Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

Characterization of recovery and neuropsychological consequences of orbitofrontal lesion: A case study.

We present a case study of a patient with acquired prefrontal lesion involving mainly ventromedial and orbital structures (VM-PFD). The patient showed behavioral and emotional disturbances one year after the injury. In a follow-up examination seven years later, we evaluated her performance in tasks found theoretically to be sensitive to orbital and medial lesions. In contrast to our hypothesis, her performance was in the normal range. We suggest that a possible explanation for her magnificent recovery may include a high cognitive reserve and the specific characteristics of her injury.

The neuroanatomical basis of understanding sarcasm and its relationship to social cognition.

The authors explored the neurobiology of sarcasm and the cognitive processes underlying it by examining the performance of participants with focal lesions on tasks that required understanding of sarcasm and social cognition. Participants with prefrontal damage (n=25) showed impaired performance on the sarcasm task, whereas participants with posterior damage (n=16) and healthy controls (n=17) performed the same task without difficulty. Within the prefrontal group, right ventromedial lesions were associated with the most profound deficit in comprehending sarcasm. In addition, although the prefrontal damage was associated with deficits in theory of mind and right hemisphere damage was associated with deficits in identifying emotions, these 2 abilities were related to the ability to understand sarcasm. This suggests that the right frontal lobe mediates understanding of sarcasm by integrating affective processing with perspective taking.

Comprehensive analysis suggests simple processes underlying EEG/ERP - demonstration with the go/no-go paradigm in ADHD.

BACKGROUND: Current basic or more advanced methods for analysis of averaged EEG/ERP are based on assumptions on the underlying processes, which are not necessarily precise. NEW METHOD: In this work we present the findings of a method which obviates such assumptions and aims at a comprehensive analysis of the averaged EEG/ERP signal. RESULTS: For the sake of demonstration we chose the established go/no-go paradigm in the context of ADHD. Our analysis method characterized two spatiotemporally distinct neurophysiologic processes which underlie the sampled signal: one which may be related to attention and the other which may be more related to perception. COMPARISON WITH EXISTING METHOD(S): We show how these processes accord with and provide insight on the waveforms reported in the literature. CONCLUSIONS: Finally we suggest that application of our method on averaged EEG/ERP data sampled from other paradigms may point at a similarly parsimonious set of underlying neurophysiologic processes which underlie the signal.

Germline mutational analysis of presenilin 1 and APP genes in Jewish-Israeli individuals with familial or early-onset Alzheimer disease using denaturing gradient gel electrophoresis (DGGE).

Germ line mutations in three genes have been detected in patients with familial Alzheimer's disease (FAD) and sporadic, early onset disease: amyloid precursor protein (APP), presenilin 1 (PS-1), and presenilin 2 (PS-2). The relative proportions in which mutations in these genes occur among AD patients in Israel has not been evaluated. To that end, we screened 52 Jewish-Israeli patients with AD: 22 with sporadic, early-onset disease (below 65 years), and 30 with FAD. Mutation screen employed denaturing gradient gel electrophoresis (DGGE) of exon-specific PCRs and restriction enzyme digest. Five patients from three different families displayed mutations within the PS-1 gene: three patients of one family showed a mis-sense mutation in codon 120 (Glu 120Lys), and two other unrelated patients showed an identical mis-sense mutation in codon 318 (Glu318Gly). No patient showed an abnormal migration on DGGE (for APP) or mutant restriction digest pattern (for PS-2) genes. These data may indicate the existence of another familial Alzheimer disease (FAD) gene locus in the Israeli Jewish population.

Vascular dementia and dementia of the Alzheimer type. Cognition, ventricular size, and leuko-araiosis.

Multi-infarct dementia (MID) and dementia of the Alzheimer type (DAT) were compared with regard to ventricular size and leuko-araiosis (LA) on computed tomographic scans. Ninety-seven percent of patients with MID and 55.5% of patients with DAT had evidence of LA. The severity of LA was scored with a 0 through 4 rating system, and LA was found to be significantly more severe in patients with MID than in patients with DAT. Patients with MID, but not those with DAT, exhibited correlations between enlargement of the third and lateral ventricles and severity of cognitive impairment.

Increased sympathetic and decreased parasympathetic cardiac innervation in patients with Alzheimer's disease.

To assess whether Alzheimer's disease affects the sympathetic and parasympathetic influences on the heart rate, we used power spectrum analysis of heart rate variability derived from simple body-surface electrocardiography. We calculated the energy ratio of low- to high-frequency bands. This ratio was significantly higher in patients with Alzheimer's disease than in normal controls (upright posture, 0.41 +/- 0.21 vs 0.23 +/- 0.08). The parasympathetically mediated baroreceptor activity reflected by the energy ratio of medium- to low- and high-frequency bands was significantly depressed in patients with Alzheimer's disease (upright posture, 0.12 +/- 0.02 vs 0.07 +/- 0.03; supine posture, 0.11 +/- 0.02 vs 0.085 +/- 0.025). Compared with normal volunteer controls, patients with Alzheimer's disease manifested a relatively hypersympathetic, hypoparasympathetic state.

