Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer. Herein, we aimed to characterize the molecular features of ...RSPOfp/RNF43 mutated (mut) compared with wild-type (WT) colorectal cancers to gain insights into potential rationales for therapeutic strategies.
A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and IHC. An independent cohort was used to validate our findings.
The discovery cohort consisted of 7,245 colorectal cancer samples. RSPOfp and RNF43 mutations were detected in 1.3% (n = 94) and 6.1% (n = 443) of cases. We found 5 RSPO fusion events that had not previously been reported (e.g., IFNGR1-RSPO3). RNF43-mut tumors were associated with right-sided primary tumors. No RSPOfp tumors had RNF43 mutations. In comparison with WT colorectal cancers, RSPOfp tumors were characterized by a higher frequency of BRAF, BMPR1A, and SMAD4 mutations. APC mutations were observed in only a minority of RSPOfp-positive compared with WT cases (4.4% vs. 81.4%). Regarding RNF43 mutations, a higher rate of KMT2D and BRAF mutations were detectable compared with WT samples. Although RNF43 mutations were associated with a microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) phenotype (64.3%), and a tumor mutation burden ≥10 mt/Mb (65.8%), RSPOfp was not associated with MSI-H/dMMR. The validation cohort replicated our genetic findings.
This is the largest series of RSPOfp/RNF43-mut colorectal cancers reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO/RNF43 and suggested potential alternative strategies to overcome the low clinical impact of Wnt-targeted agents and immunotherapy.
Neuropsychological research has been limited in the representation of cultural diversity due to various issues, raising questions regarding the applicability of findings to diverse populations. ...Nonetheless, culture-dependent differences in fundamental psychological processes have been demonstrated. One of the most basic of these, self-construal (individualism, collectivism), is central to how many other differences are interpreted. Self-construals may have possible consequences on social interactions, emotions, motivation, and cognition. This study aimed to evaluate the impact of self-construal on neurocognitive functions in older adults. A total of 86 community-dwelling older adults 60 years and older were assessed with three common self-report measures of self-construal along individualism and collectivism (IC). A cognitive battery was administered to assess verbal and non-verbal fluency abilities. Latent profile analysis (LPA) was used to categorize individuals according to IC, and one-way analyses of covariance (ANCOVA), including relevant covariates (e.g., ethnicity, gender, linguistic abilities), were used to compare neurocognitive functions between individualists and collectivists. Collectivists outperformed individualists on left frontally-mediated measures of verbal fluency (action, phonemic) after controlling for relevant covariates,
= 6.942,
= 0.010,
= 0.061. Groups did not differ on semantic fluency, non-verbal fluency, or attention/working memory (all
s > 0.05). These findings suggest a cognitive advantage in collectivists for verbal processing speed with an additional contribution of left frontal processes involved in lexicosemantic retrieval. Self-construal may provide a meaningful descriptor for diverse samples in neuropsychological research and may help explain other cross-cultural differences.
Introduction
Apolipoprotein E (APOE) interacts with Alzheimer's disease pathology to promote disease progression. We investigated the moderating effect of APOE on independent associations of amyloid ...and tau positron emission tomography (PET) with cognition.
Methods
For 297 nondemented older adults from the Alzheimer's Disease Neuroimaging Initiative, regression equations modeled associations between cognition and (1) cortical amyloid beta (Aβ) PET levels adjusting for tau and (2) medial temporal lobe (MTL) tau PET levels adjusting for Aβ, including interactions with APOE ε4‐carrier status.
Results
Adjusting for tau PET, Aβ was not associated with cognition and did not interact with APOE. In contrast, adjusting for Aβ PET, MTL tau was associated with all cognitive domains. Further, there was a stronger moderating effect of APOE on MTL tau and memory associations in ε4‐carriers, even among Aβ‐negative individuals.
Discussion
Findings suggest that APOE may interact with tau independently of Aβ and that elevated MTL tau confers negative cognitive consequences in Aβ‐negative ε4 carriers.
A delayed-match-to-sample for spatial location task was used to measure spatial pattern separation and working memory. On each trial, an object covered a baited food well in one of 15 spatial ...locations along a row of food wells perpendicular to the start box. Once the rat exited the start box, displaced the object to receive a food reward and then returned to the startbox, the same food well was then quickly re-baited, an identical object was positioned to cover the food well and another identical object was positioned in a different location along the row of food wells covering a different unbaited food well. On the ensuing choice phase, the animal was allowed to choose between the two objects. The object that covered the same food well as the object in the sample phase was the correct choice and the second foil object was the incorrect choice. Five spatial separations (15–105
cm) were randomly used to separate the correct object from the foil object during the choice phase. Once a preoperative criterion was met, each rat received bilateral intracranial infusions of either ibotenic acid or the vehicle into the CA3 subregion of the dorsal hippocampus. Following surgery, rats with CA3 lesions were significantly impaired relative to controls across all spatial separations suggesting that CA3 lesions impaired working memory. Although the dorsal CA3 subregion of the hippocampus may play a role in pattern separation, the data suggest that this region is critically involved in spatial working memory.
