Cognitive impairment in sporadic ALS: a pathologic continuum underlying a multisystem disorder.

BACKGROUND: Traditionally considered a motor neuron-selective disorder, the clinical manifestations of ALS can include a frontotemporal dementia. Although the pathologic substrate of cognitive impairment remains to be defined, the presence of ubiquitin-immunoreactive (Ub+) intraneuronal inclusions in cortical regions has been suggested to constitute a pathologic marker of this process. METHODS: The authors compared the neuropathological features of four cognitively impaired patients with ALS, four cognitively intact patients with ALS, and four neurologically normal patients. The extent and load of Ub+ neuronal inclusions, Ub+ dystrophic neurites, and superficial linear spongiosis (SLS) was determined among a number of cortical, hippocampal, and subcortical regions. RESULTS: Although Ub+, alpha-synuclein-negative, and tau-negative neuronal inclusions were observed in both cognitively impaired and cognitively intact patients with ALS, their density and extent was greater among the former, with the difference greatest in the cingulate gyrus. Ub+ neurites were observed in a similar distribution. Only the presence of SLS, affecting the first and second cortical layers, reliably distinguished between the cognitively impaired and cognitively intact ALS subpopulations. In three of four cognitively impaired patients with ALS, SLS was associated with transcortical microglial activation, in the absence of detectable differences in astrocytosis, density of calbindin or parvalbumin neurons, or optical density of synaptophysin and SNAP-25. CONCLUSIONS: Although intraneuronal Ub+ inclusions and dystrophic neurites are observed in both ALS subpopulations, the presence of cognitive impairment was associated with a greater distribution and load of both neuropathologic features, suggesting a disease continuum. Moreover, cognitive impairment was uniformly associated with superficial linear spongiosis, a pathologic feature common to several forms of frontotemporal dementia.

Misidentification syndromes related to face specific area in the fusiform gyrus.

The "delusional misidentification syndromes" are a group of uncommon and varied disorders in which, in typical form, the patient thinks that a particular familiar person is someone else or a certain familiar place is a duplicate. Although first identified and considered a memory disorder by Pick, evidence in support of this has been difficult to identify. They have been most often seen in various psychotic and organic brain diseases but lesions have been generally diffuse although the right temporal lobe has been implicated. A patient was investigated who abruptly developed a disorder wherein she misidentified her husband as her deceased sister and claimed that her home was a duplicate of her real home that were typical of Frégoli syndrome and Pick's reduplicative paramnesia, respectively. A discrete area of brain damage, probably ischaemic, in this patient was seen on MRI in the anterior part of the right fusiform gyrus and a smaller area in the nearby anterior middle and inferior temporal gyri with associated parahippocampal and hippocampal atrophy. A high order nervous system function that is devoted to the identification of faces is located in the adjacent midportion of the fusiform gyrus and a similar locus for environmental scenes, termed the parahippocampal place area, is present in the bordering parahippocampal gyrus. The misidentification phenomena in this case can be explained by disruption of the connections of these highly specialised areas with the most anterior inferior and medial part of the right temporal lobe where long term memory and mechanisms for the retrieval of information that are required for the visual recognition of faces and scenes are stored.

Cognitive outcome following pallidotomy: the influence of side of surgery and age of patient at disease onset.

OBJECT: The authors studied the neuropsychological correlates of stereotactically guided lesioning of the right and left posteroventral globus pallidus internus (GPi) in a prospective series of patients suffering from Parkinson's disease (PD). METHODS: Eighteen patients with PD who underwent stereotactically guided lesioning of the GPi (left side in 10 patients and right side in eight) completed neuropsychological evaluations before and after surgery. Patients served as their own controls. Multiple two-by-two repeated-measures analyses of variance were used to assess neuropsychological changes as a function of the side in which lesioning was performed (lesioning on the left side compared with that on the right) and surgery (presurgery compared with postsurgery). Relationships between cognitive variables and patient age at disease onset, age at surgery, and disease duration were examined using a linear regression model. The most striking findings were evident from results of a phonemic word fluency test in which patients in whom a left-sided pallidotomy had been performed achieved a mean performance score that was lower than the score of patients in whom a right-sided pallidotomy had been performed; this score declined even more as a result of surgery. Change in performance on the word fluency test across pre- and postoperative assessments was also related to patient age at onset of PD in those who had undergone left-sided pallidotomy, with patients of an older age at disease onset showing the greatest decline in performance. CONCLUSIONS: These preliminary findings indicate that the side on which surgery was performed and patient age at onset of PD are important in the prediction of postoperative cognitive outcome. The findings also indicate that stereotactically guided lesioning of the GPi presents a relatively mild cognitive risk.

