Oculomotor Dysfunction in Idiopathic and LRRK2-Parkinson's Disease and At-Risk Individuals.

Background: Video-oculography constitutes a highly-sensitive method of characterizing ocular movements, which could detect subtle premotor changes and contribute to the early diagnosis of Parkinson's disease (PD). Objective: To investigate potential oculomotor differences between idiopathic PD (iPD) and PD associated with the G2019S variant of LRRK2 (L2PD), as well as to evaluate oculomotor function in asymptomatic carriers of the G2019S variant of LRRK2. Methods: The study enrolled 129 subjects: 30 PD (16 iPD, 14 L2PD), 23 asymptomatic carriers, 13 non-carrier relatives of L2PD patients, and 63 unrelated HCs. The video-oculographic evaluation included fixation, prosaccade, antisaccade, and memory saccade tests. Results: We did not find significant differences between iPD and L2PD. Compared to controls, PD patients displayed widespread oculomotor deficits including larger microsaccades, hypometric vertical prosaccades, increased latencies in all tests, and lower percentages of successful antisaccades and memory saccades. Non-carrier relatives showed oculomotor changes with parkinsonian features, such as fixation instability and hypometric vertical saccades. Asymptomatic carriers shared multiple similarities with PD, including signs of unstable fixation and hypometric vertical prosaccades; however, they were able to reach percentages of successful antisaccade and memory saccades similar to controls, although at the expense of longer latencies. Classification accuracy of significant oculomotor parameters to differentiate asymptomatic carriers from HCs ranged from 0.68 to 0.74, with BCEA, a marker of global fixation instability, being the parameter with the greatest classification accuracy. Conclusions: iPD and LRRK2-G2019S PD patients do not seem to display a differential oculomotor profile. Several oculomotor changes in asymptomatic carriers of LRRK2 mutations could be considered premotor biomarkers.

Plasma Phosphorylated Tau 231 Increases at One-Year Intervals in Cognitively Unimpaired Subjects.

Background: Plasma biomarkers of Alzheimer's disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid.

Where Should I Draw the Line: PET-Driven, Data-Driven, or Manufacturer Cut-Off?

Background: The optimal cut-off for Alzheimer's disease (AD) CSF biomarkers remains controversial. Objective: To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aß1-42, pTau, tTau, and Aß1-42/Aß1-40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods: CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) were performed in all the patients. We established a cut-off for each single biomarker and Aß1-42/Aß1-40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results: One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aß1-42/Aß1-40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions: We established our sample's best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer's.

Influence of Physiological Variables and Comorbidities on Plasma Aß40, Aß42, and p-tau181 Levels in Cognitively Unimpaired Individuals.

Plasma biomarkers for Alzheimer's disease (AD) are a promising tool that may help in early diagnosis. However, their levels may be influenced by physiological parameters and comorbidities that should be considered before they can be used at the population level. For this purpose, we assessed the influences of different comorbidities on AD plasma markers in 208 cognitively unimpaired subjects. We analyzed both plasma and cerebrospinal fluid levels of Aß40, Aß42, and p-tau181 using the fully automated Lumipulse platform. The relationships between the different plasma markers and physiological variables were studied using linear regression models. The mean differences in plasma markers according to comorbidity groups were also studied. The glomerular filtration rate showed an influence on plasma Aß40 and Aß42 levels but not on the Aß42/Aß40 ratio. The amyloid ratio was significantly lower in diabetic and hypertensive subjects, and the mean p-tau181 levels were higher in hypertensive subjects. The glomerular filtration rate may have an inverse relationship on plasma Aß40 and Aß42 levels but not on the amyloid ratio, suggesting that the latter is a more stable marker to use in the general population. Cardiovascular risk factors might have a long-term effect on the amyloid ratio and plasma levels of p-tau181.

Age-related hearing loss is not linked to cerebrospinal fluid levels of ß-amyloid or p-tau181.

INTRODUCTION: As Hearing loss and dementia affect people with the same profile, several epidemiological studies have evaluated their relationship. However, the link between age-related hearing loss and Alzheimer's disease is still unclear. METHODS: We selected subjects with no history of exposure to loud noises, blasts, head trauma with hearing loss, or sudden sensorineural hearing loss from a cohort intended to study preclinical phases of Alzheimer's disease. Participants are volunteers over 55 years without cognitive impairment. We correlated the results of an objective auditory evaluation with brain amyloid and p-tau181 levels and with the outcomes of a comprehensive neuropsychological assessment. RESULTS: Fifty-five subjects at different stages of the Alzheimer's disease continuum were evaluated. There were no statistically significant correlations between amyloid-ß and p-tau levels and any of the objective auditory measures. A weak but significant correlation was found between amyloid-ß values and the Hearing Handicap Inventory for the Elderly. The neuropsychological domains more correlated to hearing loss were executive function and processing speed. DISCUSSION: Age-related hearing loss is not linked to any pathological markers of Alzheimer's disease nor to neuropsychological domains typically affected in this disease. The Hearing Handicap Inventory for the Elderly has an important component of subjectivity and further studies are needed to explore its relationship with amyloid-ß levels.

