The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score is commonly used, although the utility regarding this score in staging dementia severity is not well established.
To investigate the effectiveness of CDRSOB scores in staging dementia severity compared with the global CDR score.
Texas Alzheimer's Research Consortium minimum data set cohort.
A total of 1577 participants (110 controls, 202 patients with mild cognitive impairment, and 1265 patients with probable Alzheimer disease) were available for analysis.
Main Outcome Measures
Receiver operating characteristic curves were generated from a derivation sample to determine optimal cutoff scores and ranges, which were then applied to the validation sample.
Optimal ranges of CDR-SOB scores corresponding to the global CDR scores were 0.5 to 4.0 for a global score of 0.5, 4.5 to 9.0 for a global score of 1.O, 9.5 to 15.5 for a global score of 2.0, and 16.0 to 18.0 for a global score of 3.0. When applied to the validation sample, κ scores ranged from 0.86 to 0.94 (P <.001 for all), with 93.0% of the participants falling within the new staging categories.
The CDR-SOB score compares well with the global CDR score for dementia staging. Owing to the increased range of values, the CDR-SOB score offers several advantages over the global score, including increased utility in tracking changes within and between stages of dementia severity. Interpretive guidelines for CDR-SOB scores are provided.
To determine whether low concentrations of a dopamine agonist worsen parkinsonism, which would suggest that activation of presynaptic dopamine autoreceptors causes a super-off state.
Randomized, double-blind, placebo-controlled, crossover clinical trial.
Academic movement disorders center.
Patients with Parkinson disease and motor fluctuations.
Fourteen patients with Parkinson disease and motor fluctuations were randomized to receive 1 of 6 possible sequences of placebo, low-dose (sub-threshold) apomorphine hydrochloride, and high-dose (threshold to suprathreshold) apomorphine hydrochloride infusions. Subthreshold doses of apomorphine hydrochloride (12.5 μg/kg/h every 2 hours and 25 μg/kg/h every 2 hours), threshold to suprathreshold doses of apomorphine hydrochloride (50 μg/kg/h every 2 hours and 100 μg/kg/h every 2 hours), and placebo were infused for 4 hours daily for 3 consecutive days.
Main Outcome Measures
Finger and foot tapping rates.
There was no decline in finger or foot tapping rates during the low-dose apomorphine hydrochloride infusions relative to placebo. The high-dose infusions increased foot tapping (P<.001) and trended toward increasing finger tapping compared with placebo infusions.
Subthreshold concentrations of apomorphine did not worsen parkinsonism, suggesting that pre-synaptic dopamine autoreceptors are not important to the motor response in moderate to advanced Parkinson disease.
Multiple sclerosis (MS) and fragile X–associated tremor/ataxia syndrome (FXTAS) have overlapping clinical signs and symptoms.
To present a case with evidence of both MS and FXTAS and to discuss the relationship of both disorders.
Fragile X Research and Treatment Center at the University of California, Davis, Medical Center.
Woman with the FMR1 premutation who died of MS at the age of 52 years.
Main Outcome Measures
Magnetic resonance imaging, physical examination, and neuropathologic examination results.
Magnetic resonance imaging, physical examination, and autopsy neuropathologic examination revealed diagnostic features of MS and FXTAS.
The molecular mechanism of RNA toxicity, including the elevation of αB-crystallin levels observed in FXTAS, may lead to enhanced predisposition to autoimmune diseases.
Neuritic plaques (NPs) and neurofibrillary tangles (NFTs) in the brain, especially in the hippocampus, entorhinal cortex, and isocortex, are hallmark lesions of Alzheimer disease and dementia in the elderly. However, this association has not been extensively studied in the rapidly growing population of the very old.
To assess the relationship between estimates of cognitive function and NP and NFT pathologic conditions in 317 autopsied persons aged 60 to 107 years.
We studied the relationship between severity of dementia and the density of these characteristic lesions of Alzheimer disease in young-old, middle-old, and oldest-old persons. The relationship of the severity of dementia as measured by the Clinical Dementia Rating scale to the density of NPs and NFTs was then assessed in each age group.
