Subjective cognitive dysfunction associated with drug-induced parkinsonism in schizophrenia

The authors investigated the subjective cognitive dysfunction associated with drug-induced parkinsonism (DIP) among 58 stabilized schizophrenic outpatients. Subjective cognitive dysfunction was comprehensively assessed using the Frankfurt Complaint Questionnaire (FCQ). Multivariate analysis revealed that the DIP group scored significantly higher on the total FCQ score than the non-DIP group. In phenomenological subscale scores, the DIP group had significantly higher scores on “deterioration of discrimination”, “psychomotor disorder”, and “perceptual disorder” than the non-DIP group. These results suggest that DIP is significantly associated with subjective cognitive-perceptual dysfunction, reflecting the complex nature of DIP that includes motor and cognitive aspects.     

Genotype–phenotype correlates in Taiwanese patients with early‐onset recessive parkinsonism

We screened for mutations in the PARKIN, DJ‐1, and PINK1 genes in a Taiwanese cohort (68 probands; 58 sporadic and 10 familial) with early‐onset parkinsonism (EOP, onset <50 years of age). We identified 9 patients harboring mutations in PARKIN (three compound heterozygous and six single heterozygous carriers), 3 patients with heterozygous PINK1 mutations (including two novel substitutions M341I and P209A), and no DJ‐1 mutations. Our frequencies of PARKIN (two allele mutation, 4.4%; single allele, 8.8%) and PINK1 (single heterozygous, 4.4%) mutations in Taiwanese–Chinese are similar to those in Caucasian and other Asian EOP patients. Although the role of heterozygosity of recessive genes in EOP remains to be resolved, molecular analysis and functional imaging will play a decisive role in differential diagnosis and determined therapeutic strategy. © 2008 Movement Disorder Society     

Homozygous THAP1 mutations as cause of early‐onset generalized dystonia

To identify the underlying genetic cause in a consanguineous family with apparently recessively inherited dystonia, we performed genome‐wide homozygosity mapping. This revealed 2 candidate regions including the THAP1 gene, where heterozygous mutations cause dystonia 6. A homozygous missense mutation in THAP1 (c.95T>A; p.Leu32His) was found in all 3 affected siblings. Symptoms started in childhood in the legs and became generalized within a few years. Three heterozygous mutation carriers were unaffected. Because THAP1 regulates the expression of the DYT1 gene, we used reporter gene assays to show that DYT1 expression was significantly increased for Leu32His. However, this increase was less pronounced than for other THAP1 mutations that cause dystonia in the heterozygous state. Our data suggest that homozygous THAP1 mutations cause dystonia and may be associated with a less severe dysfunction of the encoded protein compared with heterozygous disease‐causing mutations. © 2011 Movement Disorder Society     

Novel mutations in SPG11 cause hereditary spastic paraplegia associated with early‐onset levodopa‐responsive Parkinsonism

Background: Autosomal recessive hereditary spastic paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with spastic paraplegia. Methods: We describe one Italian autosomal recessive hereditary spastic paraplegia with thin corpus callosum patient who unusually presented at onset, 16 years, with parkinsonism‐like features, responsive to dopaminergic therapy. Then the clinical picture evolved and became more complex. A brain magnetic resonance imaging scan showed thin corpus callosum and hyperintense T₂‐weighted lesions in periventricular regions, and the ¹²³I‐ioflupane single‐photon emission coupled tomography was abnormal. Results: Genetic analysis detected two novel mutations, a c.3664insT variant in compound heterozygosity with a c.6331insG mutation, in SPG11. Discussion: This case confirms the high genetic and clinical heterogeneity associated with SPG11 mutations. It also offers further evidence that parkinsonism may initiate autosomal recessive hereditary spastic paraplegia with thin corpus callosum and that parkinsonian symptoms can have variable dopaminergic response in these patients. © 2011 Movement Disorder Society     

Dopamine signals and physiological origin of cognitive dysfunction in Parkinson's disease

The pathological hallmark of Parkinson's disease (PD) is the degeneration of midbrain dopamine neurons. Cognitive dysfunction is a feature of PD patients even at the early stages of the disease. Electrophysiological studies on dopamine neurons in awake animals provide contradictory accounts of the role of dopamine. These studies have established that dopamine neurons convey a unique signal associated with rewards rather than cognitive functions. Emphasizing their role in reward processing leads to difficulty in developing hypothesis as to how cognitive impairments in PD are associated with the degeneration of dopamine circuitry. A hint to resolve this contradiction came from recent electrophysiological studies reporting that dopamine neurons transmit more diverse signals than previously thought. These studies suggest that dopamine neurons are divided into at least two functional subgroups, one signaling “motivational value” and the other signaling “salience.” The former subgroup fits well with the conventional reward theory, whereas the latter subgroup has been shown to transmit signals related to salient but non‐rewarding experiences such as aversive stimulations and cognitively demanding situations. This article reviews recent advances in understanding the non‐reward functions of dopamine, and then discusses the possibility that cognitive dysfunction in PD is at least partially caused by the degeneration of the dopamine neuron subgroup signaling the salience of events in the environment. 2015 International Parkinson and Movement Disorder Society     