Accuracy of plasma Aß40, Aß42, and p-tau181 to detect CSF Alzheimer's pathological changes in cognitively unimpaired subjects using the Lumipulse automated platform.

BACKGROUND: The arrival of new disease-modifying treatments for Alzheimer's disease (AD) requires the identification of subjects at risk in a simple, inexpensive, and non-invasive way. With tools allowing an adequate screening, it would be possible to optimize the use of these treatments. Plasma markers of AD are very promising, but it is necessary to prove that alterations in their levels are related to alterations in gold standard markers such as cerebrospinal fluid or PET imaging. With this research, we want to evaluate the performance of plasma Aß40, Aß42, and p-tau181 to detect the pathological changes in CSF using the automated Lumipulse platform. METHODS: Both plasma and CSF Aß40, Aß42, and p-tau181 have been evaluated in a group of 208 cognitively unimpaired subjects with a 30.3% of ApoE4 carriers. We have correlated plasma and CSF values of each biomarker. Then, we have also assessed the differences in plasma marker values according to amyloid status (A - / +), AD status (considering AD + subjects to those A + plus Tau +), and ATN group defined by CSF. Finally, ROC curves have been performed, and the area under the curve has been measured using amyloid status and AD status as an outcome and different combinations of plasma markers as predictors. RESULTS: Aß42, amyloid ratio, p-tau181, and p-tau181/Aß42 ratio correlated significantly between plasma and CSF. For these markers, the levels were significantly different in the A + / - , AD + / - , and ATN groups. Amyloid ratio predicts amyloid and AD pathology in CSF with an AUC of 0.89. CONCLUSIONS: Plasma biomarkers of AD using the automated Lumipulse platform show good diagnostic performance in detecting Alzheimer's pathology in cognitively unimpaired subjects.

"This looks like a movie": a case report of post-surgical amnesia.

A 52-year-old male patient with a background of adaptive personality disorder was admitted for mitral valve repair and cardiac ablation for atrial fibrillation. He suffered intraoperative complications with severe mitral insufficiency that suffered ischemia.. Post-operatively, he demonstrated acute loss of retrograde autobiographical memory, prosopagnosia and a loss of public semantic memory. His CT scan was normal and MRI was not possible due to intra-cardiac leads. An initial diagnosis of hypoxic-ischemic encephalopathy was considered. A neuropsychological examination undertaken 20 days after his surgery showed a severe alteration of retrograde autobiographical memory, marked alteration of semantic knowledge and prosopagnosia. He demonstrated an average performance in tasks measuring constructional praxis, visuospatial ability, and executive functions. 34 days after surgery, and after a short nap, the patient "returns" to the day before admission and consequently recovers his memory. Repeat neuropsychological assessment demonstrated performance within the normal range across all previously tested domains. This sudden recovery of memory, together with a normal MRI, led to a rethinking of the diagnosis of dissociative amnesia. This case illustrates the long-standing discussion about the organic or functional origin of some memory disorders, in which, despite advances in neuroimaging techniques, it is still difficult to know their etiology .

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.

Síndrome de Behçet / Behçet síndrome

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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.

Atrophy of Basal Forebrain Initiates with Tau Pathology in Individuals at Risk for Alzheimer's Disease.

Evidence suggests that the basal forebrain (BF) cholinergic system degenerates early in the course of Alzheimer's disease (AD), likely due to the vulnerability of BF cholinergic neurons to tau pathology. However, it remains unclear whether the presence of tauopathy is the only requirement for initiating the BF degeneration in asymptomatic subjects at risk for AD (AR-AD), and how BF structural deficits evolve from normal aging to preclinical and prodromal AD. Here, we provide human in vivo magnetic resonance imaging evidence supporting that abnormal cerebrospinal fluid levels of phosphorylated tau (T+) are selectively associated with bilateral volume loss of the nucleus basalis of Meynert (nbM, Ch4) in AR-AD individuals. Spreading of atrophy to medial septum and vertical limb of diagonal band Broca (Ch1-Ch2) occurred in both preclinical and prodromal AD. With the exception of A+, all groups revealed significant correlations between volume reduction of BF cholinergic compartments and atrophy of their innervated regions. Overall, these results support the central role played by tauopathy in instigating the nbM degeneration in AR-AD individuals and the necessary coexistence of both AD proteinopathies for spreading damage to larger BF territories, thus affecting the core of the BF cholinergic projection system.

The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE ε4 Non-carriers.

An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE ε4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE ε4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE ε4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE ε4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load.