Functional and Structural MRI in Alzheimer’s Disease: A Multimodal Approach

Alzheimer’s disease (AD) is strongly influenced by genetic factors as evidenced by numerous family and twin studies. Over the past two decades, others and we have co-discovered three early-onset familial AD genes, APP, PSEN1, and PSEN2, which can carry any of >200 fully penetrant mutations characterized by mendelian inheritance. For late-onset AD, the most prevalent and highest impact risk factor is the epsilon 4 variant of APOE, which increases risk by 3.7-fold in the heterozygous state and >10-fold when two copies are inherited. As part of our Alzheimer’s Genome Project funded by the Cure Alzheimer’s Fund and the NIMH, we have been identifying novel AD candidate genes. In Bertram et al. (2008), we reported genome-wide association of AD with several loci including the spinocerebellar ataxia 1 gene, ATXN1, and the SIGLEC3 gene, CD33. Functional studies of the ATXN1 gene carried out both in vitro and in vivo in ATXN1 knockout mice show that ATXN1 can regulate Aβ levels via modulation of β-secretase. CD33 is just one of several genes (TREM2, CR1, etc) involved in the innate immune system of the brain that have been associated with AD risk. In addition, we discovered association of AD with ADAM10, which encodes the major α-secretase in the brain. Re-sequencing of this gene in the best associated AD families led to two rare mutations that tightly co-segregated with AD in seven (of 1000) AD families screened, all with average age of onset ~70 years. We have shown both mutations to impair ADAM10 non-amyloidogenic cleavage of APP in vitro and in transgenic mice, including double trangenics with AD (tg2576) mice. Thus, these are the first rare, highly penetrant mutations reported for late-onset AD. We have also carried out genome-wide association studies on >800 well-characterized late-onset AD families (NIMH and NIA-LOAD samples) using Affymetrix genotyping arrays containing either one million (6.0) or 20,000 coding SNPs. More recently, we have performed whole genome sequencing (Illumina, Hiseq) on over 1500 samples from AD families/sibships. The elucidation of the genes and functional variants influencing risk for AD should continue to enhance our understanding of AD etiology and pathogenesis. Ultimately, these genes will be used to predict risk for AD and guide novel the development of therapies for the effective treatment and prevention of this terrible disease.

Alzheimer’s disease (AD) is a common form of neurodegeneration that entails a progressive breakdown of cognitive functions. Cognitive impairments commonly begin with noticeable difficulties in remembering recent events (Gold & Budson, 2008; Ally, Gold & Budson, 2009), as well as spatial disorientation (Duffy, Cushman & Kavcic, 2004) and semantic memory impairments (Milberg, McGlinchey-Berroth, Duncan & Higgins, 1999). As the disease progresses, AD also entails impairments to visual cognition, which encompasses processes that help us to understand what we see (Cronin-Golomb, 1995). The purpose of this chapter is to review recent progress towards understanding aspects of visual cognition in AD, including visual memory and visual attention, and then explore how this research can be applied to assist in the daily living of AD patients. Humans normally rely tremendously on vision for interacting with the world. Therefore, there is a profound impact on everyday activities when visual impairments develop. For example, Perry and Hodges (2000) showed that measures of visuospatial functions, semantic memory, and attention correlated significantly with measures of daily living in patients with AD, but measures of episodic and verbal short-term memory did not. Further, impairments to visual attention and memory in patients with mild-to-moderate AD lead to poor performance in complex situations like driving (Rizzo, Sparks, McEvoy, Viamonte, Kellison & Vecera, 2009) and measures of financial responsibility (Sherod, Griffith, Copeland, Belue, Krzywanski et al., 2009). Finally, certain visual abilities, like assembling an image from its parts, deteriorate as AD progresses, providing a reliable means of tracking the progress of AD in a given patient (Paxton, Peavy, Jenkins, Rice, Heindel & Salmon, 2007). Changes in everyday visual abilities can be observed very early in the disease, even in patients with mild cognitive impairment (MCI), which is thought to be a precursor to AD (Farias, Mungas, Reed, Harvey et al., 2006). Together, these studies suggest that measurable visual impairments in AD are strongly related to deterioration in everyday activities. Since the decline of visual abilities can have a very profound effect on daily living, a better understanding of AD-related changes to visual cognition, and the development of subsequent interventional strategies, promise to lead to improvements in patients’ quality of life. This chapter will place an emphasis on visual short-term memory (VSTM) in patients with AD, which has only recently been investigated. We will first describe the basic process of VSTM and then review the changes known to occur in AD. Then, we will review the interaction between visual attention and VSTM in AD patients and indicate how these two

