Intellectual, neuropsychological, and academic functioning in long-term survivors of leukemia

OBJECTIVE: To assess the effects of treatment for acute lymphoblastic leukemia (ALL) on children's cognitive functioning. METHOD: Participants were long-term survivors of ALL treated with cranial irradiation and central nervous system (CNS) chemotherapy (n = 20), or CNS chemotherapy only (n = 21), healthy children (n = 21), and children with chronic asthma (n = 21). The groups were compared on measures of intellectual, neuropsychological, and academic functioning. RESULTS: CNS chemotherapy, with and without cranial irradiation, was associated with significantly lower levels of intellectual and academic functioning. Children with chronic asthma obtained lower scores than healthy controls, but these differences were not significant. Tests of neuropsychological functioning did not consistently separate the groups. CONCLUSIONS: CNS chemotherapy and, to a lesser extent, chronic illness both contribute to the poorer performance of long-term survivors of ALL on measures of intellectual and academic functioning.     

Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia.

Treatment-related cognitive impairments have been reported for survivors of childhood leukemia following prophylactic central nervous system (CNS) treatment with craniospinal radiation. We examined the neurocognitive status of 46 children with acute lymphocytic leukemia (ALL) to assess the impact of a regimen consisting of systemic chemotherapy and prophylactic CNS chemotherapy. By comparing three groups of ALL children (i.e., patients whose diagnosis was recent, patients 1 year postdiagnosis currently receiving CNS prophylactic chemotherapy, and off-therapy patients who had been treated with chemotherapy for 3 years) and their healthy siblings on measures of sequential and simultaneous processing, we were able to examine the effects of CNS prophylactic and systemic chemotherapy at various points during treatment. Results indicate that the children who had received a 3-year course of chemotherapy (off-therapy patients) were more impaired on tasks involving right-hemisphere simultaneous processing than were sibling controls or ALL children whose diagnosis was recent and whose treatment had just begun. Age at diagnosis did not interact with the effects of chemotherapy. These findings support the need for continued evaluation of cognitive functioning in ALL, children receiving CNS prophylactic chemotherapy to identify potential harmful neurocognitive sequelae of treatment.     

Cognitive effects of childhood leukemia therapy: a case for four specific deficits

Prophylactic treatment of the central nervous system (CNS) with cranial irradiation and antineoplastic drugs has made childhood acute lymphoblastic leukemia (ALL) a survivable disease, but at the same time there have been many reports of iatrogenic effects, including deficits in cognitive functioning. Previous research suggests a particular effect on the Freedom from Distractibility factor of the WISC-R, memory, and attention. These particular abilities are tested in a group of 43 ALL survivors, with comparisons against solid tumor as well as sibling controls. The results indicate that four cognitive processes are affected by CNS prophylaxis for ALL: short-term memory, speed of processing, visuomotor coordination, and sequencing ability. Younger children have a more severe speed of processing deficit and children treated with a less rigorous protocol appear to be slightly less affected generally. The specific cognitive deficits found are related to neurological evidence on both theoretical and empirical grounds. Results suggest that children who have received CNS prophylaxis are able to learn, but may be slower to acquire new material and may benefit from bimodal presentation.     

Neuropsychological sequelae of central nervous system prophylaxis in survivors of childhood acute lymphoblastic leukemia

We assessed neuropsychologically 106 children with acute lymphoblastic leukemia (ALL) who had all received cranial irradiation for the prevention of central nervous system (CNS) leukemia 1-13 years previously. Children were assessed for adverse late effects of their therapy, using age-appropriate Wechsler measures of overall intellectual ability and supplementary tests. Forty-five siblings near in age to the patients were tested as controls. The patients who had had the most intensive central nervous system (CNS) prophylaxis were found to have a WISC-R Full Scale IQ 17 points lower than the sibling control group. Performance IQ was more affected than verbal IQ. The patients were more easily distracted and less able to concentrate. The severity of the aftereffects was related to younger age at the time of CNS prophylaxis and to a higher dose of cranial irradiation but not to time since CNS prophylaxis. CNS prophylaxis using a combination of cranial irradiation and intrathecal methotrexate has lowered the incidence of CNS relapse in childhood ALL but is associated with considerable long-term morbidity in survivors.     

