The retinal ganglion cell layer reflects neurodegenerative changes in cognitively unimpaired individuals.

BACKGROUND: To evaluate a wide range of optical coherence tomography (OCT) parameters for possible application as a screening tool for cognitively healthy individuals at risk of Alzheimer's disease (AD), assessing the potential relationship with established cerebrospinal fluid (CSF) core AD biomarkers and magnetic resonance imaging (MRI). METHODS: We studied 99 participants from the Valdecilla Study for Memory and Brain Aging. This is a prospective cohort for multimodal biomarker discovery and validation that includes participants older than 55 years without dementia. Participants received a comprehensive neuropsychological battery and underwent structural 3-T brain MRI, lumbar puncture for CSF biomarkers (phosphorylated-181-Tau (pTau), total Tau (tTau), beta-amyloid 1-42 (Aß 1-42), and beta-amyloid 1-40 (Aß 1-40)). All individuals underwent OCT to measure the retinal ganglion cell layer (GCL), the retinal nerve fiber layer (RFNL), the Bruch's membrane opening-minimum rim width (BMO-MRW), and choroidal thickness (CT). In the first stage, we performed a univariate analysis, using Student's t-test. In the second stage, we performed a multivariate analysis including only those OCT parameters that discriminated at a nominal level, between positive/negative biomarkers in stage 1. RESULTS: We found significant differences between the OCT measurements of pTau- and tTau-positive individuals compared with those who were negative for these markers, most notably that the GCL and the RNFL were thinner in the former. In stage 2, our dependent variables were the quantitative values of CSF markers and the hippocampal volume. The Aß 1-42/40 ratio did not show a significant correlation with OCT measurements while the associations between pTau and tTau with GCL were statistically significant, especially in the temporal region of the macula. Besides, the multivariate analysis showed a significant correlation between hippocampal volume with GCL and RNFL. However, after false discovery rate correction, only the associations with hippocampal volume remained significant. CONCLUSIONS: We found a significant correlation between Tau (pTau) and neurodegeneration biomarkers (tTau and hippocampus volume) with GCL degeneration and, to a lesser degree, with damage in RFNL. OCT analysis constitutes a non-invasive and unexpensive biomarker that allows the detection of neurodegeneration in cognitively asymptomatic individuals.

Sleep Time Estimated by an Actigraphy Watch Correlates With CSF Tau in Cognitively Unimpaired Elders: The Modulatory Role of APOE.

There is increasing evidence of the relationship between sleep and neurodegeneration, but this knowledge is not incorporated into clinical practice yet. We aimed to test whether a basic sleep parameter, as total sleep estimated by actigraphy for 1 week, was a valid predictor of CSF Alzheimer's Disease core biomarkers (amyloid-ß-42 and -40, phosphorylated-tau-181, and total-tau) in elderly individuals, considering possible confounders and effect modifiers, particularly the APOE ε4 allele. One hundred and twenty-seven cognitively unimpaired volunteers enrolled in the Valdecilla Study for Memory and Brain Aging participated in this study. Seventy percent of the participants were women with a mean age of 65.5 years. After adjustment for covariates, reduced sleep time significantly predicted higher t-tau and p-tau. This association was mainly due to the APOE ε4 carriers. Our findings suggest that total sleep time, estimated by an actigraphy watch, is an early biomarker of tau pathology and that APOE modulates this relationship. The main limitation of this study is the limited validation of the actigraphy technology used. Sleep monitoring with wearables may be a useful and inexpensive screening test to detect early neurodegenerative changes.

Major Surgery Affects Memory in Individuals with Cerebral Amyloid-ß Pathology.