Alzheimer’s disease (AD) is a neurodegenerative disorder with progressive decline of cognitive function. The characteristic pathological features of the postmortem brain of AD patients include, among other features, the presence of numerous neurite plaques (NPs) in the brain, which contain a compact deposit of proteinaceous amyloid fiilaments surrounded by dystrophic neurites, activated microglia, and fiibrillary astrocytes1. The amyloid filaments are composed of 39–43-amino acid amyloid β-peptides (As), which are derived proteolytically from a larger transmembrane glycoprotein, the amyloid precursor protein (APP)2. Several reports suggest that As-related peptides can be secreted constitutively under normal conditions2. It is likely that an overproduction, lack of degradation, and / or clearance mechanisms may trigger amyloid deposition and the development of AD pathogenesis. Indeed, several missense mutations in the APP or presenilin (PSI and PS2) genes, which have been linked to familial AD, result in either excess generation of As peptides or in a shift to the production of longer, more amyloidogenic As peptides1. The severity of dementia has been suggested to correlate positively with the As deposition observed in the postmortem brains of AD patients3. Furthermore, transgenic mice overexpressing human APP gene display cognitive impairments and / or some pathological features of AD brain, including NPs4, even though neurotoxic effects of As in vivo have been somewhat controversial5. These observations, together with several other lines of evidence6 implicate As deposition as an initiating and / or contributing factor in AD pathogenesis.

Concern over the amyloid vaccine: amyloid heterogeneity and Fc receptor signaling.

INTRODUCTION:Various chronic pain conditions go along with functional and structural brain changes. This study aimed to investigate functional and structural brain changes by magnetic resonance imaging (MRI) in inflammatory bowel disease (IBD) patients with chronic abdominal pain.METHODS:Sixty-four subjects were included in the final analysis (32 IBD patients with chronic abdominal pain; 32 age-matched and sex-matched controls). All patients suffered from chronic abdominal pain, defined as a score of ≥3/10 on the visual analog scale for at least 3 months in the past 6 months. Besides structural MRI, resting state functional MRI was used to compare functional connectivity of 10 networks between groups.RESULTS:Patients with IBD showed no structural brain alterations but a significantly increased resting state functional connectivity of the secondary somatosensory cortex within the salience network.DISCUSSION:Because the secondary somatosensory cortex saves sensory stimuli and compares novel information with latter experiences, these functions may be maladaptive in IBD patients with abdominal pain.

Alzheimer's Disease (AD) is considered one of the most debilitating illness in modern societies and the leading cause of dementia. This study is a new approach to detect early AD Electroencephalogram (EEG) temporal events in order to improve early AD diagnosis. For that, Self-Organized Maps (SOM) were used, and it was found that there are sequences of EEG energy variation, characteristic of AD, that appear with high incidence in Mild Cognitive Impairment (MCI) patients. Those AD events are related to the first cognitive changes in patients that interfered with the normal EEG signal pattern. Moreover, there are significant differences concerning the propagation time of those events between the study groups(p=0.0082<0.05), meaning that, as AD progresses the brain dynamics are progressively affected, what is expected because AD causes brain atrophy.

Alzheimer disease (AD), the most common form of dementia, is a neurodegenerative disorder characterized by neuronal and synaptic loss. Despite its high prevalence and great cost to society, there is no definitive premortem test for AD (1)(2). The diagnosis of probable or possible AD is based on a history of insidious onset and progressive impairment of memory as well as loss of other cognitive functions (3). The most important clinical task is the exclusion of reversible causes of dementia, most commonly vascular dementia. It is of little comfort to treating physicians and family members that postmortem examination of the brain by the pathologist is the only reliable diagnostic test for AD. Typically, microscopic examination of stained sections of brain taken from cortical and limbic brain regions reveals the hallmark changes of AD, namely, accumulation of intracellular neurofibrillary tangles and extracellular amyloid plaques. Neurofibrillary tangles are composed mainly of abnormally hyperphosphorylated tau protein (P-TAU). The extracellular amyloid plaques are composed of the 40- and 42-amino acid-long β-amyloid peptides [Aβ(1–40) and Aβ(1–42)]. Several neuropathologic subtypes of AD have been described, depending principally on the cortical regions most affected by neuronal loss, and the rates …

