Alteraciones reversibles en los núcleos dentados y atrofia cerebral de rápida instauración debido a neurotoxicidad por litio / Reversible alterations in the dentate nuclei and rapid-onset cerebral atrophy due to neurotoxicity caused by lithium

Introducción. El tratamiento con litio puede ocasionar diversos efectos adversos neurológicos, incluso con niveles terapéuticos. Caso clínico. Mujer de 49 años, con trastorno bipolar y depresión, en tratamiento con litio, antidepresivos y antipsicóticos, que ingresó por un cuadro de alucinaciones visuales con una litemia elevada de 2,1 mEq/L (rango terapéutico: 0,6-1,2 mEq/L). Progresó a una encefalopatía grave que requirió asistencia respiratoria en la unidad de cuidados intensivos. La resonancia magnética cerebral inicial mostró una hiperintensidad simétrica bilateral reversible en los núcleos dentados en las secuencias T2 y T2-FLAIR. A lo largo de los meses posteriores desarrolló de forma progresiva un síndrome pancerebeloso con evidencia de una marcada pérdida de volumen bilateral en el cerebelo, sobre todo a expensas del vermis, que se acompañó clínicamente de un síndrome cerebeloso permanente e invalidante. Conclusiones. Aunque el tratamiento con litio ocasiona efectos adversos neurológicos variados, éstos suelen ser reversibles. Puede dar lugar a secuelas permanentes e incapacitantes, como la paciente descrita, con una atrofia cerebelosa marcada y progresiva, acompañada de secuelas permanentes en forma de síndrome cerebeloso invalidante. La neurotoxicidad cerebelosa del litio debe considerarse en el amplio diagnóstico diferencial que representa la ataxia cerebelosa del adulto (AU)

Introduction. Treatment with lithium can cause several neurological side effects, even at therapeutic levels. Case report. We report the case of a 49-year-old woman, with bipolar disorder and depression, undergoing treatment with lithium, antidepressants and antipsychotics, who was admitted to hospital due to a clinical picture of visual hallucinations with an elevated lithaemia of 2.1 mEq/L (therapeutic range: 0.6-1.2 mEq/L). The patient developed a severe encephalopathy that required the use of assisted ventilation in the intensive care unit. Initial magnetic resonance imaging showed a reversible bilateral symmetrical hyperintensity in the dentate nuclei in T2 and T2-FLAIR sequences. Over the following months she gradually developed a pancerebellar syndrome with evidence of a marked loss of bilateral volume in the cerebellum, above all at the expense of the vermis, which was accompanied by a permanent and disabling cerebellar syndrome. Conclusions. Although treatment with lithium can cause a variety of neurological side effects, they are usually reversible. However, they occasionally give rise to permanent and disabling sequelae, as in the case of the patient reported here, with a marked and progressive cerebellar atrophy, accompanied by permanent sequelae in the form of a disabling cerebellar syndrome. The cerebellar neurotoxicity of lithium must be taken into account in the broad differential diagnosis of cerebellar ataxia in adults (AU)

Improving functional disability and cognition in Parkinson disease: randomized controlled trial.

OBJECTIVES: To examine the efficacy of an integrative cognitive training program (REHACOP) to improve cognition, clinical symptoms, and functional disability of patients with Parkinson disease (PD). METHODS: Forty-two patients diagnosed with PD in Hoehn & Yahr stages 1 to 3 were randomly assigned to either the cognitive training group (REHACOP) or the control group (occupational activities) for 3 months (3 sessions, 60 min/wk). Primary outcomes were change on processing speed, verbal memory, visual memory, executive functioning, and theory of mind. Secondary outcomes included changes on neuropsychiatric symptoms, depression, apathy, and functional disability. The trial was registered with clinicaltrials.gov (NCT02118480). RESULTS: No baseline group differences were found. Bootstrapped analysis of variance results showed significant differences in the mean change scores between the REHACOP group and control group in processing speed (0.13 [SE = 0.07] vs -0.15 [SE = 0.09], p = 0.025), visual memory (0.10 [SE = 0.10] vs -0.24 [SE = 0.09], p = 0.011), theory of mind (1.00 [SE = 0.37] vs -0.27 [SE = 0.29], p = 0.013), and functional disability (-5.15 [SE = 1.35] vs 0.53 [SE = 1.49], p = 0.012). CONCLUSIONS: Patients with PD receiving cognitive training with REHACOP demonstrated statistically significant and clinically meaningful changes in processing speed, visual memory, theory of mind, and functional disability. Future studies should consider the long-term effect of this type of intervention. These findings support the integration of cognitive training into the standard of care for patients with PD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with PD, an integrative cognitive training program improves processing speed, visual memory, theory of mind, and functional disability.

