Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years

Presenilin 1 (PSEN1) mutations cause autosomal dominant familial Alzheimer's disease (FAD). PSEN1 mutation carriers undergo the course of cognitive deterioration, which is typical for sporadic Alzheimer's disease but disease onset is earlier and disease progression is faster. Here, we sought to detect signs of FAD in presymptomatic carriers of the PSEN1 mutation (C410Y) by use of a neuropsychological examination, functional MRI during learning and memory tasks and MRI volumetry. We examined five non-demented members of a FAD family and 21 non-related controls. Two of the five family members were carrying the mutation; one was 20 years old and the other 45 years old. The age of clinical manifestation of FAD in the family studied here is ∼48 years. Neuropsychological assessments suggested subtle problems with episodic memory in the 20-year-old mutation carrier. The middle-aged mutation carrier fulfilled criteria for amnestic mild cognitive impairment. The 20-year-old mutation carrier exhibited increased, while the middle-aged mutation carrier exhibited decreased brain activity compared to controls within memory-related neural networks during episodic learning and retrieval, but not during a working-memory task. The increased memory-related brain activity in the young mutation carrier might reflect a compensatory effort to overcome preclinical neural dysfunction caused by first pathological changes. The activity reductions in the middle-aged mutation carrier might reflect gross neural dysfunction in a more advanced stage of neuropathology. These data suggest that functional neuroimaging along with tasks that challenge specifically those brain areas which are initial targets of Alzheimer's disease pathology may reveal activity alterations on a single-subject level decades before the clinical manifestation of Alzheimer's diseas

Translational Application of Microfluidics and Bioprinting for Stem Cell-Based Cartilage Repair

Cartilage defects can impair the most elementary daily activities and, if not properly treated, can lead to the complete loss of articular function. The limitations of standard treatments for cartilage repair have triggered the development of stem cell-based therapies. In this scenario, the development of efficient cell differentiation protocols and the design of proper biomaterial-based supports to deliver cells to the injury site need to be addressed through basic and applied research to fully exploit the potential of stem cells. Here, we discuss the use of microfluidics and bioprinting approaches for the translation of stem cell-based therapy for cartilage repair in clinics. In particular, we will focus on the optimization of hydrogel-based materials to mimic the articular cartilage triggered by their use as bioinks in 3D bioprinting applications, on the screening of biochemical and biophysical factors through microfluidic devices to enhance stem cell chondrogenesis, and on the use of microfluidic technology to generate implantable constructs with a complex geometry. Finally, we will describe some new bioprinting applications that pave the way to the clinical use of stem cell-based therapies, such as scaffold-free bioprinting and the development of a 3D handheld device for the in situ repair of cartilage defects

Better Memory and Neural Efficiency in Young Apolipoprotein E ε4 Carriers

The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer's disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE ε4 with better episodic memory compared with APOE ε2 and ε3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas ε2 and ε3 carriers increased activity. This smaller neural investment of ε4 carriers into learning reappeared during retrieval: ε4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE ε4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy human

Calmodulin-binding transcription activator 1 (CAMTA1) alleles predispose human episodic memory performance

Little is known about the genes and proteins involved in the process of human memory. To identify genetic factors related to human episodic memory performance, we conducted an ultra-high-density genome-wide screen at > 500000 single nucleotide polymorphisms (SNPs) in a sample of normal young adults stratified for performance on an episodic recall memory test. Analysis of this data identified SNPs within the calmodulin-binding transcription activator 1 (CAMTA1) gene that were significantly associated with memory performance. A follow up study, focused on the CAMTA1 locus in an independent cohort consisting of cognitively normal young adults, singled out SNP rs4908449 with a P-value of 0.0002 as the most significant associated SNP in the region. These validated genetic findings were further supported by the identification of CAMTA1 transcript enrichment in memory-related human brain regions and through a functional magnetic resonance imaging experiment on individuals matched for memory performance that identified CAMTA1 allele-specific upregulation of medial temporal lobe brain activity in those individuals harboring the ‘at-risk' allele for poorer memory performance. The CAMTA1 locus encodes a purported transcription factor that interfaces with the calcium-calmodulin system of the cell to alter gene expression patterns. Our validated genomic and functional biological findings described herein suggest a role for CAMTA1 in human episodic memor

