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1.  Frontotemporal Degeneration, the Next Therapeutic Frontier: Molecules and Animal Models for FTD drug development (Part 1 of 2 articles) 
Frontotemporal Degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug’s success in treating FTD may predict efficacy in more common diseases such as Alzheimer’s disease (AD). A variety of regulatory incentives, clinical features of FTD, such as rapid disease progression, and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other more common neurodegenerative diseases such as AD. In March 2011, the Frontotemporal Dementia Treatment Study Group (FTSG) sponsored a conference entitled,“ FTD, the Next Therapeutic Frontier,” focused on pre-clinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development, epidemiological, genetic and neuropathological features of FTD, FTD animal models and how best to use them and examples of successful drug-development collaborations in other neurodegenerative diseases.
doi:10.1016/j.jalz.2012.03.002
PMCID: PMC3542408  PMID: 23043900
2.  The Advantages of FTD Drug Development (Part 2 of FTD: The Next Therapeutic Frontier) 
Frontotemporal Degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language and motor phenotypes for which there are currently no effective therapies. This manuscript is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Dementia Treatment Study Group (FTSG), a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This manuscript discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease (AD). Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw upon this experience to create a roadmap for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.
doi:10.1016/j.jalz.2012.03.003
PMCID: PMC3562382  PMID: 23062850
3.  Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criteria for Alzheimer’s disease 
Background
The promise of Alzheimer’s disease (AD) biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging (MRI) measure in AD and thus represents the most rational target for an initial effort at standardization.
Methods and Results
The authors of this position paper propose a path toward this goal. The steps include: 1) Establish and empower an oversight board to manage and assess the effort, 2) Adopt the standardized definition of anatomic hippocampal boundaries on MRI arising from the EADC-ADNI hippocampal harmonization effort as a Reference Standard, 3) Establish a scientifically appropriate, publicly available Reference Standard Dataset based on manual delineation of the hippocampus in an appropriate sample of subjects (ADNI), and 4) Define minimum technical and prognostic performance metrics for validation of new measurement techniques using the Reference Standard Dataset as a benchmark.
Conclusions
Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent is to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry is envisioned as a template that could be applied to other imaging biomarkers.
doi:10.1016/j.jalz.2011.04.007
PMCID: PMC3396131  PMID: 21784356
Alzheimer’s disease; biomarkers; Magnetic resonance imaging; hippocampus; biomarker standards
4.  Patient self-report for evaluating mild cognitive impairment and prodromal Alzheimer's disease 
Patient-reported outcome (PRO) measures are used to evaluate disease and treatments in many therapeutic areas, capturing relevant aspects of the disorder not obtainable through clinician or informant report, including those for which patients may have a greater level of awareness than those around them. Using PRO measures in mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) presents challenges given the presence of cognitive impairment and loss of insight. This overview presents issues relevant to the value of patient report with emphasis on the role of insight. Complex activities of daily living functioning and executive functioning emerge as areas of particular promise for obtaining patient self-report. The full promise of patient self-report has yet to be realized in MCI and prodromal AD, however, in part because of lack of PRO measures developed specifically for mild disease, limited use of best practices in new measure development, and limited attention to psychometric evaluation. Resolving different diagnostic definitions and improving clinical understanding of MCI and prodromal AD will also be critical to the development and use of PRO measures.
doi:10.1186/alzrt97
PMCID: PMC3308024  PMID: 22152342
5.  Evaluation of the exposure equivalence of oral versus intravenous temozolomide 
Purpose
Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration.
Methods
Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m2 of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m2 temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day.
Results
Ratio of log-transformed means (intravenous:oral) of area under the concentration–time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8–1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration.
Conclusions
This study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.
doi:10.1007/s00280-009-1078-6
PMCID: PMC2808524  PMID: 19641919
Temozolomide; Pharmacokinetics; AUC; Exposure equivalence; Oral; Intravenous

Results 1-5 (5)