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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

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.

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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 activation in 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.

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.

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.

The Montreal Cognitive Assessment (MoCA) is a widely used screening test for evaluation of mild cognitive impairment (MCI), with a single cutoff for all ages. We examined whether it is associated with age in a sample of cognitively-intact elderly (CIE). The average MoCA score was negatively correlated with age and was significantly higher for younger than older CIE. Additionally, 42% of the older elderly fell below the proposed MCI cutoff score, although all subjects were CIE. Thus, cognitive abilities captured by the MoCA test decrease with age, even in CIE. Therefore, cutoff scores by age for the MoCA are needed.