Spinal cord decompression sickness in sport diving.

OBJECTIVE: To summarize 16 years' experience in the diagnosis and treatment of spinal cord decompression sickness in Israel. DESIGN: The survey data were collected firsthand by physicians trained in underwater diving medicine. SETTING: The Israeli Naval Medical Institute, Israel's national hyperbaric referral center. PATIENTS: Sixty-eight sport divers diagnosed as having spinal cord decompression sickness. INTERVENTIONS: Hydration and 100% oxygen breathing until the patient reached the hyperbaric chamber. All patients received recompression therapy on US Navy treatment tables using oxygen, except for six who were treated by Comex Treatment Table CX-30, which uses helium in addition to oxygen. MAIN OUTCOME MEASURES: Neurological examination after the completion of recompression therapy. RESULTS: Forty-one percent of the dives were performed within the decompression limits of the US Navy standard decompression tables. Risk factors were fatigue, circumstances suggesting dehydration, and extreme physical effort. The most common presenting symptoms were paresthesias, weakness of the legs, lower back pain, or abdominal pain. Full recovery was achieved in 79% of the patients. Spinal symptoms appeared immediately on surfacing in six of the eight patients who continued to have multiple neurological sequelae. CONCLUSIONS: United States Navy air decompression tables appear not to be completely safe for sport divers. Even mild spinal symptoms identified on surfacing should be treated vigorously. High-pressure oxygen-helium therapy seems to be a promising alternative in cases of severe spinal cord decompression sickness.

Two-dimensional tracing and tracking in patients with Parkinson's disease.

We investigated the execution of two-dimensional, visually guided hand movements in patients with Parkinson's disease (PD) and in control subjects. Testing involved moving an unseen handle along a straight line or a sinusoidal path over a horizontally placed digitizing tablet. The path was displayed on a computer screen together with a pointer that represented the handle's location. The size of all video displays corresponded, with a 1:1 ratio, to the actual movements. We used the following tests. (1) Tracing, in which each subject was asked to move the pointer over the entire path, from left to right, with no speed requirements. (2) Tracking along a displayed path: a small circle moved along the path at a speed of 4, 7, or 10 mm/sec. The subject was asked to maintain the pointer inside the circle throughout its movement. When missed, the circle stopped moving until the pointer was again brought inside it. (3) Tracking along an unseen path: same as (2), except that the path was not displayed. Analysis of movement accuracy and of movement kinematics revealed that the patient's ability to control the direction of hand movement was impaired and that this impairment was evident in tracing as well as in tracking, was greater for sinusoidal than for straight-movement paths, and was independent of movement speed.

Sleep-wake cycles in multi-infarct dementia and dementia of the Alzheimer type.

We monitored by actigraphs minute-by-minute activity of 10 patients with multi-infarct dementia (MID), 15 patients with dementia of the Alzheimer type (DAT), and 11 control volunteers for eight consecutive 24-hour periods to assess sleep-wake cycles and sleep quality. MID patients had disrupted sleep-wake cycles associated with decreased sleep quality. In contrast, ambulatory DAT patients maintained a relatively normal sleep-wake cycle that did not differ significantly from controls. There was no correlation between the severity of intellectual deterioration and the degree of sleep-wake cycle disintegration in either group of dementia patients.

SPECT diagnosis of Creutzfeld-Jacob disease.

SPECT with 99mTc-HMPAO was performed on a 65-yr-old patient with Creutzfeld-Jacob disease. Cerebral blood flow was heterogeneously decreased throughout the brain, differing from the pattern observed in other common types of dementia. These results suggest that HMPAO-SPECT may provide useful information in the differential diagnosis of dementia, specifically when Creutzfeld-Jacob disease is suspected.

[Visual hemineglect as presenting symptom of right parietal tumors].

4 patients with malignant right parietal brain tumors (2 with gliomas and 2 with metastases) presented with difficulties in driving due to visual hemineglect, thought at first to be due to absent-mindedness or forgetfulness. Visual neglect is one aspect of the syndrome of unilateral neglect, which is a selective disturbance in the internal representation of the body image and processing of information from the extrapersonal space. The cerebral mechanisms underlying the phenomenon are reviewed.

Introducing a novel approach of network oriented analysis of ERPs, demonstrated on adult attention deficit hyperactivity disorder.

OBJECTIVE: Introducing a network-oriented analysis method (brain network activation [BNA]) of event related potential (ERP) activities and evaluating its value in the identification and severity-grading of adult ADHD patients. METHODS: Spatio-temporal interrelations and synchronicity of multi-sited ERP activity peaks were extracted in a group of 13 ADHD patients and 13 control subjects for the No-go stimulus in a Go/No-go task. Participants were scored by cross-validation against the most discriminative ensuing group patterns and scores were correlated to neuropsychological evaluation scores. RESULTS: A distinct frontal-central-parietal pattern in the delta frequency range, dominant at the P3 latency, was unraveled in controls, while central activity in the theta and alpha frequency ranges predominated in the ADHD pattern, involving early ERP components (P1-N1-P2-N2). Cross-validation based on this analysis yielded 92% specificity and 84% sensitivity and individual scores correlated well with behavioral assessments. CONCLUSIONS: These results suggest that the ADHD group was more characterized by the process of exerting attention in the early monitoring stages of the No-go signal while the controls were more characterized by the process of inhibiting the response to that signal. SIGNIFICANCE: The BNA method may provide both diagnostic and drug development tools for use in diverse neurological disorders.

