Objective

To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy.

Design

Observational, retrospective case series.

Setting

Mayo Clinic Health System.

Patients

Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each.

Intervention

Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide.

Main Outcome Measure

Seizure frequency.

Results

After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone.

Conclusion

When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.

Objective

To determine Parkinson disease (PD) life expectancy in the United States and identify demographic, geographic and clinical factors that influence survival.

Design

Retrospective cohort study of 138,000 Medicare beneficiaries with incident PD were identified in 2002 and followed through 2008.

Main Outcome Measures

Confounder adjusted six year risk of death as influenced by three groups of factors: 1) race, sex, age at diagnosis 2) geography, environmental factors 3) clinical conditions. We examined hospitalization diagnoses in terminal PD, compared PD mortality to that of other common diseases.

Results

Thirty-five percent of PD cases lived more than six years. Sex and race significantly predicted survival: female (HR 0.74, 0.73– 0.75), Hispanic (HR 0.72, 0.65–0.80) and Asian (HR 0.86, 0.82–0.91) cases had a lower adjusted risk of death than white males. Dementia/cognitive impairment, diagnosed in 69.6% of cases, most often in Blacks (78.2%) and women (71.5%), was associated with a greater likelihood of death (HR 1.72, 1.69–1.75). PD cases had greater mortality than many common life threatening diseases. Terminal PD patients were hospitalized frequently for cardiovascular disease (15.06%) and infection (29.52%), rarely for PD related illness (4.2%). Regional survival rates were similar, but urban PD cases living in a high industrial metal emission area had a slightly higher adjusted risk of death (HR 1.19, 1.10–1.29).

Conclusions

Demographic and clinical factors impact PD survival. Dementia is highly prevalent in PD and is associated with a significant increase in mortality. More research is needed to understand if environmental exposures influence PD course or survival.

Objective

To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.

Design

Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Patients

Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.

Main Outcome Measures

The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).

Results

Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.

Conclusions

Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.

Increasing evidence shows that the central nervous system and the immune system interact in complex ways, and better insight into these interactions may be relevant to the treatment of patients with stroke and other forms of central nervous system injury. Atherosclerosis, autoimmune disease, and physiological stressors, such as infection or surgery, cause inflammation that contributes to vascular injury and increases the risk of stroke. In addition, the immune system actively participates in the acute pathogenesis of stroke. Thrombosis and hypoxia trigger an intravascular inflammatory cascade, which is further augmented by the innate immune response to cellular damage occurring in the parenchyma. This immune activation may cause secondary tissue injury, but it is unclear whether modulating the acute immune response to stroke can produce clinical benefits. Attempts to dampen immune activation after stroke may have adverse effects because central nervous system injury causes significant immunodepression that places patients at higher risk of infections, such as pneumonia. The activation of innate immunity after stroke sets the stage for an adaptive immune response directed against brain antigens. The pathogenic significance of adaptive immunity and its long-term effects on the postischemic brain remains unclear, but it cannot be ruled out that a persistent autoimmune response to brain antigens has deleterious and long-lasting consequences. Further research will be required to determine what role, if any, immunity has in long-term outcomes after stroke, but elucidation of potential mechanisms may open promising avenues for the development of new therapeutics to improve neurological recovery after brain injury.

Objective

APOE ε4 status has been associated with greater cortical amyloid deposition whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.

Method

APOE genotyping and a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with PET-PIB. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.

Subjects

201 cognitively normal adults (135 females) aged 45–88 were recruited from the Knight Alzheimer Disease Research Center at Washington University. CSF samples were collected from 165 participants. Amyloid imaging was performed on 163 participants.

Results

APOE ε4 carriers evidenced higher PIB binding (p<.001) and lower CSF Aβ42 levels (p<.001) than non-carriers. Our previous findings of higher PIB binding (p=.005) and lower CSF Aβ42 levels (p=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p=.008) such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε4 carriers (p=.013) but not for ε4 non-carriers (p=.208). All findings remained significant after controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems, history of depression and interval between assessments.

Conclusion

Collectively, these results suggest that cognitively normal sedentary APOE ε4+ individuals may be at augmented risk for cerebral amyloid deposition.