Cognitive and Academic Late Effects Among Children Previously Treated for Acute Lymphocytic Leukemia Receiving Chemotherapy as CNS Prophylaxis

Objective: Examine cognitive and academic late effects amongchildren and adolescents who had received central nervous system(CNS) prophylactic chemotherapy alone for acute lymphocyticleukemia (ALL); none had received whole brain radiation therapy(RT). Method: Subjects included 47 children and adolescents from 5to 22 years of age who were treated on the same protocol andhad been off treatment from 2 to 7 years at the time of assessment. Results: As a group the survivors displayed generally averageperformance on measures of cognitive and academic abilities,although they differed from normative means on tests of nonverbalskills. Girls performed more poorly than the normative sampleon nonverbal tasks, while no differences were found for boys.Age at diagnosis and time off treatment were not significantlyassociated with cognitive and academic functioning for survivorsof this particular chemotherapy-only protocol. Conclusions: Data were interpreted to support generally modestpotential late effects in specific areas for children and adolescentssurviving ALL. These findings suggest a need for monitoringnonverbal cognitive skills for childhood survivors of ALL, particularlyfor girls.     

Intellectual functioning of childhood leukemia survivors - relation to Tau protein - a marker of white matter injury

PurposeChemo- and radiotherapy used in acute lymphoblastic leukemia (ALL) can influence on brain functioning in the future. In a prospective study we analysed the cognitive functions of ALL survivors in relation to Tau protein as a marker of white matter injury.Material and methodsThirty-one survivors of childhood ALL (6.3 years after diagnosis); without the signs of CNS involvement, treated with chemotherapy alone, rested in first remission; underwent Intelligence tests- Wechsler Intelligence Scales (WISC-R, WAIS-R). Their results were analyzed in relation to the levels of Tau in cerebrospinal fluid (CSF) obtained during the treatment.ResultsThe analysis showed that all survivors attained the average scores in intelligence tests. A negative correlation was found between methotrexate (MTX) doses and Freedom from Distractibility (FFD). Females had higher values of Performance Intelligence Quotient (PIQ) than males. A negative correlation was noted of Tau protein levels obtained from the last CSF with: Total and Verbal Intelligence Quotient, PIQ, Perceptual Organisation Index and FFD but not with Verbal Comprehension Index.ConclusionOur results suggest the possibility of white matter injury during the treatment for ALL with chemotherapy alone. Elevated Tau protein level in CSF at the end of treatment might indicate future difficulties in neurocognitive functioning.     

Sex differences in cognitive processing in children treated with CNS prophylaxis for acute lymphoblastic leukemia

Evaluated cognitive processing in 51 children (27 female, 24 male) who had been treated for acute lymphoblastic leukemia (ALL) with CNS prophylaxis (cranial radiation in combination with intrathecal chemotherapy) and were continuously disease-free for 5 to 12 years. The control group comprised 15 children treated for Wilm's tumor. Functions assessed included visuoperceptual skills, generation of organizational strategies, sensitivity to organizational structure, and attention. The ALL group showed performance deficits relative to the solid tumor controls in appreciating the organization inherent in complex visuospatial material and alertness, with females more severely affected than males. Sex differences favoring males on IQ and academic achievement were related to these cognitive processes.     

Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia.

Medical treatment for acute lymphoblastic leukemia (ALL) has improved survival rates to 70% for children currently diagnosed with this disease. Intrathecal (IT) chemotherapy replaced CNS radiation therapy (CRT) for those with a favorable diagnosis as research revealed cognitive deficits associated with CRT. The literature pertaining to the potential adverse intellectual and neurophysiological consequences of IT chemotherapy is reviewed. It is concluded that IT chemotherapy may not be a benign form of treatment, although its effects may be more subtle than those produced by CRT. Future studies implementing more comprehensive test batteries are needed to illuminate these deficits so that remediation may be possible for ALL survivors.     

Leukemia in the central nervous system

The frequency of central nervous system (CNS) leukemia was studied in patients aged 15-59 with acute leukemia, who had received induction treatment in the years 1971-1986. Twelve out of 103 patients with acute lymphoblastic leukemia (ALL) developed CNS leukemia in spite of prophylaxis consisting of intrathecal methotrexate. Ten out of 217 patients with acute myelogenous leukemia (AML) developed CNS leukemia. None had been given preventive treatment. Leukemic blasts with either M4 or M5 morphology appeared to increase the risk of CNS relapse. Treatment was adjusted to the clinical problem of each patient, but always included intrathecal methotrexate. Median survival after a diagnosis of CNS leukemia was 8 and 6 months in ALL and AML respectively, with bone marrow failure due to hematologic relapse as the leading cause of death. CNS leukemia, if properly treated, does probably not shorten survival. An active approach to diagnosis and treatment is therefore mandatory.     