BACKGROUND: Major surgery has been associated with perioperative neurocognitive disorders (PND), but the contributing factors and long-term prognosis are uncertain. We hypothesize that preclinical Alzheimer's disease (AD) might predispose to cognitive deterioration after surgery. OBJECTIVE: To analyze the effect of amyloid-ß on the cognitive trajectory after orthopedic surgery in a sample of non-demented subjects. METHODS: Non-demented individuals older than 65 years that were on the waiting list for orthopedic surgery with spinal anesthesia underwent a neuropsychological assessment before and after surgery. During surgery, cerebrospinal fluid samples were obtained to determine AD biomarkers. RESULTS: Cumulative incidence of PND was 55.2%during a mean follow-up of nine months. The most affected cognitive domains were executive function and constructional praxis. The presence of abnormal levels of amyloid-ß was associated to a postoperative impairment in verbal and visual memory tests. According to their AD biomarker profile, participants were categorized as either Amyloid Positive (A+) or Amyloid Negative (A-). The incidence of PND did not differ between both groups. The A- group showed a tendency similar to the global sample, worsening in executive function tests and improving on memory scales due to practice effects. In contrast, the A + group showed a notable worsening on memory performance. CONCLUSION: Our findings support the hypothesis that surgery may promote or accelerate memory decline in cognitively asymptomatic subjects with brain amyloid-ß deposits.

Evaluation of choroidal thickness in prodromal Alzheimer's disease defined by amyloid PET.

OBJECTIVE: To assess and compare the involvement of choroidal thickness (CT) in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) defined by amyloid PET and healthy controls (HC). METHODS: Sixty-three eyes from 34 AD patients [12 eyes (19.0%) with dementia and 51 eyes (80.9%) with MCI], positive to 11C-labelled Pittsburgh Compound-B with positron emission tomography (11C-PiB PET/CT), and the same number of sex- and age-paired HC were recruited. All participants underwent enhanced depth imaging optical coherence tomography (EDI-OCT) assessing CT at 14 measurements from 2 B-scans. Paired Student t-test was used to compare CT measurements between MCI, dementia and sex- and age-paired HC. A univariate generalized estimating equations model (GEE) test was performed to compare MCI and dementia individually with all HC included. RESULTS: Compared with HC, eyes from patients with positive 11C-PiB PET/CT showed a significant CT thinning in 5 selected locations (in foveal thickness in vertical scan, in temporal scan at 1500µm, in superior scan at 500µm and in inferior scan at 1000µm and 1500µm, p = 0.020-0.045) whilst few significant CT reduction data was reported in MCI or dementia individually versus HC. However, the GEE test identified significant CT thinning in AD compared with all HC included (p = 0.015-0.046). CONCLUSIONS: To our knowledge, the present study is the first measuring CT in eyes from MCI and dementia eyes positive to 11C-PiB PET/CT reporting a significant trend towards CT thinning in MCI patients which became more pronounced in dementia stage. We support further investigation involving larger and prospective OCT studies in AD population characterized with available biomarkers to describe whether choroidal vascular damage occurs specifically in prodromal stages of AD.

A snake that bites its own tail. Acquisition and loss of concepts in children and semantic dementia patients through the analysis of drawings.

OBJECTIVE: The structure of the semantic network is constructed and organized during childhood development. Previous publications have hypothesized that neurodegenerative diseases would lead to a disruption of this network reversing the steps acquired in childhood. Semantic Dementia (SD) is a subtype of frontotemporal lobe degeneration in which the main symptom is a specific loss of semantic memory. We aimed to describe the sequential acquisition of concepts in 3-8 years old children evaluated through the production of drawings and, in parallel, their progressive loss in SD patients. METHODS: 104 children between 40 and 96 months categorized into tertiles according to their age, 21 SD patients categorized into tertiles according to their score on a category fluency task and 34 healthy volunteers were asked to draw 12 items with, a priori, different age of acquisition and familiarity, belonging to four different semantic categories. We employed the drawings of the healthy volunteers to build a scoring scheme. We considered that a concept was acquired in children when 50% or more of its features were present in their drawings, and it was lost in patients when more than 50% were missing. RESULTS: Those concepts which the children were able to acquire earlier, according to our scoring scheme, tended to remain in patients with more advanced SD. While the items that children acquired later, were, in general, those that the SD patients lost at earlier disease stages. CONCLUSION: The patterns of concept acquisition in children were the mirror image of the loss in patients with SD. Our study supports the hypothesis that the sequence of concept acquisition in childhood is reversed in SD patients.