Three hundred seventeen brains of persons aged 60 years and older were selected to have either no remarkable neuropathological lesions or only NP and NFT lesions. Brains with any other neuropathological conditions, either alone or in addition to Alzheimer disease findings, were excluded. The study cohort was then stratified into the youngest quartile (aged 60–80 years), middle 2 quartiles (aged 81–89 years), and oldest quartile (aged 90–107 years).
While the density of NPs and NFTs rose significantly by more than 10-fold as a function of the severity of dementia in the youngest-old group, significant increases in the densities of NPs and NFTs were absent in the brains of the oldest-old. This lack of difference in the densities of NPs and NFTs was due to reduced lesion densities in the brains of oldest-old persons with dementia rather than to increased density of these lesions in the brains of nondemented oldest-old persons.
These findings suggest that the neuropathological features of dementia in the oldest-old are not the same as those of cognitively impaired younger-old persons and compel a vigorous search for neuropathological indices of dementia in this most rapidly growing segment of the elderly population.
Observational studies have shown reduced risk of Alzheimer dementia in users of nonsteroidal anti-inflammatory drugs.
To evaluate the effects of naproxen sodium and celecoxib on cognitive function in older adults.
Randomized, double-masked chemoprevention trial.
Six US memory clinics.
Men and women aged 70 years and older with a family history of Alzheimer disease; 2117 of 2528 enrolled had follow-up cognitive assessment.
Celecoxib (200 mg twice daily), naproxen sodium (220 mg twice daily), or placebo, randomly allocated in a ratio of 1:1:1.5, respectively.
Main Outcome Measures
Seven tests of cognitive function and a global summary score measured annually.
Longitudinal analyses showed lower global summary scores over time for naproxen compared with placebo (−0.05 SDs; P=.02) and lower scores on the Modified Mini-Mental State Examination over time for both treatment groups compared with placebo (−0.33 points for celecoxib [P=.04] and −0.36 points for naproxen [P=.02]). Restriction of analyses to measures collected from persons without dementia attenuated the treatment group differences. Analyses limited to measures obtained while participants were being issued study drugs produced results similar to the intention-to-treat analyses.
Use of naproxen or celecoxib did not improve cognitive function. There was weak evidence for a detrimental effect of naproxen.
clinicaltrials.gov identifier: NCT00007189
Semantic dementia (SD) is a syndrome within the spectrum of frontotemporal lobar degenerations (FTLD) characterized by fluent progressive aphasia (particularly anomia) and loss of word meaning.
To report a unique case of very early semantic dementia with slowly progressive course allowing insights into the early natural history of this disorder.
Tertiary care university hospital and academic center.
A 62-year-old female retired teacher presenting with “memory” complaints.
Main Outcome Measures
Clinical course, neuropsychological data, MRI.
The patient was first evaluated when standard neuropsychological measures were normal, but subtle left anterior temporal lobe atrophy was present. Over the follow-up period of eight years, she developed profound anomia and loss of word meaning associated with progressive left anterior temporal lobe atrophy consistent with semantic dementia. In more recent years, anterograde memory impairment as well as mild prosopagnosia have evolved in association with left hippocampal atrophy and subtle atrophy in the homologous gyri of the right anterior temporal lobe. She remains functionally independent despite her current deficits.
Early identification of patients who will develop semantic dementia is difficult and might be missed with standard clinical, neuropsychological, and structural neuroimaging evaluations. Recognition of this relatively rare syndrome is important for early diagnosis and prognostication, and particularly for therapeutic interventions in the future.
frontotemporal lobar degeneration; semantic dementia; MRI; neuropsychology
Periventricular leukomalacia (PVL) is the predominant form of brain injury and the leading known cause of cerebral palsy and cognitive deficits in premature infants. The number of low-birth-weight infants who survive to demonstrate these neurologic deficts is increasing. Magnetic resonance imaging–based neuroimaging techniques provide greater diagnostic sensitivity for PVL than does head ultrasonography and often document the involvement of telencephalic gray matter and long tracts in addition to periventricular white matter. The neuropathologic hallmarks of PVL are microglial activation and focal and diffuse periventricular depletion of premyelinating oligodendroglia. Premyelinating oligodendroglia are highly vulnerable to death caused by glutamate, free radicals, and proinflammatory cytokines. Studies in animal models of PVL suggest that pharmacologic interventions that target these toxic molecules will be useful in diminishing the severity of PVL.