Alzheimer's disease (AD) is the leading cause of dementia in the population. Difficulties in diagnosing AD have served as an incentive for actively studying different current methods that increase the accuracy of diagnosis of the current neurodegenerative process in this disease. One of these areas is the post-processing of magnetic resonance imaging (MRI) data, by exactly calculating the volume of various anatomical formations, namely MRI morphometry.Objective:to determine the possible relationship between the results of evaluating the higher brain functions and the reduction in the hippocampal volume calculated by MRI morphometry in AD patients with mild and moderate dementia and in healthy controls.Patients and methods.Examinations were made in 41 AD patients aged 70.63±8.38 years with mild and moderate dementia and in healthy individuals. All study participants underwent neuropsychological testing that included the Mini-Mental State Examination (MMSE), the frontal lobe dysfunction battery (FLDB); immediate and delayed 12-word recall trials (12-word test); Benton's revised visual retention test; test of literal and categorical associations; clock drawing test; and series number test, Part A. MRI was performed on a Siemens Magnetom Skyra 3T MRI scanner. Statistical Parametric Mapping software was used to convert images and the volume of the hippocampus was estimated by FMRIB Software Library.Results and discussion.A statistically significant decrease in hippocampal volumes was established in patients with AD compared with healthy individuals. No statistically significant differences in hippocampal volumes were found in patients with varying degrees of dementia. Patients with mild and moderate dementia differed in all indicators of neuropsychological tests, with exception for the 12-word test and Benton's test. There was a statistically significant correlation of the total volume of the hippocampi with the indicators of MMSE, FLDB, 12- word test, clock drawing test, and test of categorical associations.Conclusion.Hippocampal MRI morphometry in combination with neuropsychological tests is an informative technique in the diagnosis of AD. There is a relationship between the degree of hippocampal atrophy and the neuropsychological characteristics of patients.

Speech features extracted from automated remote cognitive assessments correlate with performance on traditional cognitive tasks in individuals at risk of Alzheimer's Disease (AD), demonstrating their potential to support early diagnosis. However, the capability of these features to signal early AD-related brain changes remains less explored. Within the PROSPECT-AD study, 234 participants ranging from cognitively normal to mild cognitive impairment were recruited from the German DZNE longitudinal cohorts DELCODE and DESCRIBE. At home, all participants completed the phone-based and chatbot-guided Semantic Verbal Fluency task (SVF) and the Rey Auditory Verbal Learning Test (RAVLT). Linguistic and acoustic features were automatically extracted from phone call recordings using an AI model to calculate task-specific and composite cognitive scores. Structural MRI, functional MRI, and various paper-and-pencil cognitive scores were collected during cohort visits. We employed multiple linear regression, mixed-effects models, and independent component analysis (ICA), followed by voxel-wise post hoc analyses, to assess associations between digital speech-based indicators and: (1) cross-sectional brain atrophy (n=108), (2) longitudinal brain atrophy (n=90), (3) cross-sectional resting-state functional connectivity (n=86), and additionally (4) trajectories of cognitive decline (n=146). SVF correct counts were positively associated with brain volumes in the left temporal pole, left inferior, middle, and superior temporal gyri (The t(100) values ranged from 4.48 to 4.96) in voxel-wise analyses (Figure 1a). Longitudinal analyses indicated that higher SVF correct counts were linked to slower rates of hippocampal and anterior cingulate atrophy (Figure 1b). Functional connectivity analyses suggested that SVF features, such as word frequency, were associated with rsFC areas within the default mode network (The t(71) values ranged from 3.65 to 3.85) (Figure 1c). Higher composite cognitive scores, along with SVF and RAVLT features, were associated with slower cognitive decline, as measured by established paper-and-pencil cognitive assessments, including the Preclinical Alzheimer Cognitive Composite (PACC) 5, SVF, and RAVLT delayed recall (Figure 2). Phone-based cognitive assessments hold promise as a remote and scalable tool for identifying AD-related structural and functional brain changes. They offer predictive value for cognitive trajectories in pre-dementia populations. This approach could aid in identifying individuals at risk while guiding further evaluation, broadening their utility beyond cognitive screening.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia. Aging is among the most significant risk factors. Today, AD can be diagnosed with certainty only post mortem, detecting insoluble beta-amyloid peptide (Abeta) aggregates in the patient's brain tissue. We have developed an ultrasensitive assay for early and non-invasive diagnosis of AD. This highly specific and sensitive assay uses fluorescence correlation spectroscopy (FCS) and is sensitive enough to detect even single aggregates in body fluids of AD patients. We investigate the correlation of aggregated Abeta concentrations in body fluids with clinical symptoms of AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Substantial evidence suggests a role for nutrition in the management of AD and especially suggests that interventions with combinations of nutrients are more effective than single-nutrient interventions. The specific multi-nutrient combination Fortasyn™Connect (FC), shown to improve memory in AD, provides phosphatide precursors and cofactors and is designed to stimulate the formation of phospholipids, neuronal membranes, and synapses. The composition comprises nucleotides, omega-3 polyunsaturated fatty acids (n3 PUFA), choline, B-vitamins, phospholipids, and antioxidants. The current study explored the protective properties of FC in a membrane toxicity model of AD, the amyloid-β 1-42 (Aβ42) infused rat, which shows reduced exploratory behavior in an Open Field and impaired cholinergic functioning. To this end, rats were fed an FC enriched diet or a control diet and five weeks later infused with vehicle or Aβ42 into the lateral ventricle. Ten weeks post-infusion Aβ42-rats fed the FC diet showed increased membrane n3 PUFA and phosphatidylcholine content while they did not show the reductions in exploratory behavior or in choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunoreactivity that were seen in Aβ42-rats fed the control diet. We conclude that FC protects the cholinergic system against Aβ42-induced toxicity and speculate that the effects of FC on membrane formation and composition might be supportive for this protective effect. Based on these data a long-term intervention study was started in the prodromal stages of AD (NTR1705, LipiDiDiet, EU FP7).

