Loss of memory is among the first symptoms reported by patients suffering from Alzheimer's disease (AD) and by their caretakers. Working memory and long-term declarative memory are affected early during the course of the disease. The individual pattern of impaired memory functions correlates with parameters of structural or functional brain integrity. AD pathology interferes with the formation of memories from the molecular level to the framework of neural networks. The investigation of AD memory loss helps to identify the involved neural structures, such as the default mode network, the influence of epigenetic and genetic factors, such as ApoE4 status, and evolutionary aspects of human cognition. Clinically, the analysis of memory assists the definition of AD subtypes, disease grading, and prognostic predictions. Despite new AD criteria that allow the earlier diagnosis of the disease by inclusion of biomarkers derived from cerebrospinal fluid or hippocampal volume analysis, neuropsychological testing remains at the core of AD diagnosis.

Memory loss in Alzheimer's disease.

Proton magnetic resonance spectroscopy (1H MRS) has been applied to numerous clinical studies, especially for neurological disorders. This technique can non-invasively evaluate brain metabolites and neurochemicals in selected brain regions and is particularly useful for assessing neuroinflammatory disorders. Neurometabolites assessed with MRS include the neuronal markers N-acetylaspartate (NAA) and glutamate (Glu), as well as the glial marker myo-inositol (MI). Therefore, the concentrations of these metabolites typically correspond to disease severity and often correlate well with clinical variables in the various brain disorders. Neuroinflammation with activated astrocytes and microglia in brain disorders are often associated with elevated MI, and to a lesser extent elevated total creatine (tCr) and choline containing compounds (Cho), which are found in higher concentrations in glia than neurons, while neuronal injury is indicated by lower than normal levels of NAA and Glu. This review summarizes the neurometabolite abnormalities found in MRS studies performed in patients with neuroinflammatory disorders or neuropathic pain, which also may be associated with neuroinflammation. These brain disorders include multiple sclerosis, neuroviral infections (including Human Immunodeficiency virus and Hepatitis C), degenerative brain disorders (including Alzheimer’s disease and Parkinson’s disease), stimulant abuse (including methamphetamine and cocaine) as well as several chronic pain syndromes.

Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain

The neurochemical profile quantified by in vivo 1H NMR spectroscopy

Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer's disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies.

Developing new therapies for Alzheimer's disease (AD) is critically important to avoid the impending public health disaster imposed by this common disorder. Means must be found to prevent, delay the onset, or slow the progression of AD. These goals will be achieved by identifying disease-modifying therapies and testing them in clinical trials. Biomarkers play an increasingly important role in AD drug development. In preclinical testing, they assist in decisions to develop an agent. Biomarkers in phase I provide insights into toxic responses and drug metabolism and in Phase II proof-of-concept trials they facilitate go/no-go decisions and dose finding. Biomarkers can play a role in identifying presymptomatic patients or specific patient subgroups. They can provide evidence of target engagement before clinical changes can be expected. Brain imaging can serve as a primary outcome in Phase II trials and as a key secondary outcome in Phase III trials. Magnetic resonance imaging is currently best positioned for use in large multicenter clinical trials. Cerebrospinal fluid (CSF) measures of amyloid beta protein (Aβ), tau protein, and hyperphosphorylated tau (p-tau) protein are sensitive and specific to the diagnosis of AD and may serve as inclusion criteria and possibly as outcomes in clinical trials targeting relevant pathways. Plasma measures of Aβ are of limited diagnostic value but may provide important information as a measure of treatment response. A wide variety of measures of detectable products of cellular processes are being developed as possible biomarkers accessible in the cerebrospinal fluid and plasma or serum. Surrogate markers that can function as outcomes in pivotal trials and reliably predict clinical outcomes are needed to facilitate primary prevention trials of asymptomatic persons where clinical measures may be of limited value. Fit-for-purpose biomarkers are increasingly available to guide AD drug development decisions.

Biomarkers in Alzheimer's disease drug development

Ultra Fast T2-weighted TSE sequences using Flip Angle Sweep with Half-Fourier and SENSE at 3T

Objective: The need for biological markers of Alzheimer disease (AD) is constantly increasing. Proton magnetic resonance spectroscopy ( 1 H-MRS) studies have provided consistent evidence for a reduction of the neuronal marker N -acetylaspartate (NAA) in patients with AD. Within the German Competence Network on Dementia, we conducted a 1 H-MRS study in patients with mild dementia and mild cognitive impairment (MCI) at four sites to investigate the multicenter feasibility of 1 H-MRS. Methods: In total, 130 patients with dementia (98 AD, 32 non-AD), 136 subjects with MCI (70 of AD type, 66 of non-AD type), and 45 unimpaired control subjects were included. Single-volume 1 H-MRS of the left medial temporal lobe was performed at long and short echo times. Metabolites were quantified and metabolic ratios were determined. Results: We found a significant reduction of NAA concentration in patients with AD as compared to healthy volunteers and compared to patients with MCI of AD type. NAA/Cr (creatine/phosphocreatine) was also lower in patients with AD compared to control subjects. NAA, choline compounds, and Cr were lower in patients with AD compared to patients with non-AD dementia. Conclusions: We demonstrated the multicenter feasibility of proton magnetic resonance spectroscopy ( 1 H-MRS) of the medial temporal lobe in mild dementia and mild cognitive impairment, which is a prerequisite for the application of 1 H-MRS in large-scale clinical trials. Since the concentration measures of the metabolites are adjusted for brain tissue volume, these findings are indicators of biochemical pathology beyond brain atrophy.

A multicenter 1H-MRS study of the medial temporal lobe in AD and MCI

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Ultra Fast T2-weighted TSE sequences using Flip Angle Sweep with Half-Fourier and SENSE at 3T

A multicenter 1H-MRS study of the medial temporal lobe in AD and MCI