Maximal aerobic capacity is associated with hippocampal cognitive reserve in older adults with amnestic mild cognitive impairment.

Maximal aerobic capacity (MAC) has been associated with preserved neural tissue or brain maintenance (BM) in healthy older adults, including the hippocampus. Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease. While aMCI is characterized by hippocampal deterioration, the MAC-hippocampal relationship in these patients is not well understood. In contrast to healthy individuals, neurocognitive protective effects in neurodegenerative populations have been associated with mechanisms of cognitive reserve (CR) altering the neuropathology-cognition relationship. We investigated the MAC-hippocampal relationship in aMCI (n = 29) from the perspectives of BM and CR mechanistic models with structural MRI and a memory fMRI paradigm using both group-level (higher-fit patients vs. lower-fit patients) and individual level (continuous correlation) approaches. While MAC was associated with smaller hippocampal volume, contradicting the BM model, higher-fit patients demonstrated statistically significant lower correlation between hippocampal volume and memory performance compared with the lower-fit patients, supporting the model of CR. In addition, while there was no difference in brain activity between the groups during low cognitive demand (encoding of familiar stimuli), higher MAC level was associated with increased cortical and sub-cortical activation during increased cognitive demand (encoding of novel stimuli) and also with bilateral hippocampal activity even when controlling for hippocampal volume, suggesting for an independent effect of MAC. Our results suggest that MAC may be associated with hippocampal-related cognitive reserve in aMCI through altering the relationship between hippocampal-related structural deterioration and cognitive function. In addition, MAC was found to be associated with increased capacity to recruit neural resources during increased cognitive demands.

Can the RAVLT predict deterioration from MCI to dementia? Data from long term follow up.

OBJECTIVE: To assess whether the Rey Auditory Verbal Learning Test (RAVLT) could differentiate deterioration from Mild Cognitive Impairment (MCI) to dementia. METHODS: Twenty-six participants who were diagnosed with MCI performed the RAVLT and the Mini Mental State Examination (MMSE) at baseline and after nearly a decade (M = 8.8 years, SD = 3.16), in order to evaluate whether they progressed to dementia. RESULTS: Twelve participants [5 males, 7 females; age M = 63.7 (7.7)] kept their diagnoses of MCI; 14 participants [11 males, 3 females; age M = 75.0 (6.5)] converted to dementia. Both groups had similar MMSE scores at baseline [26.6 (0.6); and 26.6 (0.7) respectively]. Significant differences between dementia and MCI groups were found on most measures of the RAVLT at baseline: Immediate memory [p = .04], delayed recall [p = .003], total learning [p = .01], learning rate [p = .002], retrieval efficiency [p = .004], and false alarms [p = .004]. Thus, the RAVLT results were significantly worse at baseline in those who later converted. The results remain the same when controlling for age. CONCLUSION: The results extend previous findings with follow-up of nearly a decade demonstrating that most of the RAVLT measures are sensitive to differentiate conversion from MCI to dementia.

Is the Cutoff of the MoCA too High? Longitudinal Data From Highly Educated Older Adults.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is widely used to evaluate cognitive decline in older individuals. Although, age and education-related norms have been published, the vast majority of diagnostic clinicians use the MoCA cutoff score to identify patients with cognitive impairment. AIM: To identify whether the MoCA cutoff is too stringent for cognitively normal older adults. METHODS: Twenty-seven participants aged 68 to 83 (mean = 75.07, standard deviation [SD] = 4.62), with high education level (mean = 17.14 years, SD = 3.21) underwent cognitive assessment once a year for 5 consecutive years. The cognitive assessment included MoCA; Rey Auditory Verbal Learning Test; Rey Osterrieth Complex Figure test; Wechsler Adult Intelligence Scale Information and Digit Span Subtest; Trail Making Test; Verbal Fluency Test; and Beck Depression Inventory questionnaire. Repeated measures analysis of variance (ANOVA) was used to analyze all standardized scores as well as MoCA standardized and raw scores across all years. RESULTS: Repeated-measures ANOVA for MoCA raw scores yielded significant decline across the years (P < .05). From the second year and forward, the average MoCA total score was below the cutoff of 26/30. However, in substantial contrast, all other neuropsychological scores and the MoCA standardized scores were within the normal range and even above in all years. CONCLUSION: Our study demonstrates that the currently used MoCA cutoff is too high even for highly educated, cognitively normal older adults. Therefore, it is crucial to use the age- and education-related norms for the MoCA in order to avoid misdiagnosis of cognitive decline.

