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While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68, Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS-Ex) patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP-43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer's disease (AD) pathology. Tau and Aβ pathology increased with age. A lower MMSE score correlated with tau pathology in hippocampus and SMT gyrus, and with Aβ pathology in limbic and most cortical regions. Tau and Aβ pathology did not correlate with executive measures. We conclude that microglial activation and TDP-43 pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to increasing age and associated with a poorer performance on the MMSE.

Background/aims: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity., Methods: Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion., Results: Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease., Conclusions: This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

Background: It is becoming increasingly important to study common and distinct etiologies, clinical and pathological features, and mechanisms related to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration. These comparative studies rely on powerful database tools to quickly generate data sets that match diverse and complementary criteria set by them., Methods: In this article, we present a novel integrated neurodegenerative disease (INDD) database, which was developed at the University of Pennsylvania (Penn) with the help of a consortium of Penn investigators. Because the work of these investigators are based on Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal lobar degeneration, it allowed us to achieve the goal of developing an INDD database for these major neurodegenerative disorders. We used the Microsoft SQL server as a platform, with built-in "backwards" functionality to provide Access as a frontend client to interface with the database. We used PHP Hypertext Preprocessor to create the "frontend" web interface and then used a master lookup table to integrate individual neurodegenerative disease databases. We also present methods of data entry, database security, database backups, and database audit trails for this INDD database., Results: Using the INDD database, we compared the results of a biomarker study with those using an alternative approach by querying individual databases separately., Conclusions: We have demonstrated that the Penn INDD database has the ability to query multiple database tables from a single console with high accuracy and reliability. The INDD database provides a powerful tool for generating data sets in comparative studies on several neurodegenerative diseases., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: Most people with Parkinson disease (PD) eventually develop cognitive impairment (CI). However, neither the timing of onset nor the severity of cognitive symptoms can be accurately predicted. We sought plasma-based biomarkers for CI in PD., Methods: A discovery cohort of 70 PD patients was recruited. Cognitive status was evaluated with the Mattis Dementia Rating Scale-2 (DRS) at baseline and on annual follow-up visits, and baseline plasma levels of 102 proteins were determined with a bead-based immunoassay. Using linear regression, we identified biomarkers of CI in PD, that is, proteins whose levels correlated with cognitive performance at baseline and/or cognitive decline at follow-up. We then replicated the association between cognitive performance and levels of the top biomarker, using a different technical platform, with a separate cohort of 113 PD patients., Results: Eleven proteins exhibited plasma levels correlating with baseline cognitive performance in the discovery cohort. The best candidate was epidermal growth factor (EGF, p < 0.001); many of the other 10 analytes covaried with EGF across samples. Low levels of EGF not only correlated with poor cognitive test scores at baseline, but also predicted an 8-fold greater risk of cognitive decline to dementia-range DRS scores at follow-up for those with intact baseline cognition. A weaker, but still significant, relationship between plasma EGF levels and cognitive performance was found in an independent replication cohort of 113 PD patients., Interpretation: Our data suggest that plasma EGF may be a biomarker for progression to CI in PD., (Copyright © 2010 American Neurological Association.)

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive disease leading to paralysis and death. Recently, intermediate length polyglutamine (polyQ) repeats of 27-33 in ATAXIN-2 (ATXN2), encoding the ATXN2 protein, were found to increase risk for ALS. In ATXN2, polyQ expansions of ≥ 34, which are pure CAG repeat expansions, cause spinocerebellar ataxia type 2. However, similar length expansions that are interrupted with other codons, can present atypically with parkinsonism, suggesting that configuration of the repeat sequence plays an important role in disease manifestation in ATXN2 polyQ expansion diseases. Here we determined whether the expansions in ATXN2 associated with ALS were pure or interrupted CAG repeats, and defined single nucleotide polymorphisms (SNPs) rs695871 and rs695872 in exon 1 of the gene, to assess haplotype association. We found that the expanded repeat alleles of 40 ALS patients and 9 long-repeat length controls were all interrupted, bearing 1-3 CAA codons within the CAG repeat. 21/21 expanded ALS chromosomes with 3CAA interruptions arose from one haplotype (GT), while 18/19 expanded ALS chromosomes with <3CAA interruptions arose from a different haplotype (CC). Moreover, age of disease onset was significantly earlier in patients bearing 3 interruptions vs fewer, and was distinct between haplotypes. These results indicate that CAG repeat expansions in ATXN2 associated with ALS are uniformly interrupted repeats and that the nature of the repeat sequence and haplotype, as well as length of polyQ repeat, may play a role in the neurological effect conferred by expansions in ATXN2.

TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.

Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Ante-mortem diagnosis of neurodegenerative disorders based on clinical features alone is associated with variable sensitivity and specificity, and biomarkers can potentially improve the accuracy of clinical diagnosis. In patients suspected of having Alzheimer's disease (AD), alterations in cerebrospinal fluid (CSF) biomarkers that reflect the neuropathologic changes of AD strongly support the diagnosis, although there is a trade-off between sensitivity and specificity due to similar changes in cognitively healthy subjects. Here, we review the current approaches in using CSF AD biomarkers (total tau, p-tau(181), and Abeta42) to predict the presence of AD pathology, and our recent work using multi-analyte profiling to derive novel biomarkers for biofluid-based AD diagnosis. We also review our use of the multi-analyte profiling strategy to identify novel biomarkers that can distinguish between subtypes of frontotemporal lobar degeneration, and those at risk of developing cognitive impairment in Parkinson's disease. Multi-analyte profiling is a powerful tool for biomarker discovery in complex neurodegenerative disorders, and analytes associated with one or more diseases may shed light on relevant biological pathways and potential targets for intervention.

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

The assessment of psychological morbidity in patients with ALS has centered around depression, hopelessness, and anxiety. The Brief Symptom Inventory (BSI) offers an opportunity to explore psychological morbidity more broadly. We administered this instrument to 111 patients with ALS as part of a larger study of quality of life. Scores of ALS patients on the Global Severity Index and Positive Symptom Distress Index were comparable to the majority of distressed psychiatric outpatients and significantly higher than those of non-patient adults. Among BSI subscales, scores on the Anxiety, Depression, Phobic Anxiety, and Somatization subscales also were not significantly different from distressed adult psychiatric outpatients, and were greater than normal mean scores for a non-patient population sample. Based on these data, ALS patients appear to be significantly more distressed than non-patients in the identified areas, and as distressed as approximately 68% of a distressed psychiatric outpatient sample. In conclusion, a substantial number of individuals with ALS experience psychological distress of various types. Because psychological health impacts lifespan and quality of life in these individuals, broadly-based mental health assessment and treatment should remain an important part of care for patients with ALS. The effects of physical symptoms on responses to questions used to assess psychological distress must be considered.

Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer's disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Abeta42, tau and p-tau(181)). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Abeta42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1alpha), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1alpha, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1alpha and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.

Throwing velocity and vertical jumping ability are essential components for shooting and passing in water polo. The purpose of this study was to determine whether there is a relationship between throwing velocity and water jump height in highly skilled female water polo players. Throwing velocity and head height at ball release were measured in twenty-two female players (age 20.41 years (6.16); weight 68.28 kg (8.87)) with two 50 frames per second cameras while shooting at goal. Water jump height was also measured with a modified Yardstick device. Multiple regression analyses showed that peak lower limb power was the most significant predictor of maximal velocity. Power alone accounted for 62% of the variance in maximum velocity (p<0.001). Once power was entered into the model none of the other physical characteristics (lean mass, fat mass, land jump height and anthropometry) made a significant contribution to throwing velocity. After controlling for the effect of power, head height at ball release accounted for an additional significant proportion of the variance in maximal velocity (R(2) change 7%; p=0.049). Lower body power was a significant predictor of higher throwing velocity in highly skilled female water polo players. Players with relatively higher underlying levels of lower limb power who are able to generate greater elevation out of the water are able to throw the ball faster., (Copyright 2009 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Background: Mutation in the progranulin gene (GRN) can cause frontotemporal dementia (FTD). However, it is unclear whether some rare FTD-related GRN variants are pathogenic and whether neurodegenerative disorders other than FTD can also be caused by GRN mutations., Objectives: To delineate the range of clinical presentations associated with GRN mutations and to define pathogenic candidacy of rare GRN variants., Design: Case-control study., Setting: Clinical and neuropathology dementia research studies at 8 academic centers., Participants: Four hundred thirty-four patients with FTD, including primary progressive aphasia, semantic dementia, FTD/amyotrophic lateral sclerosis (ALS), FTD/motor neuron disease, corticobasal syndrome/corticobasal degeneration, progressive supranuclear palsy, Pick disease, dementia lacking distinctive histopathology, and pathologically confirmed cases of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U); and 111 non-FTD cases (controls) in which TDP-43 deposits were a prominent neuropathological feature, including subjects with ALS, Guam ALS and/or parkinsonism dementia complex, Guam dementia, Alzheimer disease, multiple system atrophy, and argyrophilic grain disease., Main Outcome Measures: Variants detected on sequencing of all 13 GRN exons and at least 80 base pairs of flanking introns, and their pathogenic candidacy determined by in silico and ex vivo splicing assays., Results: We identified 58 genetic variants that included 26 previously unknown changes. Twenty-four variants appeared to be pathogenic, including 8 novel mutations. The frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases, 21.4% (9 of 42) of cases with a pathological diagnosis of FTLD-U, 16.0% (28 of 175) of FTD-spectrum cases with a family history of a similar neurodegenerative disease, and 56.2% (9 of 16) of cases of FTLD-U with a family history., Conclusions: Pathogenic mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases. Haploinsufficiency of GRN is the predominant mechanism leading to FTD.