Nonmotor symptoms in LRRK2 G2019S associated Parkinson's disease.

BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. CONCLUSION: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD.

The source of the memory impairment in Parkinson's disease: acquisition versus retrieval.

Memory deficits are common in persons with Parkinson's disease (PD) even without the presence of a frank dementia. These memory deficits have traditionally been attributed to inability of patients to retrieve information from long-term memory, referred to as the "retrieval failure hypothesis." However, some studies additionally document problems in recognition memory, noted to be inconsistent with the retrieval failure hypothesis. Given the neuroanatomical abnormalities observed in the hippocampus of PD patients and the role of the hippocampus in learning new information, the current study was designed to specifically examine learning abilities in a nondemented PD sample through the application of a learning paradigm, the Open Trial Selective Reminding Test. We examined 27 patients with PD without dementia and 27 age-, gender-, and education-matched healthy controls (HCs) with a neuropsychological test battery designed to assess new learning and memory. Results indicated a significant difference between the groups in terms of their ability to learn a list of 10 semantically related words. However, once the groups were equated on learning abilities, no significant difference was noted between the PD and HC participants in recall or recognition of the newly learned material. The memory deficit observed in nondemented PD patients is thus largely the result of a deficit in learning new information. This finding should be used to guide treatment for memory deficits in persons with PD, and future research should seek to identify novel means of improving new learning in this population.

Olfaction and imaging biomarkers in premotor LRRK2 G2019S-associated Parkinson disease.

OBJECTIVE: To ascertain in a cross-sectional study whether substantia nigra (SN) echogenicity, olfaction, and dopamine transporter (DaT)-SPECT are reliable premotor biomarkers in a cohort of asymptomatic carriers of the LRRK2 G2019S mutation (AsG2019S+). METHODS: These biomarkers were evaluated in 49 AsG2019S+ patients, and we also studied olfaction and SN echogenicity in 29 patients with G2019S-associated Parkinson disease (PD-G2019S), 47 relatives who were noncarriers of the LRRK2 G2019S mutation (AsG2019S-), 50 patients with idiopathic Parkinson disease (iPD), and 50 community controls. RESULTS: Eighty-five percent of unaffected mutation carriers (AsG2019S+) showed pathologic SN hyperechogenicity, with a similar proportion observed among both PD-G2019S and iPD cases, and 41% of AsG2019S- also showing increased SN echogenicity. The proportion of hyposmic individuals was not statistically different in patients with PD-G2019S (50%) and iPD (82%), but hyposmia was significantly less common in both AsG2019S+ (26%) and AsG2019S- (28%). In AsG2019S+ cases, reduced striatal uptake in DaT-SPECT was observed in 43.7%. CONCLUSIONS: Independently of age at examination, the most frequently altered premotor biomarker in LRRK2 G2019S-associated PD was SN hyperechogenicity, whereas abnormal DaT-SPECT predominated in older, unaffected mutation carriers.

Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease.

Recent genome-wide association studies of Parkinson's disease have nominated 3 new susceptibility loci (PARK16-18) and confirmed 2 known risk genes (MAPT and SNCA) in populations of European ancestry. We sought to replicate these findings. We genotyped single-nucleotide polymorphisms in each of these genes/loci in 1445 Parkinson's disease patients and 1161 controls from northern Spain. Logistic regression was used to test for association between genotype and Parkinson's disease under an additive model, adjusting for sex, age, and site. We also performed analyses stratified by age at onset. Single-nucleotide polymorphisms in MAPT (rs1800547; P = 3.1 × 10(-4) ) and SNCA (rs356219; P = 5.5 × 10(-4) ) were significantly associated with Parkinson's disease. However, none of the markers in PARK16-18 associated with Parkinson's disease in the overall sample, or in any age stratum, with P values ranging from .09 to .88. Although our data further validate MAPT and SNCA as Parkinson's disease susceptibility genes, we failed to replicate PARK16, PARK17, and PARK18. Potential reasons for the discordance between our study and previous genome-wide association studies include effects of population structure, power, and population-specific environmental interactions. Our findings suggest that additional studies of PARK16-18 are necessary to establish the role of these loci in modifying risk for Parkinson's disease in European-derived populations. © 2011 Movement Disorder Society.

GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias.