Our study examined age-related differences across the adult lifespan using a recently developed test assessing memory for "who, when, and where" in addition to associations among these elements. ...Young (ages 18-25), middle-aged (ages 40-55), and older adults (ages 60+) were asked to remember a sequence of pictures of different faces paired with different places and place the pairs in the correct sequence. Young adults remembered significantly mores face-place pairs in the correct sequence than middle-aged (p < .05) and older adults (p < .05), but there were no significant differences between middle-aged and older adults. Furthermore, young adults remembered significantly more face-place pairs irrespective of sequence than older adults (p < .05). However, there were no other significant differences among the groups.Using a rapidly administered test that integrates aspects of everyday episodic memory, we found evidence for age-related differences in test performance beginning in middle age.
Coaggregation is a process by which genetically distinct bacteria become attached to one another via specific molecules. Cumulative evidence suggests that such adhesion influences the development of ...complex multi-species biofilms. Once thought to occur exclusively between dental plaque bacteria, there are increasing reports of coaggregation between bacteria from other biofilm communities in several diverse habitats. A general role for coaggregation in the formation of multi-species biofilms is discussed.
The ε4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE ε4 exerts its negative impact on cognition is poorly ...understood. The present study aimed to determine whether APOE genotype (ε4+ vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness CT, volume Vo) on verbal memory performance.
Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4+, 76 ε4-) between the ages of 64 and 89 (mean age = 73).
Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT.
Findings suggest that older adult APOE ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.
•Effect of entorhinal blood flow on memory differs by APOE ε4 and cortical thickness.•Negative effect of entorhinal blood flow on memory in non-carriers with higher cortical thickness.•Positive effect of entorhinal blood flow on memory in non-carriers with lower cortical thickness.•Negative effect of entorhinal blood flow on memory in ε4 carriers with lower cortical thickness.
With the rising number of individuals in their 50s and 60s who are infected with HIV, concerns have emerged about possible increases in the rates of non-HIV-associated dementias. The current study ...examined the prevalence of mild cognitive impairment (MCI) in older HIV-infected adults, since MCI is an intermediate state between typical cognitive aging and dementia that emerges in this age range. Participants included 75 adults with HIV disease aged 50 years and older who were on combination antiretroviral therapy (cART) and had undetectable plasma viral loads and 80 demographically similar HIV-seronegative comparison subjects. Participants completed a research neuropsychological evaluation that was used to classify MCI according to the comprehensive diagnostic scheme described by Bondi et al. (J Alzheimers Dis 42:275–289, 2014). HIV-infected persons were over seven times more likely to have an MCI designation (16 %) than their seronegative counterparts (2.5 %). Within the HIV+ cohort, MCI had minimal overlap with diagnoses of asymptomatic neurocognitive impairment and was significantly associated with older age, lower Karnofsky Scale of Performance Scores, and mild difficulties performing instrumental activities of daily living (iADLs). HIV infection in older adults is associated with a notably elevated concurrent risk of MCI, which may increase the likelihood of developing non-HIV-associated dementias as this population ages further.
INTRODUCTIONHuntington's disease (HD) is a progressive neurodegenerative disorder with motor, cognitive, and psychiatric symptoms that typically manifest in middle adulthood. Balance assessments may ...be useful for predicting disease onset and progression, but studies are limited. We aimed to enhance estimates of HD onset using an inexpensive and practical body sway assessment device i.e., Wii Balance Board (WBB). METHODSWe assessed total body sway (TBS) on 64 HD gene carriers Presymptomatic HD (PsHD; n = 16); Prodromal HD (ProHD; n = 16); HD (n = 32) and 21 demographically similar normal controls (NC) employing a WBB and custom-designed laptop software. Participants completed balance test trials that included combinations of eyes open or closed while standing on a stable versus unstable surface. Non-parametric analyses were conducted to assess group differences in TBS conditions. RESULTSThe HD group had significantly higher TBS in most balance conditions relative to NC, PsHD, and ProHD groups (ps < .05). Importantly, the ProHD group demonstrated higher TBS relative to NC in all balance conditions (ps < .05) with medium to large effect size ranges (r≥ 0.40). No differences in TBS were exhibited between NC and PsHD groups (ps > .05). CONCLUSIONSIncreased body sway, easily evaluated using a brief, objective balance assessment, may serve as an important functional marker in patients with, and during the transition to, HD. Further studies are needed to confirm and extend these findings.
Although cohort effects on IQ measures have been investigated extensively, studies exploring cohort differences on verbal memory tests, and the extent to which they are influenced by ...socioenvironmental changes across decades (e.g. educational attainment; ethnic makeup), have been limited.
We examined differences in performance between the normative samples of the CVLT-II from 1999 and the CVLT3 from 2016 to 2017 on the immediate- and delayed-recall trials, and we explored the degree to which verbal learning and memory skills might be influenced by the cohort year in which norms were collected versus demographic factors (e.g. education level).
Multivariate analysis of variance tests and follow-up univariate tests yielded evidence for a negative cohort effect (also referred to as negative Flynn effect) on performance, controlling for demographic factors (p = .001). In particular, findings revealed evidence of a negative Flynn effect on the attention/working memory and learning trials (Trial 1, Trial 2, Trial 3, Trials 1-5 Total, List B; ps < .007), with no significant cohort differences found on the delayed-recall trials. As expected, education level, age group, and ethnicity were significant predictors of CVLT performance (ps < .01). Importantly, however, there were no interactions between cohort year of norms collection and education level, age group, or ethnicity on performance.
The clinical implications of the present findings for using word list learning and memory tests like the CVLT, and the potential role of socioenvironmental factors on the observed negative Flynn effect on the attention/working memory and learning trials, are discussed.
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