Brendan J. Kelley

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative

BACKGROUND The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders. METHODS We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT). FINDINGS Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimers disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele. INTERPRETATION Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.

Prominent phenotypic variability associated with mutations in Progranulin

Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimers disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.

Vascular risk factors and cognitive impairment in a stroke-free cohort

Objective: To examine vascular risk factors, as measured by the Framingham Stroke Risk Profile (FSRP), to predict incident cognitive impairment in a large, national sample of black and white adults age 45 years and older. Methods: Participants included subjects without stroke at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with at least 2 cognitive function assessments during the follow-up (n = 23,752). Incident cognitive impairment was defined as decline from a baseline score of 5 or 6 (of possible 6 points) to the most recent follow-up score of 4 or less on the Six-item Screener (SIS). Subjects with suspected stroke during follow-up were censored. Results: During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment. Baseline FSRP score was associated with incident cognitive impairment. An adjusted model revealed that male sex (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.43–1.77), black race (OR = 2.09, 95% CI 1.88–2.35), less education (less than high school graduate vs college graduate, OR = 2.21, 95% CI 1.88–2.60), older age (10-year increments, OR = 2.11, per 10-year increase in age, 95% CI 2.05–2.18), and presence of left ventricular hypertrophy (LVH, OR = 1.29, 95% CI 1.06–1.58) were related to development of cognitive impairment. When LVH was excluded from the model, elevated systolic blood pressure was related to incident cognitive impairment. Conclusions: Total FSRP score, elevated blood pressure, and LVH predict development of clinically significant cognitive dysfunction. Prevention and treatment of high blood pressure may be effective in preserving cognitive health.

C9ORF72 repeat expansions in cases with previously identified pathogenic mutations

Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management.

Seizures have been recognized to occur in multiple sclerosis (MS) since early descriptions of the disease. Various studies have attempted to determine the incidence and prevalence of seizures in MS; although they differ in the reported prevalence, seizures do appear to be more common in MS cohorts than in the general population.The pathological underpinning of seizures in MS remains indeterminate. Cortical and subcortical demyelination and inflammation may explain the increased frequency of seizures in MS, although this hypothetical correlation remains to be proven.Management of seizures in MS is similar to the management of seizures in other patients. Consideration of the underlying neurological deficits related to MS may be necessary, and dosages of antiepileptic drugs should be adjusted if increased sensitivity to the adverse effects of these agents or interaction with other centrally acting medications is suspected. The prognosis of epilepsy in patients with MS remains uncertain, with some studies suggesting a more favourable prognosis than others.

Young-Onset Dementia: Demographic and Etiologic Characteristics of 235 Patients

BACKGROUND Onset of dementia before age 45 years presents a difficult clinical circumstance, having a broad differential diagnosis and numerous psychosocial implications for the patient and their family. Few data exist regarding the demographics characterizing this population or the etiologic diagnoses among those affected. OBJECTIVES To characterize the demographic characteristics and the etiologic causes of dementia with age at onset younger than 45 years. DESIGN Observational, retrospective, single-cohort study. SETTING Multispecialty group academic medical center. PATIENTS We searched the Mayo Clinic Rochester electronic Medical Record Linkage System to identify individuals who were seen for evaluation of progressive cognitive decline between the ages of 17 and 45 years from January 1996 through December 2006. This search identified 235 individuals who met the established inclusion and exclusion criteria. MAIN OUTCOME MEASURES All available clinical, laboratory, magnetic resonance imaging, and pathological data were reviewed. RESULTS Causes varied, with neurodegenerative etiologies accounting for 31.1% of the cohort; Alzheimer disease was uncommon. Autoimmune or inflammatory causes accounted for 21.3%. At last follow-up, 44 patients (18.7%) had an unknown etiology, despite exhaustive evaluation. Cause varied with age, with inborn errors of metabolism being more common before age 30 years and with neurodegenerative etiologies being more common after age 35 years. CONCLUSIONS Young-onset dementia (age at onset, <45 years) includes a broad variety of etiologies, with few patients having a potentially treatable disorder. The etiologic spectrum and the relative percentages of patients within etiologic groups differed in important ways from existing reports of early-onset dementia (ie, age at onset, <65 years).