Although risk factors for Alzheimer disease have been well studied, much less is known about risk factors for primary progressive aphasia (PPA).
To demonstrate that learning disabilities (LDs) are more common in patients with PPA and their first-degree family members.
Design, Setting, and Patients
Self-report endorsement of an individual and family history of an LD in a sample of 699 subjects from the Northwestern Alzheimer’s Disease Center registry. We compared 3 dementia groups (PPA, typical amnestic Alzheimer disease, and the behavioral variant of frontotemporal dementia) and 1 elderly control group. A retrospective medical record review in the PPA probands was used to obtain additional information.
Main Outcome Measure
Prevalence of LDs among probands and their first-degree relatives.
The patients with PPA and their first-degree family members had a significantly higher frequency of LD compared with the other dementia groups and the controls. Some of the families of patients with PPA displayed unusual concentrations of LD, especially dyslexia.
These results suggest that LD may constitute a risk factor for PPA, providing additional clues concerning the determinants for the selective vulnerability of the language network in this syndrome.
Distal neuropathy is part of the clinical phenotype in most males with the fragile X–associated tremor/ataxia syndrome (FXTAS) caused by the 55 to 200 CGG repeat expansion.
We performed nerve conduction studies in 16 male carriers with FXTAS, 11 non-FXTAS carriers, and 11 control subjects and assessed the outcomes with respect to the fragile X mental retardation 1 genotype (FMR1) (Online Mendelian Inheritance in Man [OMIM] 309550; NT011681) and messenger RNA expression.
Men with FXTAS had slower tibial nerve conduction velocities and prolonged F-wave latencies compared with controls (z=2.06, P=.04; and z=2.73, P=.005) and unaffected premutation males (z=1.98, P=.04; and z=2.00, P=.04). Compound muscle action potential amplitudes were smaller in the FXTAS group relative to controls. Sural nerve action potential amplitudes were reduced in the FXTAS group compared with controls. After controlling for age, there was a significant relationship between the longer CGG repeat number and tibial nerve conduction velocity slowing (r=−0.42, P=.04) and between elevated messenger RNA levels and reduction of the tibial compound muscle action potential velocity (r=−0.52, P=.01) in the permutation group.
Male premutation carriers had significant conduction abnormalities of motor and sensory nerves that correlated with molecular measures, suggesting that the premutation FMR1 genotype is a causal factor. There was also evidence of nerve conduction abnormalities in non-FXTAS carriers compared with controls, which suggests that the neuropathy can occur without the full clinical presentation of FXTAS.
While adults who drink low to moderate amounts of alcohol have lower rates of cardiovascular disease (CVD) than other adults, the impact of alcohol on the brain is less clear. There is evidence that drinking large amounts of alcohol is tied to brain atrophy. It is uncertain whether consumption of smaller amounts of alcohol also negatively affects brain volume or may be protective in reducing the well-documented age-related decline in brain volume.
Participants were 1839 subjects from the Framingham Offspring Study who had a brain MRI between 1999-2001. Total cerebral brain volume (TCBV) was computed correcting for head size. Multivariate linear regression models were used to evaluate the association between five categories of alcohol consumption (abstainers, former drinkers, low, moderate, high) and TCBV, adjusting for age, sex, education, height, body-mass index (BMI) and the Framingham Stroke Risk Profile (FSRP). Pair-wise comparisons were also conducted between the alcohol consumption groups.
Most participants reported low alcohol consumption and males were more likely than females to be moderate or heavy drinkers. There was a significant negative linear relationship between alcohol consumption and TCBV (r = -0.25, p < 0.001). This relationship was modified by sex, with alcohol consumption having a stronger association with TCBV in females than males (r=-0.29 vs. -0.20).
In contrast to studies on CVD, this study found that moderate alcohol consumption was not protective against normal age-related differences in total brain volume. Rather, the more alcohol consumed, the smaller the total brain volume.
