Food deprivation has been shown to deleteriously affect human cognition, but findings are equivoc... more Food deprivation has been shown to deleteriously affect human cognition, but findings are equivocal, and few studies have examined several cognitive domains. In this study, the authors used computerized testing to describe the profile of shifts in cognition attributable to short-term religious fasting. Multiple cognitive domains were evaluated at midday and late afternoon following complete abstention from eating and drinking beginning at midnight. Cross-domain, fasting-related deficits were found for tasks requiring perception of spatial relations. Fasting-related information processing deficits were found for response time but not accuracy for test levels of intermediate difficulty. Time-of-day effects often reflected poorer afternoon performance. These findings provide a detailed profile of cognitive consequences of food deprivation, affected by time of day, task demands, and type of outcome.
We describe the effects of the asymmetry of cycles and non-stationarity in time series on the pha... more We describe the effects of the asymmetry of cycles and non-stationarity in time series on the phase synchronization method. We develop a modified method that overcomes these effects and apply this method to study parkinsonian tremor. Our results indicate that there is synchronization between two different hands and provide information about the time delay separating their dynamics. These findings suggest that this method may be useful for detecting and quantifying weak synchronization between two non-stationary signals.
Dysrhythmia is one of the features frequently associated with the motor disturbance in Parkinson&... more Dysrhythmia is one of the features frequently associated with the motor disturbance in Parkinson's disease (PD). The mechanism responsible for this phenomenon is not known. To assess the rhythmic movements of the hand in PD patients in general and in parkinsonian subtypes. Fifty-one PD patients (32 males) with mean age 66.3 +/- 9.1 years (6.6 years of symptoms) and 36 healthy controls (age 64.9 +/- 13.2, range 40-85) were studied. Subjects were asked to tap with their dominant or less affected arm on a digitized switch board at their most comfortable pace (16 s), fastest tapping speed (12 s), and at different frequencies provided by a metronome. The mean rhythm and the tap-to-tap variation were compared. Performance of the PD patients and control subjects were compared, as there were different subtypes of PD patients. Patients were subclassified into: tremor predominant (TP) (14 patients), freezing predominant (FP) (11 patients), akinetic-rigid (AR) (12 patients) and an unclassified group (UC) (14 patients). Results. There was no significance difference between patients and controls in the self-chosen, most comfortable tapping rate or in the tap-to-tap variation of the self-paced task. PD patients tapped at a significantly slower rate than controls when asked to tap at their fastest rate (4.39 +/- 1.32 vs. 5.14 +/- 1.31 Hz; p < 0.01). This difference was the result of an especially slow performance of the TP and AR subgroups (3.85+/-1.20 and 3.88+/-1.46, respectively; p < 0.01 compared to the control group). TP was the only subgroup to show an increased tap-to-tap variation at their fastest tapping rate compared to the control group (0.070 +/- 0.057 vs. 0.029 +/- 0.025 s, respectively, p < 0.05). The TP subgroup also showed hastening when they followed an externally given rhythm of 2.5 Hz and they tapped at 2.73 +/- 0.36 Hz p < 0.05). Externally driven and self-paced tapping are preserved in patients with PD, when examined at their best 'on' state. The tremor predominant subgroup seems to have specific pacing disturbances.
We found that in vitro migration and interferon-␥ production by lymphocytes derived from primary ... more We found that in vitro migration and interferon-␥ production by lymphocytes derived from primary progressive multiple sclerosis patients preselected on the basis of a high T2-weighted lesion volume (>10 cm 3 ) on magnetic resonance imaging, were increased compared with that in primary progressive multiple sclerosis patients with a low T2-weighted lesion volume (<3 cm 3 ) and controls. Whether the heterogeneity of immune function within the primary progressive population will correlate with response to therapy remains to be established.
This study compares some characteristics of the disynaptic excitatory pathways from the lateral v... more This study compares some characteristics of the disynaptic excitatory pathways from the lateral vestibular nucleus (LVN) and medial longitudinal fasciculus (MLF) to lumbosacral α-motoneurons in the decerebrate cat. We used the spatial facilitation technique to test whether disynaptic LVN and MLF excitatory postsynaptic potentials (EPSPs) are produced by common last-order interneurons in the lumbosacral segments of the spinal cord. Of 77 motoneurons examined, 26 exhibited disynaptic EPSPs from both supraspinal sources. No spatial facilitation was found between LVN and MLF EPSPs in 21 of 24 cells that were adequately tested. In 3 of 23 cells (all flexor motoneurons), some spatial facilitation was found in some but not all trials. These observations suggest that stimulation of the LVN and MLF produces disynaptic EPSPs in motoneurons through largely separate populations of last-order interneurons. Disynaptic MLF and LVN EPSPs showed parallel patterns of modulation during fictive locomotion. Maximal disynaptic EPSP amplitudes occurred during the phase of the step cycle when the recorded motoneuron, whether flexor or extensor, exhibited depolarizing locomotor drive potentials and the corresponding muscle nerve was active. These observations, taken together, suggest that disynaptic LVN and MLF EPSPs are produced in motoneurons by at least four separate populations of segmental last-order excitatory interneurons, with separate populations projecting to flexor versus extensor cells. The results also suggest that the modulation of the disynaptic EPSPs during fictive locomotion is mainly due to premotoneuronal convergence of input from the respective descending systems and from the segmental central pattern generator for locomotion onto common interneurons.