Physical Activity Is Associated With Better Executive Function in University Students.

Introduction: In recent years, the study of the benefits that physical exercise has on brain health has acquired special relevance. In order to implement exercise as an intervention to protect the brain, it is important to have a more clear idea of its effect in the young population. However, few studies have been carried out on these ages. Objective: The main objective of our study was to evaluate the association between physical activity (PA) with memory and executive function, in university students, analyzing the modulatory effect of sex. Methodology: We collected socio-demographic and life habit information, as well as data on the PA that was carried out during the previous week using the international PAquestionnaire short version (IPAQ-SF) questionnaire in 206 university students (mean age 19.55 ± 2.39; 67.5% women). Memory and executive function were assessed using a comprehensive battery of validate cognitive tests. Univariate and multivariate analyses were performed to correlate PA with cognitive tests scores and to evaluate the potential synergistic role of sex. Results: The main finding was that the total amount of PA correlated positively with several tests that evaluated aspects of executive function, specifically Stroop Colors (Pearson's r = 0.17; p = 0.01) and the Stroop Test Color-Word (Pearson's r = 0.15. p = 0.03). These results were adjusted by a large number of possible confounders and modifying variables in a multivariate analysis, like age, sex, academic record, day of the week, and time at which the test was performed. Additionally, we found out that sex had a synergistic effect with PA on the executive test Trail making test-A (TMTA), and in women, this association was stronger than in men. The more PA women reported, the better they performed, that is to say that they took less time to finalize the TMT-A (interaction term between PA and sex: b = -0.0009; p = 0.014). Conclusion: Our study adds evidence of the benefit of PA in cognition in the young population, specifically in the executive inhibitory control, and more significantly in women.

Distinctive Oculomotor Behaviors in Alzheimer's Disease and Frontotemporal Dementia.

Oculomotor behavior can provide insight into the integrity of widespread cortical networks, which may contribute to the differential diagnosis between Alzheimer's disease and frontotemporal dementia. Three groups of patients with Alzheimer's disease, behavioral variant of frontotemporal dementia (bvFTD) and semantic variant of primary progressive aphasia (svPPA) and a sample of cognitively unimpaired elders underwent an eye-tracking evaluation. All participants in the discovery sample, including controls, had a biomarker-supported diagnosis. Oculomotor correlates of neuropsychology and brain metabolism evaluated with 18F-FDG PET were explored. Machine-learning classification algorithms were trained for the differentiation between Alzheimer's disease, bvFTD and controls. A total of 93 subjects (33 Alzheimer's disease, 24 bvFTD, seven svPPA, and 29 controls) were included in the study. Alzheimer's disease was the most impaired group in all tests and displayed specific abnormalities in some visually-guided saccade parameters, as pursuit error and horizontal prosaccade latency, which are theoretically closely linked to posterior brain regions. BvFTD patients showed deficits especially in the most cognitively demanding tasks, the antisaccade and memory saccade tests, which require a fine control from frontal lobe regions. SvPPA patients performed similarly to controls in most parameters except for a lower number of correct memory saccades. Pursuit error was significantly correlated with cognitive measures of constructional praxis and executive function and metabolism in right posterior middle temporal gyrus. The classification algorithms yielded an area under the curve of 97.5% for the differentiation of Alzheimer's disease vs. controls, 96.7% for bvFTD vs. controls, and 92.5% for Alzheimer's disease vs. bvFTD. In conclusion, patients with Alzheimer's disease, bvFTD and svPPA exhibit differentiating oculomotor patterns which reflect the characteristic neuroanatomical distribution of pathology of each disease, and therefore its assessment can be useful in their diagnostic work-up. Machine learning approaches can facilitate the applicability of eye-tracking in clinical practice.

Cognitive and Behavioral Profiles of Left and Right Semantic Dementia: Differential Diagnosis with Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease.