Clinical and functional imaging evidence suggests that cerebellar dysfunction occurs in essential tremor (ET). In recent postmortem studies, we documented increased numbers of torpedoes (Purkinje cell axonal swellings) in ET patients without Lewy bodies. Purkinje cell loss, however, has never been rigorously assessed.
To quantitatively assess the number of Purkinje cells in brains of ET patients and similarly aged controls.
Postmortem cerebellar tissue was available in 14 ET cases (6 with Lewy bodies and 8 without Lewy bodies) and 11 controls. Calbindin immunohistochemistry was performed on paraffin sections of the cerebellum. Images were digitally recorded and blinded measurements of the number of Purkinje cells per millimeter of cell layer (linear density) were made.
Purkinje cell linear density was inversely correlated with age (r=-0.53, P=.006) and number of torpedoes (r=-0.42, P=.04). Purkinje cell linear density differed by diagnosis (mean [SD], controls, 3.46 [1.27] cells/mm; ET cases with Lewy bodies, 3.33 [1.06] cells/mm; and ET cases without Lewy bodies, 2.14 [0.82] cells/mm; P=.04), with the most significant difference between ET cases without Lewy bodies and controls, where the reduction was 38.2% (P=.04). In an adjusted linear regression analysis that compared ET cases without Lewy bodies with controls, decreased linear density (outcome variable) was associated with ET (β=.56, P=.03).
We demonstrated a reduction in Purkinje cell number in the brains of patients with ET who do not have Lewy bodies. These data further support the view that the cerebellum is anatomically, as well as functionally, abnormal in these ET cases.
Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found.
To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease.
Design, Setting, and Participants
Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer’s Genetics Study).
Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2−68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer’s Genetics sample showed the same direction of association as the case-control sample.
To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets.
To estimate the risk of Parkinson's disease in individuals with mutations in the Parkin gene.
We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 PD probands with age at onset ≤50 and 104 control probands enrolled in the Genetic Epidemiology of PD study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and the relationship of the relative to the proband .
Parkin mutations were identified in 25 PD probands (10.1%), 72% of whom were heterozygotes. One Parkin homozygote reported 2 siblings with PD. The cumulative incidence of PD to age 65 in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% CI: 0.4-71.9%) compared to 1.7% (95% CI: 0.8-3.4%) in non-carrier relatives of cases (p=0.59) and 1.1% (95% CI: 0.3-3.4%), in relatives of controls ( compared to non-carriers p=0.52).
The cumulative risk of PD to age 65 in a non-carrier relative of a case with AAO ≤50 is not significantly greater than the general population risk among controls. Age specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study.
Parkin; Mutations; Parkinson's disease; Kin-cohort study; Early onset
To examine whether reported age at onset (AAO) of dementia symptoms among participants with Alzheimer’s disease (AD) is later for those with fewer years of education and, if so, to see if it is attributed to delayed detection of symptoms.
National Alzheimer’s Coordinating Center Minimum Data Set (N=21,880 participants) and Washington University Alzheimer’s Disease Research Center (N=1,449 participants).
Reported AAO of dementia symptoms is slightly earlier for participants with more education. Participants with fewer years of education show greater clinical severity of AD at first assessment.
Symptoms of AD are recognized later among those with less education.
Adult patients with X-linked adrenoleukodystrophy (X-ALD) remain at risk for progressive neurological deterioration. Phenotypes vary in their pathology, ranging from axonal degeneration to inflammatory demyelination. The severity of symptoms is poorly explained by conventional imaging.
To test the hypothesis that neurochemistry in normal appearing brain differs among adult phenotypes of X-ALD, and that neurochemical changes correlate with the severity of symptoms.
Patients and Methods
Using a 7 Tesla scanner we performed structural and proton MRSI in 13 adult patients with X-ALD, including 4 patients with adult cerebral ALD (ACALD), 5 with adrenomyeloneuropathy (AMN) and 4 female heterozygotes. Studies were also performed in nine healthy controls.