Recent evidence points to involvement of central nervous system oscillators in Parkinson's diseas... more Recent evidence points to involvement of central nervous system oscillators in Parkinson's disease (PD) rest tremor. It remains unknown whether one or multiple oscillators cause tremor in multiple limbs. Based on the prediction that multiple oscillators would cause low coherence even with similar average frequency, we studied 22 PD patients using accelerometers on multiple limbs. Records were digitized and spectral analysis was performed. Peak frequencies in the arms, legs, and chin were similar, indicating that biomechanical factors did not determine the frequency. Coherence between different axes of individual accelerometers and between different segments of the same limb was high. However, coherence between tremor in different limbs was low. There was no consistent pattern across patients of ipsi- vs. contralateral predominance of coherence. These data suggest that tremor in PD is generated by multiple oscillatory circuits, which operate on similar frequencies.
Background Freezing of gait (FOG) is a common and very disabling parkinsonian symptom, which is p... more Background Freezing of gait (FOG) is a common and very disabling parkinsonian symptom, which is poorly understood and responds unsatisfactorily to medical treatment. We recently reported a unique patient with Parkinson's disease (PD) who had significant alleviation of FOG shortly after she was injected with botulinum toxin type A (BTX-A) for foot dystonia (Giladi et al. 1997). Objective To assess the effect of BTX-A injections into the calf muscles of parkinsonian patients on FOG. Method BTX-A was injected in an open fashion into the calf muscles of 10 parkinsonian patients (age 55–75 years) with FOG as a predominant symptom. Response of FOG was assessed subjectively by the patient from worsening (–1) to marked improvement (+3). One patient was injected in a single blind fashion with saline or BTX-A after he had an initial good response. Results Seven patients reported different rates of improvement of FOG severity in 15 out of 17 therapeutic sessions. Four patients (40%) reported marked improvement (+3) of FOG in 5 sessions. Two patients reported no effect in two sessions. The mean duration of improvement was 6 weeks (range 1–12 weeks) with definite deterioration afterwards. The patient who was injected in a single blind fashion did not respond to saline injections but improved significantly with BTX-A treatment. Conclusions We observed a clear temporal relationship between BTX-A injections into the calf muscles of parkinsonian patients and improvement of FOG. A double blind placebo controlled prospective study is needed before any conclusions can be drawn about the role of BTX-A injection in FOG.
Background. Freezing of Gait (FOG) is one of the most disturbing and least understood symptom in ... more Background. Freezing of Gait (FOG) is one of the most disturbing and least understood symptom in advanced stage of Parkinson's disease (PD). The contribution of the underlying pathological process and the antiparkinsonian treatment to the development of FOG are controversial. Objective. To study the relationships between clinical features of PD and therapeutic modalities in patients with advanced PD and FOG. Methods. Consecutive patients with 5 years or more of PD symptoms (n = 172) (99 men) with mean age at symptoms onset of 58.3 ± 13.2 years and mean symptoms duration of 11.8 ± 5.6 years were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patients' charts, and other documents. A patient was considered as "freezer" if he/she reported recent experience that the legs got stuck to the ground while trying to walk. The presence of dyskinesia, early morning dystonia or significant postural reflex abnormalities were assessed through history and neurological examination. Duration of treatment with antiparkinsonian drugs was calculated from history charts. Chi square and t test were used to compare the patients with and without FOG. Logistic regression was used for the comparison of association between the presence of FOG (dependent variable) disease duration and disease stage (explanatory variables) and duration of treatment with anti-parkinsonian drugs. Results. The study population consisted of 45 patients at Hoehn and Yahr (H&Y) stage 2.5 (26%), 104 patients at stage 3 (60.5%), and 23 patients at H&Y stages 4–5 (13.5%). Ninety one patients (53%) reported FOG at the time of the study. Severity of the disease expressed by H&Y stage at "off" was a significant contributing factor for FOG with a significant trend (z = 4.38, p < 0.0001), as was longer duration of levodopa treatment, and confirmed by FOG using the multivariate logistic regression (p = 0.01 and p = 0.004, respectively). Using a univariate model, longer duration of treatment with dopamine agonists contribute to the appearance of FOG (p = 0.07) while longer duration of amantadine treatment decreased the appearance of FOG (p = 0.09). There was a significant association between FOG and the presence of dyskinesia (p < 0.002), early morning foot dystonia (p < 0.003) and significant postural instability (p < 0.0005). Conclusion. FOG is a common symptom in advanced PD. It is mainly related to disease progression and levodopa treatment.
