Outcomes Assessment in Clinical Trials of Alzheimer's Disease and its Precursors: Readying for Short-term and Long-term Clinical Trial Needs.

An evolving paradigm shift in the diagnostic conceptualization of Alzheimer's disease is reflected in its recently updated diagnostic criteria from the National Institute on Aging-Alzheimer's Association and the International Working Group. Additionally, it is reflected in the increased focus in this field on conducting prevention trials in addition to improving cognition and function in people with dementia. These developments are making key contributions towards defining new regulatory thinking around Alzheimer's disease treatment earlier in the disease continuum.

Translational issues in cochlear synaptopathy.

Understanding the biology of the previously underappreciated sensitivity of cochlear synapses to noise insult, and its clinical consequences, is becoming a mission for a growing number of auditory researchers. In addition, several research groups have become interested in developing therapeutic approaches that can reverse synaptopathy and restore hearing function. One of the major challenges to realizing the potential of synaptopathy rodent models is that current clinical audiometric approaches cannot yet reveal the presence of this subtle cochlear pathology in humans.

Gene expression elucidates functional impact of polygenic risk for schizophrenia.

Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability.

Schizophrenia research in 2013: are we making progress?

The diagnostic category of schizophrenia encompasses a range of disabilities with distinct phenotypic features typically manifesting in young adulthood. Classically the purview of psychiatrists, it is now apparent that close cross disciplinary collaboration and iterative comparison of datasets is a must if we intend to make significant in-roads in preventing both the slide into full blown disease and ensuring that susceptible individuals maintain best quality of life as they age. For example, understanding whether there are specific development windows that permit environmental triggers acting on specific genetic backgrounds to unmask and ensconce the relevant phenotypes is one area where epidemiology, clinicians, and basic neuroscientists likely possess key pieces of the puzzle.

Pilot study of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood stem cells in amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons in the brain, brainstem, and spinal cord. It has been proposed that bone marrow (BM)-derived cells might supply motor neurons and other cells with a cellular milieu more conducive to survival in ALS. Direct injection of stem cells in ALS is problematic because of the large expanse of the neuraxis that would need to be injected.

Elevation of the Hsp70 chaperone does not effect toxicity in mouse models of familial amyotrophic lateral sclerosis.

Mutations in copper/zinc superoxide dismutase (SOD1) account for 10-20% of a familial form of amyotrophic lateral sclerosis (ALS). A common feature of SOD1 mutants is abnormal aggregation of the aberrant SOD1 in neurons and glia. We now report that in ALS transgenic mouse models the constitutively expressed heat shock protein 70 (Hsp70) is mislocalized into aggregates together with mutant SOD1 and ubiquitin.

Surgery for Parkinson disease in the United States, 1996 to 2000: practice patterns, short-term outcomes, and hospital charges in a nationwide sample.

Object: The surgical treatment of Parkinson disease (PD) has undergone a dramatic shift, from stereotactic ablative procedures toward deep brain stimulaion (DBS). The authors studied this process by investigating practice patterns, mortality and morbidity rates, and hospital charges as reflected in the records of a representative sample of US hospitals between 1996 and 2000.

Methods: The authors conducted a retrospective cohort study by using the Nationwide Inpatient Sample database; 1761 operations at 71 hospitals were studied.

Outcomes following staged bilateral pallidotomy in advanced Parkinson's disease.

The authors assessed clinical outcome for up to one year after staged bilateral pallidotomy in 14 patients with advanced PD. One year after surgery, dyskinesias were virtually abolished and there were significant reductions in "off" time (67%) and activities of daily living "off" scores (24%), as well as nonsignificant reduction in "off" motor score (39%); "on" scores were unchanged. One patient developed a visual field deficit; two had transient confusion.

Partial deficiency of manganese superoxide dismutase exacerbates a transgenic mouse model of amyotrophic lateral sclerosis.

The pathogenesis of neuronal cell death as a consequence of mutations in copper/zinc superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis may involve oxidative damage and mitochondrial dysfunction. We examined whether crossing transgenic mice with the G93A SOD1 mutation with transgenic mice with a partial depletion of manganese superoxide dismutase (SOD2) would affect the disease phenotype. Compared with G93A mice alone, the mice with partial deficiency of SOD2 and the G93A SOD1 mutation showed a significant decrease in survival and an exacerbation of motor deficits detected by rotorod testing.

Stereotactic pallidotomy performed without using microelectrode guidance in patients with Parkinson's disease: surgical technique and 2-year results.

Object: Pallidotomy for the treatment of medically refractory Parkinson's disease (PD) has enjoyed renewed popularity. However, the optimal surgical technique, lesion location, and long-term effectiveness of pallidotomy remain subjects of debate. In this article the authors describe their surgical technique for performing pallidotomy without using microelectrode guidance, and the clinical and radiological results of this procedure.

Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscle.

A role for oxidative damage in normal aging is supported by studies in experimental animals, but there is limited evidence in man. We examined markers of oxidative damage to DNA, lipids, and proteins in 66 muscle biopsy specimens from humans aged 25 to 93 years. There were age-dependent increases in 8-hydroxy-2-deoxyguanosine (OH8dG), a marker of oxidative damage to DNA, in malondialdehyde (MDA), a marker of lipid peroxidation, and to a lesser extent in protein carbonyl groups, a marker of protein oxidation.

The importance of accurate lesion placement in posteroventral pallidotomy. Report of two cases.

Pallidotomy has become a widely used treatment for medically refractory Parkinson's disease. However, the optimal lesion size and location within the pallidum have not yet been determined, and the role of repeated pallidotomy remains undefined. The authors present two patients who had unsatisfactory results after their first unilateral pallidotomy but attained dramatic and long-lasting improvement with repeated surgery.

Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis.

Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage may play a role in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined markers of oxidative damage to protein, lipids, and DNA in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Protein carbonyl and nuclear DNA 8-hydroxy-2'-deoxyguanosine (OH8dG) levels were increased in SALS motor cortex but not in FALS patients.

Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation.

Mutations in copper/zinc superoxide dismutase (SOD1) cause a subset of cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). Transgenic mice that express these point mutations develop progressive paralysis and motor neuron loss thought to be caused by a gain-of-function of the enzyme. The gain-of-function may be an enhanced ability of the mutant SOD1 to generate .

Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease.

Mounting evidence suggests that defects in energy metabolism contribute to the pathogenesis of Alzheimer disease (AD). Cytochrome c oxidase (CO) is kinetically abnormal, and its activity is decreased in brain and peripheral tissue in late-onset AD. CO is encoded by both the mitochondrial and the nuclear genomes.

Manganese injection into the rat striatum produces excitotoxic lesions by impairing energy metabolism.

There is compelling evidence that excessive exposure to manganese (Mn) produces neurotoxicity, especially in the basal ganglia, resulting in a dystonic Parkinsonian disorder. Several experimental or clinical observations suggest that Mn neurotoxicity could involve impairment of energy metabolism. We examined the neurotoxic effects of Mn following local intrastriatal injection.

Enhancement of Ca2+-sensitive myosin ATPase activity by cadmium.

The effects of Cd2+ on Ca2+-sensitive myosin ATPase activity were examined. In the absence of Ca2+, the Ca2+-dependent myosin ATPase activity was enhanced by Cd2+ to the same extent as with Ca2+ at concentrations ranging from 10(-6) to 10(-3) M. At 10(-2) M, however, no activation was observed.