect of aerobic and non-aerobic physical activities was also compared. All models were adjusted with age, sex and years of education. Results:PA, but not IA, was negatively related to WMH volume (b1⁄43.45, p<.05). IA (b1⁄43.81, p<.001) contributed to the MoCA scores. Only IA, but not PA, has main effect towards MoCA score after stroke/TIA (b1⁄43.81, p<.001). Significant interaction with WMH volume was found for PA (b1⁄40.27, p<.01) but not with IA. Such interaction was found in the lower education group (b1⁄4.28, p<.01) but not in the higher education group. Conclusions: In patients with stroke or TIA, IA confers general cognitive benefits. Regular participation of PA negatively correlated with patients WMH volume and in patients with low education, cognitive benefits of PA increases with severity of WMH.