Retinal peri-arteriolar versus peri-venular amyloidosis, hippocampal atrophy, and cognitive impairment: exploratory trial.

The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.

Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance.

Introduction: The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition. Methods: Using scanning laser ophthalmoscopy, we quantified retinal peri-arteriolar and peri-venular curcumin-positive APs in the first, secondary and tertiary branches in twenty-eight subjects. Perivascular AP burden among cognitive states was correlated with neuroimaging and cognitive measures. Results: Peri-arteriolar exceeded peri-venular AP count (p<0.0001). Secondary branch AP count was significantly higher in cognitively impaired (p<0.01). Secondary small and tertiary peri-venular AP count strongly correlated with clinical dementia rating, hippocampal volumes, and white matter hyperintensity count. Discussion: Our topographic analysis indicates greater retinal amyloid accumulation in the retinal peri-arteriolar regions overall, and distal peri-venular regions in cognitively impaired individuals. Larger longitudinal studies are warranted to understand the temporal-spatial relationship between vascular dysfunction and perivascular amyloid deposition in AD. Highlights: Retinal peri-arteriolar region exhibits more amyloid compared with peri-venular regions.Secondary retinal vascular branches have significantly higher perivascular amyloid burden in subjects with impaired cognition, consistent across sexes.Cognitively impaired individuals have significantly greater retinal peri-venular amyloid deposits in the distal small branches, that correlate with CDR and hippocampal volumes.

Cross-validation of RAVLT performance validity indicators and the RAVLT/RO discriminant function in a large known groups sample.

OBJECTIVE: To cross-validate RAVLT performance validity cut-offs and the RAVLT/RO discriminant function in a large neuropsychological sample. METHOD: RAVLT scores and the RAVLT/RO discriminant function were compared in credible (n = 100) and noncredible (n = 353) neuropsychology referrals. RESULTS: Noncredible patients scored lower than credible patients on RAVLT scores and the RAVLT/RO discriminant function. With cut-offs set to ≥90% specificity, highest sensitivities were observed for the discriminant function (cut-off ≤.064; 55.8%), recognition total (cut-off ≤9; 53.1%), the recognition combination score (≤10; 47.7%), and total learning across trials (cut-off ≤31; 45.3%). Individuals with histories of learning difficulties were over-represented in the 10% of credible patients exceeding cut-offs. When these individuals were removed, cut-offs could be tightened while still maintaining at least 90% specificity, and thereby increasing sensitivity (e.g., recognition total cut-off ≤10, 65% sensitivity; RAVLT/RO discriminant function cut-off ≤.176, 58% sensitivity). When three of the most sensitive, non-overlapping scores were considered in combination, 17% of credible patients failed ≥1 of the three cut-offs, while 3% failed two, and only 1% failed all three. In contrast, in the noncredible sample, more than two-thirds failed one or more of the three cut-offs, nearly half failed ≥2, and nearly a quarter failed all three. CONCLUSIONS: RAVLT PVT cut-offs and the RAVLT/RO discriminant function achieve approximately 50% sensitivity, and approach 65% sensitivity when cut-offs specific to samples without histories of learning problems are employed, confirming that RAVLT cut-offs and the RAVLT/RO discriminant function continue to be valuable techniques in the identification of performance invalidity.

Retinal Venular Tortuosity Jointly with Retinal Amyloid Burden Correlates with Verbal Memory Loss: A Pilot Study.

INTRODUCTION: Retinal imaging is a non-invasive tool to study both retinal vasculature and neurodegeneration. In this exploratory retinal curcumin-fluorescence imaging (RFI) study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status. METHODS: We used quantitative RFI in a cohort of patients with cognitive impairment to automatically compute retinal amyloid burden. Retinal blood vessels were segmented, and the vessel tortuosity index (VTI), inflection index, and branching angle were quantified. We assessed the correlations between retinal vascular and amyloid parameters, and cognitive domain Z-scores using linear regression models. RESULTS: Thirty-four subjects were enrolled and twenty-nine (55% female, mean age 64 ± 6 years) were included in the combined retinal amyloid and vascular analysis. Eleven subjects had normal cognition and 18 had impaired cognition. Retinal VTI was discriminated among cognitive scores. The combined proximal mid-periphery amyloid count and venous VTI index exhibited significant differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs. 0.91 ± 1.4, p = 0.006), and correlated with both the Wechsler Memory Scale-IV and SF-36 mental component score Z-scores (p < 0.05). CONCLUSION: This pilot study showed that retinal venular VTI combined with the proximal mid-periphery amyloid count could predict verbal memory loss. Future research is needed to finesse the clinical application of this retinal imaging-based technology.

Sectoral segmentation of retinal amyloid imaging in subjects with cognitive decline.

