Current Alzheimer Research - Volume 8, Issue 3, 2011

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A significant expansion of knowledge in the last few years, especially in the molecular biology of frontotemporal dementia (FTD) is summarized. This condition, formerly known as Pick's disease and considered rare, is estimated to be 12-15% of all dementias and 30-50% early onset ones. The clinical picture is protean, mainly a behavioural and language impairment, but the extrapyramidal syndromes of CBD and PSP are often seen and conversely FTD and progressive aphasia often has motor symptoms, including ALS . These seemingly different presentations converge, as one or other areas in the brain are affected. Our experience with FTD in a clinical cohort, with high rate of autopsy confirmation is presented. Less than half of the cases are tauopathies, the majority has been discovered to have a TDP-43 and most recently a FUS proteinopathy, shared with ALS, opening potential opportunities for pharmacological approaches to treatment. Tau and progranulin mutations on Ch-17 and some others, point to molecular mechanisms. A glossary is provided to navigate the complex terminology.

Frontotemporal Lobar degeneration (FTLD) is one of the most important neurodegenerative conditions, affecting in the presenium, but more recently recognized also in aged population. The strong genetic background, along with autopsy determinations prompted the identification of the two major genes associated to the disease: MAPT gene, and Progranulin (PGRN) gene. In this review, we highlighted the milestones of these discoveries, and their implication for the development of future therapeuthical approaches.

Two proteins have recently received considerable attention in the neurodegenerative research field: TDP-43 and FUS/TLS. The reason is that both proteins have been found to represent major protein components of the intracellular inclusions occurring in the neuronal tissues of patients affected by Fronto Temporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. One of the most interesting features of this discovery is that both proteins have in common several structural properties. In particular, they are multifunctional RNA-binding proteins (RBPs) already known to play a role in several cellular processes such as transcription, pre-mRNA splicing, and mRNA stability. The potential consequences of changes in their intracellular localization and protein modification status (phosphorylation, ubiquitination, and cleavage) on neuronal metabolism represent one of the major research challenges faced today by researchers. There is hope that a detailed knowledge of the gain- or loss-of-function mechanisms mediated by alterations in these proteins in the neuronal environment may provide novel therapeutic strategies for the treatment of these diseases. Here, we aim to provide an updated review of ways by which TDP-43 and FUS/TLS influence gene expression. In particular, we will focus on the characterized properties of both proteins that involve gene transcription and also RNA splicing, transport and stability processes.

CHMP2B mutations are a rare cause of autosomal dominant frontotemporal dementia (FTD). The best studied example is frontotemporal dementia linked to chromosome 3 (FTD-3) which occurs in a large Danish family, with a further CHMP2B mutation identified in an unrelated Belgian familial FTD patient. These mutations lead to C-terminal truncations of the CHMP2B protein and we will review recent advances in our understanding of the molecular effects of these mutant truncated proteins on vesicular fusion events within the endosome-lysosome and autophagy degradation pathways. We will also review the clinical features of FTD caused by CHMP2B truncation mutations as well as new brain imaging and neuropathological findings. Finally, we collate the current data on CHMP2B missense mutations, which have been reported in FTD and motor neuron disease.

Inclusion body myopathy (IBM) associated with paget's disease of the bone (PDB) and fronto-temporal dementia (FTD) or IBMPFD, is a rare multisystem degenerative disorder due to mutations in valosin containing protein (VCP). VCP is a ubiquitously expressed protein that facilitates the degradation of proteins via the ubiquitin proteasome and autophagy pathways. Affected brain and muscle tissue in IBMPFD have ubiquitinated and TAR DNA binding protein- 43 (TDP-43) inclusions. In skeletal muscle, this pathology is consistent with IBM. While in the CNS, IBMPFD is a frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) subtype. Recent studies suggest that IBMPFD mutations in VCP disrupt its function in protein degradation. This review will explore the clinical phenotype and pathology of IBMPFD with an emphasis on central nervous system degeneration. In addition, we will discuss the current understanding regarding VCP's function in terminally differentiated tissue and how disease associated mutations result in both myo- and neurodegeneration.

We review the practical importance of lobar atrophy in frontotemporal dementia (FTD), for diagnosis and prognosis. We discuss specific patterns of frontotemporal atrophy that denote clinical and pathological subtypes of FTD (e.g. semantic dementia). We also discuss the unsatisfactory clinical experience of interpreting MRI scans in individual FTD cases, especially the behavioural presentations (without aphasic or motor impairments). This issue is explored by examining the FTD phenocopy concept. Lobar atrophy emerges as a key observation in defining behavioural FTD patients whose symptoms are likely to progress. In a situation where objective clinical data are few, we highlight the importance of applying caution before diagnosing FTD is the absence of visible brain atrophy.

The primary progressive aphasias (PPA) are a group of clinically, genetically and pathologically heterogeneous neurodegenerative disorders caused by FTLD-tau, FTLD-TDP or Alzheimer's disease pathology. Clinically, three subtypes are recognized, the semantic, logopenic and nonfluent variants but there remains ongoing discussions over how the clinical subtypes should be dissected. This review looks at the genetic and pathological basis of PPA and argues that with the advent of clinical trials in PPA, establishing the underlying pathology accurately during life will become increasingly important. Current and future biomarkers that may help make a pathological diagnosis in life, i.e. PPA-tau, PPA-TDP and PPA-AD, are reviewed including clinical and neuropsychological data, neuroimaging, blood and CSF markers.