Among adult X-ALD phenotypes, MI/Cr was 46% higher and Cho/Cr 21% higher in normal appearing white matter of ACALD compared to AMN (p < 0.05). Both NAA/Cr and Glu/Cr ratios were lower in AMN patients (p = 0.028 and p = 0.036, respectively) than in controls. There were no significant differences between AMN and female heterozygotes. In cortex, ACALD patients had lower values of NAA/Cr compared to female heterozygotes and controls (p = 0.022). The global MI/Cr ratio demonstrated a significant association with the EDSS (Spearman ρ = 0.66, p = 0.039).
7 Tesla proton MRSI reveals differences in the neurochemistry of ACALD but is unable to distinguish AMN from female heterozygotes. MI/Cr correlates with the severity of the symptoms and may be a meaningful biomarker in adult X-ALD.
Mutations in the glucocerebrosidase (GBA) gene have been reported to modify risk for Parkinson disease (PD) and dementia with Lewy bodies (DLB). However, these findings have not been consistently replicated, and most studies have had substantial methodological shortcomings.
To better assess the role of GBA variants in altering risk for Lewy body disorders.
Four movement disorder clinics in the Seattle, Washington, area.
Seven hundred twenty-one patients with PD, 554 healthy control subjects, and 57 patients with DLB.
Main Outcome Measures
Disease status and presence or absence of the 2 most common GBA mutations (N370S and L444P).
We observed a significantly higher heterozygote frequency for the 2 mutations in patients with PD (2.9%; P<.001) and those with DLB (3.5%; P=.045) compared with control subjects (0.4%).
Our findings suggest that GBA mutations exert a large effect on susceptibility for Lewy body disorders at the individual level but are associated with a modest (approximately 3%) population-attributable risk in individuals of European ancestry.
TDCS - Transcranial Direct Current Stimulation - is an emerging technique of non-invasive brain stimulation that has been found useful in examining cortical function in normal subjects and in facilitating treatments of various neurological disorders. A better understanding of adaptive as well as maladaptive post-stroke neuroplasticity and its modulation through non-invasive brain stimulation has opened up experimental treatment options using TDCS for patients recovering from stroke. We will review TDCS’s role as a facilitator of stroke recovery, the different modes of transcranial direct current stimulation, and the potential mechanisms underlying the neural effects of TDCS.
TDCS; Transcranial Direct Current Stimulation; Brain polarization; stroke; rehabilitation; recovery; adaptation; mal-adaptation; plasticity
To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid.
Design, Setting, and Participants
Uptake of N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroybenzothiazole, or [11C]PIB for “Pittsburgh Compound-B,” was measured for participants assessed between August 15, 2003 and January 8, 2008 at the Washington University Alzheimer’s Disease Research Center and diagnosed either as nondemented (N=161) or with dementia of the Alzheimer type (N=37). Multiple regression was used to determine whether [11C]PIB uptake interacted with level of educational attainment to predict cognitive function.
Main Outcome Measures
Scores on the Clinical Dementia Rating - Sum of Boxes (CDR-SB), Mini-Mental State Exam (MMSE), and Short Blessed Test (SBT), and individual measures from a psychometric battery.
[11C]PIB uptake interacted with years of education in predicting scores on the CDR-SB (p=.003), the MMSE (p<.001), the SBT (p=.03) and a measure of verbal abstract reasoning and conceptualization (p=.02), such that performance on these measures increased with increasing education for participants with elevated PIB uptake. Education was unrelated to global cognitive functioning scores among those with lower PIB uptake.
These results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathology and cognition.
To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load.
Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen.
The median CPE rank was 1.5 (interquartile range, 1–2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count.
Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies.
Combine MRI measures of disease severity into a multiple sclerosis (MS) composite score.
Retrospectively analysis of prospectively collected data
Community-based and referral subspecialty clinic in an academic hospital
103 patients with MS [age (mean ± SD) 42.7 ± 9.1 years, disease duration 14.1 ± 9.2 years, EDSS score 3.3 ± 2.2, 60% (n=62) relapsing-remitting (RR), 32% (n=33) secondary progressive (SP), and 8% (n=8) primary progressive].
Main outcome measures
Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume, and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1/T2 ratio.
