Michael Geschwind | University of California, San Francisco (original) (raw)

Papers by Michael Geschwind

Continuum, Dec 1, 2015

Purpose of Review-This article presents an update on the clinical aspects of human prion disease,... more Purpose of Review-This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations. Recent Findings-Prion diseases, a group of disorders caused by abnormally shaped proteins called prions, occur in sporadic (Jakob-Creutzfeldt disease), genetic (genetic Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia), and acquired (kuru, variant Jakob-Creutzfeldt disease, and iatrogenic Jakob-Creutzfeldt disease) forms. This article presents updated information on the clinical features and diagnostic methods for human prion diseases. New antemortem potential diagnostic tests based on amplifying prions in order to detect them are showing very high specificity. Understanding of the diversity of possible presentations of human prion diseases continues to evolve, with some genetic forms progressing slowly over decades, beginning with dysautonomia and neuropathy and progressing to a frontalexecutive dementia with pathology of combined prionopathy and tauopathy. Unfortunately, to date, all human prion disease clinical trials have failed to show survival benefit. A very rare polymorphism in the prion protein gene recently has been identified that appears to protect against prion disease; this finding, in addition to providing greater understanding of the prionlike mechanisms of neurodegenerative disorders, might lead to potential treatments. Summary-Sporadic Jakob-Creutzfeldt disease is the most common form of human prion disease. Genetic prion diseases, resulting from mutations in the prion-related protein gene (PRNP), are classified based on the mutation, clinical phenotype, and neuropathologic features and can be difficult to diagnose because of their varied presentations. Perhaps most relevant to this Continuum issue on neuroinfectious diseases, acquired prion diseases are caused by accidental transmission to humans, but fortunately, they are the least common form and are becoming rarer as awareness of transmission risk has led to implementation of measures to prevent such occurrences.

Journal of Infectious Diseases and Therapy, Sep 25, 2017

The spectrum of human prion diseases Statement of the Problem: Diagnosis of human prion diseases ... more The spectrum of human prion diseases Statement of the Problem: Diagnosis of human prion diseases can be difficult as they can present similar to many other conditions, and many other conditions can clinically mimic prion disease. Correct diagnosis of prion disease is important in order to prevent accidental transmission of the prions, to prevent further unnecessary diagnostic testing and to provide a realistic prognosis to the patient and family. Methodology & Theoretical Orientation: Our center has evaluated more than 2500 cases of rapidly progressive dementia (RPD), including more than 600 cases of prion disease through our clinical research program. Most patients undergo a comprehensive evaluation including clinical history, cognitive testing, CSF analysis, research brain MRI protocol and other testing. These data are analyzed to identify measures that might improve diagnostic accuracy of prion disease compared to other non-prion RPDs. Findings: The clinical presentation, including presenting symptoms, duration of disease, and laboratory findings are quite varied in prion disease. Brain MRI with diffusion sequences showed high diagnostic accuracy for human prion disease. Unfortunately, radiologists in the USA often miss the radiological diagnosis of prion disease, despite the MRIs showing classic features. A relatively new CSF test called RT-QuIC shows high specificity, although not as good sensitivity, for prion disease diagnosis. Conclusion & Significance: Our ability to diagnosis prion disease has improved over the past few years to the point at which brain biopsies are rarely needed. Improved diagnosis will be important for future treatment trials and prevention of accidental transmission of these potentially infectious diseases. Biography Michael D Geschwind is a Professor of Neurology at the UCSF Memory and Aging Center who specializes in the assessment, treatment and management of rapidly progressive dementias, including prion diseases such as Jakob-Creutzfeldt disease (JCD) and autoimmune encephalopathies, and other cognitive/movement disorder syndromes. He helped to establish a program for the assessment of rapidly progressive dementias at UCSF Medical Center, the first of its kind in the country. He helped to run the first US treatment trial for sporadic disease, at UCSF. He has also helped to establish and co-direct a clinic for patients with autoimmune encephalopathy. He Co-directs the Huntington's Disease Society of America Center of Excellence (HDSA COE) and Ataxia Clinic at the UCSF Memory and Aging Center. His research interests include rapidly progressive dementias, cognitive dysfunction in movement disorders, such as Huntington's disease, spinocerebellar ataxia, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and other Parkinsonian dementias.