Reliability of monosynaptic sensory transmission in brain stem neurons in vitro

The timing of events within the nervous system is a critical feature of signal processing and integration. In neurotransmission, the synaptic latency, the time between stimulus delivery and appearance of the synaptic event, is generally thought to be directly related to the complexity of that pathway. In horizontal brain stem slices, we examined synaptic latency and its shock-to-shock variability (synaptic jitter) in medial nucleus tractus solitarius (NTS) neurons in response to solitary tract (ST) electrical activation. Using a visualized patch recording approach, we activated ST 1-3 mm from the recorded neuron with short trains (50-200 Hz) and measured synaptic currents under voltage clamp. Latencies ranged from 1.5 to 8.6 ms, and jitter values (SD of intraneuronal latency) ranged from 26 to 764 micros (n = 49). Surprisingly, frequency of synaptic failure was not correlated with either latency or jitter (P > 0.147; n = 49). Despite conventional expectations, no clear divisions in latency were found from the earliest arriving excitatory postsynaptic currents (EPSCs) to late pharmacologically polysynaptic responses. Shortest latency EPSCs (<3 ms) were mediated by non-N-methyl-D-aspartate (non-NMDA) glutamate receptors. Longer latency responses were a mix of excitatory and inhibitory currents including non-NMDA EPSCs and GABAa receptor-mediated currents (IPSC). All synaptic responses exhibited prominent frequency-dependent depression. In a subset of neurons, we labeled sensory boutons by the anterograde fluorescent tracer, DiA, from aortic nerve baroreceptors and then recorded from anatomically identified second-order neurons. In identified second-order NTS neurons, ST activation evoked EPSCs with short to moderate latency (1.9-4.8 ms) but uniformly minimal jitter (31 to 61 micros) that were mediated by non-NMDA receptors but had failure rates as high as 39%. These monosynaptic EPSCs in identified second-order neurons were significantly different in latency and jitter than GABAergic IPSCs (latency, 2.95 +/- 0.71 vs. 5.56 +/- 0.74 ms, mean +/- SE, P = 0.027; jitter, 42.3 +/- 6.5 vs. 416.3 +/- 94.4 micros, P = 0.013, n = 4, 6, respectively), but failure rates were similar (27.8 +/- 9.0 vs. 9.7 +/- 4.4%, P = 0.08, respectively). Such results suggest that jitter and not absolute latency or failure rate is the most reliable discriminator of mono- versus polysynaptic pathways. The results suggest that brain stem sensory pathways may differ in their principles of integration compared with cortical models and that this importantly impacts synaptic performance. The unique performance properties of the sensory-NTS pathway may reflect stronger axosomatic synaptic processing in brain stem compared with dendritically weighted models typical in cortical structures and thus may reflect very different strategies of spatio-temporal integration in this NTS region and for autonomic regulation.     

Evoked potential changes and neuropsychological performance in Parkinson's disease

Auditory brainstem responses (ABRs) and long latency exogenous and endogenous auditory evoked potentials (EPs) were investigated in 16 patients with Parkinson's disease and 11 control subjects. Parkinson's disease patients were impaired on mental status testing. While ABRs and the N1 component of the auditory EP were of normal latency in Parkinson patients, the endogenous components, N2 and P3, were prolonged. Prolongation of P3 latency in Parkinson's disease correlated with mental status decline, but not with severity of motoric disturbance. Thirteen PD patients also received neuropsychological evaluation. P3 latency was correlated with tests requiring learning or mental manipulation of information, but not with measures of verbal performance, immediate memory, or depression. P3 latency prolongation appears to have a selective relationship to intellectual changes in PD, and may be most sensitive to deficits requiring significant cognitive effort.     

Central Nervous System Relapse in Adults with Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n = 8; combined bone marrow and CNS relapse, n = 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P = .002), and pretransplantation CNS involvement was the only risk factor for post-transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P = .10) and without previous CNS involvement (P = .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.     