Objectives. To study the relationships between clinical features of Parkinson's disease (PD) and ... more Objectives. To study the relationships between clinical features of Parkinson's disease (PD) and the development of dementia, depression or psychosis in patients with long-standing disease. Background. The natural history of dementia and depression in PD, and its relation to psychosis in long standing PD, are unclear. Method. 172 consecutive patients (99 men and 73 women, mean age at symptoms onset 58.3 ± 13.2 years) with 5 years or more of PD (mean symptom duration of 11.8 ± 5.6 years) were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patient charts and outside documents. Dementia and depression were diagnosed according to DSM-IV criteria, while psychosis was diagnosed if hallucinations or delusions were present. Chi-square and t tests were used to compare the patient characteristics among those with vs. those without mental complications of the disease at different disease stages. Logistic regression was used for the comparison of associations between the presence of dementia or depression (dependent variable) and age at onset of PD, duration of PD and disease staging (explanatory variables). Results. The study population consisted of 45 patients at Hoehn & Yahr (H&Y) stage ≤2.5 (26%), 104 patients at stage 3 (60.5%) and 23 patients at H&Y stage 4–5 (13.5%). Sixty one patients (36%) had dementia, 55 patients had depression (33%) and 50 patients (27%) had psychosis. Dementia and depression were significantly associated with disease severity as reflected in the H&Y scale (P = 0.0003, Z = 3.59; P = 0.006, Z = 3.22, respectively). These associations were significant also for the older age of PD onset (≥59 years n = 89) subgroup (p = 0.001, Z = 3.2 for dementia and p = 0.02, Z = 2.9 for depression), but not for younger onset cases (<59 years n = 83). Dementia was significantly associated with older age of PD onset (β = 0.04, p = 0.009) while depression was inversely associated with age of PD onset (β = −0.04, p = 0.02). The presence of dementia was also significantly associated with depression (β = 1.49, p = 0.0006). Dementia and depression were found to be independent explanatory variables for the development of psychosis (logistic regression, odds ratio (OR) = 26.0, p < 0.0001; OR = 10.2, p < 0.0001, respectively). In patients with younger age of PD onset, depression more than dementia was strongly correlated with the appearance of psychosis. Conclusion. Dementia in PD was related to older age of symptoms onset and old age. Depression was associated with dementia or early age of PD onset. Depression seemed to contribute to the appearance of psychosis even more than dementia, especially in patients with younger age of symptoms onset.
groups with the Word list memory task achieving the best results. Discussion will focus on the di... more groups with the Word list memory task achieving the best results. Discussion will focus on the differential sensitivity and specificity of these measures and work that aims to refine the 'gold standard' for diagnosis of MCI and AAMI.
master gene of chondrocytic cell differentiation, reflects the chondrocytic phenotype of our cell... more master gene of chondrocytic cell differentiation, reflects the chondrocytic phenotype of our cell lines. Genes involved in extracellular matrix formation, such as collagens, were also significantly expressed by these cells in our culture conditions. We also investigated the potential of SV40 expressing MPS IVA chondrocytes to produce and accumulate KS.
Background: While several paper-based screening tools exist for assessment of moderate to severe ... more Background: While several paper-based screening tools exist for assessment of moderate to severe dementia, there is a need for more brief but comprehensive assessment of cognitive function in these individuals for purposes of longitudinal tracking and monitoring of treatment effects. Objective: To evaluate the validity of a 15-minute computerized battery for cognitive assessment of moderate to severe cognitive impairment in the elderly. Methods: 97 older adults (age: 76.6Ϯ11.0; education: 10.4Ϯ4.6 years; 13% computer users) completed the 15minute technician-administered computerized Moderate-Severe Impairment Battery (MODS; NeuroTrax Corp., NJ) assessing orientation, memory, executive function, visual spatial processing, and verbal function. Participants received an expert clinical diagnosis of cognitively healthy (nϭ4), MCI (nϭ24), or dementia (nϭ55) and were staged according to the Clinical Dementia Rating (CDR) scale. Overall MODS score was compared across CDR stages by between-groups ANOVA. The Pearson correlation between MODS score and CDR sum of the boxes (CDR-SB) was computed. Effect sizes (Cohens d) were computed for differences in MODS score as a function of caregiver-reported cognitive symptoms and activities of daily living (ADLs). Results: MODS performance was significantly poorer with increasing CDR stage (pϽ0.0001), and all pairwise comparisons were significant (pϽ0.004); there were no differences in age (pϭ0.47) or education (pϭ0.36). A correlation of 0.71 (pϽ0.0001) was found between MODS score and CDR-SB. Large effect sizes were obtained for caregiverreported difficulty managing finances (dϭ1.25) and medications (dϭ1.03); there were medium effect sizes for decline over 6 months (dϭ0.67) and difficulty remembering (dϭ0.54) or finding the right words (dϭ0.46). Conclusions: A 15-minute computerized battery demonstrates good discriminant validity across CDR severity stages, high construct validity, and meaningful relationship with ADLs. Thus the Moderate-Severe Impairment Battery is valid and practical for tracking change in patients with impaired function.
Background: There is a critical need for practical and effective methods for office-based assessm... more Background: There is a critical need for practical and effective methods for office-based assessment of cognitive decline. We propose a hierarchical approach that has high diagnostic accuracy and considers reimbursement and cost and resource constraints of a busy office. The 3-tiered evaluation algorithm defines appropriate roles for short screening tools, point-of-care comprehensive assessment, and referral to a neuropsychologist. The present focus is on novel point-of-care comprehensive assessment that provides research-quality data and aids in differential diagnosis and longitudinal tracking. Objective: Develop a practical approach for officebased assessment of cognitive decline. Methods: Entry into the algorithm is either via cognitive complaint from the patient or informant or by the physician's clinical suspicion. Initial neurobehavioral assessment includes the history, examination, chart review, and a brief screening test and results in a determination of whether comprehensive assessment is warranted. For point-of-care cognitive assessment, we used the Mindstreams (NeuroTrax Corp., NY) computerized system. Endpoints were discriminant validity as well as measures of usability and practicality. Results: Previous studies demonstrated better discriminant validity for Mindstreams in early cognitive decline than for paper-based neuropsychological tests and that Mindstreams is robust to the presence of depressive symptoms and low socioeconomic status. The present multi-ethnic cohort was from an ongoing longitudinal study of MCI and mild dementia (Nϭ73; ageϭ73Ϯ10.5). Mindstreams results were summarized for each cognitive domain, and a composite MCI Score was computed. ROC curve analysis revealed good discriminability (area under the curve: 0.91, sens 80%, spec 86%). Ease of use and practicality of Mindstreams was measured in a real-life cohort from 9 medical offices (Nϭ680; ageϭ61.6Ϯ19.6) of which 37% had no computer experience. Each patient and test administrator separately completed 4 questions regarding ease of use, scored on a 5-point Likert scale. Only 9% of administrators and 8% of patients rated Mindstreams difficult to use, and only 7% rated it hard to understand. Further, office administrators reported success in reimbursement. Conclusions: The advent of valid, objective, and practical computerized assessment affords a solution for point-of-care assessment and makes a hierarchical approach feasible. This should lead to better standardized patient care and system-wide cost savings.
