Faculty Bibliography

Background: The p75 neurotrophin receptor modulates multiple signaling pathways that are likely to be involved in degenerative signaling that occurs in AD . In previous work, we found that oligomeric preparations of beta-amyloid failed to induce neurite degeneration in cultures of neurons derived from p75 mutant mice. Moreover, crossing p75 mutant mice with APPLond/ Swe mice resulted in a significant decrease in neurite degeneration with no change in amyloid levels. These studies demonstrated that amyloid- induced toxicity is dependent on normal p75 function. Methods: Our team has developed non-peptide, small molecule ligands that bind specifically to p75 and modulate its function at low nanomolar concentrations. These compounds have been applied to in vitro and in vivo AD models. Results: In in vitro studies, these ligands inhibit the ability of amyloid beta to: induce degenerative signaling, promote excess tau phosphorylation, trigger tau missorting and impair synaptic function. In AD mouse models, oral administration of p75 ligands capable of crossing the blood brain barrier inhibits synaptic and neuronal degeneration, blocks excess tau phosphorylation and improves function in multiple behavioral analyses. One ligand is under phase I safety and pharmacokinetic testing in healthy young and elderly subjects. Conclusions: Modulation of p75 signaling by orally available small molecule ligands might serve to delay onset or slow progression of Alzheimer's and also constitutes a candidate approach for augmenting effects of amyloid lowering strategies

Mitochondrial Ca(2)(+) uptake exerts dual effects on mitochondria. Ca(2)(+) accumulation in the mitochondrial matrix dissipates membrane potential (DeltaPsim), but Ca(2)(+) binding of the intramitochondrial enzymes accelerates oxidative phosphorylation, leading to mitochondrial hyperpolarization. The levels of matrix free Ca(2)(+) ([Ca(2)(+)]m) that trigger these metabolic responses in mitochondria in nerve terminals have not been determined. Here, we estimated [Ca(2)(+)]m in motor neuron terminals of Drosophila larvae using two methods: the relative responses of two chemical Ca(2)(+) indicators with a 20-fold difference in Ca(2)(+) affinity (rhod-FF and rhod-5N), and the response of a low-affinity, genetically encoded ratiometric Ca(2)(+) indicator (D4cpv) calibrated against known Ca(2)(+) levels. Matrix pH (pHm) and DeltaPsim were monitored using ratiometric pericam and tetramethylrhodamine ethyl ester probe, respectively, to determine when mitochondrial energy metabolism was elevated. At rest, [Ca(2)(+)]m was 0.22 +/- 0.04 muM, but it rose to ~26 muM (24.3 +/- 3.4 muM with rhod-FF/rhod-5N and 27.0 +/- 2.6 muM with D4cpv) when the axon fired close to its endogenous frequency for only 2 s. This elevation in [Ca(2)(+)]m coincided with a rapid elevation in pHm and was followed by an after-stimulus DeltaPsim hyperpolarization. However, pHm decreased and no DeltaPsim hyperpolarization was observed in response to lower levels of [Ca(2)(+)]m, up to 13.1 muM. These data indicate that surprisingly high levels of [Ca(2)(+)]m are required to stimulate presynaptic mitochondrial energy metabolism.

Hearts utilize fatty acids as a primary source of energy. The sources of those lipids include free fatty acids and lipoprotein triglycerides. Deletion of the primary triglyceride-hydrolyzing enzyme lipoprotein lipase (LPL) leads to cardiac dysfunction. Whether heart LPL-knockout (hLPL0) mice are compromised due a deficiency in energetic substrates is unknown. To test whether alternative sources of energy will prevent cardiac dysfunction in hLPL0 mice, two different models were used to supply nonlipid energy. 1) hLPL0 mice were crossed with mice transgenically expressing GLUT1 in cardiomyocytes to increase glucose uptake into the heart; this cross-corrected cardiac dysfunction, reduced cardiac hypertrophy, and increased myocardial ATP. 2) Mice were randomly assigned to a sedentary or training group (swimming) at 3 mo of age, which leads to increased skeletal muscle production of lactate. hLPL0 mice had greater expression of the lactate transporter monocarboxylate transporter-1 (MCT-1) and increased cardiac lactate uptake. Compared with hearts from sedentary hLPL0 mice, hearts from trained hLPL0 mice had adaptive hypertrophy and improved cardiac function. We conclude that defective energy intake and not the reduced uptake of fat-soluble vitamins or cholesterol is responsible for cardiac dysfunction in hLPL0 mice. In addition, our studies suggest that adaptations in cardiac metabolism contribute to the beneficial effects of exercise on the myocardium of patients with heart failure.