Concentration and memory deficits in patients with fibromyalgia syndrome.

The present study compared 30 patients with Fibromyalgia Syndrome (FS) to 30 healthy control subjects matched for age, sex, and estimated intellectual level on standardized measures of attention, concentration, and memory as well as subjective ratings of memory abilities and sleep quality. In addition, in order to investigate the relationship between cognitive functioning and other physical and psychological symptoms, subjects with FS completed psychological measures of pain severity, trait anxiety, and depression. Results indicated that patients with FS performed more poorly on tests of immediate and delayed recall, and sustained auditory concentration, and their ratings of both their memory abilities and sleep quality were lower than those of controls. Furthermore, perceived memory deficits of the FS subjects were disproportionately greater than their objective deficits. Results indicated significant correlations between performance on memory and concentration measures and scores on questionnaires of pain severity and trait anxiety. Implications of these results for multidisciplinary treatment programs are discussed.

A prospective study of cognitive impairment in ALS.

OBJECTIVE: To characterize prospectively the cognitive profile in ALS. METHODS: Clinically definite ALS patients (11 men, 2 women), age 39.9 to 74.0 years (mean age, 54.2 +/- 9.6 years; mean disease duration, 21.1 +/- 10.5 months) underwent neuropsychologic, language, and speech testing followed by MR 1H spectroscopy (4 T). Five spousal control subjects completed an identical protocol. Eight ALS patients participated in follow-up studies at a 6-month interval. RESULTS: Relative to control subjects, ALS patients showed mild impairment in word generation, recognition memory (faces), and motor-free visual perception. Bulbar-onset patients showed greater impairment in a number of measures (working memory, problem solving/cognitive flexibility, visual perception, and recognition memory for words and faces), and cognitive impairment appeared more progressive over time. ALS patients demonstrated anomia on a confrontation naming test, with no significant problems following commands or repeating. Speech motor performance scores and intelligibility scores were not significantly different. No significant declines in forced vital capacity, forced expiratory volume, or peak expiratory flow rates were observed. Although normal at initial testing (T1), MR 1H spectroscopy demonstrated a reduction of the N-acetylaspartate/creatine (NAA/Cr) ratio in the nondominant precentral motor strip across the two testing intervals. In contrast, the NAA/Cr ratio obtained from the anterior cingulate gyrus at T1 was already reduced in bulbar-onset patients (p < 0.001), whereas no deficits were observed in limb-onset individuals in the same region. CONCLUSIONS: Bulbar-onset ALS patients with cognitive impairments and neuronal loss in the anterior cingulate gyrus subsequently developed more profound neuropsychological dysfunction whereas both language and speech capabilities remained relatively preserved. Of note, the absence of bulbar signs did not predict an absence of cognitive decline.

Cognition, language, and speech in amyotrophic lateral sclerosis: a review.

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disorder manifesting as a relentless loss of motor capabilities and, ultimately, death. Traditionally thought to affect solely the lower motor neurons and corticospinal tracts, recent studies suggest that the pathogenic process of ALS is more extensive, involving dysfunction of cortical grey and white matter with clinical correlates of impairment in cognition and language. The impact of speech and motor deficits are discussed in relation to the issues of assessment of cognition and language. Three case studies are presented for illustrative purposes. Finally, direction for future research to investigate cognitive dysfunction in ALS are presented.

New serologic tests for early detection of coccidioidomycosis.

