Foveal avascular zone and choroidal thickness are decreased in subjects with hard drusen and without high genetic risk of developing Alzheimer’s disease

A family history (FH+) of Alzheimer’s disease (AD) and ɛ4 allele of the ApoE gene are the main genetic risk factors for developing AD, whereas ɛ4 allele plays a protective role in age-related macular degeneration. Ocular vascular changes have been reported in both pathologies. We analyzed the choroidal thickness using optical coherence tomography (OCT) and the foveal avascular zone (FAZ) using OCT-angiography and compared the results with ApoE gene expression, AD FH+, and the presence or absence of hard drusen (HD) in 184 cognitively healthy subjects. Choroidal thickness was statistically significantly different in the (FH−, ɛ4−, HD+) group compared with (i) both the (FH−, ɛ4−, HD−) and the (FH+, ɛ4+, HD+) groups in the superior and inferior points at 1500 μm, and (ii) the (FH+, ɛ4−, HD+) group in the superior point at 1500 μm. There were statistically significant differences in the superficial FAZ between the (FH+, ɛ4−, HD+) group and (i) the (FH+, ɛ4−, HD−) group and (ii) the (FH+, ɛ4+, HD−) group. In conclusion, ocular vascular changes are not yet evident in participants with a genetic risk of developing AD

Characterization of retinal drusen in subjects at high genetic risk of developing sporadic Alzheimer’s disease: An exploratory analysis

Having a family history (FH+) of Alzheimer’s disease (AD) and being a carrier of at least one ε4 allele of the ApoE gene are two of the main risk factors for the development of AD. AD and age-related macular degeneration (AMD) share one of the main risk factors, such as age, and characteristics including the presence of deposits (Aβ plaques in AD and drusen in AMD); however, the role of apolipoprotein E isoforms in both pathologies is controversial. We analyzed and characterized retinal drusen by optical coherence tomography (OCT) in subjects, classifying them by their AD FH (FH-or FH+) and their allelic characterization of ApoE ε4 (ApoE ε4-or ApoE ε4+) and considering cardiovascular risk factors (hypercholesterolemia, hypertension, and diabetes mellitus). In addition, we analyzed the choroidal thickness by OCT and the area of the foveal avascular zone with OCTA. We did not find a relationship between a family history of AD or any of the ApoE isoforms and the presence or absence of drusen. Subjects with drusen show choroidal thinning compared to patients without drusen, and thinning could trigger changes in choroidal perfusion that may give rise to the deposits that generate drusen

Age and APOE genotype affect the relationship between objectively measured physical activity and power in the alpha band, a marker of brain disease

BACKGROUND: Electrophysiological studies show that reductions in power within the alpha band are associated with the Alzheimer\u27s disease (AD) continuum. Physical activity (PA) is a protective factor that has proved to reduce AD risk and pathological brain burden. Previous research has confirmed that exercise increases power in the alpha range. However, little is known regarding whether other non-modifiable risk factors for AD, such as increased age or APOE ε4 carriage, alter the association between PA and power in the alpha band. METHODS: The relationship between PA and alpha band power was examined in a sample of 113 healthy adults using magnetoencephalography. Additionally, we explored whether ε4 carriage and age modulate this association. The correlations between alpha power and gray matter volumes and cognition were also investigated. RESULTS: We detected a parieto-occipital cluster in which PA positively correlated with alpha power. The association between PA and alpha power remained following stratification of the cohort by genotype. Younger and older adults were investigated separately, and only younger adults exhibited a positive relationship between PA and alpha power. Interestingly, when four groups were created based on age (younger-older adult) and APOE (E3/E3-E3/E4), only younger E3/E3 (least predicted risk) and older E3/E4 (greatest predicted risk) had associations between greater alpha power and higher PA. Among older E3/E4, greater alpha power in these regions was associated with improved memory and preserved brain structure. CONCLUSION: PA could protect against the slowing of brain activity that characterizes the AD continuum, where it is of benefit for all individuals, especially E3/E4 older adults

Caracterización de personas con alto riesgo para el desarrollo de demencia mediante técnicas de neuroimagen

