Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer's disease mutations.
ABSTRACT BACKGROUND: Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer's disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer's disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives. METHODS: Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects. RESULTS: MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume. CONCLUSIONS: Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD.
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ABSTRACT: Neurodegenerative diseases are still a challenge for researchers and clinicians due to its complexity. Traditional medicines usually do not provide sufficient protection against these diseases due to drug resistance and relapse. The discovery of the therapeutic potential of stem cells offers new opportunities for the treatment of incurable neurological diseases. Based on their biological properties, stem cells can differentiate into specific tissue type and maintain the cellular tissue/organ homeostasis in physiological and pathological conditions. Recently, it has been demonstrated that somatic cells of patients can be reprogrammed to a pluripotent state from which neural lineage cells can be derived. Potential strategies such as cell replacement therapy and gene transfer to the diseased or injured brain have opened a new line of therapeutic approach for a broad spectrum of human neurological diseases. Thus, stem cell replacement therapy for central and peripheral nervous system disorders aims at repopulating the affected neural tissue with new neurons. However, the limiting factors that have hampered the development of this promising therapeutic approach are the lack of suitable cell types for cell replacement therapy in patients suffering from neurological disorders. In this review, we have discussed the recent advances in stem cell replacement therapy with particular emphasis to neurological disorders.Molecular Neurobiology 09/2014; · 5.29 Impact Factor
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ABSTRACT: As the need to develop a successful disease-modifying treatment for Alzheimer's disease (AD) becomes more urgent, imaging is increasingly used in therapeutic trials. We provide an overview of how the different imaging modalities are used in AD studies and the current regulatory guidelines for their use in clinical trials as endpoints. We review the current literature for results of imaging endpoints of efficacy and safety in published clinical trials. We start with trials in mild to moderate AD, where imaging (largely magnetic resonance imaging (MRI)) has long played a role in inclusion and exclusion criteria; more recently, MRI has been used to identify adverse events and to measure rates of brain atrophy. The advent of amyloid imaging using positron emission tomography has led to trials incorporating amyloid measurements as endpoints and incidentally to the recognition of the high proportion of amyloid-negative individuals that may be recruited into these trials. Ongoing and planned trials now commonly include multimodality imaging: amyloid positron emission tomography, MRI and other modalities. At the same time, the failure of recent large profile trials in mild to moderate AD together with the realisation that there is a long prodromal period to AD has driven a push to move studies to earlier in the disease. Imaging has particularly important roles, alongside other biomarkers, in assessing efficacy because conventional clinical outcomes may have limited ability to detect treatment effects in these early stages.Alzheimer's Research and Therapy 01/2014; 6(9):87. · 3.50 Impact Factor
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ABSTRACT: Background: Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia. Objective: We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimer's disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume. Methods: Twenty-five individuals with bvFTD (n = 11) and early-onset AD (n = 14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry. Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores. Results: The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant. Conclusions: Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB appears to measure symptoms of emotional blunting that are localized to the right anterior temporal lobe.Journal of Alzheimer's disease: JAD 03/2014; · 3.61 Impact Factor