Background: While several paper-based screening tools exist for assessment of moderate to severe ... more Background: While several paper-based screening tools exist for assessment of moderate to severe dementia, there is a need for more brief but comprehensive assessment of cognitive function in these individuals for purposes of longitudinal tracking and monitoring of treatment effects. Objective: To evaluate the validity of a 15-minute computerized battery for cognitive assessment of moderate to severe cognitive impairment in the elderly. Methods: 97 older adults (age: 76.6Ϯ11.0; education: 10.4Ϯ4.6 years; 13% computer users) completed the 15minute technician-administered computerized Moderate-Severe Impairment Battery (MODS; NeuroTrax Corp., NJ) assessing orientation, memory, executive function, visual spatial processing, and verbal function. Participants received an expert clinical diagnosis of cognitively healthy (nϭ4), MCI (nϭ24), or dementia (nϭ55) and were staged according to the Clinical Dementia Rating (CDR) scale. Overall MODS score was compared across CDR stages by between-groups ANOVA. The Pearson correlation between MODS score and CDR sum of the boxes (CDR-SB) was computed. Effect sizes (Cohens d) were computed for differences in MODS score as a function of caregiver-reported cognitive symptoms and activities of daily living (ADLs). Results: MODS performance was significantly poorer with increasing CDR stage (pϽ0.0001), and all pairwise comparisons were significant (pϽ0.004); there were no differences in age (pϭ0.47) or education (pϭ0.36). A correlation of 0.71 (pϽ0.0001) was found between MODS score and CDR-SB. Large effect sizes were obtained for caregiverreported difficulty managing finances (dϭ1.25) and medications (dϭ1.03); there were medium effect sizes for decline over 6 months (dϭ0.67) and difficulty remembering (dϭ0.54) or finding the right words (dϭ0.46). Conclusions: A 15-minute computerized battery demonstrates good discriminant validity across CDR severity stages, high construct validity, and meaningful relationship with ADLs. Thus the Moderate-Severe Impairment Battery is valid and practical for tracking change in patients with impaired function.
Alzheimer&amp;#x27;s &amp;amp; Dementia: The Journal of the Alzheimer&amp;#x27;s Asso... more Alzheimer&amp;#x27;s &amp;amp; Dementia: The Journal of the Alzheimer&amp;#x27;s Association, Volume 4, Issue 4, Pages T393, July 2008, Authors:Ely S. Simon; Efrat Sasson; Glen M. Doniger; Ofer Pasternak; Yaniv Assaf. ...
Background: Computerized cognitive assessment tools have been developed to make precise neuropsyc... more Background: Computerized cognitive assessment tools have been developed to make precise neuropsychological assessment readily available to clinicians. Mindstreams batteries for mild impairment have been validated previously. We examined the validity of a Mindstreams battery designed specifically for evaluating those with moderate cognitive impairment.
Background: Only 10 to 15% of individuals diagnosed with amnestic MCI convert to dementia each ye... more Background: Only 10 to 15% of individuals diagnosed with amnestic MCI convert to dementia each year, and the clinician is insufficiently equipped to predict who is at risk. The present report is an interim analysis of a study for prospective identification of elderly at high risk for dementia. Objective: To compare the cognitive profile of MCI patients declining after 1-year with those not declining in an ongoing two-site multi-ethnic cohort study. Methods: Participants were 44 MCIs (Petersen's criteria for amnestic MCI; age: 72.4Ϯ10.1; education: 13.8Ϯ4.1) and 21 controls (age: 72.7Ϯ11.2; education: 15.2Ϯ3.1) in a prospective study who completed the Mindstreams Global Assessment Battery (NeuroTrax Corp., NY) at baseline and 1-year. MCIs were defined as "decliners" or "non-decliners" depending upon 1-year 'MCI Score' classification. Between-groups analysis was by Mann-Whitney U test. Dependent measures were age-and education-normalized Memory, Executive Function, Visual Spatial, and Attention summary scores, a Global Cognitive Score summarizing battery performance, and Lawton iADL category scores. MCI decliners performed worse than controls at 1-year in executive function (pϭ0.02), visual spatial (pϭ0.04), and global performance (pϭ0.009). In contrast, change in nondecliners was not different from controls for any measure (p'sϾ0.11). MCI decliners exhibited greater change than MCI non-decliners in executive function (pϽ0.001), attention (pϭ0.04) and battery performance (pϭ0.007); decliners also performed worse in ability to use the telephone (pϭ0.03). MCI decliners performed more poorly at baseline in executive function (pϭ0.005) and attention (pϭ0.04); decliners were also more functionally dependent in telephone use (pϭ0.003), shopping (pϭ0.02), and food preparation (pϭ0.02). Conclusions: Computerized cognitive assessment can assist clinicians in identifying MCI patients likely to convert to dementia. These preliminary findings suggest that executive function at baseline is an important predictor of subsequent cognitive decline in amnestic MCI.