The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders belong to the most important recent discoveries. FTD and ALS are the focus of this review which aims to: 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to their onset and development. Advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.

Progressive Supranuclear Palsy (PSP) has been used to denote a unifying disorder with progressive parkinsonism with early falls, vertical supranuclear gaze palsy, pseudobulbar dysfunction and cognitive decline. Over the last decade, heterogeneity of the disease into different clinical subtypes has been recognized in clinicopathological studies. Although neuroimaging features and laboratory findings may support the diagnosis, true biomarkers are still lacking in the clinical setting. Neuronal and glial tau positive aggregates are predominantly found in basal ganglia and brainstem, and the significant association of PSP with the common H1 tau haplotype likely points to a pathophysiological role of the tau protein in the disease process. Future genetic studies of familial cases and an ongoing genome-wide association study of large series of pathological-proven cases may reveal additional genetic factors in the near future.

Elevated serum total cholesterol (TC) has been considered a risk factor for Alzheimer's disease (AD), but conflicting results have confused understanding of the relationships of serum lipids to the presence of AD in the elderly. Methods: To clarify these issues, we evaluated correlations of admission TC, low-density (LDL) and high-density (HDL) cholesterol directly with the densities of Alzheimer hallmarks--neuritic plaques (NP) and neurofibrillary tangles (NFT)--in nursing home residents (n=281). Results: Significant positive associations of TC and LDL with NP densities were found in both the neocortex (TC: r=0.151, p=0.013 and LDL: r=0.190, p=0.005) and the hippocampal/entorhinal (allocortical) region (TC: r=0.182, p=0.002 and LDL: r=0.203, p=0.003). Associations of HDL with NP were less strong but also significant. In contrast, after adjustment for confounders, no correlations of NFT with any lipid were significant.When subjects with any non-AD neuropathology (largely vascular) were excluded, the TC-plaque and LDL-plaque associations for the remaining “Pure AD” subgroup were consistently stronger than for the full sample. The TC- and LDL-plaque correlations were also stronger for the subgroup of 87 subjects with an APOE ε4 allele. Conclusions: The findings indicate that serum TC and LDL levels clearly relate to densities of NP, but not to densities of NFT. The stronger associations found in the subgroup that excluded all subjects with non-AD neuropathology suggest that cerebrovascular involvement does not explain these lipid-plaque relationships. Since the associations of TC/LDL with NP were particularly stronger in ε4 carriers, varying prevalence of this allele may explain some discrepancies among prior studies.

Mutations in the presenilin genes cause the majority of early-onset familial Alzheimer's disease. Recently, presenilin mutations have been identified in patients with dilated cardiomyopathy (DCM), a common cause of heart failure and the most prevalent diagnosis in cardiac transplantation patients. However, the molecular mechanisms, by which presenilin mutations lead to either AD or DCM, are not yet understood. We have employed transgenic Drosophila models and optical coherence tomography imaging technology to analyze cardiac function in live adult Drosophila. Silencing of Drosophila ortholog of presenilins (dPsn) led to significantly reduced heart rate and remarkably age-dependent increase in end-diastolic vertical dimensions. In contrast, overexpression of dPsn increased heart rate. Either overexpression or silencing of dPsn resulted in irregular heartbeat rhythms accompanied by cardiomyofibril defects and mitochondrial impairment. The calcium channel receptor activities in cardiac cells were quantitatively determined via real-time RT-PCR. Silencing of dPsn elevated dIP3R expression, and reduced dSERCA expression; overexprerssion of dPsn led to reduced dRyR expression. Moreover, overexpression of dPsn in wing disc resulted in loss of wing phenotype and reduced expression of wingless. Our data provide novel evidence that changes in presenilin level leads to cardiac dysfunction, owing to aberrant calcium channel receptor activities and disrupted Wnt signaling transduction, indicating a pathogenic role for presenilin mutations in DCM pathogenesis.

Background: The Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) has become the de facto gold standard for assessing the efficacy of anti-dementia treatments. However, manual administration of the ADAS-Cog is subject to procedural inconsistencies, including scoring and transcription errors, which can introduce unwanted variance and compromise data quality within and across sites and trials. To address such concerns, a computerized version was developed that integrates, rather than replaces, the examiner, standardizes administration, and uses electronic data capture at the point of patient contact. The examiner can control administration and pacing, pause or repeat digitized instructions, score verbal report and overt behavioral performance, and freely interact with the subject. Purpose: To conduct psychometric comparisons of traditional, paper-based administration of the standard ADAS-Cog (sADAS) with examiner- assisted administration of the computerized ADAS-Cog (cADAS). Methods: Eighty-eight patients (39M; 49F) with mild to moderate Alzheimer's disease were tested on three occasions with each version over a period of one year with one month between paired visits. Results: Intraclass Correlation Coefficients (ICC) comparisons between sADAS and cADAS were significant for total score (ICC=0.96) and all subscores (ICCs ranged 0.78-0.93), with no significant differences on paired t-tests. The mean ICCs across cADAS scores for test-retest reliability for short-term (mean ICC=0.96) and long-term (mean ICC=0.91) comparisons were significantly higher than across sADAS scores (mean ICCs were 0.87 and 0.84, respectively). Conclusions: These results indicate that examiner-assisted, computerized administration is equivalent to traditional, paper-based administration, and shows significantly greater test-retest reliability.