Imaging genetics refers to the use of anatomical or physiological imaging technologies as phenotypic assays to evaluate genetic variation. Scientists that first used the term imaging genetics were interested in how genes influence psychopathology and used functional neuroimaging to investigate genes that are expressed in the brain (neuroimaging genetics). [1]
Imaging genetics uses research approaches in which genetic information and fMRI data in the same subjects are combined to define neuro-mechanisms linked to genetic variation. [2] With the images and genetic information, it can be determined how individual differences in single nucleotide polymorphisms, or SNPs, lead to differences in brain wiring structure, and intellectual function. [3] Imaging genetics allows the direct observation of the link between genes and brain activity in which the overall idea is that common variants in SNPs lead to common diseases. [4] A neuroimaging phenotype is attractive because it is closer to the biology of genetic function than illnesses or cognitive phenotypes. [5]
By combining the outputs of the polygenic and neuro-imaging within a linear model, it has been shown that genetic information provides additive value in the task of predicting Alzheimer's disease (AD). [6] AD traditionally has been considered a disease marked by neuronal cell loss and widespread gray matter atrophy and the apolipoprotein E allele (APOE4) is a widely confirmed genetic risk factor for late-onset AD. [7]
Another gene risk variant is associated with Alzheimer's, which is known as the CLU gene risk variant. The CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life. [7] Each CLU-C allele was associated with lower FA in frontal, temporal, parietal, occipital, and subcortical white matter. [7] Brain regions with lower FA included corticocortical pathways previously demonstrated to have lower FA in AD patients and APOE4 carriers. [7] CLU-C related variability found here might create a local vulnerability important for disease onset. [7] These effects are remarkable as they already exist early in life and are associated with a risk gene that is very prevalent (~36% of Caucasians carry two copies of the risk conferring genetic variant CLU-C.) [7] Quantitative mapping of structural brain differences in those at genetic risk of AD is crucial for evaluating treatment and prevention strategies. If the risk for AD is identified, appropriate changes in lifestyle may limit the apprehension of AD; exercise and body mass index-have an effect on brain structure and the level of brain atrophy [7]
If suitable biomarkers are found and applied in clinical use, we will be able to give the diagnosis of the AD spectrum at an even earlier stage. [8] In the proposal, the AD spectrum is divided into the three stages (i) the preclinical stage; (ii) mild cognitive impairment; and (iii) clinical AD. [8] In the preclinical stage, only changes in a specific biomarker are observed with neither cognitive impairment nor clinical signs of AD. The mild cognitive impairment stage may include those showing biomarker changes as well as mild cognitive decline but no clinical signs and symptoms of AD. AD is diagnosed in patients with biomarker changes and clinical signs and symptoms of AD. This concept will promote understanding of the continuous transition from preclinical stage to AD via mild cognitive impairment, in which biomarkers can be utilized to discriminate and clearly define each stage of the AD spectrum. The new criteria will promote earlier detection of the subjects who will develop AD in later life, and also to initiate intervention aiming for the prevention of AD.
Imaging genetics must develop methods that will allow relating the effects of a large number of genetic variants on equally multi-dimensional neuroimaging phenotypes. [9] Additionally, the field of imaging epigenetics is emerging with particular relevance, for example, to the understanding of intergenerational transmission of trauma-related psychopathology and related disturbances of maternal care. [10]
Medication, hospitalization history, or associated behaviors ranging such as smoking can affect imaging. [9]
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Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions. Memory loss is not always an early symptom. The disease worsens over time and is usually diagnosed when cognitive impairment interferes with normal daily functioning. Together with Parkinson's disease dementia, DLB is one of the two Lewy body dementias. It is a common form of dementia, but the prevalence is not known accurately and many diagnoses are missed. The disease was first described by Kenji Kosaka in 1976.