Food deprivation has been shown to deleteriously affect human cognition, but findings are equivoc... more Food deprivation has been shown to deleteriously affect human cognition, but findings are equivocal, and few studies have examined several cognitive domains. In this study, the authors used computerized testing to describe the profile of shifts in cognition attributable to short-term religious fasting. Multiple cognitive domains were evaluated at midday and late afternoon following complete abstention from eating and drinking beginning at midnight. Cross-domain, fasting-related deficits were found for tasks requiring perception of spatial relations. Fasting-related information processing deficits were found for response time but not accuracy for test levels of intermediate difficulty. Time-of-day effects often reflected poorer afternoon performance. These findings provide a detailed profile of cognitive consequences of food deprivation, affected by time of day, task demands, and type of outcome.
We describe the effects of the asymmetry of cycles and non-stationarity in time series on the pha... more We describe the effects of the asymmetry of cycles and non-stationarity in time series on the phase synchronization method. We develop a modified method that overcomes these effects and apply this method to study parkinsonian tremor. Our results indicate that there is synchronization between two different hands and provide information about the time delay separating their dynamics. These findings suggest that this method may be useful for detecting and quantifying weak synchronization between two non-stationary signals.
Dysrhythmia is one of the features frequently associated with the motor disturbance in Parkinson&... more Dysrhythmia is one of the features frequently associated with the motor disturbance in Parkinson&#39;s disease (PD). The mechanism responsible for this phenomenon is not known. To assess the rhythmic movements of the hand in PD patients in general and in parkinsonian subtypes. Fifty-one PD patients (32 males) with mean age 66.3 +/- 9.1 years (6.6 years of symptoms) and 36 healthy controls (age 64.9 +/- 13.2, range 40-85) were studied. Subjects were asked to tap with their dominant or less affected arm on a digitized switch board at their most comfortable pace (16 s), fastest tapping speed (12 s), and at different frequencies provided by a metronome. The mean rhythm and the tap-to-tap variation were compared. Performance of the PD patients and control subjects were compared, as there were different subtypes of PD patients. Patients were subclassified into: tremor predominant (TP) (14 patients), freezing predominant (FP) (11 patients), akinetic-rigid (AR) (12 patients) and an unclassified group (UC) (14 patients). Results. There was no significance difference between patients and controls in the self-chosen, most comfortable tapping rate or in the tap-to-tap variation of the self-paced task. PD patients tapped at a significantly slower rate than controls when asked to tap at their fastest rate (4.39 +/- 1.32 vs. 5.14 +/- 1.31 Hz; p &lt; 0.01). This difference was the result of an especially slow performance of the TP and AR subgroups (3.85+/-1.20 and 3.88+/-1.46, respectively; p &lt; 0.01 compared to the control group). TP was the only subgroup to show an increased tap-to-tap variation at their fastest tapping rate compared to the control group (0.070 +/- 0.057 vs. 0.029 +/- 0.025 s, respectively, p &lt; 0.05). The TP subgroup also showed hastening when they followed an externally given rhythm of 2.5 Hz and they tapped at 2.73 +/- 0.36 Hz p &lt; 0.05). Externally driven and self-paced tapping are preserved in patients with PD, when examined at their best &#39;on&#39; state. The tremor predominant subgroup seems to have specific pacing disturbances.
We found that in vitro migration and interferon-␥ production by lymphocytes derived from primary ... more We found that in vitro migration and interferon-␥ production by lymphocytes derived from primary progressive multiple sclerosis patients preselected on the basis of a high T2-weighted lesion volume (>10 cm 3 ) on magnetic resonance imaging, were increased compared with that in primary progressive multiple sclerosis patients with a low T2-weighted lesion volume (<3 cm 3 ) and controls. Whether the heterogeneity of immune function within the primary progressive population will correlate with response to therapy remains to be established.
This study compares some characteristics of the disynaptic excitatory pathways from the lateral v... more This study compares some characteristics of the disynaptic excitatory pathways from the lateral vestibular nucleus (LVN) and medial longitudinal fasciculus (MLF) to lumbosacral α-motoneurons in the decerebrate cat. We used the spatial facilitation technique to test whether disynaptic LVN and MLF excitatory postsynaptic potentials (EPSPs) are produced by common last-order interneurons in the lumbosacral segments of the spinal cord. Of 77 motoneurons examined, 26 exhibited disynaptic EPSPs from both supraspinal sources. No spatial facilitation was found between LVN and MLF EPSPs in 21 of 24 cells that were adequately tested. In 3 of 23 cells (all flexor motoneurons), some spatial facilitation was found in some but not all trials. These observations suggest that stimulation of the LVN and MLF produces disynaptic EPSPs in motoneurons through largely separate populations of last-order interneurons. Disynaptic MLF and LVN EPSPs showed parallel patterns of modulation during fictive locomotion. Maximal disynaptic EPSP amplitudes occurred during the phase of the step cycle when the recorded motoneuron, whether flexor or extensor, exhibited depolarizing locomotor drive potentials and the corresponding muscle nerve was active. These observations, taken together, suggest that disynaptic LVN and MLF EPSPs are produced in motoneurons by at least four separate populations of segmental last-order excitatory interneurons, with separate populations projecting to flexor versus extensor cells. The results also suggest that the modulation of the disynaptic EPSPs during fictive locomotion is mainly due to premotoneuronal convergence of input from the respective descending systems and from the segmental central pattern generator for locomotion onto common interneurons.
