Lorne Zinman - Academia.edu (original) (raw)
Papers by Lorne Zinman
Brain : a journal of neurology, Jan 31, 2015
Muscle & Nerve, 2006
Repetitive stimulation of the facial nerve is commonly performed in cases of suspected myasthenia... more Repetitive stimulation of the facial nerve is commonly performed in cases of suspected myasthenia gravis (MG) because bulbar weakness is often present, but the most sensitive facial muscle is unknown. We compared the sensitivity of repetitive nerve stimulation (RNS) to the frontalis and nasalis muscles in 244 patients with suspected MG. We found no difference in sensitivity of RNS when recording from these muscles in both ocular and generalized MG. In addition, we confirmed the low sensitivity of RNS for ocular (18%) or generalized (47%) MG. The specificity of facial RNS for both muscles was 100% and, in certain circumstances, may obviate the need for further diagnostic testing.
The Lancet Neurology, 2014
Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis... more Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial. This three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622. Stage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0·51 units per month, 95% CI 0·02 to 1·00; p=0·0416), but in stage 3 functional decline between the treatment groups did not differ (0·09, -0·06 to 0·24; p=0·2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0·0004; hepatobiliary, 211 [62%] vs 19 [11%],…
Einstein (São Paulo, Brazil)
To describe the prevalence and severity of periodic limb movements during sleep in amyotrophic la... more To describe the prevalence and severity of periodic limb movements during sleep in amyotrophic lateral sclerosis patients and to explore this fact as a predictor of severity of the condition with respect to mortality. In this case-control study, questionnaire and polysomnographic data were analyzed from 35 amyotrophic lateral sclerosis patients. Controls were matched by age, genre, and body mass index. A Kaplan-Meier curve was used to compare the survival time of patients with periodic limb movements of sleep index below or above 5. The number of amyotrophic lateral sclerosis patients with an index greater than five was higher than controls (19 (53%) versus 4 (11%); p < 0.0001), and the mean index was higher (23.55 ± 40.07 versus 3.28 ± 8.96; p = 0.0009). Earlier mortality was more common in patients with more than five periodic limb movements per hour of sleep than patients with less than five periodic limb movements per hour of sleep (7/19 (37%) versus 1/16 (6%); p = 0.04) in t...
The Lancet Neurology, 2010
Clinical trials of potential treatments for amyotrophic lateral sclerosis (ALS) are hindered by t... more Clinical trials of potential treatments for amyotrophic lateral sclerosis (ALS) are hindered by the relative rarity of the disease and the large number of drugs to test. If we tested each drug in a trial of 6001000 patients, in 10 years we would have tested only two or three drugs. Our ...
The Journal of the Acoustical Society of America, 2013
ABSTRACT Previous acoustic studies on speech deterioration in amyotrophic lateral sclerosis (ALS)... more ABSTRACT Previous acoustic studies on speech deterioration in amyotrophic lateral sclerosis (ALS) demonstrated that those at more advanced stages of disease show reduced F2 (second formant) slopes presumably due to disease-related changes in the tongue. Other studies have shown that patients with ALS use their jaw to compensate for decreased tongue function in speech. However, no study to date has examined the compensatory role that the jaw has on maintaining the acoustic signatures of vocalic segments. This study will report F2 slope differences in vowels and diphthongs produced with and without jaw stabilization via a bite block. Based on previous studies, I hypothesized that the bite block will affect F2 slope measures in individuals with significant tongue impairment on the oral-motor examination and low speech intelligibility scores. Thirty participants repeat a carrier phrase "Say _ again" with words "wax, sip, yo-yo, sight" three times with and without the bite block. Kinematic measures of the distance, time, and speed, and acoustic measures of F2 slope are reported. The data will be discussed in the context of the role of the tongue in vowel production.
