Sex and laterality differences in parkinsonian impairment and transcranial ultrasound in never-treated schizophrenics and their first degree relatives in an Andean population

Abstract

We tested the hypothesis that loss of substantia nigra neurons in subjects at risk of schizophrenia (1), as reflected by midbrain hyperechogenicity (2) and parkinsonian motor impairment (3), is asymmetric and influenced by sex. We evaluated 62 subjects with never-treated chronic schizophrenia, 80 of their adult, unaffected first degree relatives and 62 healthy controls (matched by sex and age to the cases), part of an Andean population of Northern Argentina. Parkinsonism was scored blindly using UPDRS-3 (Unified Parkinson's Disease Rating Scale) on videotaped exams by 2 independent raters. Trancranial ultrasound was performed by an expert sonographist blind to subject condition with a 2.5 MHz transducer through a temporal bone window. Quantification of echogenic area was carried out on saved images by a different evaluator. We found a significant difference in parkinsonian motor impairment between patients, their relatives as well as controls. All three groups showed worse parkinsonism on the left side than the right, corresponding with increased echogenicity on the right substantia nigra compared with the left. Females had significantly more right echogenicity than males, and patients and unaffected relatives were significantly more echogenic than controls on that side. On the left, only female patients had significant echogenicity. Our data supports the notion that unaffected relatives of schizophrenic subjects have increased parkinsonism and concomitant brainstem abnormalities which may represent a vulnerability to the disease. Both motor and brainstem abnormalities are asymmetric and influenced by sex.

Prediction of Neurocognitive Deficits by Parkinsonian Motor Impairment in Schizophrenia: A Study in Neuroleptic-Naïve Subjects, Unaffected First-Degree Relatives and Healthy Controls From an Indigenous Population

“…8 Briefly, parkinsonism was scored blindly using the Unified Parkinson Disease Rating Scale, motor (UPDRS-3) on videotaped exams by 2 independent raters certified on its use. Items (rated on a 0 to 4 scale) include speech, facial expression, tremor, bradykinesia, akinesia, rigidity, posture and postural instability, and gait.…”

“…6 Over the past decade we have studied endophenotypes and predictors of treatment outcome in subjects with chronic schizophrenia (and therefore with stable symptoms) free of the influence of antipsychotic medications, as well as in their unaffected first-degree relatives, in the Kolla people of Jujuy (Northern Argentina). [7][8][9] This population afforded a unique opportunity to study spontaneous parkinsonism and its correlates in stable, chronic patients free of the confounding effects of antipsychotic medications, and further to assess the impact of long durations of untreated psychosis on the individuals response to medications. 10 Motor parkinsonian impairment has been well documented in first-episode, untreated patients with schizophrenia, [11][12][13][14][15] and we found it also present in subjects with chronic untreated symptoms and in their at-risk, unaffected first-degree relatives.…”

“…10 Motor parkinsonian impairment has been well documented in first-episode, untreated patients with schizophrenia, [11][12][13][14][15] and we found it also present in subjects with chronic untreated symptoms and in their at-risk, unaffected first-degree relatives. 8 In affected subjects, parkinsonism predated exposure to antipsychotic medications. Transcranial ultrasound studies of the brainstem demonstrated a relationship between increased echogenicity of the substantia nigra (SN) and motor impairment in patients with Parkinson disease.…”

“…Likewise, regarding the correlation between cell loss and hyperechogenicity has not been established because no anatomopathological studies are available, but in animal models iron deposition (and hyperechogenicity) is correlated with dopaminergic neuronal death following 6OHDA injection. 25 In schizophrenia, SN hyperechogenicity is present in neuroleptic-naive subjects, as well as in their unaffected first-degree relatives 8 ; it also correlates with the severity of parkinsonian motor impairment prior to treatment initiation 8 and susceptibility to drug-induced parkinsonism. 26 Both, hyperechogenicity and parkinsonism severity is greatest in affected cases, intermediate in unaffected relatives, and nearly absent in healthy matched controls.…”

“…26 Both, hyperechogenicity and parkinsonism severity is greatest in affected cases, intermediate in unaffected relatives, and nearly absent in healthy matched controls. 8,27 Therefore, we proposed severity of parkinsonian motor disturbances would reflect a possible pathogenic mechanism of genetic liability to the disease. 8,27,28 Since deficits in the performance of tasks that require working memory or executive function are a well-established marker of risk in unaffected relatives of subjects with schizophrenia, [29][30][31] we now tested the possibility of a causal link between such predictors.…”