Recent evidence points to involvement of central nervous system oscillators in Parkinson's diseas... more Recent evidence points to involvement of central nervous system oscillators in Parkinson's disease (PD) rest tremor. It remains unknown whether one or multiple oscillators cause tremor in multiple limbs. Based on the prediction that multiple oscillators would cause low coherence even with similar average frequency, we studied 22 PD patients using accelerometers on multiple limbs. Records were digitized and spectral analysis was performed. Peak frequencies in the arms, legs, and chin were similar, indicating that biomechanical factors did not determine the frequency. Coherence between different axes of individual accelerometers and between different segments of the same limb was high. However, coherence between tremor in different limbs was low. There was no consistent pattern across patients of ipsi- vs. contralateral predominance of coherence. These data suggest that tremor in PD is generated by multiple oscillatory circuits, which operate on similar frequencies.
Background Freezing of gait (FOG) is a common and very disabling parkinsonian symptom, which is p... more Background Freezing of gait (FOG) is a common and very disabling parkinsonian symptom, which is poorly understood and responds unsatisfactorily to medical treatment. We recently reported a unique patient with Parkinson's disease (PD) who had significant alleviation of FOG shortly after she was injected with botulinum toxin type A (BTX-A) for foot dystonia (Giladi et al. 1997). Objective To assess the effect of BTX-A injections into the calf muscles of parkinsonian patients on FOG. Method BTX-A was injected in an open fashion into the calf muscles of 10 parkinsonian patients (age 55–75 years) with FOG as a predominant symptom. Response of FOG was assessed subjectively by the patient from worsening (–1) to marked improvement (+3). One patient was injected in a single blind fashion with saline or BTX-A after he had an initial good response. Results Seven patients reported different rates of improvement of FOG severity in 15 out of 17 therapeutic sessions. Four patients (40%) reported marked improvement (+3) of FOG in 5 sessions. Two patients reported no effect in two sessions. The mean duration of improvement was 6 weeks (range 1–12 weeks) with definite deterioration afterwards. The patient who was injected in a single blind fashion did not respond to saline injections but improved significantly with BTX-A treatment. Conclusions We observed a clear temporal relationship between BTX-A injections into the calf muscles of parkinsonian patients and improvement of FOG. A double blind placebo controlled prospective study is needed before any conclusions can be drawn about the role of BTX-A injection in FOG.
Background. Freezing of Gait (FOG) is one of the most disturbing and least understood symptom in ... more Background. Freezing of Gait (FOG) is one of the most disturbing and least understood symptom in advanced stage of Parkinson's disease (PD). The contribution of the underlying pathological process and the antiparkinsonian treatment to the development of FOG are controversial. Objective. To study the relationships between clinical features of PD and therapeutic modalities in patients with advanced PD and FOG. Methods. Consecutive patients with 5 years or more of PD symptoms (n = 172) (99 men) with mean age at symptoms onset of 58.3 ± 13.2 years and mean symptoms duration of 11.8 ± 5.6 years were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patients' charts, and other documents. A patient was considered as "freezer" if he/she reported recent experience that the legs got stuck to the ground while trying to walk. The presence of dyskinesia, early morning dystonia or significant postural reflex abnormalities were assessed through history and neurological examination. Duration of treatment with antiparkinsonian drugs was calculated from history charts. Chi square and t test were used to compare the patients with and without FOG. Logistic regression was used for the comparison of association between the presence of FOG (dependent variable) disease duration and disease stage (explanatory variables) and duration of treatment with anti-parkinsonian drugs. Results. The study population consisted of 45 patients at Hoehn and Yahr (H&Y) stage 2.5 (26%), 104 patients at stage 3 (60.5%), and 23 patients at H&Y stages 4–5 (13.5%). Ninety one patients (53%) reported FOG at the time of the study. Severity of the disease expressed by H&Y stage at "off" was a significant contributing factor for FOG with a significant trend (z = 4.38, p < 0.0001), as was longer duration of levodopa treatment, and confirmed by FOG using the multivariate logistic regression (p = 0.01 and p = 0.004, respectively). Using a univariate model, longer duration of treatment with dopamine agonists contribute to the appearance of FOG (p = 0.07) while longer duration of amantadine treatment decreased the appearance of FOG (p = 0.09). There was a significant association between FOG and the presence of dyskinesia (p < 0.002), early morning foot dystonia (p < 0.003) and significant postural instability (p < 0.0005). Conclusion. FOG is a common symptom in advanced PD. It is mainly related to disease progression and levodopa treatment.