Objective

To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).

Design

Conditional logistic regression models and survival analysis.

Setting

Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.

Participants

Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.

Main Outcome Measures

Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.

Results

In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P<.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects.

Conclusions

APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

Objective

Alexander disease typically results from dominant mutations in GFAP that arise de novo. However, several instances of multigenerational familial cases have been reported, with some of the most extensive having been described prior to the identification of GFAP as the related gene. These historically seminal families continue to be of interest due to their clinical variability and suggestions of recessive inheritance or germline mosaicism. We here describe genetic analyses of the two most thoroughly studied historical families, as well as one newly discovered family.

Design

Clinical histories were obtained and DNA was analyzed from blood, cheek epithelial cells, or fixed paraffin embedded surgical samples.

Subjects

Affected and unaffected adult members of three families and affected children were included.

Results

Family A contains four siblings in whom we found a novel p.Ser247Pro mutation that was paternally inherited. The phenotypes of these siblings include one unaffected adult, one juvenile onset, and two adult onset. Family B spans four generations, including the first described adult-onset patient originally reported in 1968. Analysis of members of the later generations revealed a novel p.Asp417Ala mutation. Family C contains three generations. We detected a novel p.Gln426Leu mutation that is the farthest C-terminal mutation known.

Conclusions

These families display clear evidence of variable phenotypes, but do not support recessive inheritance. While germline mosaicism cannot be excluded for one family (A), we propose that for genetic counseling purposes the risk of germline mosaicism should be described as less than 1%.

Objective

To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS).

Design

Retrospective, cross-sectional cohort study.

Setting

Academic MS center.

Patients

Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort.

Main Outcome Measures

Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire. Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated.

Results

Current pain was more common in subjects with NMO (n=29) vs MS (n=66) (86.2% vs 40.9%; P<.001) and more severe on a 10-point scale (5.38 vs 1.85; P <.001). Pain remained more common after controlling for disability and number of spinal cord segments (P=.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS (75.9% vs 37.8%; P<.001), often requiring more than 1 medication (65.5% vs 15.2%; P<.001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P=.006).

Conclusions

Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management.

Background

Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations.

Objective

To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred.

Patients

An American kindred of Northern European and Cherokee American Indian descent.

Results

Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls.

Conclusions

Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.

Background

TAR DNA-binding protein 43, encoded by the TARDBP gene, has been identified as the major pathological protein of frontotemporal lobar dementia (FTLD) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Subsequently, mutations in the TARDBP gene have been detected in 2% to 3% of patients with ALS (both familial and sporadic ALS). However, to our knowledge, there is only 1 description of 2 patients with FTLD and TARDBP gene mutations who later developed motor neuron disease.

Objective

To describe cognitive abnormalities in 3 Italian families with familial ALS and TARDBP gene mutations.

Design, Setting, and Participants

Genetic, neuropsychological, and neuroimaging analyses in 36 patients with familial non–superoxide dismutase 1 gene (SOD1) ALS and 280 healthy controls.

Main Outcome Measure

We identified 3 index cases of familial ALS carrying the p.Ala382Thr missense mutation of the TARDBP gene and with clinical, neuroimaging, and neuropsychological features of FTLD.

Results

The p.Ala382Thr missense mutation of the TARDBP gene was absent in the 280 controls. It was present in all affected members of the 3 families for whom DNA was available. All affected members of the 3 families developed FTLD after the onset of ALS, confirmed by neuropsychological testing and hypometabolism in frontal associative areas assessed with fludeoxyglucose F 18 positron emission tomography and computed tomography.

Conclusions

Three apparently unrelated families with familial ALS carrying the p.Ala382Thr TARDBP missense mutation developed FTLD. In these families, FTLD co-segregates with ALS. Patients with ALS carrying TARDBP mutations may develop FTLD.

Objectives

Diagnostic challenges exist for differentiating HIV associated neurocognitive disorders (HAND) from symptomatic Alzheimer’s disease (AD) in HIV+ participants. Both disorders have cerebral amyloid containing plaques associated with abnormalities in amyloid beta protein 1–42 (Aβ42) metabolism. We evaluated if the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB) could discriminate AD from HAND in middle-aged HIV+ participants.