The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers.

OBJECTIVE: In view of the fact that cancer patterns in patients with Parkinson disease (PD) differ from the general population, we aimed to verify whether patients with PD with LRRK2 mutations have an increased risk for particular cancer types. METHODS: In this cross-sectional study, eligible consenting Jewish patients with PD were genotyped for the predominant LRRK2 G2019S mutation. Oncologic data were obtained by personal interview and reviewing patients' files. Stepwise logistic regression was applied to model the probability of cancer occurrence in carriers vs noncarriers. RESULTS: Overall, 79/490 (16.1%) genotyped patients carried the G2019S mutation. Seventy-seven (16%) were diagnosed with cancer; of those, 67 (14%) with a non-skin cancer. Eighteen (23%) carriers vs 49 (12%) noncarriers had a non-skin cancer (p = 0.01, odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.19-3.99). A significant ethnicity effect was noted (p = 0.045, OR = 1.84, 95% CI 1.02-3.34). Among Ashkenazi patients, age and LRRK2 emerged as significant using stepwise logistic regression including age, gender, and LRRK2 status as explanatory variables. The OR for LRRK2 mutation carriers adjusted for age was 3.38 (95% CI 1.64-6.97, p = 0.0009). CONCLUSIONS: Ashkenazi Jewish patients with PD who harbor the G2019S LRRK2 mutation are more likely to have a concomitant non-skin cancer than noncarriers.

The origins of originality: the neural bases of creative thinking and originality.

Although creativity has been related to prefrontal activity, recent neurological case studies postulate that patients who have left frontal and temporal degeneration involving deterioration of language abilities may actually develop de novo artistic abilities. In this study, we propose a neural and cognitive model according to which a balance between the two hemispheres affects a major aspect of creative cognition, namely, originality. In order to examine the neural basis of originality, that is, the ability to produce statistically infrequent ideas, patients with localized lesions in the medial prefrontal cortex (mPFC), inferior frontal gyrus (IFG), and posterior parietal and temporal cortex (PC), were assessed by two tasks involving divergent thinking and originality. Results indicate that lesions in the mPFC involved the most profound impairment in originality. Furthermore, precise anatomical mapping of lesions indicated that while the extent of lesion in the right mPFC was associated with impaired originality, lesions in the left PC were associated with somewhat elevated levels of originality. A positive correlation between creativity scores and left PC lesions indicated that the larger the lesion is in this area the greater the originality. On the other hand, a negative correlation was observed between originality scores and lesions in the right mPFC. It is concluded that the right mPFC is part of a right fronto-parietal network which is responsible for producing original ideas. It is possible that more linear cognitive processing such as language, mediated by left hemisphere structures interferes with creative cognition. Therefore, lesions in the left hemisphere may be associated with elevated levels of originality.

Impaired "affective theory of mind" is associated with right ventromedial prefrontal damage.

OBJECTIVE: To examine the hypothesis that patients with ventromedial (VM) frontal lesions are impaired in the affective rather than cognitive facets of theory of mind (ToM). BACKGROUND: Prefrontal brain damage may result in impaired social behavior, especially when the damage involves the orbitofrontal/VM prefrontal cortex (PFC). It has been previously suggested that deficits in ToM may account for such aberrant behavior. However, inconsistent results have been reported, and different regions within the frontal cortex have been associated with ToM impairment. METHOD: The performance of 26 patients with localized lesions in the PFC was compared with responses of 13 patients with posterior lesions and 13 normal control subjects. Three ToM tasks differing in the level of emotional processing involved were used: second-order false belief task, understanding ironic utterances, and identifying social faux pas. RESULTS AND CONCLUSIONS: The results indicated that patients with VM (but not dorsolateral) prefrontal lesions were significantly impaired in irony and faux pas but not in second-order false belief as compared with patients with posterior lesions and normal control subjects. Lesions in the right VM area were associated with the most severe ToM deficit. These results are discussed in terms of the cognitive and affective facets of "mind-reading" processes mediated by the VM cortex.

The neural correlates of understanding the other's distress: a positron emission tomography investigation of accurate empathy.

The purpose of the present study was to assess the relationship between brain metabolism and empathic response. Six right-handed healthy volunteers were scanned with PET and fluorodeoxyglucose twice: during an interview about neutral story themes and during an empathic response eliciting interview about a story of a character in distress. Metabolic values in the medial and superior frontal gyrus, occipitotemporal cortices, thalamus and the cerebellum were higher during empathic response than during the neutral theme interview. Furthermore, the subjects' empathy scores were positively correlated with metabolism in the medial aspects of the superior frontal gyrus. Our results suggest that empathy consists of both affective and cognitive components and hence may involve cortices that mediate simulation of emotional processing and mental state attribution.