Better Memory and Neural Efficiency in Young Apolipoprotein E 4 Carriers

The apolipoprotein E (APOE) epsilon4 allele is the major genetic risk factor for Alzheimer's disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE epsilon4 with better episodic memory compared with APOE epsilon2 and epsilon3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas epsilon2 and epsilon3 carriers increased activity. This smaller neural investment of epsilon4 carriers into learning reappeared during retrieval: epsilon4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE epsilon4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans

Genetic influences on memory performance, memory-related brain activity, and neuroanatomy investigated with functional and structural magnetic resonance imaging

In dieser Doktorarbeit wurden genetische Analysen, bildgebende Verfahren und quantitative, neuropsychologische und experimentalpsychologische Methoden kombiniert, um genetische Einflüsse auf die Gedächtnisfunktion, die gedächtnisbezogene Hirnaktivität und Neuroanatomie zu untersuchen. In zwei unabhängigen Studien wurden die Effekte des ApolipoproteinE Gens (APOE) und die Effekte einer Mutation (C410Y) im Presenilin 1 Gen (PSEN1) erforscht. Das ε4 Allel des APOE Gens (APOE4) ist der wichtigste genetische Risikofaktor für die sporadische Form der Alzheimer Demenz (AD). Ausserdem kann dieses Allel im Alter eine schädigende Wirkung auf die Kognition und weitere biologische Prozesse ausüben. Die Resultate aus der ersten Studie zeigen, dass das APOE4 mit einem besseren episodischen Gedächtnis und mit reduzierter gedächtnisbezogener Hirnaktivität in gesunden, jungen Erwachsenen assoziiert ist. Es scheint, dass dieses Allel zu einem ökonomischen Gebrauch neuronaler Ressourcen führt und einen positiven Effekt auf die Gedächtnisfunktion im jungen Erwachsenenalter ausüben kann.Die C410Y Mutation im PSEN1 Gen wird autosomal dominant vererbt und führt zu familiärer AD (FAD). In der zweiten Studie wird eine erhöhte gedächtnisbezogene Hirnaktivität in einem jungen Mutationsträger aus einer Familie mit FAD gezeigt. Diese erhöhte Hirnaktivität wird als kompensatorischer Mechanismus interpretiert, welcher erste AD-bezogene neuronale Dysfunktionen auszugleichen versucht. In Zukunft könnte sich die funktionelle Magnetresonanztomographie als wertvolles Instrument zur Früherkennung von Alzheimer erweisen. In this doctoral thesis genetic analyses, neuroimaging, quantitative neuropsychological assessments, and methods from experimental psychology were combined to detect genetic influences on memory capacity, memory-related brain activity, and neuroanatomy. In two independent studies effects of the Apolipoprotein E gene (APOE) and effects of a mutation (C410Y) in the presenilin 1 gene (PSEN1) have been examined. The ε4 allele of the APOE gene (APOE4) is a major genetic risk factor for the development of sporadic Alzheimer's disease (AD) and exerts detrimental effects on cognition and several biological processes in later life stages. The results from the first study show that APOE4 was associated with better episodic memory and reduced memory-related neural activity in healthy young adults. It appears that this allele leads to an economic use of neural resources and therefore might confer a beneficial effect on memory processing in early adulthood. The C410Y mutation in the PSEN1 gene is transmitted in an autosomal dominant manner and causes familial AD (FAD). The results from the second study show that memory-related brain activity was increased in a young mutation carrier from a family with FAD when compared to a control group. This enhancement of brain activity might reflect compensatory mechanisms to overcome early AD-related neural dysfunction. In the future functional magnetic resonance imaging could be a valuable tool for the early detection of AD markers

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

There is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain beta-amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46 TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TT-homozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between. Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TT-homozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences beta-amyloid metabolism. CYP46 C-carriers are privileged both in terms of beta-amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated

Sexual dimorphism in the parietal substrate associated with visuospatial cognition independent of general intelligence

