Paul E. Schulz

Prevalence and patterns of cognitive impairment in sporadic ALS

Objective: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study. Methods: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes. Results: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance. Conclusions: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Parkinsonism due to Manganism in a Welder

A 33-year-old right-handed male presented complaining of a 2-year history of progressive cognitive slowing, rigidity, tremors, slowing of movements, and gait instability leading to falls. On examination, he had a Mini-Mental Status Examination (MMSE) score of 29, slowed saccadic eye pursuit, hypomimia, cogwheel rigidity, a 3- to 4-Hz tremor, and a “cock-walk” gait. His symptoms and signs were similar to idiopathic Parkinsons disease; however, he was young, inattention and forgetfulness occurred early in the course of the disorder, levodopa was unhelpful, and his gait was atypical. His work up for secondary causes of parkinsonism was negative, except for increased signal intensity on T1-weighted magnetic resonance image (MRI) in the bilateral basal ganglia. Typical etiologies for that finding were ruled-out, which led to further inquiries into the patients lifestyle. He was a welder, and discussion with his employer revealed that he used a steel-manganese alloy, he often worked in a confined ships hold, and he did not use a respiratory mask. Because manganese toxicity can produce increased T1-weighted signal intensities in the basal ganglia, the authors tested his serum and urine manganese, and both were elevated. This patient emphasizes the importance of a careful occupational history in persons presenting with atypical manifestations of a neurodegenerative disorder. It also lends support to the hypothesis that welding can produce enough exposure to manganese to produce neurologic impairment.

Detecting frontotemporal dysfunction in ALS: Utility of the ALS Cognitive Behavioral Screen (ALS-CBS™)

Abstract Up to half of patients with ALS develop cognitive impairment during the course of the illness. Despite this, there is no simple tool for screening patients in the clinical setting. This study examines the sensitivity, specificity and accuracy of the ALS Cognitive Behavioral Screen (ALS-CBS™). We administered the measure to 112 ALS patients, including 31 who also underwent comprehensive neuropsychological testing. Screen results were validated by determining the accuracy against the full battery. Optimal cut-off scores for predicting the correct diagnosis were determined, and mean scores were compared between patients, controls and different diagnostic groups. The results demonstrated that mean cognitive scores differed between ALS and normal controls (p <0.0001). The cognitive section differentiated ALS-FTD from other ALS patients with 100% accuracy. Cognitively normal ALS patients could be distinguished from those with any cognitive deficit with 71% specificity and 85% sensitivity. A separate behavioral score was significantly lower in the ALS cohort compared to controls (p <0.0001) and predicted ALS-FTD with 80% sensitivity and 88% specificity. In conclusion, the ALS-CBS™ can aid in detecting cognitive and behavioral impairment in a clinical setting, although it does not replace formal diagnostic assessment. Further validation with larger sample sizes will clarify its clinical utility.

The Link Between Post-traumatic Stress Disorder and Physical Comorbidities: A Systematic Review

Context Returning veterans from Afghanistan and Iraq will increase frequency of post-traumatic stress disorder (PTSD). Little is known about its impact on physical health. Objective Systematic literature review focusing on the association between PTSD and specific physical disorders. Data Sources An electronic search using PUBMED and hand search of four journals with an anxiety focus for studies published between January 1981 and July 2008, plus a manual search of article bibliographies. Study Selection Original research reports focusing on PTSD and its association with physical health. Studies investigating only PTSD symptoms, trauma and physical disorders classified at the organ-system level were excluded. Eighty studies were reviewed and seven selected for final analysis. Data Extraction Specific physical-health diagnoses were organized by system and tabulated. They were considered positive only if results were statistically significant. Total number of positive and negative studies for each diagnosis was then calculated for review. Results Seven studies examined the relationship between PTSD and specific physical disorders. Arthritis was associated with PTSD in most studies. Data conflicted regarding diabetes, coronary heart disease, and stroke. Conclusions Few studies have examined the relationship between PTSD and physical health. Large, prospective epidemiological trials are needed.

Does use of antihypertensive drugs affect the incidence or progression of dementia? A systematic review