Design

11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. χ2 and t-tests assessed differences in clinical and demographic variables between HIV+ participants and community-living individuals followed by Alzheimer Disease Research Center (ADRC). An analysis of variance (ANOVA) assessed for regional differences in Aβ42 using 11C-PiB.

Setting

ADRC and HIV clinic

Participants

16 HIV+ participants (11 cognitively normal, 5 with HAND) and 19 ADRC participants (8 cognitively normal, 11 with symptomatic AD).

Main Outcome Measure(s)

Mean and regional 11C-PiB binding potentials

Results

Symptomatic AD were older (p < 0.001), had lower CSF Aβ42 (p < 0.001), and had higher CSF tau levels (p < 0.001) than other groups. Regardless of degree of impairment, HIV+ participants did not have increased 11C-PiB. Mean and regional binding potentials were elevated for symptomatic AD participants (p <0.0001).

Conclusions

Middle-aged HIV+ participants, even with HAND, do not exhibit increased 11C-PiB while symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV+ participants. Future cross sectional and longitudinal studies are required to assess utility of 11C-PiB in older HAND individuals.

Objective

To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.

Design

Prospective cohort study.

Setting

Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985–1988) and were followed up prospectively for the development of AD and all-cause dementia.

Participants

Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.

Main Outcome Measures

We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.

Results

Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00–1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00–1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03–2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13–3.10; P=.01) as compared with those with values less than the median.

Conclusion

In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

Objective

To perform an extensive screening for mutations of amyotrophic lateral sclerosis (ALS)–related genes in a consecutive cohort of Sardinian patients, a genetic isolate phylogenically distinct from other European populations.

Design

Population-based, prospective cohort study.

Patients

A total of 135 Sardinian patients with ALS and 156 healthy control subjects of Sardinian origin who were age- and sex-matched to patients.

Intervention

Patients underwent mutational analysis for SOD1, FUS, and TARDBP.

Results

Mutational screening of the entire cohort found that 39 patients (28.7%) carried the c.1144G A (p.A382T) missense mutation of the TARDBP gene. Of these, 15 had familial ALS (belonging to 10 distinct pedigrees) and 24 had apparently sporadic ALS. None of the 156 age-, sex-, and ethnicity-matched controls carried the pathogenic variant. Genotype data obtained for 5 ALS cases carrying the p.A382T mutation found that they shared a 94–single-nucleotide polymorphism risk haplotype that spanned 663 Kb across the TARDBP locus on chromosome 1p36.22. Three patients with ALS who carry the p.A382T mutation developed extrapyramidal symptoms several years after their initial presentation with motor weakness.

Conclusions

The TARDBP p.A382T missense mutation accounts for approximately one-third of all ALS cases in this island population. These patients share a large risk haplotype across the TARDBP locus, indicating that they have a common ancestor.

Objectives

To evaluate associations between mid- and late-life obesity and risk of dementia.

Design

Prospective cohort followed 5.4 years from 1992/4 through 1999.

Setting

Community-dwelling sample in four US sites recruited from Medicare eligibility files.

Participants

2,798 adults without dementia, mean age 74.7 years, 59.1% women, participating in the Cardiovascular Health Cognition Study completing a magnetic resonance image, measured for height and weight at baseline (late-life) and self-reporting weight at age 50 (mid-life). Body mass index (BMI) was calculated at both times.

Main Outcome Measures

Dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) classified by a multidisciplinary committee using standardized criteria.

Results

Classification resulted in 480 persons with incident dementia, 245 with AD (no VaD) and 213 with VaD (with or without AD). In evaluations of mid-life obesity, an increased risk of dementia was found for obese (BMI >30) compared to normal (BMI 20-25) persons adjusted for demographics (HR: 1.39, 95% CI: 1.03-1.87) and for caradiovascularl risk factors (HR: 1.36, 95% CI: 0.94-1.95). The risk estimates reversed in assessments of late-life BMI. Underweight persons (BMI < 20) had an increased risk of dementia (HR: 1.62, 95% CI: 1.02-2.64) while being overweight (BMI 25-30) was not associated (HR: 0.92, 95% CI: 0.72-1.18) and being obese reduced the risk of dementia (HR: 0.63, 95% CI: 0.44-0.91) compared to those with normal BMI.

