Frank Faltraco

The future of Alzheimer's disease: the next 10 years

Alzheimers disease (AD) is a fast growing world-wide epidemic. AD is a genetically complex, slowly progressive, and irreversible neurodegenerative disease of the brain. During decades of asymptomatic progression multiple interactive systems, pathways and molecular mechanisms (e.g. protein processing, aberrant signaling, inflammation and immune system, lipid transport, endocytosis, apoptosis, oxidative damage and response to stress, tau pathology, neuron and synapse loss, energy metabolism), contribute to the development of the early clinical prodromal stage with episodic memory deficits and to further decline and loss of general cognitive functioning during the final syndromal dementia stage. The non-mendelian genetically complex sporadic AD type is the most common form of dementia affecting people usually over the age of 65. Despite considerable progress of AD research in recent years and evolving paradigm shifts in both pathophysiological concepts as well as in diagnostic criteria fundamental challenges have not yet been resolved. The strong age-related incidence, the recent failure and complete lack of disease-modifying or preventive therapy that may delay onset or substantially affect the pathophysiology of AD, result in an enormous burden posed both on individuals, their families and care givers, and the societies at large, and these call for urgent concerted worldwide measures. Based on the meeting of the German Task Force on Alzheimers Disease (GTF-AD) in Paris on July 19th 2011, the present position paper provides an overview on the current state and future developments in epidemiology, pathophysiology, disease conceptualization, diagnostic criteria and their use in research and clinical practice, as well as preventive and symptomatic therapeutic approaches. Particular emphasis is placed on a discussion of the different approaches to diagnostics and therapy taken by preventive/public health medicine, methodologically advanced academic research propagating the use of sophisticated biomarkers, and everyday clinical practice focusing on patient-centered care. During the next 10 years, major advances both in early detection as well as in therapy and comprehensive AD care seem mandatory. These still unmet needs call for ever more concerted and focused efforts in research across the world to combat the erupting and as yet uncontrolled epidemic of AD.

The alternative splicing of tau exon 10 and its regulatory proteins CLK2 and TRA2-BETA1 changes in sporadic Alzheimer's disease

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in tauopathies, which include Alzheimers disease (AD). Tau is a microtubule‐associated protein whose transcript undergoes alternative splicing in the brain. Exonu200310 encodes one of four microtubule‐binding repeats. Exonu200310 inclusion gives rise to tau protein isoforms containing four microtubule‐binding repeats (4R) whereas exclusion leads to isoforms containing only three repeats (3R). The ratio between 3R and 4R isoforms is tightly controlled via alternative splicing in the human adult nervous system and distortion of this balance results in neurodegeneration. Previous studies showed that several splicing regulators, among them hTRA2‐beta1 and CLK2, regulate exonu200310 alternative splicing. Like most splicing factors, htra2‐beta and clk2 pre‐mRNAs are regulated by alternative splicing. Here, we investigated whether human postmortem brain tissue of AD patients reveal differences in alternative splicing patterns of the tau, htra2‐beta, presenilin 2 and clk2 genes when compared with age‐matched controls. We found that the splicing patterns of all four genes are altered in affected brain areas of sporadic AD patients. In these affected areas, the amount of mRNAs of tau isoforms including exonu200310, the htra2‐beta1 isoform and an inactive form of clk2 are significantly increased. These findings suggest that a misregulation of alternative splicing seems to contribute to sporadic AD.

Comprehensive dissection of the medial temporal lobe in AD: measurement of hippocampus, amygdala, entorhinal, perirhinal and parahippocampal cortices using MRI