Objective: To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment., Design: Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review., Setting: An academic medical center., Participants: We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment., Main Outcome Measure: Neuronal and glial TDP-43 pathology., Results: We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology., Conclusion: These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.

Background: Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described., Objective: To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS., Design: Performance of an immunohistochemical whole-central nervous system scan for evidence of pathological TDP-43 in ALS patients., Setting: An academic medical center., Participants: We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants., Main Outcome Measures: Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology., Results: In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls., Conclusions: These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.

Background: TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1)., Methods: TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families., Findings: We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available., Interpretation: The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U., Funding: National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.

Direct intra-cerebral administration of substances into the brain parenchyma is a common technique used by researchers in neuroscience. However, inflammatory responses to the needle may confound the results obtained following injection of these substances. In this paper we show that the use of a glass micro-needle for intra-cerebral injection reduces mechanical injury, blood-brain barrier breakdown and neutrophil recruitment in response to the injection of vehicle or interleukin-1, compared to using a 26-gauge Hamilton syringe. Therefore, the use of a glass micro-needle to inject substances intra-cerebrally appears to cause minimal injection artefact and should be the method of choice.

Motor neuron disease (MND) is a neurodegenerative condition long thought to be associated only with motor weakness. Recent work now shows that cognitive difficulties are present in up to half of the patients with this disorder. About 5-10% of patients with MND have a frank dementia that resembles frontotemporal lobar degeneration (FTLD). Imaging studies show quantitative abnormalities that resemble FTLD. Moreover, biochemical studies of ubiquinated histopathologic abnormalities in MND and FTLD reveal identical inclusions of TDP-43. These findings underline a fundamental link between MND and FTLD. This paper reviews this body of work.

Background: Amyotrophic lateral sclerosis, Parkinson's disease, atypical parkinsonian syndromes, and multiple sclerosis are progressive neurologic disorders that cumulatively afflict a large number of people. Effective end-of-life palliative care depends upon an understanding of the clinical aspects of each of these disorders., Objectives: The authors review the unique and overlapping aspects of each of these disorders with an emphasis upon the clinical management of symptoms., Design: The authors review current management and the supporting literature., Conclusions: Clinicians have many effective therapeutic options to choose from when managing the symptoms produced by these disorders.

ALS is a neurodegenerative disease that affects nerve cells in the brain and spinal cord that control voluntary skeletal muscle. The muscle weakness that results from ALS is relentlessly progressive and rehabilitative attempts to strengthen affected muscles usually fail. When managing swallowing and communication disorders in individuals with ALS, the goals are to maximize function and safety through the use of compensatory strategies, energy conservation, and patient and caregiver education and counseling. This paper will review the current methods of assessment and treatment used with this population in the outpatient setting.

The variable clinical course of Amyotrophic Lateral Sclerosis (ALS) confronts the clinician, the patient and caregivers with many ethical challenges from the moment of breaking the news of the diagnosis and throughout the relentlessly progressive trajectory of the disease. Each patient faces the prospect of life-threatening bulbar and respiratory muscle dysfunction that may ensue soon after disease onset or after months or years of progressive weakness. This reality eventually forces the patient to choose life extension via gastrostomy tube insertion, mechanical ventilation or both or to forego these treatments in favor of terminal palliative care. Faced with these prospects some patients contemplate voluntary cessation of food and water, physician assisted suicide or euthanasia. Depending upon the presence and severity of frontotemporal dementia (FTD) related to frontotemporal lobar degeneration (FTLD) the capacity to make these forced choices may be compromised. Clinicians caring for ALS patients should appreciate and communicate the significance of life threatening symptoms, monitor capacity for decision making, anticipate and manage multiple possible end of life scenarios, and aggressively manage symptoms.

