Michael D. Geschwind

Regulated Release and Polarized Localization of Brain-Derived Neurotrophic Factor in Hippocampal Neurons

The site and regulation of neurotrophic factor release from neurons is poorly understood. We used a combination of model cell lines and primary culture systems to study the polarity of BDNF sorting and the regulation of its release from hippocampal neurons. Transfection and expression of a human BDNF cDNA in a mouse pituitary cell line, AtT20, resulted in the colocalization of BDNF with the secretory granule marker, chromogranin A. Furthermore, stimulation of these cells with 56 mM KCl or with 5 mM 8-bromo-cAMP increased the release of BDNF approximately 10-to 15-fold within 30 min. To study BDNF release from primary cultures of hippocampal neurons, cells were infected with a defective Herpes Simplex Viral (HSV) vector expressing human BDNF. Depolarizing conditions increased the release of BDNF 5-fold from these cells, further verifying that secretion is regulated. Immunocytochemical analysis using highly specific antibodies determined that endogenous BDNF was predominantly localized to the somatodentritic domain of hippocampal neurons. These findings support the view that BDNF functions as a target-derived signal for afferents to hippocampal pyramidal cells and that it may serve as a regulator of hippocampal plasticity.

Expression of bcl-2 From a Defective Herpes Simplex Virus–1 Vector Limits Neuronal Death in Focal Cerebral Ischemia

BACKGROUND AND PURPOSE A process resembling programmed cell death appears to contribute to postischemic neuronal loss in several models of stroke. Because the expression of the bcl-2 gene has been shown to rescue neurons from programmed cell death due to other causes, we determined whether it would be similarly neuroprotective in stroke. METHODS Replication of defective herpes viral vectors that transduce bcl-2 (HSVbcl2) or Escherichia coli lacZ (HSVlac) were injected into two sites in the rat cerebral cortex 24 hours before induction of neocortical focal ischemia by tandem permanent occlusion of the right middle cerebral artery and ipsilateral common carotid artery. Local ischemic damage was determined 24 hours after occlusion by staining with 2% 2,3,5-triphenyltetrazolium chloride. RESULTS Expression of bcl-2 in cerebral cortex was confirmed by immunohistochemistry in animals injected with the HSVbcl2 expression vector. Viable tissue was significantly increased at the injection sites in HSVbcl2- but not HSVlac-injected animals. The protection observed in the HSVbcl2 animals was localized to the injection sites. CONCLUSIONS These data indicate that bcl-2 expression protects neurons in vivo from ischemic injury and suggest the feasibility of gene therapy for stroke and perhaps other neurological diseases in which programmed cell death is involved.

Rapidly Progressive Dementia

In contrast with more common dementing conditions that typically develop over years, rapidly progressive dementias can develop subacutely over months, weeks, or even days and be quickly fatal. Because many rapidly progressive dementias are treatable, it is paramount to evaluate and diagnose these patients quickly. This review summarizes recent advances in the understanding of the major categories of RPD and outlines efficient approaches to the diagnosis of the various neurodegenerative, toxic‐metabolic, infectious, autoimmune, neoplastic, and other conditions that may progress rapidly. Ann Neurol 2008;64:97–108

Seizures and epileptiform activity in the early stages of Alzheimer disease.

IMPORTANCE Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease. OBJECTIVE To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity. DESIGN Retrospective observational study from 2007 to 2012. SETTING Memory and Aging Center, University of California, San Francisco. PATIENTS We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7). MAIN OUTCOMES AND MEASURES Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications. RESULTS Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin. CONCLUSIONS AND RELEVANCE Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.

Clinicopathological correlations in corticobasal degeneration.

To characterize cognitive and behavioral features, physical findings, and brain atrophy patterns in pathology‐proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology.

Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein

The objective of the study is to report 2 new genotypic forms of protease‐sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV).

Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

The pathogenic mechanisms of frontotemporal dementia (FTD) remain poorly understood. Here we generated multiple induced pluripotent stem cell lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel heterozygous GRN mutation (progranulin [PGRN] S116X). In neurons and microglia differentiated from PGRN S116X induced pluripotent stem cells, the levels of intracellular and secreted PGRN were reduced, establishing patient-specific cellular models of PGRN haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by PGRN expression. Our findings identify cell-autonomous, reversible defects in patient neurons with PGRN deficiency, and provide a compelling model for studying PGRN-dependent pathogenic mechanisms and testing potential therapies.

The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS

To explore the respective roles of highly active antiretroviral therapy (HAART) and alpha-interferon in improving survival of patients with AIDS-related PML, we retrospectively analyzed all patients with AIDS and PML who were referred to Johns Hopkins University HIV Neurology Program from 1985 to 2000. For 97 evaluable patients, we compared survival of those who were on HAART (three or more antiretroviral drugs) to those who were not on HAART. The effect of alpha-interferon was also studied. Multivariate analysis showed no difference in survival among patients on none, one, or two forms of antiretrovirals; however, survival was significantly greater for those on HAART. Whereas alpha-interferon use was shown to be associated with longer survival (P < 0.057), this effect was not independent of the effects of HAART. HAART significantly increases survival for patients with PML and AIDS; however, alpha-interferon does not appear to provide additional benefit.

First symptom in sporadic Creutzfeldt–Jakob disease

Established clinical criteria for diagnosing sporadic Creutzfeldt–Jakob disease (sCJD) rely heavily on symptoms that appear late in the disease, such as myoclonus or akinetic mutism.1,2 Previous studies identified cognitive, cerebellar, and behavioral symptoms as common early symptoms of CJD (table).3-6 These studies designated symptoms as “early” based on chart reviews or based on existing symptoms when patients first presented to a physician. This study evaluates the very first symptom, which often occurs before patients present to medical attention, in a large cohort of patients with sCJD. View this table: Table 1 Comparison of UCSF first symptom study with a number of previous early symptom studies We reviewed over 400 potential CJD cases referred to the University of California San Francisco (UCSF) Memory and Aging Center from 2001 to 2004 and identified all cases of sCJD in which first symptoms were well documented. We included only cases of definite (pathology-proven) or probable CJD (World Health Organization [WHO] or modified Masters criteria).1,2 Cases …

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.