Journal of Neuropathology and Experimental Neurology, 2007
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by ... more Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the presence of various types of ubiquitinated inclusions in the cytoplasm of affected motor neurons. The identification of the ubiquitinated targets within these inclusions has represented a major challenge, as this may provide new gene candidates and/or clues to understanding the neurodegenerative mechanism(s) underlying the disease. As such, the nuclear factor TAR DNA-binding protein (TDP-43) was recently identified as a component of ubiquitinated skein-like inclusions and round inclusions in ALS. This identification combined with biochemical evidence led to the suggestion that TDP-43 is the key ubiquitinated target and major disease protein in ALS. Here, using 3-dimensional deconvolution imaging, we have obtained remarkable resolution of skein-like inclusions and round inclusions in ALS. Surprisingly we have found that in contrast to current thinking, TDP-43 is not the major ubiquitinated target within these types of inclusions. These findings raise the possibility that TDP-43 may not necessarily be the key disease protein in ALS and indicate that the major target(s) of ubiquitination remain to be identified.
Diabetes Care, 2004
OBJECTIVE-Low-intensity laser therapy (LILT) has been advocated for treatment of chronic pain dis... more OBJECTIVE-Low-intensity laser therapy (LILT) has been advocated for treatment of chronic pain disorders. Although the mechanism of pain relief is uncertain, this therapy has been suggested for relief of painful symptoms of diabetic sensorimotor polyneuropathy (DSP). The objective of this study was to determine whether LILT relieves the pain of DSP.
Diabetes Care, 2004
OBJECTIVE -Cooling detection threshold testing may be an important quantitative method for assess... more OBJECTIVE -Cooling detection threshold testing may be an important quantitative method for assessing polyneuropathy, in that it has traditionally been viewed as a measure of small-fiber involvement. The present study sought to determine the agreement between two common testing devices and to determine whether these are concordant in their association with predictor variables for diabetic sensory polyneuropathy.
Annals of Neurology, 2009
Objective: In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1)... more Objective: In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1) mutations (fALS1), SOD1 toxicity has been linked to its propensity to misfold and aggregate. It has recently been proposed that misfolded SOD1 may be causative of all types of ALS, including sporadic cases (sALS). In the present study, we have used a specific antibody to test for the presence of monomer/misfolded SOD1 in sALS. Methods: Sections from lumbar spinal cords of 5 fALS1 cases, 13 sALS cases, and 1 non-SOD1 fALS case were labeled immunocytochemically using SOD1-exposed-dimer-interface (SEDI) antibody, which we have previously validated as being specific for pathological monomer/misfolded forms of SOD1. Results: Monomer/misfolded SOD1 was detected with SEDI antibody in all 5 of the fALS1 cases, localizing predominantly to hyaline conglomerate inclusions, a specific pathological feature of fALS1. In contrast, monomer/misfolded SOD1 was not detected in any of the 13 sALS cases or in the non-SOD1 fALS cases. These results were confirmed by immunoprecipitation. Interpretation: Although SEDI antibody does not necessarily label all misfolded forms of SOD1, these findings show a distinct difference between fALS1 and sALS, and do not support that monomer/misfolded SOD1 is a common disease entity linking all types of ALS. This is important to our understanding of ALS disease pathogenesis and to considerations of the applicability of using therapeutics that target misfolded SOD1 to non-SOD1-related cases.
Amyotrophic Lateral Sclerosis, 2008
Statin medications for elevated cholesterol are one of the most commonly prescribed medications w... more Statin medications for elevated cholesterol are one of the most commonly prescribed medications worldwide. The aim of this study was to determine if statin medications affect the rate of disease progression, the severity and frequency of muscle cramping, and serum CK levels in patients with ALS. We conducted a prospective cohort study in patients diagnosed with ALS with statin medication as the predetermined exposure variable and the rate of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) as the primary outcome. One hundred and sixty-four consecutive patients with laboratory supported probable, clinically probable, or clinically definite ALS were evaluated from January 2006 to September 2007. Thirty-two patients (20%) were taking statin medications and 132 were in the control group. After adjusting for covariates, we found a highly significant increase in the rate of decline in the ALSFRS-R for the statin group (1.71 units/month) compared to the control group (1.05 units/month, pB0.0001) representing a 63% increase in the rate of functional decline. Patients on statin therapy also reported a significant increase in muscle cramp frequency and severity (pB0.0001). This study has demonstrated a strong association between statin medications and an increased rate of functional decline and muscle cramping in patients with ALS. Although this association does not prove a causal relationship, it is prudent to exercise caution and discuss discontinuation or replacement of statin medications in patients with ALS.