La demencia es un síndrome caracterizado por la pérdida de capacidades intelectuales que acaban afectando a las actividades diarias de las personas que lo sufren. Normalmente es un proceso crónico y progresivo cuyas consecuencias varían desde los estadios intermedios, donde empieza a afectar a ciertas funciones, hasta los estadios severos, donde la persona depende por completo de terceros para realizar las actividades diarias. Entre las muchas causas de demencia, como los cuerpos de Lewy o la demencia vascular, la enfermedad de Alzhéimer (AD, por sus siglas en inglés) es la causa más común de demencia. Como proceso neurodegenerativo, AD evoluciona lentamente y empeora a lo largo de los años. Más aún, la neuropatología asociada a AD podría empezar décadas antes de que se observen los primeros síntomas neuropsicológicos. La progresión de AD ha sido dividida en tres fases basadas en la evolución de ciertos aspectos neuropsicológicos: la fase sin deterioro cognitivo, donde algunas personas pueden llegar a reportar quejas subjetivas de memoria; la fase de deterioro cognitivo, donde las personas pueden realizar actividades diarias de manera independiente pero ciertos problemas cognitivos aparecen en actividades más complejas; la fase de demencia, donde el deterioro afecta gravemente a la vida diaria de las personas y éstas dejan de ser autosuficientes. Durante décadas, la comunidad científica ha propuesto distintos modelos de progresión de AD y esta progresión ha sido caracterizada usando distintas técnicas, como la tomografía por emisión de positrones, la resonancia magnética, la electroencefalografía o la magnetoencefalografía. En los últimos años, ha habido un creciente interés por caracterizar las fases preclínicas de la enfermedad de Alzhéimer. Este interés está motivado, en parte, por la necesidad de aplicar tratamientos o estrategias que ralenticen la progresión de la enfermedad antes de que se haya producido un deterior severo de las capacidades cognitivas. Así, la tesis que presento se engloba en el campo de la neurociencia de detección temprana del Alzhéimer. El principal objetivo de la tesis es el estudio y caracterización del deterioro temprano, si hubiera alguno, debido a AD en una población joven y cognitivamente sana con un alto riesgo de desarrollar demencia. Esta tesis se compone de tres estudios que evalúan el efecto de este riesgo incrementado en distintas y esenciales características del cerebro: 1.- El primer estudio evalúa la conectividad funcional. 2.- El segundo estudio evalúa la conectividad estructural (o anatómica). 3.- El tercer estudio evalúa la relación entre conectividad funcional y estructural y sus posibles alteraciones. ----------ABSTRACT---------- Dementia is a syndrome characterized by the loss of intellectual abilities to the extent that it interferes with daily life activities. It is usually a chronic and progressive process that ranges in severity from the mildest stage, when it is just beginning to affect a person’s functioning, to the most severe stage, when the person must depend entirely on others for daily activities living. Among the different causes of dementia, such as Lewy body dementia or vascular dementia, Alzheimer’s disease (AD) is the most common cause of dementia. As a neurodegenerative process, AD develops slowly and gets worse over the years. Furthermore, the neuropathology associated with AD might start decades before the first neuropsychological symptoms are noticed. The AD continuum has been divided into three stages based on the evolution of different neuropsychological aspects: the cognitively unimpaired stage, where a subset of cognitively unimpaired individuals may report subjective cognitive decline; the mild cognitive impair stage, where the individuals perform daily life activities independently, but the cognitive difficulty may impact on the more complex activities of daily life; the dementia stage, where the impairment results in an evident functional impact on daily life and the individual is no longer entirely independent. For decades, the scientific community has proposed AD progression models, and this progression has been characterized using different techniques, such as positron emission tomography, magnetic resonance imaging, electroencephalography, or magnetoencephalography. In recent years, there has been an increased interest in characterizing the preclinical stages of AD. This interest is partly motivated by applying treatments or strategies to slow the AD progression before severe cognitive abilities impairments are produced. Thus, the thesis presented here is framed in this neuroscience field of early detection of AD. This thesis's main objective is to study and characterize early impairments, if any, due to AD in a young cognitively healthy population at increased risk of developing dementia. This thesis comprises three studies that evaluate the effect of this increased risk in different brain features: 1.- The first study evaluates the functional connectivity; 2.- The second study evaluates the structural (or anatomical) connectivity; 3.- The third study evaluates the association between functional and structural connectivity and its possible alterations