Human Brain Mapping

Grey matter involvement is a well‐known feature in sporadic Creutzfeldt–Jakob disease (sCJD), yet... more Grey matter involvement is a well‐known feature in sporadic Creutzfeldt–Jakob disease (sCJD), yet precise anatomy‐based quantification of reduced diffusivity is still not fully understood. Default Mode Network (DMN) areas have been recently demonstrated as selectively involved in sCJD, and functional connectivity has never been investigated in prion diseases. We analyzed the grey matter involvement using a quantitatively multi‐parametric MRI approach. Specifically, grey matter mean diffusivity of 37 subjects with sCJD was compared with that of 30 age‐matched healthy controls with a group‐wise approach. Differences in mean diffusivity were also examined between the cortical (MM(V)1, MM(V)2C, and VV1) and subcortical (VV2 and MV2K) subgroups of sCJD for those with autopsy data available (n = 27, 73%). We also assessed resting‐state functional connectivity of both ventral and dorsal components of DMN in a subset of subject with a rs‐fMRI dataset available (n = 17). Decreased diffusivit...

Neurology - Neuroimmunology Neuroinflammation

Background and ObjectivesTo study human leukocyte antigen (HLA) allele associations in anti-leuci... more Background and ObjectivesTo study human leukocyte antigen (HLA) allele associations in anti-leucine–rich glioma-inactivated 1 (LGI1) encephalitis.MethodsA multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ2, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.ResultsDRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, p < 10e−50) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, p = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger (p = 0.003) and more frequent...

Creutzfeldt-Jakob disease (CJD) is an uncommon neurodegenerative disorder with an incidence of 1 ... more Creutzfeldt-Jakob disease (CJD) is an uncommon neurodegenerative disorder with an incidence of 1 per 1000,000 per year typically characterized by rapidly progressive dementia, ataxia, myoclonus and behavioral changes. Genetic prion diseases, which develop due to a mutations in the prion protein gene (PRNP), account for an estimated 10 to 15 % of all CJD cases. We report a 75-yr-old woman with familial CJD carrying a V180I mutation which features late onset, slow progression, no periodic sharp wave complexes on electroencephalography, and extensive cortical ribboning with spared the cerebellum and the medial occipital lobes posterior to the parieto-occipital sulcus on MRI. To our knowledge, this is the first documented case of a point mutation at codon 180 in South Korea.

Tienda online donde Comprar Non-Alzheimer's Dementia al precio 108,29 € de Michael D. Geschwi... more Tienda online donde Comprar Non-Alzheimer's Dementia al precio 108,29 € de Michael D. Geschwind | Caroline Racine, tienda de Libros de Medicina, Libros de Neurologia - Neurologia general

Neurology, 2016

OBJECTIVE: To develop expert consensus guidelines for dementia evaluation. BACKGROUND: Currently ... more OBJECTIVE: To develop expert consensus guidelines for dementia evaluation. BACKGROUND: Currently in the US, the majority of patients suspected to have a neurodegenerative disease are identified, evaluated, diagnosed, and cared for by primary care physicians (PCPs). However, due to gaps in PCPs knowledge of these conditions, and heterogeneity of approaches across clinicians and sites, many patients are missed at the Mild Cognitive Impairment (MCI) phase, do not undergo timely or appropriate diagnostic procedures, are miscategorized, and are not referred to a neurology specialist when clinically warranted. METHODS: To directly address this growing public health concern, a panel of experts in dementia diagnosis and care (neurologists, neuropsychologists, psychiatrists, geriatricians, PCPs, nurses) convened for two days in March 2015 to determine a common approach to dementia screening and diagnostic assessment. Panelists continue to refine the dementia care pathway and are writing a co...

Neurology, 2013

OBJECTIVE: Identify and discuss the ethical issues relevant to human prion diseases including the... more OBJECTIVE: Identify and discuss the ethical issues relevant to human prion diseases including the resulting consequences for individuals, their families, and society. BACKGROUND: Human prion diseases are currently untreatable, rapidly progressive, fatal neurodegenerative conditions that are unique in medicine in that they occur three in sporadic, genetic, and acquired forms. As a major clinical research center for prion diseases, and having run the first U.S. CJD treatment trial, we have seen more than 500 cases of rapidly progressive dementias, including many prion diseases, in the past 10 years and have dealt with several challenging ethical issues. DESIGN/METHODS: Literature, clinical database, and record review with case presentations. RESULTS: Some ethical issues faced include: •Conducting randomized, placebo-controlled clinical trial in fatal disease •Delay of appropriate medical intervention for fear of prion contamination of limited medical equipment required for other patie...