Gender differences in visuospatial cognition (VSC) with male advantage are frequently reported in the literature. There is evidence for sexual dimorphisms in the human brain, one of which postulates more gray matter (GM) in females and more white matter (WM) in males relative to total intracranial volume. We investigated the neuroanatomy of VSC independent of general intelligence (g) in gender-separated populations, homogenous in age, education, memory performance, a memory- and brain morphology-related gene, and g. VSC and g were assessed with the Wechsler adult intelligence scale. The influence of g on VSC was removed using a hierarchical factor analysis and the Schmid-Leiman solution. Structural high-resolution magnetic resonance images were acquired and analyzed with voxel-based morphometry. As hypothesized, the clusters of positive correlations between local volumes and VSC performance independent of g were found mainly in parietal areas, but also in pre- and postcentral regions, predominantly in the WM in males, whereas in females these correlations were located in parietal and superior temporal areas, predominantly in the GM. Our results suggest that VSC depends more strongly on parietal WM structures in males and on parietal GM structures in females. This sex difference might have to do with the increased axonal and decreased somatodendritic tissue in males relative to females. Whether such gender-specific implementations of the VSC network can be explained genetically as suggested in investigations into the Turner syndrome or as a result of structural neural plasticity upon different experience and usage remains to be shown

Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations.

BACKGROUND In a high proportion of patients with favorable outcome after aneurysmal subarachnoid hemorrhage (aSAH), neuropsychological deficits, depression, anxiety, and fatigue are responsible for the inability to return to their regular premorbid life and pursue their professional careers. These problems often remain unrecognized, as no recommendations concerning a standardized comprehensive assessment have yet found entry into clinical routines. METHODS To establish a nationwide standard concerning a comprehensive assessment after aSAH, representatives of all neuropsychological and neurosurgical departments of those eight Swiss centers treating acute aSAH have agreed on a common protocol. In addition, a battery of questionnaires and neuropsychological tests was selected, optimally suited to the deficits found most prevalent in aSAH patients that was available in different languages and standardized. RESULTS We propose a baseline inpatient neuropsychological screening using the Montreal Cognitive Assessment (MoCA) between days 14 and 28 after aSAH. In an outpatient setting at 3 and 12 months after bleeding, we recommend a neuropsychological examination, testing all relevant domains including attention, speed of information processing, executive functions, verbal and visual learning/memory, language, visuo-perceptual abilities, and premorbid intelligence. In addition, a detailed assessment capturing anxiety, depression, fatigue, symptoms of frontal lobe affection, and quality of life should be performed. CONCLUSIONS This standardized neuropsychological assessment will lead to a more comprehensive assessment of the patient, facilitate the detection and subsequent treatment of previously unrecognized but relevant impairments, and help to determine the incidence, characteristics, modifiable risk factors, and the clinical course of these impairments after aSAH

Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations

Background: In a high proportion of patients with favorable outcome after aneurysmal subarachnoid hemorrhage (aSAH), neuropsychological deficits, depression, anxiety, and fatigue are responsible for the inability to return to their regular premorbid life and pursue their professional careers. These problems often remain unrecognized, as no recommendations concerning a standardized comprehensive assessment have yet found entry into clinical routines. Methods: To establish a nationwide standard concerning a comprehensive assessment after aSAH, representatives of all neuropsychological and neurosurgical departments of those eight Swiss centers treating acute aSAH have agreed on a common protocol. In addition, a battery of questionnaires and neuropsychological tests was selected, optimally suited to the deficits found most prevalent in aSAH patients that was available in different languages and standardized. Results: We propose a baseline inpatient neuropsychological screening using the Montreal Cognitive Assessment (MoCA) between days 14 and 28 after aSAH. In an outpatient setting at 3 and 12months after bleeding, we recommend a neuropsychological examination, testing all relevant domains including attention, speed of information processing, executive functions, verbal and visual learning/memory, language, visuo-perceptual abilities, and premorbid intelligence. In addition, a detailed assessment capturing anxiety, depression, fatigue, symptoms of frontal lobe affection, and quality of life should be performed. Conclusions: This standardized neuropsychological assessment will lead to a more comprehensive assessment of the patient, facilitate the detection and subsequent treatment of previously unrecognized but relevant impairments, and help to determine the incidence, characteristics, modifiable risk factors, and the clinical course of these impairments after aSAH