Objectives. To study the relationships between clinical features of Parkinson's disease (PD) and ... more Objectives. To study the relationships between clinical features of Parkinson's disease (PD) and the development of dementia, depression or psychosis in patients with long-standing disease. Background. The natural history of dementia and depression in PD, and its relation to psychosis in long standing PD, are unclear. Method. 172 consecutive patients (99 men and 73 women, mean age at symptoms onset 58.3 ± 13.2 years) with 5 years or more of PD (mean symptom duration of 11.8 ± 5.6 years) were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patient charts and outside documents. Dementia and depression were diagnosed according to DSM-IV criteria, while psychosis was diagnosed if hallucinations or delusions were present. Chi-square and t tests were used to compare the patient characteristics among those with vs. those without mental complications of the disease at different disease stages. Logistic regression was used for the comparison of associations between the presence of dementia or depression (dependent variable) and age at onset of PD, duration of PD and disease staging (explanatory variables). Results. The study population consisted of 45 patients at Hoehn & Yahr (H&Y) stage ≤2.5 (26%), 104 patients at stage 3 (60.5%) and 23 patients at H&Y stage 4–5 (13.5%). Sixty one patients (36%) had dementia, 55 patients had depression (33%) and 50 patients (27%) had psychosis. Dementia and depression were significantly associated with disease severity as reflected in the H&Y scale (P = 0.0003, Z = 3.59; P = 0.006, Z = 3.22, respectively). These associations were significant also for the older age of PD onset (≥59 years n = 89) subgroup (p = 0.001, Z = 3.2 for dementia and p = 0.02, Z = 2.9 for depression), but not for younger onset cases (<59 years n = 83). Dementia was significantly associated with older age of PD onset (β = 0.04, p = 0.009) while depression was inversely associated with age of PD onset (β = −0.04, p = 0.02). The presence of dementia was also significantly associated with depression (β = 1.49, p = 0.0006). Dementia and depression were found to be independent explanatory variables for the development of psychosis (logistic regression, odds ratio (OR) = 26.0, p < 0.0001; OR = 10.2, p < 0.0001, respectively). In patients with younger age of PD onset, depression more than dementia was strongly correlated with the appearance of psychosis. Conclusion. Dementia in PD was related to older age of symptoms onset and old age. Depression was associated with dementia or early age of PD onset. Depression seemed to contribute to the appearance of psychosis even more than dementia, especially in patients with younger age of symptoms onset.
groups with the Word list memory task achieving the best results. Discussion will focus on the di... more groups with the Word list memory task achieving the best results. Discussion will focus on the differential sensitivity and specificity of these measures and work that aims to refine the 'gold standard' for diagnosis of MCI and AAMI.
master gene of chondrocytic cell differentiation, reflects the chondrocytic phenotype of our cell... more master gene of chondrocytic cell differentiation, reflects the chondrocytic phenotype of our cell lines. Genes involved in extracellular matrix formation, such as collagens, were also significantly expressed by these cells in our culture conditions. We also investigated the potential of SV40 expressing MPS IVA chondrocytes to produce and accumulate KS.
Background: While several paper-based screening tools exist for assessment of moderate to severe ... more Background: While several paper-based screening tools exist for assessment of moderate to severe dementia, there is a need for more brief but comprehensive assessment of cognitive function in these individuals for purposes of longitudinal tracking and monitoring of treatment effects. Objective: To evaluate the validity of a 15-minute computerized battery for cognitive assessment of moderate to severe cognitive impairment in the elderly. Methods: 97 older adults (age: 76.6Ϯ11.0; education: 10.4Ϯ4.6 years; 13% computer users) completed the 15minute technician-administered computerized Moderate-Severe Impairment Battery (MODS; NeuroTrax Corp., NJ) assessing orientation, memory, executive function, visual spatial processing, and verbal function. Participants received an expert clinical diagnosis of cognitively healthy (nϭ4), MCI (nϭ24), or dementia (nϭ55) and were staged according to the Clinical Dementia Rating (CDR) scale. Overall MODS score was compared across CDR stages by between-groups ANOVA. The Pearson correlation between MODS score and CDR sum of the boxes (CDR-SB) was computed. Effect sizes (Cohens d) were computed for differences in MODS score as a function of caregiver-reported cognitive symptoms and activities of daily living (ADLs). Results: MODS performance was significantly poorer with increasing CDR stage (pϽ0.0001), and all pairwise comparisons were significant (pϽ0.004); there were no differences in age (pϭ0.47) or education (pϭ0.36). A correlation of 0.71 (pϽ0.0001) was found between MODS score and CDR-SB. Large effect sizes were obtained for caregiverreported difficulty managing finances (dϭ1.25) and medications (dϭ1.03); there were medium effect sizes for decline over 6 months (dϭ0.67) and difficulty remembering (dϭ0.54) or finding the right words (dϭ0.46). Conclusions: A 15-minute computerized battery demonstrates good discriminant validity across CDR severity stages, high construct validity, and meaningful relationship with ADLs. Thus the Moderate-Severe Impairment Battery is valid and practical for tracking change in patients with impaired function.
Background: There is a critical need for practical and effective methods for office-based assessm... more Background: There is a critical need for practical and effective methods for office-based assessment of cognitive decline. We propose a hierarchical approach that has high diagnostic accuracy and considers reimbursement and cost and resource constraints of a busy office. The 3-tiered evaluation algorithm defines appropriate roles for short screening tools, point-of-care comprehensive assessment, and referral to a neuropsychologist. The present focus is on novel point-of-care comprehensive assessment that provides research-quality data and aids in differential diagnosis and longitudinal tracking. Objective: Develop a practical approach for officebased assessment of cognitive decline. Methods: Entry into the algorithm is either via cognitive complaint from the patient or informant or by the physician's clinical suspicion. Initial neurobehavioral assessment includes the history, examination, chart review, and a brief screening test and results in a determination of whether comprehensive assessment is warranted. For point-of-care cognitive assessment, we used the Mindstreams (NeuroTrax Corp., NY) computerized system. Endpoints were discriminant validity as well as measures of usability and practicality. Results: Previous studies demonstrated better discriminant validity for Mindstreams in early cognitive decline than for paper-based neuropsychological tests and that Mindstreams is robust to the presence of depressive symptoms and low socioeconomic status. The present multi-ethnic cohort was from an ongoing longitudinal study of MCI and mild dementia (Nϭ73; ageϭ73Ϯ10.5). Mindstreams results were summarized for each cognitive domain, and a composite MCI Score was computed. ROC curve analysis revealed good discriminability (area under the curve: 0.91, sens 80%, spec 86%). Ease of use and practicality of Mindstreams was measured in a real-life cohort from 9 medical offices (Nϭ680; ageϭ61.6Ϯ19.6) of which 37% had no computer experience. Each patient and test administrator separately completed 4 questions regarding ease of use, scored on a 5-point Likert scale. Only 9% of administrators and 8% of patients rated Mindstreams difficult to use, and only 7% rated it hard to understand. Further, office administrators reported success in reimbursement. Conclusions: The advent of valid, objective, and practical computerized assessment affords a solution for point-of-care assessment and makes a hierarchical approach feasible. This should lead to better standardized patient care and system-wide cost savings.