The Lancet Neurology, 2020

Background-Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, t... more Background-Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein (PRNP) are strong risk factors for sCJD but, although the condition has heritability similar to other neurodegenerative disorders, no other genetic risk loci have yet been confirmed. We aimed to discover new genetic risk factors and the causal mechanisms. Methods-Genome-wide association in European ancestry populations (patients diagnosed with probable or definite sCJD; identified at national CJD referral centres from 1990-2014; cases n=5208) using genotyping arrays and exome sequencing. Conditional, transcriptional and histological analyses of implicated genes/proteins in brain tissues and tests of the effects of risk variants on clinical phenotypes using deep longitudinal clinical cohort data. Findings-We found 41 genome-wide significant single nucleotide polymorphisms and independently replicated findings at three loci associated with sCJD risk within PRNP (rs1799990; additive model P=2•68 × 10-15, OR=1•23; heterozygous model P=1.01×10-135), STX6 (rs3747957; P=9•74 × 10-9, OR=1•16) and GAL3ST1 (rs2267161; P=8•60 × 10-10, OR=1•18). Follow-up analyses suggest that associations at PRNP and GAL3ST1 are likely caused by common variants that alter the protein sequence, whereas risk variants in STX6 associate with increased expression of the major transcripts in disease-relevant brain regions. Alteration of STX6 expression does not modify prion propagation in a neuroblastoma cell model of mouse prion infection. Interpretation-We present the first evidence of statistically robust associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, implicating shared mechanisms in prion-like disorders.

Neurology - Neuroimmunology Neuroinflammation, 2020

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibo... more ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive cluster...

JAMA Neurology, 2019

IMPORTANCE Fluid biomarkers that can predict survival time in sporadic Creutzfeldt-Jakob disease ... more IMPORTANCE Fluid biomarkers that can predict survival time in sporadic Creutzfeldt-Jakob disease (sCJD) will be critical for clinical care and for treatment trials. OBJECTIVE To assess whether plasma and cerebrospinal fluid (CSF) biomarkers are associated with survival time in patients with sCJD. DESIGN, SETTING, AND PARTICIPANTS In this longitudinal cohort study, data from 193 patients with probable or definite sCJD who had codon 129 genotyping referred to a tertiary national referral service in the United States were collected from March 2004 to January 2018. Participants were evaluated until death or censored at the time of statistical analysis (range, 0.03-38.3 months). We fitted Cox proportional hazard models with time to event as the outcome. Fluid biomarkers were log-transformed, and models were run with and without nonfluid biomarkers of survival. Five patients were excluded because life-extending measures were performed. MAIN OUTCOMES AND MEASURES Biomarkers of survival included sex, age, codon 129 genotype, Barthel Index, Medical Research Council Prion Disease Rating Scale, 8 CSF biomarkers (total tau [t-tau] level, phosphorylated tau [p-tau] level, t-tau:p-tau ratio, neurofilament light [NfL] level, β-amyloid 42 level, neuron-specific enolase level, 14-3-3 test result, and real-time quaking-induced conversion test), and 3 plasma biomarkers (t-tau level, NfL level, and glial fibrillary acidic protein level). RESULTS Of the 188 included participants, 103 (54.8%) were male, and the mean (SD) age was 63.8 (9.2) years. Plasma t-tau levels (hazard ratio, 5.8; 95% CI, 2.3-14.8; P < .001) and CSF t-tau levels (hazard ratio, 1.6; 95% CI, 1.2-2.1; P < .001) were significantly associated with survival after controlling for codon 129 genotype and Barthel Index, which are also associated with survival time. Plasma and CSF t-tau levels were correlated (r = 0.74; 95% CI, 0.50-0.90; P < .001). Other fluid biomarkers associated with survival included plasma NfL levels, CSF NfL levels, t-tau:p-tau ratio, 14-3-3 test result, and neuron-specific enolase levels. In a restricted subset of 23 patients with data for all significant biomarkers, the hazard ratio for plasma t-tau level was more than 40% larger than any other biomarkers (hazard ratio, 3.4; 95% CI, 1.8-6.4). CONCLUSIONS AND RELEVANCE Cerebrospinal fluid and plasma tau levels, along with several other fluid biomarkers, were significantly associated with survival time in patients with sCJD. The correlation between CSF and plasma t-tau levels and the association of plasma t-tau level with survival time suggest that plasma t-tau level may be a minimally invasive fluid biomarker in sCJD that could improve clinical trial stratification and guide clinical care.

Reduction of native prion protein (PrP) levels in the brain is an attractive and genetically vali... more Reduction of native prion protein (PrP) levels in the brain is an attractive and genetically validated strategy for the treatment or prevention of human prion diseases. However, clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction, in the central nervous system (CNS) of a living patient. Here we evaluate the potential of enzyme-linked immunosorbent assay (ELISA)-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS-derived, supporting its relevance for monitoring the tissu...

Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases w... more Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data fromN=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essent...

Proceedings of the National Academy of Sciences, 2019

Significance Human prion disease is a rapidly fatal and incurable neurodegenerative disease. Redu... more Significance Human prion disease is a rapidly fatal and incurable neurodegenerative disease. Reduction of prion protein in the brain is a well-supported therapeutic hypothesis, and antisense oligonucleotides with this mechanism of action are currently in development. To facilitate clinical testing of prion protein-lowering drugs in prion disease, we show that with proper sample handling, brain prion protein levels can be monitored in cerebrospinal fluid, using existing tools, and exhibit suitable short-term stability for drug-dependent decreases to be reliably measured. Cerebrospinal fluid prion protein levels thus may usefully serve as a pharmacodynamic biomarker. This biomarker may open new paths for informative clinical trials in presymptomatic individuals who harbor high-risk mutations for genetic prion disease.

Neurology - Neuroimmunology Neuroinflammation, 2019

ObjectiveWe sought to validate methods for detection and confirmation of GABAA receptor (R)-IgG a... more ObjectiveWe sought to validate methods for detection and confirmation of GABAA receptor (R)-IgG and clinically characterize seropositive cases.MethodsArchived serum and CSF specimens (185 total) suspected to harbor GABAAR-IgG were evaluated by indirect immunofluorescence assay (IFA). Twenty-six specimens from 19 patients appeared suspicious for GABAAR–IgG positivity by IFA, based on prior reports and comparison with commercial GABAAR antibody staining. Aliquots of those specimens were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAAR-IgG by cell-based assays (CBAs) using HEK293-indicator cells transfected with plasmids encoding different GABAAR subunits.ResultsEight specimens (of 26 tested; 4 serums, 4 CSFs) from 5 patients were confirmed by CBA to be GABAAR-IgG positive. Patient IgGs were always reactive with α1β3 GABAAR subunits. One more patient was identified clinically after this validation study. Median age for the 6 patients at ser...

Neurology, 2006

Cellular phone use began in the United Kingdom in 1985. Sales increased slowly until 1992, more r... more Cellular phone use began in the United Kingdom in 1985. Sales increased slowly until 1992, more rapidly to 1997, before substantial growth to 2005 (figure). 1 The UK Stewart Report 2 into cellular phones and health concluded: "It is not possible at present to say that exposure to radio frequency radiation, even at levels below national guidelines, is totally without potential adverse health effects, and that the gaps in knowledge are sufficient to justify a precautionary approach." A recent case-control study from Sweden found up to fourfold risk associated with cellular phone use of 10 or more years' duration. 3 A number of studies both in Europe and the United States have found little or no evidence of an effect, 4 and a recent report from five countries suggests no substantial risk from the first decade of cellular phone use. 5 We examined time trends in national cancer registration rates of acoustic neuroma (and other benign cranial nerve neoplasms) from 1979 to 2001 in England and Wales and compared these with trends in cellular phone use. Methods. We extracted registrations of cases of acoustic neuroma (and other benign cranial nerve neoplasms; site codes International Classification of Diseases [ICD] 9 225.1 and ICD-10 D33.3, with morphology code 9560/0) for England and Wales from the National Cancer Registry, maintained by the Office for National Statistics (ONS), for the period 1979 to 2001. We calculated 3-year moving averages of the age-and sex-specific rates (hence the figure shows rates for 1980 to 2000). We also calculated directly age-standardized rates (European standard population). Annual population estimates from ONS provided denominator data. Results. From 1979 to 1997, annual registrations increased from 84 to 374 cases and then fell to 262 in 2001. Agestandardized 3-year moving average rates increased from 2.4 to 7.6 per million between 1980 and 1997 and then fell to 5.5 per million (see figure) in 2000. Trends were similar in men and women. From 1980 to 1997, 3-year moving average rates increased in all age groups, followed by a decline. This decrease was less evident in the younger groups. Discussion. The finding of increasing registrations of acoustic neuroma over recent decades is consistent with reports of in-From the

Quality of Life Research, 2016

Purpose-Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical,... more Purpose-Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL-Quality of Life in Neurological Disorders and PROMIS-Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. Methods-New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. Results-Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding sixitem short forms. A four-item short form was developed for Meaning and Purpose. Conclusions-HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD.

The Behavioral Neurology of Dementia

Geschwind/Non-Alzheimer's and Atypical Dementia, 2016