Cognitive Impairment in Acute Cocaine Withdrawal

To perform a pilot study to examine a range of cognitive flexibility tasks early in cocaine withdrawal. Background:Previous neuropsychological investigations of cocaine withdrawal have conflicted regarding whether impaired cognitive flexibility occurs. However, most studies have examined patients later in withdrawal. Anxiety and yohimbine-induced panic are greatest early in withdrawal, and both anxiety and increased noradrenergic tone can impair cognitive flexibility. Method:Twelve patients acutely withdrawing from cocaine were compared with gender-, age-, and estimated premorbid intelligence-matched control subjects on tests of cognitive flexibility as well as verbal fluency, verbal memory, spatial memory, and attention. Results:As predicted, impairments were found on the cognitive flexibility tasks. Impairments also were present in verbal fluency and verbal memory but not spatial memory or attention. Conclusions:We propose that the cognitive flexibility impairment may relate to the increased noradrenergic activation recently described in cocaine withdrawal. Impairments on verbal tasks may also relate to an impaired flexibility in the search of semantic networks. Further research will explore the effects of pharmacologic manipulation of the noradrenergic system on cognition in acute withdrawal. Recently, propranolol has been shown to benefit patients in cocaine withdrawal. Further research will explore whether impaired cognitive flexibility related to altered noradrenergic tone could serve as a mechanism for this treatment response.

Alzheimer Disease-like Phenotype Associated With the c.154delA Mutation in Progranulin

OBJECTIVE To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), with emphasis on the unique clinical features in this kindred. DESIGN Antemortem and postmortem characterization of a kindred with a familial neurodegenerative disorder. SETTING Multispecialty group academic medical center. PATIENTS Affected members of a kindred with dementia with or without parkinsonism associated with a unique mutation in PGRN. MAIN OUTCOME MEASURE Genotype-phenotype correlation. RESULTS Of 10 affected individuals identified, 6 presented with early amnestic symptoms which resulted in initial diagnoses of Alzheimer disease or amnestic mild cognitive impairment. Some individuals presented with features characteristic of frontotemporal dementia. Mean age at onset was substantially younger in generation III (75.8 years; range, 69-80 years) than in generation II (60.7 years; range, 55-66 years). The pattern of cerebral atrophy varied widely in the affected individuals. Neuropathologic features in 6 individuals included frontotemporal lobar degeneration with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U with NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), which caused a frameshift (p.Thr52HisfsX2) and, therefore, creation of a premature termination codon and a likely null allele. CONCLUSIONS In this large kindred, most affected individuals had clinical presentations that resembled Alzheimer disease or amnestic mild cognitive impairment associated with a mutation in PGRN and underlying FTLD-U with NII neuropathologic abnormalities. This finding is in distinct contrast to previously reported kindreds, in which clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age at onset between generations requires further study.

Alternative medicine and Alzheimer disease.

Background:Complimentary and alternative medicine has an extensive worldwide history and is commonly used by older patients. A number of different alternative medicines are used by patients having Alzheimer disease. It is both desirable and expected for clinicians to be acquainted with these medications. Review Summary:This paper discusses the available clinical trial evidence regarding 8 agents commonly used by people having Alzheimer disease. We provide an overview of the history and basic scientific evidence available for each agent, followed by a critical analysis of the evidence available from clinical trials, including the number of participants, trial duration, and specific outcomes evaluated. Conclusion:Although many of these compounds have been associated with interesting basic science, none has shown clear clinical benefit to date. Data available for some, such as Ginkgo biloba, curcumin, and huperzine A, suggest that further evaluation is warranted. Familiarity with this literature will allow clinicians to provide meaningful recommendations to patients who wish to use these agents.