Background: While several paper-based screening tools exist for assessment of moderate to severe ... more Background: While several paper-based screening tools exist for assessment of moderate to severe dementia, there is a need for more brief but comprehensive assessment of cognitive function in these individuals for purposes of longitudinal tracking and monitoring of treatment effects. Objective: To evaluate the validity of a 15-minute computerized battery for cognitive assessment of moderate to severe cognitive impairment in the elderly. Methods: 97 older adults (age: 76.6Ϯ11.0; education: 10.4Ϯ4.6 years; 13% computer users) completed the 15minute technician-administered computerized Moderate-Severe Impairment Battery (MODS; NeuroTrax Corp., NJ) assessing orientation, memory, executive function, visual spatial processing, and verbal function. Participants received an expert clinical diagnosis of cognitively healthy (nϭ4), MCI (nϭ24), or dementia (nϭ55) and were staged according to the Clinical Dementia Rating (CDR) scale. Overall MODS score was compared across CDR stages by between-groups ANOVA. The Pearson correlation between MODS score and CDR sum of the boxes (CDR-SB) was computed. Effect sizes (Cohens d) were computed for differences in MODS score as a function of caregiver-reported cognitive symptoms and activities of daily living (ADLs). Results: MODS performance was significantly poorer with increasing CDR stage (pϽ0.0001), and all pairwise comparisons were significant (pϽ0.004); there were no differences in age (pϭ0.47) or education (pϭ0.36). A correlation of 0.71 (pϽ0.0001) was found between MODS score and CDR-SB. Large effect sizes were obtained for caregiverreported difficulty managing finances (dϭ1.25) and medications (dϭ1.03); there were medium effect sizes for decline over 6 months (dϭ0.67) and difficulty remembering (dϭ0.54) or finding the right words (dϭ0.46). Conclusions: A 15-minute computerized battery demonstrates good discriminant validity across CDR severity stages, high construct validity, and meaningful relationship with ADLs. Thus the Moderate-Severe Impairment Battery is valid and practical for tracking change in patients with impaired function.
Alzheimer&amp;#x27;s &amp;amp; Dementia: The Journal of the Alzheimer&amp;#x27;s Asso... more Alzheimer&amp;#x27;s &amp;amp; Dementia: The Journal of the Alzheimer&amp;#x27;s Association, Volume 4, Issue 4, Pages T393, July 2008, Authors:Ely S. Simon; Efrat Sasson; Glen M. Doniger; Ofer Pasternak; Yaniv Assaf. ...
Background: Computerized cognitive assessment tools have been developed to make precise neuropsyc... more Background: Computerized cognitive assessment tools have been developed to make precise neuropsychological assessment readily available to clinicians. Mindstreams batteries for mild impairment have been validated previously. We examined the validity of a Mindstreams battery designed specifically for evaluating those with moderate cognitive impairment.
Background: Only 10 to 15% of individuals diagnosed with amnestic MCI convert to dementia each ye... more Background: Only 10 to 15% of individuals diagnosed with amnestic MCI convert to dementia each year, and the clinician is insufficiently equipped to predict who is at risk. The present report is an interim analysis of a study for prospective identification of elderly at high risk for dementia. Objective: To compare the cognitive profile of MCI patients declining after 1-year with those not declining in an ongoing two-site multi-ethnic cohort study. Methods: Participants were 44 MCIs (Petersen's criteria for amnestic MCI; age: 72.4Ϯ10.1; education: 13.8Ϯ4.1) and 21 controls (age: 72.7Ϯ11.2; education: 15.2Ϯ3.1) in a prospective study who completed the Mindstreams Global Assessment Battery (NeuroTrax Corp., NY) at baseline and 1-year. MCIs were defined as "decliners" or "non-decliners" depending upon 1-year 'MCI Score' classification. Between-groups analysis was by Mann-Whitney U test. Dependent measures were age-and education-normalized Memory, Executive Function, Visual Spatial, and Attention summary scores, a Global Cognitive Score summarizing battery performance, and Lawton iADL category scores. MCI decliners performed worse than controls at 1-year in executive function (pϭ0.02), visual spatial (pϭ0.04), and global performance (pϭ0.009). In contrast, change in nondecliners was not different from controls for any measure (p'sϾ0.11). MCI decliners exhibited greater change than MCI non-decliners in executive function (pϽ0.001), attention (pϭ0.04) and battery performance (pϭ0.007); decliners also performed worse in ability to use the telephone (pϭ0.03). MCI decliners performed more poorly at baseline in executive function (pϭ0.005) and attention (pϭ0.04); decliners were also more functionally dependent in telephone use (pϭ0.003), shopping (pϭ0.02), and food preparation (pϭ0.02). Conclusions: Computerized cognitive assessment can assist clinicians in identifying MCI patients likely to convert to dementia. These preliminary findings suggest that executive function at baseline is an important predictor of subsequent cognitive decline in amnestic MCI.
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