Correlation between cognitive capacity screening examination and cognitive evoked potential in alcohol-dependent patients

The aim of this study was to verify the significance of cognitive evoked potentials and the correlation between the auditory event-related potential and the Cognitive Capacity Screening Examination (CCSE) in alcohol dependent patients. The P300 studies using an auditory paradigm were performed on 25 alcohol dependent patients, and then the results were compared with score of the CCSE. 1) The latencies of the P300 were significantly prolonged in the patient group compared with the control group, and the scores of CCSE were significantly reduced in the patient group compared with the control group (p < 0.05). 2) There were significant negative correlation between P300 latency and scores of the CCSE (p < 0.05, r= -0.774). 3) There were no significant correlation between P300 latency and the total amount of ethanol ingestion (p > 0.05). 4) There was significant reliability in P300 latency study (alpha=0.9771). These findings suggest that the latency of P300 may be useful as a clinical electrodiagnostic measurement that can objectively reflect cognitive dysfunction in alcohol dependent patients, and it can be used as a quantitative analysis of cognitive dysfunction even for early asymptomatic alcohol dependent patients.     

Achievement and Intelligence Test-Retest Performance in Pediatric Cancer Patients at Diagnosis and One Year Later

Intellectual, achievement, and behavior evaluations were completedat diagnosis and 1 year later on 16 leukemic (ALL) and 17 solidtumor (ST) patients between 5 and 16 years of age at diagnosis.Rank order correlations between change in psychometric performanceand amount of chemotherapy received were computed for the ALLand ST groups separately. The number of significant correlationsbetween chemotherapy and change in psychometric data did notexceed chance expectations. There were no significant changesin behavior ratings over time for either the ALL or ST patients.Children with ALL younger than 8 years when diagnosed declinedin word recognition, Performance IQ and Full-scale IQ. Similarbut nonsignificant declines were observed in five young ST patients.Both ALL and ST patients over age 8 years when diagnosed hadnonsignificant changes in achievement and IQ performance. Largenegative V-P scores were noted in younger ST patients and ALLpatients of all ages both at diagnosis and 1 year later.     

气功锻炼辅助治疗对帕金森病患者事件相关电位的影响

目的：观察帕金森病人气功辅助治疗前后事件相关电位（ＥＲＰ）的变化。方法：对３３例药物治疗中期的帕金森病人作气功辅助治疗３个月,观察治疗前后的听觉ＥＲＰ的Ｐ３００,并与正常对照组２４例比较。结果：帕金森病人ＥＲＰ与对照组存在多指标差异,以Ｐ３潜伏期延长为甚,气功锻炼后其Ｎ２、Ｐ３潜伏期缩短,与对照组比较无显著性差异;同时临床症状也获得改善。结论：帕金森病人有认知功能受损,气功辅助治疗可使其获得改善或恢复。     

The effect of D-amphetamine, clonidine, and yohimbine on human information processing

Twelve subjects were tested with D-amphetamine, yohimbine, clonidine, and a placebo on a task with two levels of stimulus and two levels of response complexity. The purpose of this study was to test the hypothesis that noradrenergic drugs affect early stimulus processes. D-amphetamine speeded reaction time (RT), clonidine slowed it, and yohimbine had no effect. D-amphetamine and yohimbine decreased N1 latency and clonidine increased it. D-amphetamine and yohimbine decreased P3 latency and clonidine increased it but, in each case, only when latency estimates were based on single trials, not on averages. D-amphetamine's effect on RT, not P3, as measured by the average, is consistent with previous results. Single trial measures appear more sensitive. Speeding of N1 and single-trial P3 data indicate that noradrenergic drugs affect processing of early (visual) information. D-amphetamine's speeding of single-trial P3 estimates was attributed to its noradrenergic actions. Yohimbine's speeding of P3 without changing RT is consistent with neural net (parallel) simulations but not with a serial model. These findings support the assumption that different neurotransmitters modulate specific cognitive processes.     