BACKGROUND: The purpose of this study was to describe targeting accuracy in functional neurosurgery using incisionless transcranial magnetic resonance (MR)-guided focused ultrasound technology. METHODS: MR examinations were performed before and 2 days after the ultrasound functional neurosurgical treatment to visualize the targets on T2-weighted images and determine their coordinates. Thirty consecutive targets were reconstructed: 18 were in the central lateral nucleus of the medial thalamus (central lateral thalamotomies against neurogenic pain), 1 in the centrum medianum thalamic nucleus (centrum medianum thalamotomy against essential tremor), 10 on the pallido-thalamic tract (pallido-thalamic tractotomies against Parkinson's disease), and 1 on the cerebello-thalamic tract (cerebello-thalamic tractotomy against essential tremor). We describe a method for reconstruction of the lesion coordinates on post-treatment MR images, which were compared with the desired atlas target coordinates. We also calculated the accuracy of the intra-operative target placement, thus allowing to determine the global, planning, and device accuracies. We also estimated the target lesion volume. RESULTS: We found mean absolute global targeting accuracies of 0.44 mm for the medio-lateral dimension (standard deviation 0.35 mm), 0.38 mm for the antero-posterior dimension (standard deviation 0.33 mm), and 0.66 mm for the dorso-ventral dimension (standard deviation 0.37 mm). Out of the 90 measured coordinates, 83 (92.2%) were inside the millimeter domain. The mean three-dimensional (3D) global accuracy was 0.99 mm (standard deviation 0.39 mm). The mean target volumes, reconstructed from surface measurements on 3D T1 series, were 68.5 mm(3) (standard deviation 39.7 mm(3)), and 68.9 mm(3) (standard deviation 40 mm(3)) using an ellipsoidal approximation. CONCLUSION: This study demonstrates a high accuracy of the MR-guided focused ultrasound technique. This high accuracy is due not only to the device qualities but also to the possibility for the operator to perform on-going real-time monitoring of the lesioning process. A precise method for determination of targeting accuracy is an essential component and basic requirement of the functional neurosurgical activity, allowing an on-going control of the performed therapeutic work indispensable for any target efficiency analysis and the maintenance of a low risk profile.

BACKGROUND: Stereotactic central lateral thalamotomy (CLT) has been applied as a treatment for chronic intractable neuropathic pain. However, it is not clear whether this intervention influences the emotional and cognitive impairments observed in patients who have chronic neuropathic pain. OBJECTIVE: To investigate neuropsychological functions and emotional processing in patients with chronic neuropathic pain compared with healthy volunteers and to explore the neuropsychiatric effect of the CLT. METHODS: We investigated pain ratings, cognitive functions, emotional processes, and personality variables before and after surgery in 8 patients with intractable neuropathic pain. Patients were tested before and 3 months after CLT by the use of neuropsychological tests; clinical scales for depression, anxiety, anhedonia, and anger regulation; a personality test; and 2 experimental tasks testing the theory of mind as well as the ability to recognize facial emotional expressions. Nine age- and sex-matched control subjects were tested once using the same procedure. RESULTS: The comparison of the patient group before surgery with the control group evidenced significant differences on the cognitive assessments, the depression and anxiety scores, as well as on the somatic complaint subscale of the personality test. Three months after CLT, patients experienced a significant improvement in their depression scores. There were no additional postsurgical cognitive impairments. CONCLUSION: For our patients with chronic neuropathic pain, CLT provided pain relief and reduction of their depression scores without causing postsurgical cognitive impairments.

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 is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article 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 with 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. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.

Mutations in Amyloid-ss Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPss and ss-CTF. ss-CTF is cleaved by gamma-secretase to produce Ass. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPss/ss-CTF but not Ass. We have investigated further the pathogenic function of ss-CTF focusing on Thr(668) of ss-CTF because phosphorylation of Thr(668) is increased in AD cases. We created a knock-in mouse bearing a Thr(668)Ala mutation (APP(TA) mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr(668) is a viable therapeutic strategy for human dementias.

Unraveling the normal physiologic role of beta-amyloid is likely crucial to understanding the pathogenesis of Alzheimer's disease. However, progress on this question is currently limited by the high background of many ELISAs for murine beta-amyloid. Here, we examine the background signal of several murine beta-amyloid ELISAs, and conclude that the majority of the background is from non-APP derived proteins. Most importantly, we identify ELISAs that eliminate this background signal.

Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.