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.

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.

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.

Clinical Features of Idiopathic Normal Pressure Hydrocephalus: Critical Review of Objective Findings.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the classic clinical triad of gait, cognitive, and urinary dysfunction, albeit incomplete in a relevant proportion of patients. The clinical findings and evolution of these symptoms have been variably defined in the literature. Objectives: To evaluate how the phenomenology has been defined, assessed, and reported, we performed a critical review of the existing literature discussing the phenomenology of iNPH. The review also identified the instrumental tests most frequently used and the evolution of clinical and radiologic findings. Methods: The review was divided into 3 sections based on gait, cognitive, and urinary dysfunction. Each section performed a literature search using the terms "idiopathic normal pressure hydrocephalus" (iNPH), with additional search terms used by each section separately. The number of articles screened, duplicates, those meeting the inclusion criteria, and the number of articles excluded were recorded. Findings were subsequently tallied and analyzed. Results: A total of 1716 articles with the aforementioned search criteria were identified by the 3 groups. A total of 81 full-text articles were reviewed after the elimination of duplicates, articles that did not discuss phenomenological findings or instrumental testing of participants with iNPH prior to surgery, and articles with fewer than 10 participants. Conclusions: "Wide-based gait" was the most common gait dysfunction identified. Cognitive testing varied significantly across articles, and ultimately a specific cognitive profile was not identified. Urodynamic testing found detrusor overactivity and "overactive bladder" as the most common symptom of urinary dysfunction.

A functional magnetic resonance imaging investigation of prefrontal cortex deep transcranial magnetic stimulation efficacy in adults with attention deficit/hyperactive disorder: A double blind, randomized clinical trial.

ADHD is one of the most prevalent neurocognitive disorders. Deep Transcranial Magnetic Stimulation (dTMS) is a non-invasive neuromodulation tool that holds promise in treatment of neurocognitive disorders. Hypoactivity of the prefrontal cortex (PFC) has been observed in ADHD. This study examined the clinical, cognitive, and neural effects of dTMS to the PFC in adults with ADHD by using functional magnetic resonance imaging (fMRI). High frequency repetitive dTMS was applied to either the right or left PFC in 62 adults with ADHD in a randomized, double blind, placebo controlled protocol with 3 study groups: 2 treatment arms (rPFC, or lPFC) and a Sham arm. The study included 15 dTMS/cognitive training treatment sessions. Clinical effects were assessed with the Conners Adult ADHD Rating Scale (CAARS) self-report and the Clinical Global Impression score (CGI) as primary outcome measures. Self-report/observer questionnaires and computerized cognitive testing were also performed to assess clinical and cognitive effects. Neural effects were assessed with fMRI using working-memory (WM) and resting-state paradigms. While the study did not show improvement in the primary endpoints, significant improvements were observed in the CAARS (self-report) inattention/memory sub-scale, as well as increased activations in the rDLPFC, right parietal-cortex and right insula/IFG during WM conditions after treatment in the right stimulation group. Increased rDLPFC activation was associated with larger symptom improvement in the right stimulation group. This study indicates that dTMS is effective in modulating attention related brain networks, and is a feasible technique that may improve attention symptoms in adults with ADHD.

Neurocognitive Plasticity Is Associated with Cardiorespiratory Fitness Following Physical Exercise in Older Adults with Amnestic Mild Cognitive Impairment.