INTRODUCTION: Despite advances in imaging retinal amyloidosis, a quantitative and topographical investigation of retinal amyloid beta burden in patients with cognitive decline has never been reported. METHODS: We used the specific amyloid-binding fluorophore curcumin and laser ophthalmoscopy to assess retinal amyloid imaging (RAI) in 34 patients with cognitive decline. We automatically quantified retinal amyloid count (RAC) and area in the superotemporal retinal sub-regions and performed correlation analyses with cognitive and brain volumetric parameters. RESULTS: RAC significantly and inversely correlated with hippocampal volume (HV; r = -0.39, P = .04). The proximal mid-periphery (PMP) RAC and RA areas were significantly greater in patients with Montreal Cognitive Assessment (MOCA) score < 26 (P = .01; Cohen d = 0.83 and 0.81, respectively). PMP showed significantly more RAC and area in subjects with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to cognitively normal (P = .04; Cohen d = 0.83). CONCLUSION: Quantitative RAI is a feasible technique and PMP RAC may predict HV. Future larger studies should determine RAI's potential as a biomarker of early AD.

Meta-Analysis of Memory-Focused Training and Multidomain Interventions in Mild Cognitive Impairment.

BACKGROUND: Meta-analysis examining the efficacy of cognitive interventions on neuropsychological outcomes have suggested interventions that focus on memory may actually provide greater benefit against the cognitive declines associated with mild cognitive impairment (MCI). However, it remains unclear if memory-based training would be more effective at addressing the cognitive deficits associated with MCI than multidomain forms of intervention. OBJECTIVE: A meta-analytic review and subgroup analysis was conducted to examine the effects of cognitive training in individuals diagnosed with MCI and to compare the efficacy of memory-based training with multidomain interventions. METHODS: A total of 32 randomized controlled trials met inclusion criteria for the meta-analysis, which included 9 studies on memory-focused training and 17 studies on multidomain interventions. RESULTS: We found significant, large effects for memory-focused training (Hedges' g observed = 0.947; 95% CI [-1.668, 3.562]; Z = 2.517; p = 0.012) and significant, moderate effects for multidomain interventions (Hedges' g observed = 0.420; 95% CI [-0.4491, 1.2891]; Z = 3.525; p < 0.001). A subgroup analysis found significant point estimates for memory-based forms of training and multidomain interventions, with memory-based forms of content yielding significantly greater summary effects than multidomain interventions (SMD Z = 2.162; p = 0.031, two-tailed; all outcomes). There was no difference between effect sizes when comparing outcomes limited to its respective domain. CONCLUSION: Overall, these findings suggest that, while both interventions were beneficial, treatment interventions that were strictly memory-based were more effective at improving cognition in individuals diagnosed with MCI than interventions that targeted multiple cognitive domains.

The Efficacy of Cognitive Intervention in Mild Cognitive Impairment (MCI): a Meta-Analysis of Outcomes on Neuropsychological Measures.

Cognitive training in MCI may stimulate pre-existing neural reserves or recruit neural circuitry as "compensatory scaffolding" prompting neuroplastic reorganization to meet task demands (Reuter-Lorenz & Park, 2014). However, existing systematic reviews and meta-analytic studies exploring the benefits of cognitive interventions in MCI have been mixed. An updated examination regarding the efficacy of cognitive intervention in MCI is needed given improvements in adherence to MCI diagnostic criteria in subject selection, better defined interventions and strategies applied, increased use of neuropsychological measures pre- and post-intervention, as well as identification of moderator variables which may influence treatment. As such, this meta-analytic review was conducted to examine the efficacy of cognitive intervention in individuals diagnosed with mild cognitive impairment (MCI) versus MCI controls based on performance of neuropsychological outcome measures in randomized controlled trials (RCT). RCT studies published from January 1995 to June 2017 were obtained through source databases of MEDLINE-R, PubMed, Healthstar, Global Health, PSYCH-INFO, and Health and Psychological Instruments using search parameters for MCI diagnostic category (mild cognitive impairment, MCI, pre-Alzheimer's disease, early cognitive decline, early onset Alzheimer's disease, and preclinical Alzheimer's disease) and the intervention or training conducted (intervention, training, stimulation, rehabilitation, or treatment). Other inclusion and exclusion criteria included subject selection based on established MCI criteria, RCT design in an outpatient setting, MCI controls (active or passive), and outcomes based on objective neuropsychological measures. From the 1199 abstracts identified, 26 articles met inclusion criteria for the meta-analyses completed across eleven (11) countries; 92.31% of which have been published within the past 7 years. A series of meta-analyses were performed to examine the effects of cognitive intervention by cognitive domain, type of training, and intervention content (cognitive domain targeted). We found significant, moderate effects for multicomponent training (Hedges' g observed = 0.398; CI [0.164, 0.631]; Z = 3.337; p = 0.001; Q = 55.511; df = 15; p = 0.000; I 2 = 72.978%; τ 2 = 0.146) as well as multidomain-focused strategies (Hedges' g = 0.230; 95% CI [0.108, 0.352]; Z = 3.692; p < 0.001; Q = 12.713; df = 12; p = 0.390; I 2 = 5.612; τ 2 = 0.003). The effects for other interventions explored by cognitive domain, training type, or intervention content were indeterminate due to concerns for heterogeneity, bias, and small cell sizes. In addition, subgroup and meta-regression analyses were conducted with the moderators of MCI category, mode of intervention, training type, intervention content, program duration (total hours), type of control group (active or passive), post-intervention follow-up assessment period, and control for repeat administration. We found significant overall effects for intervention content with memory focused interventions appearing to be more effective than multidomain approaches. There was no evidence of an influence on outcomes for the other covariates examined. Overall, these findings suggest individuals with MCI who received multicomponent training or interventions targeting multiple domains (including lifestyle changes) were apt to display an improvement on outcome measures of cognition post-intervention. As such, multicomponent and multidomain forms of intervention may prompt recruitment of alternate neural processes as well as support primary networks to meet task demands simultaneously. In addition, interventions with memory and multidomain forms of content appear to be particularly helpful, with memory-based approaches possibly being more effective than multidomain methods. Other factors, such as program duration, appear to have less of an influence on intervention outcomes. Given this, although the creation of new primary network paths appears strained in MCI, interventions with memory-based or multidomain forms of content may facilitate partial activation of compensatory scaffolding and neuroplastic reorganization. The positive benefit of memory-based strategies may also reflect transfer effects indicative of compensatory network activation and the multiple-pathways involved in memory processes. Limitations of this review are similar to other meta-analysis in MCI, including a modest number studies, small sample sizes, multiple forms of interventions and types of training applied (some overlapping), and, while greatly improved in our view, a large diversity of instruments used to measure outcome. This is apt to have contributed to the presence of heterogeneity and publication bias precluding a more definitive determination of the outcomes observed.