Primary progressive aphasia (PPA) is a type of neurological syndrome in which language capabilities slowly and progressively become impaired. As with other types of aphasia, the symptoms that accompany PPA depend on what parts of the left hemisphere are significantly damaged. However, unlike most other aphasias, PPA results from continuous deterioration in brain tissue, which leads to early symptoms being far less detrimental than later symptoms. Those with PPA slowly lose the ability to speak, write, read, and generally comprehend language. Eventually, almost every patient becomes mute and completely loses the ability to understand both written and spoken language. Although it was first described as solely impairment of language capabilities while other mental functions remain intact, it is now recognized that many, if not most of those with PPA experience impairment of memory, short-term memory formation and loss of executive functions. It was first described as a distinct syndrome by M. Marsel Mesulam in 1982. Primary progressive aphasias have a clinical and pathological overlap with the frontotemporal lobar degeneration (FTLD) spectrum of disorders and Alzheimer's disease. However, PPA is not considered synonymous to Alzheimer's disease due to the fact that, unlike those affected by Alzheimer's disease, those with PPA are generally able to maintain the ability to care for themselves, remain employed, and pursue interests and hobbies. Moreover, in diseases such as Alzheimer's disease, Pick's disease, and Creutzfeldt-Jakob disease, progressive deterioration of comprehension and production of language is just one of the many possible types of mental deterioration, such as the progressive decline of memory, motor skills, reasoning, awareness, and visuospatial skills.
Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in the Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.
Cognitive reserve is the mind's and brain's resistance to damage of the brain. The mind's resilience is evaluated behaviorally, whereas the neuropathological damage is evaluated histologically, although damage may be estimated using blood-based markers and imaging methods. There are two models that can be used when exploring the concept of "reserve": brain reserve and cognitive reserve. These terms, albeit often used interchangeably in the literature, provide a useful way of discussing the models. Using a computer analogy, brain reserve can be seen as hardware and cognitive reserve as software. All these factors are currently believed to contribute to global reserve. Cognitive reserve is commonly used to refer to both brain and cognitive reserves in the literature.
Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individual's age and education but which are not significant enough to interfere with instrumental activities of daily living. MCI may occur as a transitional stage between normal aging and dementia, especially Alzheimer's disease. It includes both memory and non-memory impairments. The cause of the disorder remains unclear, as well as both its prevention and treatment, with some 50 percent of people diagnosed with it going on to develop Alzheimer's disease within five years. The diagnosis can also serve as an early indicator for other types of dementia, although MCI may remain stable or even remit.
Posterior cortical atrophy (PCA), also called Benson's syndrome, is a rare form of dementia which is considered a visual variant or an atypical variant of Alzheimer's disease (AD). The disease causes atrophy of the posterior part of the cerebral cortex, resulting in the progressive disruption of complex visual processing. PCA was first described by D. Frank Benson in 1988.
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation, mood swings, loss of motivation, self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.
Genetic heterogeneity occurs through the production of single or similar phenotypes through different genetic mechanisms. There are two types of genetic heterogeneity: allelic heterogeneity, which occurs when a similar phenotype is produced by different alleles within the same gene; and locus heterogeneity, which occurs when a similar phenotype is produced by mutations at different loci.
Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite study that aims to improve clinical trials for the prevention and treatment of Alzheimer's disease (AD). This cooperative study combines expertise and funding from the private and public sector to study subjects with AD, as well as those who may develop AD and controls with no signs of cognitive impairment. Researchers at 63 sites in the US and Canada track the progression of AD in the human brain with neuroimaging, biochemical, and genetic biological markers. This knowledge helps to find better clinical trials for the prevention and treatment of AD. ADNI has made a global impact, firstly by developing a set of standardized protocols to allow the comparison of results from multiple centers, and secondly by its data-sharing policy which makes available all at the data without embargo to qualified researchers worldwide. To date, over 1000 scientific publications have used ADNI data. A number of other initiatives related to AD and other diseases have been designed and implemented using ADNI as a model. ADNI has been running since 2004 and is currently funded until 2021.