Acta Neuropathologica, 2015
The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degene... more The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2) n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50 repeats (97 %), while small…
Annals of Neurology, 2015
Objective: A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amy... more Objective: A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It has been reported that the repeat expansion causes a downregulation of C9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis. Two protein isoforms are generated from three alternatively spliced transcripts of C9orf72; a long form (C9-L) and a short form (C9-S) and their function(s) are largely unknown due to lack of specific antibodies.
The American Journal of Human Genetics, 2015
An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic ... more An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered…
Acta neuropathologica, Jan 19, 2015
The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-bindin... more The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-binding protein 43 (TDP-43) is a characteristic of TDP-43 proteinopathy in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we have identified a novel splice variant of TDP-43 that is upregulated in ALS and generates a 35-kDa N-terminally truncated species through use of an alternate translation initiation codon (ATG(Met85)), denoted here as Met(85)-TDP-35. Met(85)-TDP-35 expressed ectopically in human neuroblastoma cells exhibited reduced solubility, cytoplasmic distribution, and aggregation. Furthermore, Met(85)-TDP-35 sequestered full-length TDP-43 from the nucleus to form cytoplasmic aggregates. Expression of Met(85)-TDP-35 in primary motor neurons resulted in the formation of Met(85)-TDP-35-positive cytoplasmic aggregates and motor neuron death. A neo-epitope antibody specific for Met(85)-TDP-35 labeled the 35-kDa lower molecular weight species on im...
Brain : a journal of neurology, Jan 31, 2015
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014
This study quantifies the &amp;amp;amp;#39;out-of-pocket&amp;amp;amp;#39; expense... more This study quantifies the &amp;amp;amp;#39;out-of-pocket&amp;amp;amp;#39; expenses incurred by individuals with amyotrophic lateral sclerosis (ALS) and their families, explores cost-driving factors and describes the current state of financial support in a Canadian cohort. We performed structured cost-of-illness interviews with 50 consecutive ALS patients and family members detailing disease-specific factors, direct and indirect costs. Direct costs were divided into &amp;amp;amp;#39;out-of-pocket&amp;amp;amp;#39; and &amp;amp;amp;#39;government/non-profit organization (NPO) supported&amp;amp;amp;#39;. Results showed that the average annual direct cost per patient was 32,337,ofwhich32,337, of which 32,337,ofwhich19,574 (61%) was paid for out-of-pocket. The most significant direct cost was disease-related home renovations, which garnered minimal government or NPO support. The costs of mobility aids, medical expenses, and private personal support workers were also substantial. Higher out-of-pocket costs were associated with an ALS Functional Rating Scale gross motor subscore of ≤ 6 (p = 0.03), limb-predominant symptoms (p = 0.04) and &amp;amp;amp;gt; 4 h/week of personal support care (p = 0.005). Annual indirect costs (lost wages) for patients with ALS and family members providing care were $56,821. In conclusion, this study quantified the substantial personal economic impact of ALS as measured by non-reimbursed, out-of-pocket expenses. Mobilization of additional resources for ALS patients and families is required to soften the economic burden of this disabling disease.
Human molecular genetics, 2014
The G₄C₂-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD... more The G₄C₂-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of the CpG-island (5'of the repeat) in DNA samples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation level was significantly higher in FTLD expansion carriers than non-carriers (P = 7.8E-13). Our results were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an...
Brain : a journal of neurology, Jan 31, 2015
Muscle & Nerve, 2006
Repetitive stimulation of the facial nerve is commonly performed in cases of suspected myasthenia... more Repetitive stimulation of the facial nerve is commonly performed in cases of suspected myasthenia gravis (MG) because bulbar weakness is often present, but the most sensitive facial muscle is unknown. We compared the sensitivity of repetitive nerve stimulation (RNS) to the frontalis and nasalis muscles in 244 patients with suspected MG. We found no difference in sensitivity of RNS when recording from these muscles in both ocular and generalized MG. In addition, we confirmed the low sensitivity of RNS for ocular (18%) or generalized (47%) MG. The specificity of facial RNS for both muscles was 100% and, in certain circumstances, may obviate the need for further diagnostic testing.