Paroxysmal exercise-induced dyskinesias (PED) are involuntary intermittent movements triggered by prolonged physical exertion. Autosomal dominant inheritance may occur. Recently, mutations in the glucose transporter 1 (GLUT1) gene (chr. 1p35-p31.3) have been identified as a cause in some patients with autosomal dominant PED. Mutations in this gene have previously been associated with the GLUT1 deficiency syndrome. We performed mutational analysis in 10 patients with apparently sporadic PED. We identified two novel GLUT1 mutations, at least one likely to be de-novo, in two of our patients. Onset was in early childhood. One of our patients had a predating history of childhood absence epilepsy and a current history of hemiplegic migraine as well as a family history of migraine. The other patient had no other symptoms apart from PED. Brain MRI showed cerebellar atrophy in one case. Mutations in GLUT1 are one cause of apparently sporadic PED. The detection of this has important implications for treatment as ketogenic diet has been reported to be beneficial.

Interaction between HMGCR and ABCA1 cholesterol-related genes modulates Alzheimer's disease risk.

A number of studies suggest that increased cellular cholesterol levels induce high amyloid beta (Abeta) production, which is central to the pathogenesis of Alzheimer's disease (AD). In the brain, glial cells have hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) as the major rate-limiting enzyme in the novo synthesis of cholesterol, which once synthesized, is secreted via the cholesterol transporter ABCA1. Overexpression of HMGCR in concert with underexpression of ABCA1 would result in increased cholesterol accumulation, induction of Abeta production, and increased AD risk. We examined two HMGCR polymorphisms located in 5'-UTR (rs3931914) and promoter (-911, rs3761740) regions of the gene, and two ABCA1 polymorphisms (-14, rs1800977; and -477, rs2422493) located in promoter region of the gene, in a group of 325 Spanish AD patients and 383 controls. Subjects carrying both the HMGCR (5'-UTR) GG genotype and the ABCA1 (-14) TT genotype (adjusted by age, sex and APOE status OR=2.77; 95% CI=1.16-6.61; p=0.02), or the ABCA1 (-477) TT genotype (adjusted by age, sex and APOE status OR=2.07; 95% CI=1.14-3.78; p=0.02) had a higher risk of developing AD than subjects without these risk genotypes, and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. Considering synergistic effects between polymorphisms in synthesis and secretion cholesterol-related genes may help in determining the risk profile for AD.

Age-dependent association of KIBRA genetic variation and Alzheimer's disease risk.

An association between memory performance in healthy young, middle aged an elderly subjects and variability in the KIBRA gene (rs17070145) has been recently described. We analyzed this polymorphism in 391 sporadic Alzheimer's disease (AD) patients and 428 cognitively normal control subjects. The current study reveals that KIBRA (rs17070145) T allele (CT and TT genotypes) is associated with an increased risk (OR 2.89; p=0.03) for very-late-onset (after the age of 86 years) AD.

Synergistic effect of heme oxygenase-1 and tau genetic variants on Alzheimer's disease risk.

Oxidative stress plays a role in tau hyperphosphorylation and the development of neurofibrillary tangles (NFT). In Alzheimer's disease (AD) brain, accumulation of hyperphosphorylated tau in NFT is associated with the induction of heme oxygenase-1 (HO-1), a potent antioxidant that downregulates the production of tau. In a case-control study of 300 AD patients and 360 healthy controls, we examined whether the combined gene effects between HO-1 (-413, rs2071746) and tau (5' of exon 1, rs242557) polymorphisms might be responsible for susceptibility to AD. Subjects carrying both the HO-1 (-413) TT and the tau (5' of exon 1) AA genotypes had a more than 6.5-time higher risk of developing AD than subjects without these risk genotypes (OR = 6.65, 95% CI 1.12-39.29; p = 0.037). These data support a role for tau-related genes in the risk of AD.

No association of genetic variants of liver X receptor-beta with Alzheimer's disease risk.

Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

Interaction between CD14 and LXRbeta genes modulates Alzheimer's disease risk.

A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). CD14 and LXRbeta are receptors involved in the regulation of inflammatory responses of microglia in response to bacterial infection or lipopolysaccharide stimulation. In a case-control study in 266 AD patients and 273 healthy controls, we examined whether the combined gene effects between CD14 (-260) polymorphism and LXRbeta (intron 5) polymorphism might be responsible for susceptibility to AD. Subjects carrying both the CD14 (-260) C/C and the LXRbeta (intron 5) G/G genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR 0.16, 95% CI 0.04-0.67, p=0.01). These data support a role for innate immune response genes in risk for AD.

Association of genetic variants of ABCA1 with Alzheimer's disease risk.

ABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimer's disease (AD), independently or in concert with the APOE epsilon4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C-14T and C-477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C-14T polymorphism modified the risk of AD in an APOE epsilon4 allele-dependent fashion: in APOE epsilon4 carriers, homozygous for the ABCA1 -14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 -14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (-14T) in concert with the APOE epsilon4 allele.