Neuropsychological and neurophysiological characterization of mild cognitive impairment and Alzheimer's disease in Down syndrome

Down syndrome (DS) has been considered a unique model for the investigation of Alzheimer’s disease AD) but intermediate stages in the continuum are poorly defined. Considering this, we investigated the neurophysiological (i.e., magnetoencephalography [MEG]) and neuropsychological patterns of mild cognitive impairment (MCI) and AD in middle-aged adults with DS. The sample was composed of four groups: Control-DS (n ¼ 14, mean age 44.64 3.30 years), MCI-DS (n ¼ 14, 51.64 3.95 years), AD-DS (n ¼ 13, 53.54 6.58 years), and Control-no-DS (healthy controls, n ¼ 14, 45.21 4.39 years). DS individuals were studied with neuropsychological tests and MEG, whereas the Control-no-DS group completed only the MEG session. Our results showed that the AD-DS group exhibited a significantly poorer performance as compared with the Control-DS group in all tests. Furthermore, this effect was crucially evident in AD-DS individuals when compared with the MCI-DS group in verbal and working memory abilities. In the neurophysiological domain, the Control-DS group showed a widespread increase of theta activity when compared with the Control-no-DS group. With disease progression, this increased theta was substituted by an augmented delta, accompanied with a reduction of alpha activity. Such spectral patterndspecifically observed in occipital, posterior temporal, cuneus, and precuneus regionsdcorrelated with the performance in cognitive tests. This is the first MEG study in the field incorporating both neuropsychological and neurophysiological information, and demonstrating that this combination of markers is sensitive enough to characterize different stages along the AD continuum in DS.Fundación Jerome LejeuneInstituto de Salud Carlos IIIComunidad de MadridMinisterio de Economía y CompetitividadDepto. de Medicina Legal, Psiquiatría y PatologíaFac. de MedicinaTRUEpu

Retinal Vascular Study Using OCTA in Subjects at High Genetic Risk of Developing Alzheimer’s Disease and Cardiovascular Risk Factors

In 103 subjects with a high genetic risk of developing Alzheimer’s disease (AD), family history (FH) of AD and ApoE ɛ4 characterization (ApoE ɛ4) were analyzed for changes in the retinal vascular network by OCTA (optical coherence tomography angiography), and AngioTool and Erlangen-Angio-Tool (EA-Tool) as imaging analysis software. Retinal vascularization was analyzed by measuring hypercholesterolemia (HCL) and high blood pressure (HBP). Angio-Tool showed a statistically significant higher percentage of area occupied by vessels in the FH+ ApoE ɛ4- group vs. in the FH+ ApoE ɛ4+ group, and EA-Tool showed statistically significant higher vascular densities in the C3 ring in the FH+ ApoE ɛ4+ group when compared with: i)FH- ApoE ɛ4- in sectors H3, H4, H10 and H11; and ii) FH+ ApoE ɛ4- in sectors H4 and H12. In participants with HCL and HBP, statistically significant changes were found, in particular using EA-Tool, both in the macular area, mainly in the deep plexus, and in the peripapillary area. In conclusion, OCTA in subjects with genetic risk factors for the development of AD showed an apparent increase in vascular density in some sectors of the retina, which was one of the first vascular changes detectable. These changes constitute a promising biomarker for monitoring the progression of pathological neuronal degeneration

Brain signal complexity in adults with Down syndrome: Potential application in the detection of mild cognitive impairment