BACKGROUND: Aerobic training has been shown to promote structural and functional neurocognitive plasticity in cognitively intact older adults. However, little is known about the neuroplastic potential of aerobic exercise in individuals at risk of Alzheimer's disease (AD) and dementia. OBJECTIVE: We aimed to explore the effect of aerobic exercise intervention and cardiorespiratory fitness improvement on brain and cognitive functions in older adults with amnestic mild cognitive impairment (aMCI). METHODS: 27 participants with aMCI were randomized to either aerobic training (n = 13) or balance and toning (BAT) control group (n = 14) for a 16-week intervention. Pre- and post-assessments included functional MRI experiments of brain activation during associative memory encoding and neural synchronization during complex information processing, cognitive evaluation using neuropsychological tests, and cardiorespiratory fitness assessment. RESULTS: The aerobic group demonstrated increased frontal activity during memory encoding and increased neural synchronization in higher-order cognitive regions such as the frontal cortex and temporo-parietal junction (TPJ) following the intervention. In contrast, the BAT control group demonstrated decreased brain activity during memory encoding, primarily in occipital, temporal, and parietal areas. Increases in cardiorespiratory fitness were associated with increases in brain activationin both the left inferior frontal and precentral gyri. Furthermore, changes in cardiorespiratory fitness were also correlated with changes in performance on several neuropsychological tests. CONCLUSION: Aerobic exercise training may result in functional plasticity of high-order cognitive areas, especially, frontal regions, among older adults at risk of AD and dementia. Furthermore, cardiorespiratory fitness may be an important mediating factor of the observed changes in neurocognitive functions.

WAIS Information Subtest as an indicator of crystallized cognitive abilities and brain reserve among highly educated older adults: A three-year longitudinal study.

The Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) Information Subtest (IS) is known as a neuropsychological "Hold" test that is relatively resistant to decline with aging. We administered neuropsychological tests among highly educated healthy older adults once a year for three subsequent years. Results showed highly stable performances on the IS across years (Mean Z score: T0 = 1.39, SD = 0.60; T1 = 1.37, SD = 0.77; T2 = 1.50, SD = 0.66; T3 = 1.48, SD = 0.66), that were significantly higher than zero (T0: t = 12.08; T1: t = 9.29; T2: t = 11.71; T3: t = 11.68; for all, p < 0.0001). In contrast, other neuropsychological tests showed differences in performance across time; some performances significantly declined (Rey Osterrieth Complex Figure test-copy, Rey-Auditory Verbal Learning Test, and Montreal Cognitive Assessment test [MoCA]), whereas others were improved, possibly due to practice effects (Rey Osterrieth Complex Figure test- delayed, Rey-Auditory Verbal Learning Test- delayed, and Trail Making Test- part A). Correlation with whole brain volumetric analysis revealed a positive correlation between gray matter volumes and IS scores (r = 0.46, p < 0.05) even when controlling for age and education (partial correlations: r = 0.43; r = 0.45, for both p < 0.05). No significant correlations were found between gray matter and other test scores. Therefore, the WAIS-III Information subtest appears to be an adequate neuropsychological measurement of crystallized ability in highly educated older adults and may be considered as a proxy measure of brain reserve.

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.

Differences in Semantic Memory Encoding Strategies in Young, Healthy Old and MCI Patients.

Associative processes, such as the encoding of associations between words in a list, can enhance episodic memory performance and are thought to deteriorate with age. Here, we examine the nature of age-related deficits in the encoding of associations, by using a free recall paradigm with visual arrays of objects. Fifty-five participants (26 young students; 20 cognitive healthy older adults; nine patients with Mild Cognitive Impairment, MCI) were shown multiple slides (experimental trials), each containing an array of nine common objects for recall. Most of the arrays contained three objects from three semantic categories, each. In the remaining arrays, the nine objects were unrelated. Eye fixations were also monitored during the viewing of the arrays, in a subset of the participants. While for young participants the immediate recall was higher for the semantically related arrays, this effect was diminished in healthy elderly and totally absent in MCI patients. Furthermore, only in the young group did the sequence of eye fixations show a semantic scanning pattern during encoding, even when the related objects were non- adjacent in the array. Healthy elderly and MCI patients were not influenced by the semantic relatedness of items during the array encoding, to the same extent as young subjects, as observed by a lack of (or reduced) semantic scanning. The results support a version of the encoding of the association aging-deficit hypothesis.

Changes in Resting-State Functional Connectivity of the Hippocampus Following Cognitive Effort Predict Memory Decline at Older Age-A Longitudinal fMRI Study.