The impact of inpatient rehabilitation on function and survival of newly diagnosed patients with glioblastoma.

OBJECTIVE: To examine the impact of an inpatient rehabilitation program on functional improvement and survival among patients with newly diagnosed glioblastoma multiforme (GBM) who underwent surgical resection of the brain tumor. DESIGN: A retrospective cohort study of newly diagnosed patients with GBM between 2003 and 2010, with survival data updated through January 23, 2013. SETTING: An urban academic nonprofit medical center that included acute medical and inpatient rehabilitation. PARTICIPANTS: Data for newly diagnosed patients with GBM were examined; of these patients, 100 underwent inpatient rehabilitation after resection, and 312 did not undergo inpatient rehabilitation. MAIN OUTCOME MEASUREMENTS: Overall functional improvement and survival time for patients who participated in the inpatient rehabilitation program. RESULTS: A total of 89 patients (93.7%) who underwent inpatient rehabilitation improved in functional status from admission to discharge, with the highest gain observed in mobility (96.8%), followed by self-care (88.4%), communication/social cognition (75.8%), and sphincter control (50.5%). The median overall survival among inpatient rehabilitation patients was 14.3 versus 17.9 months for patients who did not undergo inpatient rehabilitation (P = .03). However, after we adjusted for age, extent of resection, and Karnofsky Performance Status Scale scores, we found no statistical difference in the survival rate between patients who did and did not undergo inpatient rehabilitation (hazard ratio [HR], 0.84; P = .16). Among the patients who underwent inpatient rehabilitation, older age (HR, 2.24; P = .0006), a low degree of resection (HR, 1.67; P = .02), and lack of a Stupp regimen (HR, 1.71; P = .05) were associated with greater hazard of mortality. CONCLUSIONS: Patients who undergo inpatient rehabilitation demonstrate significant functional improvements, primarily in the mobility domain. Confounder adjusted multivariate analysis showed no survival difference between patients who did and did not undergo inpatient rehabilitation; this finding suggests that a structured inpatient rehabilitation program may level the survival field in lower-functioning patients who otherwise may be faced with a dismal prognosis.

Re-examination of a Rey auditory verbal learning test/Rey complex figure discriminant function to detect suspect effort.

Bernard (1990), and Bernard, Houston, and Natoli (1993) identified a discriminant function, derived from Rey figure recall score and RAVLT trial 1 and recognition, which discriminated simulators and controls with 77--85% accuracy. However, in the current study, application of the discriminant function to patients with suspect effort, brain injured patients, and controls, revealed excellent sensitivity (95%) but low specificity (33% for patients, 61% for controls). A new discriminant function using the same Rey figure and RAVLT scores, derived from actual patients with documented suspect effort and patients with confirmed brain injury, resulted in an overall classification of 85% correct, with only 16% of suspect effort and 15% of brain injured patients misidentified. Use of a discriminant function score of /=91%.