Anders Martin Dale is a prominent neuroscientist and professor of radiology, neurosciences, psychiatry, and cognitive science at the University of California, San Diego (UCSD), and is one of the world's leading developers of sophisticated computational neuroimaging techniques. He is the founding Director of the Center for Multimodal Imaging Genetics (CMIG) at UCSD.
Cognitive genomics is the sub-field of genomics pertaining to cognitive function in which the genes and non-coding sequences of an organism's genome related to the health and activity of the brain are studied. By applying comparative genomics, the genomes of multiple species are compared in order to identify genetic and phenotypical differences between species. Observed phenotypical characteristics related to the neurological function include behavior, personality, neuroanatomy, and neuropathology. The theory behind cognitive genomics is based on elements of genetics, evolutionary biology, molecular biology, cognitive psychology, behavioral psychology, and neurophysiology.
Florbetaben, a fluorine-18 (18F)-labeled stilbene derivative, trade name NeuraCeq, is a diagnostic radiotracer developed for routine clinical application to visualize β-amyloid plaques in the brain. It is indicated for Positron Emission Tomography (PET) imaging of β-amyloid neuritic plaque density in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment. β-amyloid is a key neuropathological hallmark of AD, so markers of β-amyloid plaque accumulation in the brain are useful in distinguishing AD from other causes of dementia. The tracer successfully completed a global multicenter phase 0–III development program and obtained approval in Europe, US and South Korea in 2014.
Alcohol-related brain damage alters both the structure and function of the brain as a result of the direct neurotoxic effects of alcohol intoxication or acute alcohol withdrawal. Increased alcohol intake is associated with damage to brain regions including the frontal lobe, limbic system, and cerebellum, with widespread cerebral atrophy, or brain shrinkage caused by neuron degeneration. This damage can be seen on neuroimaging scans.
L1 syndrome is a group of mild to severe X-linked recessive disorders that share a common genetic basis. The spectrum of L1 syndrome disorders includes X-linked complicated corpus callosum dysgenesis, spastic paraplegia 1, MASA syndrome, and X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS). It is also called L1CAM syndrome and CRASH syndrome, an acronym for its primary clinical features: corpus callosum hypoplasia, retardation, adducted thumbs, spasticity, and hydrocephalus.
Giulio Maria Pasinetti is the Program Director of the Center on Molecular Integrative Neuroresilience and is the Saunders Family Chair in Neurology at the Icahn School of Medicine at Mount Sinai (ISMMS) in New York City. Pasinetti is a Professor of Neurology, Psychiatry, Neuroscience, and Geriatrics and Palliative Medicine at ISMMS.
Czech Brain Ageing Study (CBAS) is a longitudinal, observational study on aging and dementia from two large centers in the Czech Republic combining clinical care and clinical research.
Carlos Cruchaga is a human genomicist with expertise in multi-omics, informatics, and neurodegeneration, with a focus on Alzheimer's and Parkinson's Disease. He is a Professor of Psychiatry, Neurology and Genetics and Washington University School of Medicine. He is founding director of the Neurogenomics and Informatic (NGI) center at Washington University School of Medicine.
Nicole Schupf is an American epidemiologist and neuroscientist who is Professor of Epidemiology in Neurology, Psychiatry, the Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Faculty of Medicine. She studies aging and Alzheimer's disease in individuals with Down syndrome.
Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.
Alzheimer's disease (AD) in African Americans is becoming a rising topic of interest in AD care, support, and scientific research, as African Americans are disproportionately affected by AD. Recent research on AD has shown that there are clear disparities in the disease among racial groups, with higher prevalence and incidence in African Americans than the overall average. Pathologies for Alzheimer’s also seem to manifest differently in African Americans, including with neuroinflammation markers, cognitive decline, and biomarkers. Although there are genetic risk factors for Alzheimer’s, these account for few cases in all racial groups.