The Lancet Neurology, 2014
Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis... more Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial. This three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622. Stage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0·51 units per month, 95% CI 0·02 to 1·00; p=0·0416), but in stage 3 functional decline between the treatment groups did not differ (0·09, -0·06 to 0·24; p=0·2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0·0004; hepatobiliary, 211 [62%] vs 19 [11%],…
Einstein (São Paulo, Brazil)
To describe the prevalence and severity of periodic limb movements during sleep in amyotrophic la... more To describe the prevalence and severity of periodic limb movements during sleep in amyotrophic lateral sclerosis patients and to explore this fact as a predictor of severity of the condition with respect to mortality. In this case-control study, questionnaire and polysomnographic data were analyzed from 35 amyotrophic lateral sclerosis patients. Controls were matched by age, genre, and body mass index. A Kaplan-Meier curve was used to compare the survival time of patients with periodic limb movements of sleep index below or above 5. The number of amyotrophic lateral sclerosis patients with an index greater than five was higher than controls (19 (53%) versus 4 (11%); p < 0.0001), and the mean index was higher (23.55 ± 40.07 versus 3.28 ± 8.96; p = 0.0009). Earlier mortality was more common in patients with more than five periodic limb movements per hour of sleep than patients with less than five periodic limb movements per hour of sleep (7/19 (37%) versus 1/16 (6%); p = 0.04) in t...
The Lancet Neurology, 2010
Clinical trials of potential treatments for amyotrophic lateral sclerosis (ALS) are hindered by t... more Clinical trials of potential treatments for amyotrophic lateral sclerosis (ALS) are hindered by the relative rarity of the disease and the large number of drugs to test. If we tested each drug in a trial of 6001000 patients, in 10 years we would have tested only two or three drugs. Our ...
The Journal of the Acoustical Society of America, 2013
ABSTRACT Previous acoustic studies on speech deterioration in amyotrophic lateral sclerosis (ALS)... more ABSTRACT Previous acoustic studies on speech deterioration in amyotrophic lateral sclerosis (ALS) demonstrated that those at more advanced stages of disease show reduced F2 (second formant) slopes presumably due to disease-related changes in the tongue. Other studies have shown that patients with ALS use their jaw to compensate for decreased tongue function in speech. However, no study to date has examined the compensatory role that the jaw has on maintaining the acoustic signatures of vocalic segments. This study will report F2 slope differences in vowels and diphthongs produced with and without jaw stabilization via a bite block. Based on previous studies, I hypothesized that the bite block will affect F2 slope measures in individuals with significant tongue impairment on the oral-motor examination and low speech intelligibility scores. Thirty participants repeat a carrier phrase "Say _ again" with words "wax, sip, yo-yo, sight" three times with and without the bite block. Kinematic measures of the distance, time, and speed, and acoustic measures of F2 slope are reported. The data will be discussed in the context of the role of the tongue in vowel production.
Journal of Neuropathology and Experimental Neurology, 2007
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by ... more Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the presence of various types of ubiquitinated inclusions in the cytoplasm of affected motor neurons. The identification of the ubiquitinated targets within these inclusions has represented a major challenge, as this may provide new gene candidates and/or clues to understanding the neurodegenerative mechanism(s) underlying the disease. As such, the nuclear factor TAR DNA-binding protein (TDP-43) was recently identified as a component of ubiquitinated skein-like inclusions and round inclusions in ALS. This identification combined with biochemical evidence led to the suggestion that TDP-43 is the key ubiquitinated target and major disease protein in ALS. Here, using 3-dimensional deconvolution imaging, we have obtained remarkable resolution of skein-like inclusions and round inclusions in ALS. Surprisingly we have found that in contrast to current thinking, TDP-43 is not the major ubiquitinated target within these types of inclusions. These findings raise the possibility that TDP-43 may not necessarily be the key disease protein in ALS and indicate that the major target(s) of ubiquitination remain to be identified.