BACKGROUND Hypertension appears to contribute to the development of dementia. Antihypertensive drugs may play an important role in altering the incidence or progression of dementia, particularly dementia of the vascular type; however, the neuroprotective effects of these agents in other types of dementia are not well characterized. OBJECTIVES The main aims of this review were to examine the relationship between use of antihypertensive agents and the incidence and progression of Alzheimers dementia (AD), vascular dementia (VaD), and unspecified dementia, and to consider whether these agents may be neuroprotective. METHODS A search of the English-language literature (January 1996-August 2009) was conducted using PubMed, Ovid MEDLINE, EBSCO MEDLINE, and the Cochrane Database of Systematic Reviews for publications mentioning both antihypertensive drugs and dementia. A combination of searches was performed using the following terms: antihypertensive drugs, dementia, cognitive impairment, Alzheimers dementia, vascular dementia, progression of cognitive impairment, severity of cognitive impairment, severity of dementia, prevalence, and incidence. Searches were also performed using the names of antihypertensive drug classes. The bibliographies of all retrieved articles were reviewed for additional relevant publications. The focus was on randomized controlled trials, cohort studies, and case-control studies, excluding studies in animals, patients aged <45 years, drugs other than antihypertensive agents, and the role in cognition of hormones, receptors, and enzymes. RESULTS Sixty-five potentially relevant articles were identified from the 536 publications retrieved by the literature search. After application of the exclusion criteria, 12 original studies were included in the review, all published between 1999 and 2008 and most involving patients with AD or VaD. The most frequently studied antihypertensive agents were calcium channel blockers (7 studies), diuretics (6 studies), and angiotensin-converting enzyme (ACE) inhibitors (6 studies). Overall, these medications appeared to be beneficial in dementia, but only ACE inhibitors and diuretics significantly reduced the risk for and progression of dementia in the majority of studies. CONCLUSIONS Antihypertensive medications-particularly ACE inhibitors and diuretics-may be helpful in reducing the risk for and progression of dementia. Large randomized clinical trials are warranted to further explore the relationship between antihypertensive drugs and dementia.

Greater Prevalence and Incidence of Dementia in Older Veterans with Posttraumatic Stress Disorder

To explore the association between posttraumatic stress disorder (PTSD) and dementia in older veterans.

Frontal-lobe mediated behavioral dysfunction in amyotrophic lateral sclerosis

Background:  Cognitive impairment secondary to frontal lobe atrophy exists in 40–60% of Amyotrophic Lateral Sclerosis (ALS) cases. We aimed to determine the prevalence of frontal‐lobe mediated behavioral impairment in (ALS) and to ascertain its relationship to cognitive impairment.

Does PTSD impair Cognition beyond the effect of Trauma

This systematic review analyzed data from studies examining memory and cognitive function in subjects with posttraumatic stress disorder (PTSD), compared with subjects exposed to trauma (but without PTSD). Based on analysis of 21 articles published in English from 1968 to 2009, the conclusion is that individuals with PTSD, particularly veterans, show signs of cognitive impairment when tested with neuropsychological instruments, more so than individuals exposed to trauma who do not have PTSD.

Causes of aggressive behavior in patients with dementia.

OBJECTIVE To examine factors predicting development of aggression. METHOD Community-dwelling patients over 60 years of age in a Veterans Affairs Medical Center who had a documented ICD-9-CM code for dementia within 12 months of screening and no other dementia codes recorded for 2 preceding years but no aggressive behavior during the 12 months preceding study initiation were assessed every 4 months for 24 months for aggression, depression, pain, patient/caregiver relationship quality (mutuality), involvement in pleasant events, and caregiver burden. The study was conducted from September 5, 2003, to June 10, 2005. RESULTS Of 215 patients, 89 (41%) developed aggression. In individual models, high baseline mutuality decreased risk of aggression; high burden and pain increased risk. Increases in depression and pain and declines in total mutuality also increased risk. In a full model and step-wise model, high levels of baseline caregiver burden, worst pain, and decline in mutuality over time increased risk of aggression. CONCLUSIONS Many dementia patients become aggressive. Higher levels of worst pain, caregiver burden, and declining mutuality over time increase risk of aggression.

USING PAIRED-PULSE FACILITATION TO PROBE THE MECHANISMS FOR LONG-TERM POTENTIATION (LTP)

Paired-pulse facilitation (PPF) of excitatory synaptic transmission at Schaffer collateral synapses in the hippocampus was examined in relationship to long-term potentiation (LTP). PPF is a relatively simple-to-measure presynaptic form of synaptic plasticity. It is hypothesized that if the expression of LTP includes a presynaptic component, then PPF and LTP may interfere with one another. When averaged over more than 100 experiments, we observed no change in average PPF with LTP, as reported previously by a number of investigators. When individual experiments were analyzed, however, PPF significantly increased or decreased with LTP in direct relation to the initial value of PPF. There was also a linear relationship between the change in PPF and the magnitude of LTP. The PPF changes were specific to LTP and presynaptic in origin as they were input-specific and persisted with low concentrations of CNQX, GABAA and GABAB antagonists, different interstimulus intervals, and different Ca2+ concentrations. To understand the interaction between LTP and PPF, we constructed a simple model of LTP in which potential contributions by increases in three synaptic parameters were examined: the number of neurotransmitter release sites (n), the probability of release (p), and the postsynaptic unit potential (q). The data were fit by a model in which there were increases in n that changed the average p of the population, but not by a model that increased p or q alone. This is the first experimental evidence for an increase in the number of release sites with LTP, which could be due to pre- or postsynaptic mechanisms.