Memory decline is a feature of some, but not all, healthy older adults. The neural patterns of this variability are still largely unknown. We examined the resting-state functional connectivity (RSFC) of older and younger adults before and after cognitive effort as an underlying feature for subsequent memory changes, focusing on the RSFC between the left anterior hippocampus (laHC) and the posterior hippocampi (pHC). Results showed that for younger adults, post-effort increases in laHC-pHC RSFC were related to increases in RSFC between the laHC and the hubs of the default mode network (DMN). However, for older adults, post-effort increases in the RSFC of laHC-pHC were related to decreases in the RSFC of the laHC and right precentral gyrus. Thus, the correlation between intra-HC and inter-HC RSFC was altered with cognitive effort and aging. Importantly, older adults who had lower post-effort RSFC between the laHC and the pHC demonstrated a decline in episodic memory 2 years later. Hence, the change in intra-HC RSFC following cognitive effort was able to predict subsequent memory function with aging in our sample.

How attention modulates encoding of dynamic stimuli in older adults.

Aging is marked by memory decline that is exacerbated with attentional loading. Portraying older adults' neural functions when encoding information in conditions of high and low attentional load is a necessary step toward understanding this phenomenon. Furthermore, the information gained may be used to devise strategies aimed to prevent age-related decline in memory. To address this issue, a group of older adults underwent fMRI scanning while encoding short movies under two levels of attentional loading. High attentional load was associated with increased inter-subject correlation (inter-SC) in only a subset of prefrontal regions that were previously identified in younger adults. It was also associated with lower inter-SC in task-relevant visual regions, suggesting that as load increased, visual processing became less synchronized across participants. Critically, while we have shown that inter-SC in the dorsal posterior cingulate cortex (dPCC) was increased for younger adults at high load, older adults did not generally show this effect. However, those older adults who did display this pattern also displayed a 'younger-like' memory profile. These results point to a pivotal role of the dPCC in the interplay between attention and memory across the lifespan.

Neural patterns underlying the effect of negative distractors on working memory in older adults.

Working memory (WM) declines with age. Older adults, however, perform similar to younger adults in WM tasks with negative distractors at low WM load. To clarify the neural basis of this phenomenon, older (n = 28) and younger (n = 24) adults performed an emotional n-back task during an fMRI scan, and activity in task-related regions was examined. Comparing negative with neutral distraction at low WM load, older adults demonstrated shorter reaction times (RT) and reduced activation in frontoparietal regions: bilateral middle frontal gyrus (MFG) and left parietal cortex. They also had greater coherence within the frontoparietal network, as well as greater deactivation of the ventromedial prefrontal cortex and the amygdala. These patterns probably contributed to the older adults' diminished distractibility by negative task-irrelevant stimuli. Since recruitment of control mechanisms was less required, the frontoparietal network was less activated and performance was improved. Faster RT during the negative condition was related to lesser activation of the MFG in both age groups, corroborating the functional significance of this region to WM across the lifespan.

A "dose" effect of mutations in the GBA gene on Parkinson's disease phenotype.

OBJECTIVE: Mutations in the GBA gene are associated with Parkinson's disease (PD). A definite description of the clinical characteristics of PD patients who are compound heterozygotes or homozygotes for mutations in the GBA gene (GD-PD) requires further elucidation. METHODS: We assessed motor, cognitive, olfactory and autonomic functions as well as demographic data and medical history in a cohort of Ashkenazi Jewish PD patients who were screened for seven common mutations in the GBA gene. We then compared three groups of patients (matched for age and disease duration) who were distinguished by their GBA mutation status, idiopathic PD (iPD), GBA heterozygote PD (GBA-PD) and GD-PD. RESULTS: Out of a total of 1050 AJ PD patients screened, 12 were found to be either homozygotes or compound heterozygotes for mutations in the GBA gene. These patients had an earlier age of onset, more severe motor impairment, poorer cognition and lower olfactory scores. They also had a higher prevalence of REM sleep behavior disorder and higher frequencies of hallucinations compared to both GBA-PD and iPD. CONCLUSIONS: The severity of PD phenotype is related to the burden of GBA mutations with GD-PD patients manifesting a more severe phenotype.

Sensitivity of Neuropsychological Tests to Identify Cognitive Decline in Highly Educated Elderly Individuals: 12 Months Follow up.