Diabetes Care, 2004
OBJECTIVE-Low-intensity laser therapy (LILT) has been advocated for treatment of chronic pain dis... more OBJECTIVE-Low-intensity laser therapy (LILT) has been advocated for treatment of chronic pain disorders. Although the mechanism of pain relief is uncertain, this therapy has been suggested for relief of painful symptoms of diabetic sensorimotor polyneuropathy (DSP). The objective of this study was to determine whether LILT relieves the pain of DSP.
Diabetes Care, 2004
OBJECTIVE -Cooling detection threshold testing may be an important quantitative method for assess... more OBJECTIVE -Cooling detection threshold testing may be an important quantitative method for assessing polyneuropathy, in that it has traditionally been viewed as a measure of small-fiber involvement. The present study sought to determine the agreement between two common testing devices and to determine whether these are concordant in their association with predictor variables for diabetic sensory polyneuropathy.
Annals of Neurology, 2009
Objective: In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1)... more Objective: In familial amyotrophic lateral sclerosis (fALS) harboring superoxide dismutase (SOD1) mutations (fALS1), SOD1 toxicity has been linked to its propensity to misfold and aggregate. It has recently been proposed that misfolded SOD1 may be causative of all types of ALS, including sporadic cases (sALS). In the present study, we have used a specific antibody to test for the presence of monomer/misfolded SOD1 in sALS. Methods: Sections from lumbar spinal cords of 5 fALS1 cases, 13 sALS cases, and 1 non-SOD1 fALS case were labeled immunocytochemically using SOD1-exposed-dimer-interface (SEDI) antibody, which we have previously validated as being specific for pathological monomer/misfolded forms of SOD1. Results: Monomer/misfolded SOD1 was detected with SEDI antibody in all 5 of the fALS1 cases, localizing predominantly to hyaline conglomerate inclusions, a specific pathological feature of fALS1. In contrast, monomer/misfolded SOD1 was not detected in any of the 13 sALS cases or in the non-SOD1 fALS cases. These results were confirmed by immunoprecipitation. Interpretation: Although SEDI antibody does not necessarily label all misfolded forms of SOD1, these findings show a distinct difference between fALS1 and sALS, and do not support that monomer/misfolded SOD1 is a common disease entity linking all types of ALS. This is important to our understanding of ALS disease pathogenesis and to considerations of the applicability of using therapeutics that target misfolded SOD1 to non-SOD1-related cases.
Amyotrophic Lateral Sclerosis, 2008
Statin medications for elevated cholesterol are one of the most commonly prescribed medications w... more Statin medications for elevated cholesterol are one of the most commonly prescribed medications worldwide. The aim of this study was to determine if statin medications affect the rate of disease progression, the severity and frequency of muscle cramping, and serum CK levels in patients with ALS. We conducted a prospective cohort study in patients diagnosed with ALS with statin medication as the predetermined exposure variable and the rate of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) as the primary outcome. One hundred and sixty-four consecutive patients with laboratory supported probable, clinically probable, or clinically definite ALS were evaluated from January 2006 to September 2007. Thirty-two patients (20%) were taking statin medications and 132 were in the control group. After adjusting for covariates, we found a highly significant increase in the rate of decline in the ALSFRS-R for the statin group (1.71 units/month) compared to the control group (1.05 units/month, pB0.0001) representing a 63% increase in the rate of functional decline. Patients on statin therapy also reported a significant increase in muscle cramp frequency and severity (pB0.0001). This study has demonstrated a strong association between statin medications and an increased rate of functional decline and muscle cramping in patients with ALS. Although this association does not prove a causal relationship, it is prudent to exercise caution and discuss discontinuation or replacement of statin medications in patients with ALS.
Acta Neuropathologica, 2015
The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degene... more The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2) n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;50 repeats (97 %), while small…
Annals of Neurology, 2015
Objective: A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amy... more Objective: A noncoding hexanucleotide repeat expansion in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It has been reported that the repeat expansion causes a downregulation of C9orf72 transcripts, suggesting that haploinsufficiency may contribute to disease pathogenesis. Two protein isoforms are generated from three alternatively spliced transcripts of C9orf72; a long form (C9-L) and a short form (C9-S) and their function(s) are largely unknown due to lack of specific antibodies.