MRDSS score averaged 5.1 ± 2.6. Baseline MRI and EDSS correlations were moderate for BPF, T1/T2, and MRDSS and weak for T2LV. MRDSS showed a larger effect size than any of the individual MRI components in distinguishing RR from SP patients. Models containing either T2LV or MRDSS were significantly associated with EDSS disability progression during the 3.2 ± 0.3 year observation period, when adjusting for baseline EDSS score.
Combining brain MRI lesion and atrophy measures can predict clinical progression in patients with MS and provides the basis to develop an MRI-based continuous scale as a marker of MS disease severity.
Multiple sclerosis; MRI; Volumetric MRI; Diagnostic test assessment
Frontotemporal dementia and parkinsonism (FTDP) is a major neurodegenerative syndrome, particularly for those with symptoms beginning before age 65. A spectrum of degenerative disorders can present as sporadic or familial FTDP. Mutations in the gene encoding the microtubule associated protein tau (MAPT) on chromosome 17 have been found in many kindreds with familial FTDP. Several other kindreds with FTDP had been linked to chromosome 17, but they had ubiquitin-positive inclusions rather than tauopathy pathology, and no mutations in MAPT. This conundrum was solved over this past year with the identification of mutations in the gene encoding progranulin (PGRN), which is only 1.7 Mb centromeric to MAPT on chromosome 17. In this review, we compare and contrast the demographic, clinical, radiologic, neuropathologic, genetic, and pathophysiologic features in patients with FTDP linked to mutations in MAPT and PGRN, highlighting the many similarities but also a few important differences. The findings provide an intriguing oddity of nature in which two genes can cause a similar phenotype through apparently different mechanisms yet reside so near to each other on the same chromosome.
frontotemporal dementia; parkinsonism; progranulin; tau; PGRN; MAPT
A role for vitamin D deficiency in Parkinson disease (PD) has recently been proposed.
To compare the prevalence of vitamin D deficiency in a research database cohort of patients with PD with the prevalence in age-matched healthy controls and patients with Alzheimer disease (AD).
Survey study and blinded comparison of plasma 25-hydroxyvitamin D (25[OH]D) concentrations of stored samples in a clinical research database at Emory University School of Medicine.
Referral center (PD and AD patients), primary care clinics, and community setting (controls).
Participants were recruited into the study between May 1992 and March 2007. Every fifth consecutively enrolled PD patient was selected from the clinical research database. Unrelated AD (n=97) and control (n=99) participants were randomly selected from the database after matching for age, sex, race, APOE genotype, and geographic location.
Main Outcome Measures
Prevalence of suboptimal vitamin D and mean 25(OH)D concentrations.
Significantly more patients with PD (55%) had insufficient vitamin D than did controls (36%) or patients with AD (41%; P=.02, χ2 test). The mean (SD) 25(OH)D concentration in the PD cohort was significantly lower than in the AD and control cohorts (31.9 [13.6] ng/mL vs 34.8 [15.4] ng/mL and 37.0 [14.5] ng/mL, respectively; P=.03).
This report of 25(OH)D concentrations in a predominantly white PD cohort demonstrates a significantly higher prevalence of hypovitaminosis in PD vs both healthy controls and patients with AD. These data support a possible role of vitamin D insufficiency in PD. Further studies are needed to determine the factors contributing to these differences and elucidate the potential role of vitamin D in pathogenesis and clinical course of PD.
Abnormal neuronal inclusions composed of the TAR DNA binding protein 43 (TDP-43) are the characteristic neuropathological lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP, the gene encoding for TDP-43, an interesting candidate gene for genetic screening in ALS.
To investigate the presence and frequency of TARDBP mutations in ALS.
One hundred thirty-four patiens with sporadic ALS, 31 patients with familial non-SOD1-ALS, and 400 healthy control subjects.
We identified two missense mutations in TARDBP (G348C and the novel N352S) in two small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment. The mutations located in the C-terminus of TDP-43 were absent in 400 Caucasian control individuals. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges.
Mutations in TARDBP are a rare cause of familial non-SOD1-ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.
TDP-43; ALS; TARDBP