Arizona college students suspected of having recently acquired coccidioidomycosis were tested for anticoccidioidal antibodies and circulating fungal antigens using conventional antibody detection methods and new ELISA procedures. Of 233 patients with compatible symptoms, 26 had anticoccidioidal antibodies detected by conventional tests. ELISA detected antibodies in sera from 20 of these patients and also from another 25 patients. Patients with antibodies detected by either conventional or ELISA procedures were significantly more likely to have abnormal chest radiographs, elevated erythrocyte sedimentation rates, or absent upper respiratory symptoms than were other patients. Circulating antigen was found in sera from 35 patients, 33 of whom had no detectable anticoccidioidal antibodies at that time. Detectable antigen was noted frequently in sera obtained within the first month after the onset of symptoms and was infrequently detected later when more patients exhibited antibodies. These results indicate the feasibility of developing ELISA procedures using spherule-derived antigens for earlier detection of coccidioidal infections.

Kindling with stimulation of the dentate gyrus. I. Characterization of electrographic and behavioral events.

Once daily for 60 days, hooded rats received unilateral high-frequency stimulation in the hilus of the dentate gyrus (DG), at an intensity sufficient to evoke epileptiform afterdischarge (AD). Although most rats eventually developed generalized stage-5 seizures (Generalized group), some did not progress beyond partial stage-1 or stage-2 seizures (Partial group). Hilar kindling also displayed several other characteristics that distinguished it from typical limbic kindling, including low rate of development, marked instability of the seizures, and little or no growth in duration of AD.

Kindling with stimulation of the dentate gyrus. II. Effects on evoked field potentials.

Once daily for 60 days, male hooded rats received unilateral high-frequency stimulation in the hilus of the dentate gyrus (DG), at an intensity sufficient to evoke afterdischarge (AD). Every 2nd day, evoked potentials were recorded from the hilus following stimulation of the PP with single 0.1 ms pulses at 6 current intensities. Changes in synaptic excitability of the dentate granule cells were monitored by measuring the amplitudes of the population spikes; changes in the strength of excitatory synaptic transmission were monitored by measuring the slopes of the excitatory postsynaptic potentials (EPSPs). Control rats, which were not given kindling stimulation, were tested for changes in synaptic transmission and excitability in the same way, at comparable times. In general, hilar stimulation resulted in a large decrease in population spike amplitudes to below baseline and control levels, accompanied by a paradoxical potentiation of EPSPs. Population spike amplitudes decreased more in rats that developed generalized stage-5 seizures (Generalized group) than in rats that did not progress beyond partial seizures despite 60 days of stimulation (Partial group). Conversely, EPSP slopes increased more in the Partial group than in the Generalized group. These results suggest that kindling stimulation may potentiate responsiveness of the directly activated dentate granule cells to inputs from the PP, but at the same time suppress the output of the granule cells resulting from this input. Furthermore, the results indicate that kindling is more closely allied to the suppression of output than to the potentiation of responsiveness to input.

Effect of prenatal exposure to ethanol on adult ethanol preference and response to zimelidine in rats.

The effects of prenatal ethanol (ETOH) exposure (2.8-3.5 g/kg per day) on subsequent adult ETOH preference and on ETOH consumption after treatment with zimelidine, a serotonin uptake inhibitor, were investigated. Pregnant rats were exposed to an ETOH/saccharin solution in the first, second, third, all three, or none, of the trimesters of the gestation period. As adults, the offspring were subjected to a 40-day screening procedure to determine ETOH preference (greater than 50% of total daily fluid consumption) over water (experiment 1). Only animals which preferred ETOH were included in experiment 2, in which they received either five daily injections of zimelidine (20 mg/kg) or comparable volumes of Ringer's solution. Results indicated that although there were no differences between groups in terms of ETOH preference, a significant difference was evident in ETOH intake after zimelidine treatment. All groups of rats showed a significant decrease in ETOH intake from baseline levels when given zimelidine. However, only rats prenatally exposed to ETOH in the first trimester demonstrated a significant decrease in ETOH drinking when compared to controls. These results suggest that early prenatal ETOH exposure, even in moderate doses, may induce central neurochemical alterations that are salient enough to be detected in adulthood.