BackgroundEarly pathological involvement of specific medial temporal lobe areas is characteristic for Alzheimer’s disease (AD).ObjectiveTo determine the extent of regional medial temporal lobe atrophy, including hippocampus, amygdala, and entorhinal, perirhinal, and parahippocampal cortices in mild AD patients and healthy controls, and to compare diagnostic accuracy across volumetric markers.MethodsWe studied 34 patients with clinically probable AD and 22 healthy elderly control subjects. Regional volumetric measures were obtained from volumetric T1–weighted MRI scans after accounting for global brain atrophy using affine transformation into standard space.ResultsVolumes of medial temporal lobe structures were significantly smaller in AD patients than in controls with exception of the left entorhinal cortex. The degree of atrophy was comparable between all structures. Diagnostic accuracy (number of correctly allocated cases divided by number of all cases) was highest for the right parahippocampal cortex with 85%, but only slightly lower for the right hippocampus and right entorhinal cortex with 82% and 84%. Using a linear combination of markers, the unilateral volumes of the right hippocampus, parahippocampal cortex and perirhinal cortex yielded an accuracy of 93%.ConclusionExtent of atrophy is similar between the different regions of the medial temporal lobe in mild AD.Volume measurements of medial temporal lobe structures in addition to the hippocampus only yield improved diagnostic accuracy if a combination of these structures is used.

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimers disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta‐analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total‐tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10−25). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF‐total‐tau (P = .0110) but not Aβ42 suggesting that TREM2s role in AD may involve tau dysfunction.

Blood and plasma-based proteomic biomarker research in Alzheimer's disease.

Alzheimers disease (AD) is the most important cause of dementia in the elderly. The molecular alterations preceding this neurodegenerative pathology may take place even 20 years before its clinical appearance. In this context, the discovery of biomarkers in biological fluids enabling an early presymptomatic diagnosis as well as discrimination from other types of dementia is eagerly awaited. In particular, since the traditional markers obtained both from cerebrospinal fluid inspection and neuroimaging approaches have not achieved a broad clinical application, research efforts have been focused on the development and validation of biomarkers in blood. The benefit of searching for blood-based candidate biomarkers is evident due to the easiness and non-invasiveness nature of blood samples collection compared with any other body fluid. As a result, blood may constitute a rich source of disease biomarkers. Interestingly, among the technological platforms used to perform research into the biomarker discovery arena, proteomics has attained more recent consideration. In the present review, we provide a comprehensive assessment of patterns of biomarkers detected in plasma and serum specimens for the diagnosis of AD by employing proteomic approaches. Currently, growing evidence suggests that blood protein signatures are helpful to increase the likelihood of successful diagnosis of AD. Accordingly, this area of research promises to yield exciting results in the next future.

Functional abnormalities of the visual processing system in subjects with mild cognitive impairment: An fMRI study

Subjects with mild cognitive impairment (MCI) have a higher risk of developing Alzheimers disease compared with healthy controls (HC). Sensory impairment can contribute to the severity of cognitive impairment. We measured the activation changes in the visual system between MCI and HC subjects. There were 16 MCI subjects with either amnestic MCI or multiple-domain+amnestic MCI and an HC group of 19 subjects. There were two tasks: (a) a face matching and (b) a location matching task. Brain activation was measured using functional magnetic resonance imaging. There were no differences in task performance. The HC group selectively activated the ventral and dorsal pathways during the face and location matching tasks, respectively, while the MCI group did not. The MCI group had greater activation than the HC group in the left frontal lobe during the location matching task. There were no areas of increased activation in the HC group compared with the MCI group. The MCI group, as a compensatory mechanism, activated both visual pathways and increased activation in the left frontal lobe during the location matching task compared with the healthy controls. To our knowledge, this is the first study that has examined visual processing in MCI.

Biological and methodical challenges of blood-based proteomics in the field of neurological research

Biomarker discovery is an application of major importance in todays proteomic research. There is an urgent need for suitable biomarkers to improve diagnostic tools and treatment in various neurological diseases, such as neurodegenerative disorders. Recent years have witnessed an enormous interest in proteomics, which is currently seen as an invaluable tool to shed more light on complex interacting signalling pathways and molecular networks involved in several neuropathological conditions. However, while first results of proteomic research studies have sparked much public attention, the momentum of further proteomic biomarker research in neurological disorders may suffer by its very complex methodology which is sensitive to various sources of artefacts. A major source of variability is proteome perturbation caused by sample handling/preservation (preanalytical phase) and processing/measurement (analytical phase). The aim of the present review is to summarize the current literature focusing on the crucial role played by preanalytical and analytical factors that affect the quality of samples and the reliability of the data produced in blood-based proteomic biomarker research in neurology, which may apply to Alzheimers disease (AD) as well as other neurological disorders. Procedures for sample preparation and protocols for the analysis of serum and plasma samples will be delineated. Finally, the potential usefulness of bioinformatics--allowing for the assembly, store, and processing of data--as well as its contribution to the execution of proteomic studies will be critically discussed.