Conclusions

These results help explain the “obesity paradox” as differences in dementia risk over time are consistent with physical changes in the trajectory toward disability.

Objective

To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures.

Design

Cohort study.

Setting

Academic multiple sclerosis center.

Patients

Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months.

Main Outcome Measures

Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL).

Results

An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 μm2/ms [95% confidence interval {CI}, 1.36–1.64 μm2/ms for incomplete recovery vs 1.75 μm2/ms [95% CI, 1.67–1.83 μm2/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%–70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r=0.40, P=.03), contrast sensitivity (r=0.41, P=.02), VEP amplitude (r=0.55, P<.01), VEP latency (r=−0.38, P=.04), and RNFL thickness (r=0.53, P=.02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 μm2/ms [95% CI, 1.31–1.59 μm2/ms] vs 1.19 μm2/ms [95% CI, 1.10–1.28 μm2/ms]).

Conclusions

Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.

Objective

To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies.

Methods

First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer’s Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker and haplo-type analyses. Then we explored the effect of LRRTM3 small-hairpin RNAs on amyloid precursor protein processing.

Results

One single-nucleotide polymorphism in the promoter region (rs16923760; C allele: odds ratio,−0.74, P=.03), and a block of 4 single-nucleotide polymorphisms in intron 2 (rs1925608, C allele: 0.84, P=.04; rs7082306, A allele: 0.75, P=.04; rs1925609, T allele: 1.2, P=.03; and rs10997477, T allele: 0.88, P=.05) were associated with AD in the National Institute on Aging Late-Onset Alzheimer’s Disease data set or the Caribbean His-panic data set. The corresponding haplotypes were also associated with AD risk (.01< P<.05). In addition, LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing (P<.05 to P<.01) compared with the scrambled small-hairpin RNA condition.

Conclusions

These complementary findings support the notions that genetic variation in LRRTM3 is associated with AD risk and that LRRTM3 may modulate γ-secretase processing of amyloid precursor protein. Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.

Substantial evidence has accumulated in support of the hypothesis that elevated cholesterol levels increase the risk of developing Alzheimer’s disease (AD). As a result, much work has been done investigating the potential use of lipid-lowering agents (LLAs), particularly statins, as preventive or therapeutic agents for AD. While epidemiology and preclinical statin research (described in Part 1 of this review) have generally supported an adverse role of high cholesterol regarding AD, human studies of statins (reviewed here) show highly variable outcomes, making it difficult to draw firm conclusions. We identify several confounding factors among the human studies, including differing blood-brain barrier permeabilities among statins, the stage in AD at which statins were administered, and the drugs’ pleiotropic metabolic effects, all of which contribute to the substantial variability observed to date. We recommend that future human studies of this important therapeutic topic 1) take the blood-brain barrier permeabilities of statins into account when analyzing results, 2) include specific analyses of effects on low-density and high-density lipoprotein cholesterol, and most importantly, 3) conduct statin treatment trials solely in mild AD patients, who have the best chance for disease modification.

Objectives

To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.

Design

Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.

Setting

Inpatient traumatic brain injury unit

Patients or Other Participants

Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.

Main Outcome Measure

Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.

Results

Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.

Conclusion

Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.

Over the past twenty years, evidence has accumulated that high cholesterol levels may increase the risk of developing Alzheimer’s disease (AD). With the global use of statins to treat hypercholesterolemia, this finding has led to the hope that statins could prove useful in treating or preventing AD. However, the results of work on this topic are inconsistent: some studies find beneficial effects, others do not. In this first segment of a two-part review, we examine the complex preclinical and clinical literature on cholesterol and AD. First, we review epidemiological research on cholesterol levels and the risk of AD and discuss the relevance of discrepancies among studies as regards participants’ age and clinical status. Next, we assess studies correlating cholesterol with AD-type neuropathology. The potential molecular mechanisms for cholesterol’s apparent adverse effect on the development of AD are then discussed. Finally, we review preclinical studies of statins and AD. Thus, this first portion of our review provides the background and rationale for investigating statins as potential therapeutic agents in AD patients, the subject of the second part.