BACKGROUND: Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by semantic memory loss and preserved abilities of other cognitive functions. The clinical manifestations of SD require a differential diagnosis with Alzheimer's disease (AD), especially those with early onset, and behavioral variant FTD (bvFTD). OBJECTIVE: The present study aimed to compare cognitive performances and neuropsychiatric symptoms in a population of AD, bvFTD, and left and right SD defined with the support of molecular imaging (amyloid and 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography) and assessed the accuracy of different neuropsychological markers in distinguishing these neurodegenerative diseases. METHODS: Eighty-seven participants (32 AD, 20 bvFTD, and 35 SD (17 Left-SD and 18 Right-SD) completed a comprehensive neuropsychological battery that included memory, language, attention and executive functions, visuospatial function, visuoconstructional skills, and tasks designed specifically to evaluate prosopagnosia and facial emotions recognition. The Neuropsychiatric Inventory was administered to assess neuropsychiatric symptoms. RESULTS: An episodic memory test that included semantic cues, a visuospatial test (both impaired in AD), a naming test and a prosopagnosia task (both impaired in SD) were the four most valuable cognitive metrics for the differential diagnosis between groups. Several behavioral abnormalities were differentially present, of which aggression, self-care (both more frequent in bvFTD), and eating habits, specifically overeating and altered dietary preference (more frequent in SD), were the most valuable in group discrimination. CONCLUSION: Our study highlights the value of a comprehensive neuropsychological and neuropsychiatric evaluation for the differential diagnosis between FTD syndromes and AD.

Ganglion cell layer thinning in prodromal Alzheimer's disease defined by amyloid PET.

INTRODUCTION: The objective of this study was to investigate and compare optic nerve and retinal layers in eyes of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) with paired control eyes using optical coherence tomography. METHODS: Sixty-three eyes of 34 subjects, 12 eyes with AD and 51 eyes with MCI, positive to 11C-labeled Pittsburgh Compound-B with positron emission tomography (11C-PiB PET/CT), and the same number of sex- and age-paired control eyes underwent optical coherence tomography scanning analyzing retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), Bruch's membrane opening-minimum rim width (BMO-MRW), inner plexiform layer (IPL), outer nuclear layer, and lamina cribrosa (LC). RESULTS: Compared with healthy controls, eyes of patients with positive 11C-PiB PET/CT showed a significant thinning of RNFL (P < .028) and GCL (P < .014). IPL and outer nuclear layer also showed significant thinning in two (P < .025) and one location (P < .010), respectively. No significant differences were found when optic nerve measurements BMO-MRW and LC were compared (P > .131 and P > .721, respectively). Temporal sector GCL, average RNFL, and temporal sector RNFL also exhibited significant thinning when MCI and control eyes were compared (P = .015, P = .005 and P = .050, respectively), and also the greatest area under the curve values (0.689, 0.647, and 0.659, respectively). GCL, IPL, and RNFL tend to be thinner in the AD group compared with healthy controls. DISCUSSION: Our study suggests that RNFL and GCL are useful for potential screening in the early diagnosis of AD. LC and BMO-MRW appear not to be affected by AD.

A Brief Drawing Task for the Differential Diagnosis of Semantic Dementia.

BACKGROUND: Semantic dementia (SD) is a subtype of frontotemporal lobe degeneration characterized by semantic loss, with other cognitive functions initially preserved. SD requires differential diagnosis with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Semantic knowledge can be evaluated through different tests; however, most of them depend on language. OBJECTIVE: We describe the development of a brief drawing task that may be helpful for the differential diagnosis of SD. METHODS: Seventy-two patients, including 32 AD, 19 bvFTD, and 21 SD were asked to draw 12 items with different age of acquisition and familiarity, belonging to four different semantic categories. We employed the drawings of healthy volunteers to build a scoring scheme. RESULTS: Turtle, strawberry, train, and envelope were the items of each category that best discriminated between groups and were selected for the Brief drawing task. The discriminatory power of the Brief drawing task between SD versus AD and bvFTD patients, estimated through the area under the curve was 0.84 (95% CI = 0.72-0.96, p = 0.000007). In a logistic model, the Brief drawing task (p = 0.003) and VOSP "number location" subtest (p = 0.016) were significant predictors of the diagnosis of SD versus AD and bvFTD after adjustment by the main covariates. The Brief drawing task provided clinically useful qualitative information. SD drawings were characterized by loss of the distinctive features, intrusions, tendency to prototype, and answers like "I don't know what this is". CONCLUSION: The Brief drawing task appears to reveal deficits in semantic knowledge among patients with SD that may assist in the differential diagnosis with other neurodegenerative diseases.

Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units.

The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

Biological and Psychological Factors Associated With Smoking Abstinence Six Years Post-Stroke.

Introduction: Tobacco use is a public health problem causing high morbidity and mortality, including stroke. This study evaluates predictive factors of smoking cessation in the long term after stroke. Methods: We followed a cohort of 110 consecutive smokers with stroke for up to 6 years. Sociodemographic variables, stroke severity, insular involvement, stage of change in smoking habit before stroke and disruption of addiction variable (smoking cessation, absence of relapses, having stopped smoking without difficulties and not having had urge) were evaluated. Results: Twenty patients died during follow-up and two patients were lost leaving a final cohort of 88 patients. The prevalence of smoking cessation in the remaining population was 65.9% post-stroke, 54.9% at 3-6 months, 40.9% at 1 year and 37.5% at 6 years. Prevalence was significantly higher in patients with insular involvement during the first year of follow-up, but not at 6 years. Disruption immediately after stroke (OR = 10.1; 95% CI = 2.5 to 40.1) and intention to change before having the stroke (OR = 4.8; 95% CI = 1.0 to 23.0) were predictors of abstinence at 6 years after adjusting for age, sex and stroke severity at baseline. When tobacco abstinence at the 1 year follow-up was included in the model, this factor was the best predictor of tobacco abstinence at 1 year (OR = 10.5; 95% CI = 2.2 to 49.4). Conclusions: Intention of change, having the disruption criteria, and abstinence 1 year after stroke were predictors of abstinence at 6 years. An insular lesion in the acute phase of stroke does not determine the tobacco use status at 6 years. Implications: This study is the first prospective investigation with a cohort of stroke patients to examine the long-term influence of biological and psychological factors on smoking cessation. Tobacco abstinence 1 year after stroke was the strongest predictor of abstinence at 6 years of follow-up. The effect of the insular cortex lesion on tobacco cessation, which had been relevant during the first year, no longer had an influence over the longer period studied here.

MicroRNA Profile in Patients with Alzheimer's Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples.

BACKGROUND: MicroRNAs have been postulated as potential biomarkers for Alzheimer's disease (AD). Exosomes are nanovesicles which transport microRNAs, proteins, and other cargos. It has been hypothesized that the exosome traffic might be increased in neurodegenerative disorders. OBJECTIVE: i) To assess the cerebrospinal fluid (CSF) microRNA profile in a group of AD patients and control subjects and to validate a group of microRNAs previously reported by other authors. ii) To compare microRNA levels in whole CSF and in the exosome-enriched fraction in AD patients. METHODS: A panel of 760 microRNAs was analyzed in the CSF of 10 AD patients and 10 healthy subjects. Among microRNAs differently expressed, we selected those that had been previously reported by other authors. Candidates were validated in a larger group by individual qPCR assays. MicroRNA expression was also evaluated in exosome-enriched CSF samples of patients with AD and controls. RESULTS: Fifteen microRNAs were differently expressed in AD. MiR-9-5p, miR-134, and miR-598 were selected as candidates for further analysis. MiR-9-5p and miR-598 were detected in 50 and 75% of control CSF samples, respectively, while they were not detected in any AD CSF samples. We observed an opposite pattern when we evaluated the microRNA expression in the exosome-enriched CSF AD samples. No pattern variations were noted among healthy subjects. CONCLUSION: These data propose miR-9-5p and miR-598 as potential biomarkers for AD. Further studies in plasma and other body fluids will confirm their potential role as easily accessible biomarkers. In addition, our data suggest that exosome trafficking is different between AD and control subjects raising the need to take this phenomenon into consideration in future studies of AD biomarkers.