Background: Down syndrome (DS) is considered the most frequent cause of early-onset Alzheimer’s disease (AD), and the typical pathophysiological signs are present in almost all individuals with DS by the age of 40. Despite of this evidence, the investigation on the pre-dementia stages in DS is scarce. In the present study we analyzed the complexity of brain oscillatory patterns and neuropsychological performance for the characterization of mild cognitive impairment (MCI) in DS. Materials and methods: Lempel-Ziv complexity (LZC) values from restingstatemagnetoencephalography recordings and the neuropsychological performance in 28 patients with DS [control DS group (CN-DS) (n = 14), MCI group (MCI-DS) (n = 14)] and 14 individuals with typical neurodevelopment (CN-no-DS) were analyzed. Results: Lempel-Ziv complexity was lowest in the frontal region within the MCI-DS group, while the CN-DS group showed reduced values in parietal areas when compared with the CN-no-DS group. Also, the CN-no-DS group exhibited the expected pattern of significant increase of LZC as a function of age, while MCI-DS cases showed a decrease. The combination of reduced LZC values and a divergent trajectory of complexity evolution with age, allowed the discrimination of CN-DS vs. MCI-DS patients with a 92.9% of sensitivity and 85.7% of specificity. Finally, a pattern of mnestic and praxic impairment was significantly associated in MCI-DS cases with the significant reduction of LZC values in frontal and parietal regions (p = 0.01). Conclusion: Brain signal complexity measured with LZC is reduced in DS and its development with age is also disrupted. The combination of both features might assist in the detection of MCI within this population.Ministerio de Economía y Competitividad (Instituto de Salud Carlos III)Jérôme Lejeune FoundationMinisterio de Ciencia, Innovación y UniversidadesDepto. de Medicina Legal, Psiquiatría y PatologíaFac. de MedicinaTRUEpu

Early visual alterations in individuals at-risk of Alzheimer’s disease: A multidisciplinary approach

Background: The earliest pathological features of Alzheimer’s disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease. Methods: In total, 144 healthy subjects: 105 with family history of AD and 39 without, underwent ophthalmologic analysis, magnetoencephalography recording, and genotyping. A subdivision was made to compare groups with less demographic and more risk differences: 28 high-risk subjects (relatives/APOEɛ4 +) and 16 low-risk (non-relatives/APOEɛ4 −). Differences in visual acuity, contrast sensitivity, and macular thickness were evaluated. Correlations between each variable and visual-related electrophysiological measures (M100 latency and time–frequency power) were calculated for each group. Results: High-risk groups showed increased visual acuity. Visual acuity was also related to a lower M100 latency and a greater power time–frequency cluster in the high-risk group. Low-risk groups did not show this relationship. High-risk groups presented trends towards a greater contrast sensitivity that did not remain significant after correction for multiple comparisons. The highest-risk group showed trends towards the thinning of the inner plexiform and inner nuclear layers that did not remain significant after correction. The correlation between contrast sensitivity and macular thickness, and the electrophysiological measures were not significant after correction. The difference between the high- and low- risk groups correlations was no significant. Conclusions: To our knowledge, this paper is the first of its kind, assessing the relationship between ophthalmological and electrophysiological measures in healthy subjects at distinct levels of risk of AD. The results are novel and unexpected, showing an increase in visual acuity among high-risk subjects, who also exhibit a relationship between this measure and visual-related electrophysiological activity. These results have not been previously explored and could constitute a useful object of research as biomarkers for early detection and the evaluation of potential interventions’ effectiveness

Functional Connectivity Hypersynchronization in Relatives of Alzheimer’s Disease Patients: An Early E/I Balance Dysfunction?

Alzheimer’s disease (AD) studies on animal models, and humans showed a tendency of the brain tissue to become hyperexcitable and hypersynchronized, causing neurodegeneration. However, we know little about either the onset of this phenomenon or its early effects on functional brain networks. We studied functional connectivity (FC) on 127 participants (92 middle-age relatives of AD patients and 35 age-matched nonrelatives) using magnetoencephalography. FC was estimated in the alpha band in areas known both for early amyloid accumulation and disrupted FC in MCI converters to AD. We found a frontoparietal network (anterior cingulate cortex, dorsal frontal, and precuneus) where relatives of AD patients showed hypersynchronization in high alpha (not modulated by APOE-ε4 genotype) in comparison to age-matched nonrelatives. These results represent the first evidence of neurophysiological events causing early network disruption in humans, opening a new perspective for intervention on the excitation/inhibition unbalance.Ministerio de Economía y CompetitividadComunidad de MadridFundación La CaixaDepto. de Psicología Experimental, Procesos Cognitivos y LogopediaDepto. de Radiología, Rehabilitación y FisioterapiaFac. de PsicologíaFac. de MedicinaTRUEpu