Objective

To evaluate the combination of cerebrospinal fluid biomarkers of Aβ42, tau, and phosphorylated tau (ptau181) with education and normalized whole brain volume (nWBV) to predict incident cognitive impairment and test the cognitive/brain reserve hypothesis.

Design

Longitudinal cohort study.

Setting

Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.

Participants

Convenience sample of 197 participants aged 50 years and above, with normal cognition (Clinical Dementia Rating [CDR] of 0) at baseline, followed for a mean of 3.3 years.

Main outcome measure

Time to cognitive impairment (CDR ≥ 0.5).

Results

Three-factor interactions between the baseline biomarker values, education, and nWBV were found for Cox proportional hazards models testing tau (p=.03) and ptau (p=.008). Among those with lower tau values, nWBV (hazard ratio [HR]=.54, 95% confidence interval [CI]=.31–.91; p=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (p=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment among those with higher ptau values (p=.02). In models testing Aβ42, larger nWBV was associated with a slower time to cognitive impairment (HR=.84, 95%CI=.71–.99, p=.0348), but there was no effect of Aβ42 or education.

Conclusions

Among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.

Objective

To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab.

Design

Case study.

Setting

Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver.

Patients

Four patients developing PML in the setting of rituximab therapy for RA.

Intervention

Rituximab therapy.

Main Outcome Measures

Clinical and pathological observations.

Results

Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease.

Conclusion

These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.

Background

Myotonic dystrophy type-2 (DM2) is a recently discovered adult muscular dystrophy. Similar to DM1, this disease causes progressive debilitating weakness, clinical myotonia, and early cataracts, and is thought to cause widespread physiologic dysfunction of multiple organ systems.

Objective

To analyze and compile the laboratory abnormalities of patients with DM2.

Design

Baseline DM2 laboratory data were compiled representing 68 different types of laboratory tests and 1442 total studies.

Setting

University Medical Center.

Patients

Eighty-three adults with genetically confirmed or clinically probable DM2 were identified. Of these patients, 49 had documented baseline laboratory screening.

Main Outcome Measures

The individual frequencies of abnormal values in the population with DM2 studied.

Results

Of the 1442 studies, results for 359 (24.9%) were outside of their standard reference ranges. Of the 68 types of laboratory tests studied, 43 had values from fifteen or more different patients with DM2. The relative frequency of an abnormally elevated laboratory value was greater than 50% in several tests, including the levels of creatine kinase, total cholesterol, lactate dehydrogenase, and alanine aminotransferase (ALT). In addition, serum levels of immunoglobulin G (IgG) were low in 75% of all DM2 patients tested and absolute lymphocyte counts were low in 54% of all DM2 patients tested.

Conclusion

There is a high frequency of laboratory abnormalities in patients with DM2. These abnormalities provide insight into the widespread pathologic manifestations of DM2 and may form a basis for clinical monitoring and disease screening.

Objective

To elucidate the relationship between the two hallmark proteins of Alzheimer's disease (AD), amyloid-β (Aβ) and tau, and clinical decline over time among cognitively normal older individuals.

Design

A longitudinal cohort of clinically and cognitively normal older individuals assessed with baseline lumbar puncture and longitudinal clinical assessments.

Setting

Research centers across the United States and Canada.

Patients

We examined one hundred seven participants with a Clinical Dementia Rating (CDR) of 0 at baseline examination.

Main Outcome Measures

Using linear mixed effects models, we investigated the relationship between CSF p-tau181p, CSF Aβ1-42 and clinical decline as assessed using longitudinal change in global CDR, CDR-Sum of Boxes (CDR-SB), and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog).

Results

We found a significant relationship between decreased CSF Aβ1-42 and longitudinal change in global CDR, CDR-SB, and ADAS-cog in individuals with elevated CSF p-tau181p. In the absence of CSF p-tau181p, the effect of CSF Aβ1-42 on longitudinal clinical decline was not significantly different from zero.

Conclusions

In cognitively normal older individuals, Aβ-associated clinical decline over a mean of three years may occur only in the presence of ongoing, “downstream” neurodegeneration.