Gender Differences in Pattern Reversal Evoked Potentials in Normal Elderly

Pattern reversal evoked potentials (PREPs) were recorded in 51 normal elderly subjects (27 males. 24 females). Elderly females had shorter P100 and N150 latencies, greater P100-N150 amplitudes, and higher noise power than elderly males. The N150 latency differences were significant even when P100 latency effects were partialled out statistically. Gender differences in P100-N150 amplitude Mere independent of both noise power and PREP latency measures. These results provide evidence that, in the elderly, 1) gender differences in PREP amplitude reflect factors specific to CNS processing of visual stimuli rather than global CNS anatomic or physiological factors, 2) gender differences in P100 latency reported in younger groups are also present in the elderly, and 3) there are separable factors underlying gender differences in N150 and P100 latencies in the elderly.     

The relationship of age and cardiovascular fitness to cognitive and motor processes

Older and younger aerobically trained and sedentary adults participated in an S1-S2-S3 paradigm designed to elicit event-related potential (ERP) and behavioral responses to determine the influence of cardiovascular fitness on cognitive and motor processes. The paradigm provided warning (S1) as to the difficulty level of an upcoming decision task (S2). Participants had to decide the taller of two bars on presentation of S2 but hold their response until S3, to which they indicated their choice motorically. Results revealed age-related differences for ERP measures as older participants showed increased amplitude of the stimulus preceding negativity (SPN) prior to S2, and longer latencies and equipotentiality of P3 in response to S2. Fitness effects were also observed for the contingent negative variation (CNV) with decreased amplitude for fit relative to sedentary individuals. Age interacted with fitness for P3 latency to S2 as older sedentary individuals showed the longest latency followed by older fit and both younger groups. No significant group differences were observed for reaction time (RT) to S3. Therefore, physical fitness is associated with attenuation of cognitive decline in older individuals and greater economy of motor preparation for both young and older participants.     

太极拳对遗忘型轻度认知功能障碍患者认知功能影响的研究

目的 探讨太极拳对遗忘型轻度认知功能障碍（a-MCI）患者认知功能的影响。方法 将62例a-MCI患者随机分为对照组和观察组,每组31例。对照组患者接受常规健康教育,治疗组在此基础上接受太极拳干预治疗。两组患者分别在治疗前、治疗后6个月采用简明精神状态检查量表（MMSE）、蒙特利尔认知评估量表（MoCA）以及事件相关电位P300对患者认知功能评价。结果 对照组治疗前后MMSE、MoCA评分分别比较,差异无统计学意义（P＞0.05）;治疗后观察组MMSE、MoCA评分分别为（25.12±4.17）分、     

1,25-二羟基维生素D3对脑室内注射链脲佐菌素大鼠认知功能和脑内cleaved-caspase-3表达的影响

目的 观察1,25-二羟基维生素D3对双侧脑室内注射链脲佐菌素(ICV-STZ)诱导阿尔茨海默病(AD)模型大鼠认识功能的影响,并探讨其作用机制.方法 36只SD大鼠随机分为3组:假手术组,模型组和治疗组.Morris水迷宫测试大鼠认知功能,比色法检测各组大鼠皮质和海马丙二醛(MDA)和谷胱甘肽(GSH)含量,免疫组织化学法检测脑内cleaved-caspase-3表达.结果 Morris水迷宫测试中,与假手术组大鼠逃逸潜伏期(秒)(10.31±2.33)比较,模型组大鼠逃逸潜伏期(36.54±4.56)显著延长,(P =0.000),治疗组(26.58±2.50)比模型组潜伏期显著缩短(P=0.003).与模型组大鼠皮质和海马MDA含量(nmol/mg)[(9.81±2.23),(5.09±0.74)]比较,治疗组大鼠皮质和海马MDA含量[(6.12±1.14),(3.77±0.41)]显著减少(P=0.001,P=0.002),与模型组大鼠皮质和海马GSH含量(g/L)[(1.57 ±0.56),(1.39±0.43)]比较,治疗组大鼠皮质和海马GSH含量[(2.98±0.52),(3.05±0.78)]显著增加(P =0.005,P=0.002).免疫组织化学染色显示,与模型组皮质和海马cleavedcaspase-3阳性细胞数[(32.47±8.22),(28.58±4.32)]比较,治疗组皮质和海马阳性细胞数[(16.85±7.31),(18.12±5.64)]显著减少(P=0.021,P=0.003).结论 1,25-二羟基维生素D3能够改善STZ诱导的大鼠认知功能障碍,其机制与改善脑内氧化应激和减少神经细胞凋亡有关.