Functional magnetic resonance imaging as a dynamic candidate biomarker for Alzheimer's disease.

During the last two decades, imaging of neural activation has become an invaluable tool for assessing the functional organization of the human brain in vivo. Due to its widespread application in neuroscience, functional neuroimaging has raised the interest of clinical researchers in its possible use as a diagnostic biomarker. A hallmark feature of many neurodegenerative diseases is their chronic non-linear dynamic and highly complex preclinical course. Neurodegenerative diseases unfold over years to decades through clinically silent and asymptomatic stages of early adaptive, compensatory to pathophysiological (i.e. actively neurodegenerative) and decompensatory mechanisms in the brain - phases that are increasingly being considered as critical for primary and secondary preventive and therapeutic measures. Emerging evidence supports the concept of a potentially fully reversible functional phase that may precede the onset of micro- and macrostructural and cognitive decline, a potentially late-stage neurodegenerative phase of a primary neurodegenerative disorder. Alzheimers disease serves as an ideal model to test this hypothesis supported by the neural network model of the healthy and diseased brain. Being highly dynamic in nature, brain activation and neuronal network functional connectivity represent not only candidate diagnostic but also candidate surrogate markers for interventional trials. Potential caveats of functional imaging are critically reviewed with focus on confound variables such as altered neurovascular coupling as well as parameters related to task- and study design.

Alzheimer disease: functional abnormalities in the dorsal visual pathway.

PURPOSEnTo evaluate whether patients with Alzheimer disease (AD) have altered activation compared with age-matched healthy control (HC) subjects during a task that typically recruits the dorsal visual pathway.nnnMATERIALS AND METHODSnThe study was performed in accordance with the Declaration of Helsinki, with institutional ethics committee approval, and all subjects provided written informed consent. Two tasks were performed to investigate neural function: face matching and location matching. Twelve patients with mild AD and 14 age-matched HC subjects were included. Brain activation was measured by using functional magnetic resonance imaging. Group statistical analyses were based on a mixed-effects model corrected for multiple comparisons.nnnRESULTSnTask performance was not statistically different between the two groups, and within groups there were no differences in task performance. In the HC group, the visual perception tasks selectively activated the visual pathways. Conversely in the AD group, there was no selective activation during performance of these same tasks. Along the dorsal visual pathway, the AD group recruited additional regions, primarily in the parietal and frontal lobes, for the location-matching task. There were no differences in activation between groups during the face-matching task.nnnCONCLUSIONnThe increased activation in the AD group may represent a compensatory mechanism for decreased processing effectiveness in early visual areas of patients with AD. The findings support the idea that the dorsal visual pathway is more susceptible to putative AD-related neuropathologic changes than is the ventral visual pathway.

Effects of rivastigmine on visual attention in subjects with amnestic mild cognitive impairment: A serial functional MRI activation pilot-study

A pilot study to investigate the effects of rivastigmine on the brain activation pattern due to visual attention tasks in a group of amnestic Mild Cognitive Impaired patients (aMCI). The design was an initial three-month double blind period with a rivastigmine and placebo arms, followed by a nine-month open-label period. All patients underwent serial functional magnetic resonance imaging (fMRI) at baseline, and after three and six months of follow-up. Primary endpoint was the effect of rivastigmine on functional brain changes during visual attention (face and location matching) tasks. There were five in the rivastigmine arm and two in the placebo arm. The face matching task showed higher activation of visual areas after three months of treatment but no differences compared to baseline at six months. The location matching task showed a higher activation along the dorsal visual pathway at both three and six months follow ups. Treatment with rivastigmine demonstrates a significant effect on brain activation of the dorsal visual pathway during a location matching task in patients with aMCI. Our data support the potential use of task fMRI to map specific treatment effects of cholinergic drugs during prodromal stages of Alzheimers disease (AD).