The American Journal of Human Genetics, 2015
An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic ... more An expanded G4C2 repeat in C9orf72 represents the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the lower limit for pathological expansions is unknown (the suggested cutoff is 30 repeats). It has been proposed that the expansion might have occurred only once in human history and subsequently spread throughout the population. However, our present findings support a hypothesis of multiple origins for the expansion. We report a British-Canadian family in whom a ∼70-repeat allele from the father (unaffected by ALS or FTLD at age 89 years) expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry an ∼1,750-repeat allele). Epigenetic and RNA-expression analyses further discriminated the offspring&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s large expansions (which were methylated and associated with reduced C9orf72 expression) from the ∼70-repeat allele (which was unmethylated and associated with upregulation of C9orf72). Moreover, RNA foci were only detected in fibroblasts from offspring with large expansions, but not in the father, who has the ∼70-repeat allele. All family members with expansions were found to have an ancient known risk haplotype, although it was inherited on a unique 5-Mb genetic backbone. We conclude that small expansions (e.g., 70 repeats) might be considered…
Acta neuropathologica, Jan 19, 2015
The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-bindin... more The presence of lower molecular weight species comprising the C-terminal region of TAR DNA-binding protein 43 (TDP-43) is a characteristic of TDP-43 proteinopathy in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we have identified a novel splice variant of TDP-43 that is upregulated in ALS and generates a 35-kDa N-terminally truncated species through use of an alternate translation initiation codon (ATG(Met85)), denoted here as Met(85)-TDP-35. Met(85)-TDP-35 expressed ectopically in human neuroblastoma cells exhibited reduced solubility, cytoplasmic distribution, and aggregation. Furthermore, Met(85)-TDP-35 sequestered full-length TDP-43 from the nucleus to form cytoplasmic aggregates. Expression of Met(85)-TDP-35 in primary motor neurons resulted in the formation of Met(85)-TDP-35-positive cytoplasmic aggregates and motor neuron death. A neo-epitope antibody specific for Met(85)-TDP-35 labeled the 35-kDa lower molecular weight species on im...
Brain : a journal of neurology, Jan 31, 2015
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2014
This study quantifies the &amp;amp;amp;#39;out-of-pocket&amp;amp;amp;#39; expense... more This study quantifies the &amp;amp;amp;#39;out-of-pocket&amp;amp;amp;#39; expenses incurred by individuals with amyotrophic lateral sclerosis (ALS) and their families, explores cost-driving factors and describes the current state of financial support in a Canadian cohort. We performed structured cost-of-illness interviews with 50 consecutive ALS patients and family members detailing disease-specific factors, direct and indirect costs. Direct costs were divided into &amp;amp;amp;#39;out-of-pocket&amp;amp;amp;#39; and &amp;amp;amp;#39;government/non-profit organization (NPO) supported&amp;amp;amp;#39;. Results showed that the average annual direct cost per patient was 32,337,ofwhich32,337, of which 32,337,ofwhich19,574 (61%) was paid for out-of-pocket. The most significant direct cost was disease-related home renovations, which garnered minimal government or NPO support. The costs of mobility aids, medical expenses, and private personal support workers were also substantial. Higher out-of-pocket costs were associated with an ALS Functional Rating Scale gross motor subscore of ≤ 6 (p = 0.03), limb-predominant symptoms (p = 0.04) and &amp;amp;amp;gt; 4 h/week of personal support care (p = 0.005). Annual indirect costs (lost wages) for patients with ALS and family members providing care were $56,821. In conclusion, this study quantified the substantial personal economic impact of ALS as measured by non-reimbursed, out-of-pocket expenses. Mobilization of additional resources for ALS patients and families is required to soften the economic burden of this disabling disease.
Human molecular genetics, 2014
The G₄C₂-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD... more The G₄C₂-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of the CpG-island (5'of the repeat) in DNA samples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation level was significantly higher in FTLD expansion carriers than non-carriers (P = 7.8E-13). Our results were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an...