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, whereas frontotemporal lobar degeneration (FTLD) is the most frequent neurodegenerative disorder with a pre-senile onset. The two major neuropathological hallmarks of AD are extracellular amyloid beta plaques and intracellular neurofibrillary tangles. In FTLD the deposition of tau has been observed in a number of cases, but in several brains there is no deposition of tau but instead a positivity for ubiquitin. In some families these diseases are inherited in an autosomal dominant fashion. Genes responsible for familial AD include the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2), whereas the main genes responsible for familial FTLD are microtubule-associated protein tau gene (MAPT) and progranulin (GRN). Concerning sporadic AD, it is known that the presence of the ε4 allele of the apolipoprotein E gene is a susceptibility factor. A number of additional genetic factors contribute to susceptibility for AD and FTLD.

Alzheimers disease (AD) is the most common progressive neurodegenerative illness and cause of dementia in the elderly. The critical barriers for primary prevention in AD are the lack of rapid, non-invasive, sensitive and low-cost biomarkers. As the eye and brain share essential structural and pathogenic pathways, non-invasive eye biomarkers could be identified to obtain new insights into the onset and progression of AD and its complications in the eye. In this short review, recent developments of retinal image analysis in AD and potential artificial intelligence (AI) applications are presented. Some approaches are still very much novel research techniques, others are more established and transitioning into the clinical diagnostic arena. Together they provide us with the capability to move AD detection research forwards by using novel peripheral biomarkers.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes severe deterioration of functional and cognitive abilities. As the leading cause of dementia in adults, it affects one in every 10 people who are more than 65 years of age. There is a vital need for neuroscience nurses with knowledge of AD to provide high-quality care for the growing number of patients. The use of effective nursing interventions for the management of AD can help nurses promote independence and quality of life for AD patients. Nursing care must include interventions that focus on maintaining AD patients' functional and cognitive abilities as well as on preventing further disability and decline. Nurses can implement these measures in acute, long-term, and home healthcare settings.

Alzheimer’s disease (AD) remains one of the most disabling health conditions in elderly population worldwide. The socio-economic burden of the disease is likely to increase due to increasing life expectancy. Increasing understanding of AD pathogenesis suggests heterogeneous nature of this disease, with number of underlying mechanisms operating simultaneously, contributing to the ultimate phenotype. Neuropathological hallmarks of AD include senile plaques and neurofibrillary tangles, neuronal atrophy and cortical neurodegeneration. There is currently no cure for AD and the available treatments can provide only a degree of symptomatic benefit to patients with mild-to-moderate AD. In this review, we focus on the current understanding of AD, available symptomatic treatments and potential disease modifying opportunities being pursued in the pharmaceutical industry as well as in academia