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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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lage, López-García, Bejanin, Kazimierczak, Aracil-Bolaños, Calvo-Córdoba, Pozueta, García-Martínez, Fernández-Rodríguez, Bravo-González, Jiménez-Bonilla, Banzo, Irure-Ventura, Pegueroles, Illán-Gala, Fortea, Rodríguez-Rodríguez, Lleó-Bisa, García-Cena and Sánchez-Juan.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

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 11 C-labeled Pittsburgh Compound-B with positron emission tomography ( 11 C-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 11 C-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., (© 2019 The Authors.)

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Objective: The aim of this study was to evaluate the cerebral amyloid distribution in patients with mild cognitive impairment (MCI), assessed by carbon-11-Pittsburgh compound B (C-PIB) PET/CT, after 5 years of follow-up., Patients and Methods: Ten amnestic MCI (A-MCI) and four nonamnestic (NA-MCI) patients were studied by C-PIB PET/CT and re-evaluated 5 years later by a new C-PIB PET/CT. PET/CT scans were acquired 60-90 min after the administration of 555 MBq C-PIB and analyzed visually, to obtain a score of the cerebral cortical C-PIB retention in the frontal, basal ganglia (BG), temporoparietal (TP), occipital, posterior cingulate, and cerebellum areas. Initial and 5-year follow-up C-PIB retentions were compared., Results: Initially, 9/10 A-MCI patients were C-PIB positive and one was C-PIB negative. All four NA-MCI patients were C-PIB negative. Of the C-PIB-positive A-MCI patients, seven progressed to Alzheimer's disease dementia (AD-D), one to mixed dementia and one remained as A-MCI. The C-PIB-negative A-MCI patient remained as A-MCI. Of the four C-PIB-negative NA-MCI, one progressed to semantic dementia. All changes in C-PIB retention were of low intensity. The A-MCI patients who progressed to AD-D (n=7) showed an increase in C-PIB retention in the frontal (5/7), BG (3/7), TP (3/7), occipital (1/7), and posterior cingulate (1/7) regions. The A-MCI patient who progressed to mix dementia showed an increase in C-PIB retention in the frontal region. The C-PIB-positive A-MCI patient who remained as A-MCI showed an increase in C-PIB retention in the frontal, BG, and TP areas. The amyloid deposition in the anterior part of the brain (frontal, TP, and BG) increased more than that in the posterior part (occipital and precuneus) (7/9 vs. 2/9; P<0.05)., Conclusion: PIB retention increased predominantly in the frontal, BG, and TP areas. C-PIB-positive A-MCI patients mostly progressed to AD-D, showing similar topographic changes in their cerebral C-PIB pattern than the patient who remained as A-MCI.

Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology., Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location., Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P < .05) but not in Aβ+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education., Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials., Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia., Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017., Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype., Results: Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years., Conclusions and Relevance: Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.

Objective: Amyloid imaging clinically is usually reported as positive or negative, and the role of amyloid topography has not been studied before. To evaluate in a clinical setting the regional distribution patterns of C-Pittsburgh compound B (C-PIB) and the fluorine-18-fluorodeoxyglucose (F-FDG) uptake in patients with mild cognitive impairment (MCI), we designed this study., Methods: We studied 81 consecutive MCI patients, 64 amnestic (A-MCI) and 17 nonamnestic (NA-MCI) by C-PIB and F-FDG PET/computed tomography, by visual analysis. PIB retention was classified according to the regional distribution into the following patterns: A (frontal, lateral temporal, basal ganglia and anterior cingulate) and B (global retention). F-FDG images were considered positive only if temporoparietal hypometabolism consistent with Alzheimer's disease was observed., Results: In 42 of the 64 A-MCI, C-PIB was positive. Twelve of the 42 positive A-MCI showed an A-pattern, all F-FDG negative, and 30 a B-pattern, 10 F-FDG positive and 20 F-FDG negative. Of the 17 NA-MCI, C-PIB was positive in three and F-FDG was positive in one. The different proportion of C-PIB positivity in A-MCI and NA-MCI was highly significant (P<0.001)., Conclusion: Two different C-PIB patterns were observed in MCI patients and for the A-pattern, glucose hypometabolism consistent with Alzheimer's disease is highly unlikely. These findings may contribute towards a better selection of patients for future potential treatments and also to optimize the use of F-FDG-PET/CT.

Importance: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies., Objective: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI)., Data Sources: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators., Study Selection: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity., Data Extraction and Synthesis: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies., Main Outcomes and Measures: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations., Results: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality., Conclusions and Relevance: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

The high prevalence of Alzheimer's disease, along with the possibility of new approaches in diagnosis through the use of biomarkers of cerebrospinal fluid is shifting the focus to the elderly with dementia or at risk. In this sense it seems important to review the genetic aspects of the elderly with familial Alzheimer's disease as well as those at risk. The wide distribution of genetic studies associated with this condition may also be helpful. To the classical findings of the genes for amyloid, the presenilins and apolipoprotein E, we must add other genes recently implicated in the pathogenesis of the disease, among which are found the clusterin gene, encoding the phosphatidyl-inositol-binding clathrin assembly protein gene, and the receptor for the complement C3b protein., (Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.)

Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele., (Copyright 2007 Wiley-Liss, Inc.)

Objectives: The diagnosis of prostate cancer has changed significantly with the introduction of PSA in the clinical practice. Despite screening is under controversy the use of PSA has become widespread. The objective of this paper is to know the use of PSA in our health-care area and to analyze perceived risks and benefits., Methods: From the informatic archives we analyze PSA determinations performed in our health-care area (290.956 citizens) over 2000 and 2001. We also analyzed prostate biopsies generated and number of cancers detected., Results: 25.519 PSA determinations were performed. 59% came from general practitioners (GP), 34% from urologists and 7% from the rest of specialists. 39% are performed to men older than 70 years. PSA was normal in 78.7% of the patients and higher than 4 ng/ml in 21.2%. 488 prostatic biopsies were performed diagnosing 178 cancers (diagnostic yield 36.5%). Depending on the first PSA, diagnosis was started by a GP in 44% of the cases, a urologist in 46%, and the remaining 10% by other specialists. Mean time from first PSA to diagnosis was 5 months, without significant differences between GPs and specialities . The use of PSA by GPs is variable (between 8.1 and 45.8 determinations per 100 men over 50 years), without significant differences in prostate cancer detection by number of PSAs or differences in age. In comparison with the period 1982-1993 the incidence of prostate cancer goes from 30.76 to 52.8 new cases/100.000 inhabitants/year. There is a greater incidence and increase of cancer in the rural area (from 33.52 to 221.1 new cases/ 100.000 inhabitants/year)., Conclusions: We confirm the general use of this test and the trend to screening in the primary health-care level, which participates in an important manner in the diagnosis. PSA brings forward the diagnosis of prostate cancer 5 years in our area, and shoots its incidence rates. The high use of such marker in our population of advanced age may be considered inadequate.

"Mechanic's hands" are a characteristic cutaneous sign of idiopathic inflammatory myositis. We describe the case of a 61-year-old male patient who was diagnosed with idiopathic polymyositis and non-specific interstitial lung disease in 1999, and three years later developed scaly, fissured hyperkeratotic lesions on the lateral and palmar surfaces of the first three fingers of both hands, with little pruritus. The presence of the anti-Jo-1 antisynthetase antibody in the patient's serum, the finding of skin lesions characteristic of "mechanic's hands" and the patient's other systemic clinical manifestations made it possible to establish the diagnosis of "antisynthetase syndrome."