The authors compare the cost of hospice care provided to 25 amyotrophic lateral sclerosis (ALS) patients and 159 lung cancer patients by the Wissahickon Hospice of the University of Pennsylvania. The mean length of stay was 86.7 days for ALS patients and 35.0 days for patients with lung cancer (P = .011). The mean per patient cost was 5622.93 dollars for the ALS patients and 2658.91 dollars for patients with lung cancer (P = .057) The average operating margin excluding administrative costs was 5293.04 dollars for ALS patients and 2126.74 dollars for patients with lung cancer (P = .008). The longer length of stay (LOS) accounts for this difference. Longer LOS can be accomplished by close clinical monitoring of ALS patients for the development of life threatening respiratory and/or nutritional compromise and by liberalizing the present hospice admission guidelines.

Background: Neurologic disorders may impair the normal clearance of secretions. Effective palliation requires the management of excessive oral, pharyngeal and/or tracheobronchial secretions. This requires an understanding of underlying mechanisms and familiarity with the many available medical and surgical treatment options., Objectives: The authors intend to review the relevant anatomy and physiology along with the available medical, surgical and physical therapies available to treat this commonly encountered problem., Design: A review of current management and the supporting literature., Conclusions: Clinicians have many effective therapeutic options to choose from when managing the excessive oral, pharyngeal and/or tracheobronchial secretions caused by neurologic disorders. Treatment choices that are predicated upon pathophysiologic causes and patient status are the most likely to succeed.

Breaking the news of the diagnosis of amyotrophic lateral sclerosis (ALS) is a formidable task. To evaluate the process from the perspective of patients and caregivers, we surveyed 94 patient-caregiver pairs, as well as 50 unpaired patients and 19 unpaired caregivers. We asked respondents to evaluate the physician who first broke the news of the diagnosis based on the time spent discussing the diagnosis, and six attributes of effective communication of bad news derived from the SPIKES protocol (setting, perception, invitation, knowledge, empathy, strategy). Fifty-six percent of patients rated the way the physician who broke the news as average (30.7), below average (8.6) or poor (16.4). Forty-eight percent of caregivers rated the physician as poor (14.4), below average (4.8) or average (28.8). Better performance on all attributes of effective communication as well as greater time spent discussing the diagnosis was correlated with higher patient/caregiver satisfaction. Our results suggest that there is room for improvement in breaking the news of the diagnosis of ALS. Greater adherence to certain attributes of effective communication of bad news may improve the way physicians perform this difficult task.

Background: Sport and occupation related traumatic nerve injury is a common problem in the United States. While the physical requirements of each pursuit place participants at risk for injury to certain peripheral nervous system structures, the vast numbers of professional and recreational pursuits limits the ability to become familiar with nerve injuries specific to each. A more pragmatic approach is to apply knowledge of mechanisms of injury, physiology of nerve injury, regional anatomy, and at-risk peripheral nervous system structures to the routine neurologic history and physical assessment to arrive at a localizing and etiologic diagnosis., Review Summary: The authors discuss potential mechanisms of nerve injury, the role of electrodiagnostic testing, regional peripheral nervous system anatomic considerations and lesion localization., Conclusions: Despite the wide variety of professionally and recreationally induced peripheral nerve injuries, application of anatomic, physiologic and mechanistic considerations allow the neurologist to make an etiologic and localizing diagnosis.

We conducted a retrospective review of 97 consecutive patients with amyotrophic lateral sclerosis (ALS) who were accepted into hospice care from a tertiary ALS center. Five patients met Medicare criteria at time of hospice enrollment. The mean number of hospice days was 85 (range, 1-534). All but 2 patients met hospice criteria proposed by the Columbia University ALS group. The present Medicare hospice criteria should be changed to reflect the reality of patients dying of ALS.

We describe a 45-year-old man with biopsy proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This patient demonstrated unique retinal findings, including arteriole narrowing and sheathing, irregular choroidal filling on fluorescein angiography, and patchy visual field loss. CADASIL is a hereditary, nonamyloid, nonathersclerotic microangiopathy. This disorder has been mapped to chromosome 19 with mutations in the Notch 3 gene. Deposits of granular osmiophilic material in the basal lamina of the smooth muscle cells of small vessels are considered pathognomonic for CADASIL and are typically seen only on electron microscopy. Although CADASIL is a systemic vascular disease affecting the entire arteriole tree, we are unaware of other reports describing the retinal findings observed in our patient.

This study assessed selected heterosexual male college students' use of condoms, their reasons for using condoms, and their attitudes toward sexuality and condoms. Three hundred five male subjects completed a questionnaire that assessed class standing, marital status, reasons for using condoms, number of recent sexual partners, intention to use condoms, and attitudes toward sexuality and condoms. Although no relationship between attitudes toward sexuality and attitudes toward condoms was noted, a negative correlation (-.42) was found between attitude toward condoms and intention to use condoms within the next month if the subject were to have intercourse during that time. Recommendations for increasing condom use are presented.