Highly educated individuals have a lower risk of developing dementia and Alzheimer's disease (AD). A common assumption is that their "cognitive reserve" protects them from cognitive decline and postpones the clinical manifestation of dementia. These highly educated individuals usually obtain normal scores on cognitive screening tests, although at the same time they can experience subjective cognitive decline and difficulty in multiple cognitive domains. Although comprehensive neuropsychological evaluations usually identify subtle changes in cognition, they demand extensive resources and thus are expensive and difficult to obtain. Therefore, lack of sensitivity of screening tests on the one hand, along with difficulty to acquire a comprehensive neuropsychological evaluation on the other hand, impede identification of cognitive decline at its earliest stages in this special population. Accordingly, this study aims to identify which neuropsychological tests have the highest sensitivity to detect the earliest stages of cognitive decline among highly educated elderly [n = 27, ages 66-80 (mean = 72.6 SD = 4.54), mean education level = 17.14 (SD = 3.21 range: 12-24 years)]. Baseline scores and scores at one-year follow up were obtained. We also conducted MRI scans to characterize the relation between brain volume and cognitive performance. Results show significant reductions in RVALT, Semantic verbal Fluency, ROCF copy, and MoCA scores whereas PF, TMT, ROCF delay, digit span, and knowledge tests were not significant. The study stresses the importance of using sensitive neuropsychological tests to examine this special population and the need to create norms that combine an individual's education with age.

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.

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.

High Frequency of GBA Gene Mutations in Dementia With Lewy Bodies Among Ashkenazi Jews.

IMPORTANCE: Mutations in the glucocerebrosidase (GBA) gene are a risk factor for the development of dementia with Lewy bodies (DLB). These mutations are common among Ashkenazi Jews (AJ) and appear to have an effect on the natural history of the disease. OBJECTIVES: To evaluate the clinical and genetic characteristics of an AJ cohort of patients diagnosed with DLB, assess the association of phenotype of DLB with GBA mutations, and explore the effects of these mutations on the clinical course of the disease. DESIGN, SETTING, AND PARTICIPANTS: Thirty-five consecutively recruited AJ patients with newly diagnosed clinically probable or possible DLB underwent genotyping for the 7 known AJ GBA mutations and the LRRK2 G2019S mutation. Two patients with the LRRK2 G2019S mutation were excluded from the final analysis. Data were collected from July 1, 2013, to July 31, 2015. MAIN OUTCOMES AND MEASURES: Assessment of clinical markers included the following standardized scales: Autonomic Scale for Outcomes in Parkinson's Disease (SCOPA-AUT), REM (Rapid Eye Movement) Sleep Behavior Disorder Single-Question Screen, Geriatric Depression Scale, and Montreal Cognitive Assessment. Motor symptoms were assessed with the Unified Parkinson's Disease Rating Scale motor part III. A subset of 15 patients also underwent assessment with the Color Trail Making Test, FAS verbal fluency, Digit Span, Hooper Visual Organization Test, and Stroop test. RESULTS: Among the 35 patients with DLB (23 men [66%] and 12 women [34%]; mean [SD], 69.6 [8.2] years), 11 (31%) were carriers of mutations in the GBA gene. Among the 33 patients undergoing further analysis, the GBA mutation carriers were younger at symptom onset (mean [SD] age, 65.7 [11.7] vs 72.1 [5.1] years; P = .03), had more frequent visual hallucinations that did not achieve significance (9 of 11 [82%] compared with 12 of 22 [55%]; P = .052), and had higher scores on the RBD questionnaire (mean [SD], 7.8 [2.2] vs 5.1 [3.3]; P = .03). After adjusting for age and duration of symptoms, testing revealed that GBA mutation carriers had poorer cognition as assessed by the Montreal Cognitive Assessment Battery (mean [SD] score, 18.75 [5.99] vs 23.23 [3.16]; P = .03), lower scores on tests of verbal fluency (adjusted z scores, 0.50 vs -2.02; P = .02), worse scores on tests of visuospatial function (adjusted t scores, 68.55 vs 79.57; P = .046), and higher mean (SD) scores on the Unified Parkinson's Disease Rating Scale motor part III (36.72 [10.62] vs 25.72 [10.32]; P = .03). CONCLUSIONS AND RELEVANCE: One in 3 AJ patients diagnosed with DLB were carriers of a GBA mutation, making it the most common genetic mutation identified in association with this disease and with any dementia disorder. Mutations in the GBA gene were associated with more severe motor and cognitive dysfunction, supporting a specific contribution of the GBA gene or lysosome function to this clinical syndrome.