Combined effects of cabergoline and L-dopa on parkinsonism in MPTP-treated cynomolgus monkeys

Summary The behavioral effects of L-dopa or cabergoline alone were compared with those of the joint administration of the two drugs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity and dyskinesia. Cabergoline alone at 0.2mg/kg or less improved in a dose-dependent fashion the parkinsonism without inducing hyperactivity and dyskinesia following a single subcutaneous injection. L-dopa alone improved the parkinsonism, but induced hyperactivity and dyskinesia, depending on the dose applied. Doses required for 50% amelioration by L-dopa and cabergoline were 10 and 0.038mg/kg, s.c., respectively. With low doses (50%-amelioration doses), cabergoline or L-dopa alone improved the parkinsonism without induction of hyperactivity and dyskinesia, but the duration of action was brief. Cabergoline in combination with L-dopa was highly effective in improving motor disability without induction of hyperactivity and dyskinesia. Moreover, the duration of action was more prolonged with the coadministration than with the single administration of each drug. These findings suggest that the combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with advanced Parkinson's disease.     

TL1A promotes the postoperative cognitive dysfunction in mice through NLRP3-mediated A1 differentiation of astrocytes

Aim

We investigated the mechanism, whereby tumor necrosis factor-like ligand 1A (TL1A) mediates the A1 differentiation of astrocytes in postoperative cognitive dysfunction (POCD).

Methods

The cognitive and behavioral abilities of mice were assessed by Morris water maze and open field tests, while the levels of key A1 and A2 astrocyte factors were detected by RT-qPCR. Immunohistochemical (IHC) staining was used to examine the expression of GFAP, western blot was used to assay the levels of related proteins, and enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory cytokines.

Results

The results showed that TL1A could promote the progression of cognitive dysfunction in mice. Astrocytes differentiated into A1 phenotype, while unobvious changes were noted in astrocyte A2 biomarkers. Knockout of NLRP3 or intervention with NLRP3 inhibitor could inhibit the effect of TL1A, improving the cognitive dysfunction and suppressing the A1 differentiation.

Conclusion

Our results demonstrate that TL1A plays an important role in POCD in mice, which promotes the A1 differentiation of astrocytes through NLRP3, thereby exacerbating the progression of cognitive dysfunction.     

血清组胺与脑白质疏松症认知功能障碍的相关性

目的探讨血清组胺水平与脑白质疏松症(LA)认知功能障碍的相关性。方法本文161例,根据头颅MRI表现分为LA组131例和对照组(无LA及认知功能障碍)30例。LA中根据轻度认知功能障碍(MCI)诊断标准及临床痴呆量表筛选出MCI 71例及痴呆30例,无MCI 30例。故分为LA无MCI 30例,LA伴MCI 71例;LA伴痴呆组30例,对照组30例。分析比较4组患者血清组胺值差异情况。结果 LA无MCI组血清组胺含量较正常组高(P0.05);LA伴MCI组血清组胺含量较LA无MCI组高(P0.05);LA伴痴呆组血清组胺含量较LA伴MCI组高(P0.05)。结论 LA患者血清组胺含量高于对照组提示组胺可能参与LA的发生;LA伴痴呆患者血清组胺含量高于LA伴MCI患者,而LA伴MCI患者血清组胺含量高于LA无MCI,提示组胺可能参与LA患者认知功能障碍的发生发展,且与认知功能障碍的严重程度相关。     

Graded model of diffuse axonal injury for studying head injury‐induced cognitive dysfunction in rats

Diffuse axonal injury (DAI) plays a major role in the development of cognitive dysfunction, emotional difficulties and behavioral disturbances in patients following closed head injury, even when they have no definite abnormalities on conventional MRI. This study aimed to develop a highly controlled and reproducible model for DAI that simulates post‐traumatic cognitive dysfunction in humans. Sprague‐Dawley (SD) rats were subjected to impact acceleration head injury, using a pneumatic impact targeted to a steel disc centered onto their skull. The severity of injury was graded as three levels by adjusting the driving pressure at 60, 70 or 80 pounds per square inch. In vivo MRI was obtained 2 days post‐injury. Cognitive function was evaluated using the Morris water maze at 1 and 2 weeks post‐injury. HE staining and immunohistochemistry were performed to assess neuronal and axonal damages after 2 weeks. MRI demonstrated that this model induced no gross structural modification in the brain. The degree and duration of cognitive dysfunction were dependent on the force of impact. Histological analysis revealed the force‐dependent damage of the neurons and microtubule‐associated protein 2‐positive axons in the neocortex. Hippocampal damage was much less pronounced and was not linked to cognitive dysfunction. This is the first report that precisely evaluates the threshold of impact energy to lead to neocortical damage and cognitive dysfunction in rodents. This model would be suitable for clarifying the complex mechanisms of post‐traumatic brain damage and testing novel therapeutic approaches against post‐traumatic cognitive dysfunction due to diffuse axonal damage.