Integrated late onset Alzheimer's disease (LOAD) susceptibility genes: Cholesterol metabolism and trafficking perspectives.

Late onset Alzheimer's disease (LOAD) is the most common type of dementia and is characterized by decreased amyloid-ß (Aß) clearance from the brain. Cholesterol regulates the production and clearance of Aß. Genome-wide association study (GWAS) suggests that at least 20 genes are associated with LOAD. The genes APOE, CLU, SORL1, PICALM, and BIN1 have a relatively high LOAD susceptibility. Additional experimental and bioinformatic approaches to integrate data from genetics, epigenetics, and molecular networks may further increase our understanding of LOAD in relation to cholesterol metabolism and trafficking.

Genetic markers for diagnosis and pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly and represents an important and increasing clinical challenge in terms of diagnosis and treatment. Mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are responsible for early-onset autosomal dominant AD. The ε4 allele of the apolipoprotein E (APOE) gene has been recognized as a major genetic risk factor for the more common, complex, late-onset AD. Fibrillar deposits by phosphorylated tau are also a key pathological feature of AD. The retromer complex also has been reported to late-onset AD. More recently, genome-wide association studies (GWASs) identified putative novel candidate genes associated with late-onset AD. Lastly, several studies showed that circulating microRNAs (miRNAs) in the cerebrospinal fluid (CSF) and blood serum of AD patients can be used as biomarkers in AD diagnosis. This review addresses the advances and challenges in determining genetic and diagnostic markers for complex AD pathogenesis.

Clinical MRI cutoff points for predicting lacunar stroke may not exist: need for a grading rather than a dichotomizing system.

BACKGROUND: Lacunar stroke has been defined as an infarct <15 mm in diameter in the presence of symptoms of lacunar syndromes. We investigated a new approach in predicting whether a deep infarct is caused by small arterial occlusion. METHODS: A total of 319 consecutive patients with acute symptomatic infarcts within the striatocapsular territory underwent diffusion-weighted imaging (DWI) and diagnostic workups, including vascular and cardiological studies. Predictors for nonlacunar mechanisms were evaluated by logistic regression analysis, with the size of infarct (1-mm increase) and stroke syndrome (traditional vs. atypical lacunar syndrome vs. cortical syndrome) graded rather than dichotomized. RESULTS: Amongst the 171 patients who did not meet the established criteria for lacunar stroke, that is, deep infarct of >or=15 mm or presenting symptoms of nontraditional lacunar syndrome, a documented etiology could not be determined in 97 (56.7%) patients. In contrast, amongst the 148 patients who met the criteria, 27 (18.2%) had nonlacunar mechanisms. Logistic regression analysis identified the variables that predicted nonlacunar stroke mechanisms with statistical significance as nontraditional lacunar syndromes (OR 2.19 for atypical lacunar syndrome, and OR 6.72 for cortical syndrome), infarct size on DWI (OR 1.05 per 1-mm increase), and unilateral multiple deep infarcts on DWI (OR 2.22, p < 0.05 in all cases). Receiver operating characteristic curves showed that discrimination power of the model derived from logistic regression analysis (grading system) was better than that of the previously established dichotomizing criterion in predicting nonlacunar mechanisms (p = 0.004). CONCLUSIONS: A clinically significant proportion of clinical MRI lacunae are associated with underlying nonlacunar mechanisms. Decisions regarding the extent of diagnostic procedures in patients with subcortical infarcts can be guided by the point value in terms of the stroke syndrome and infarct patterns, as well as the size of infarct.

Odour identification test and its relation to cardiac 123I-metaiodobenzylguanidine in patients with drug induced parkinsonism.

We investigated olfactory function and its relation to cardiac 123I-metaiodobenzylguanidine (MIBG) uptake in 15 patients with drug induced parkinsonism (DIP). The mean Cross Cultural Smell Identification (CCSI) score was significantly greater in patients with DIP than in those with Parkinson's disease (PD: 6.9 (1.6) vs 4.4 (2.2); p<0.001); however, the mean CCSI score in patients with DIP was not significantly different from controls. One patient with DIP, whose CCSI score was significantly reduced, also exhibited decreased cardiac MIBG uptake. DIP patients with CCSI scores within the normal range had normal cardiac MIBG uptake. Our study suggests that an olfactory function test may be a useful tool for detecting DIP unrelated to PD and for identifying patients with DIP who have subclinical PD.

Correlation between cardiac 123I-MIBG and odor identification in patients with Parkinson's disease and multiple system atrophy.

We investigated an association between olfaction and cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake in patients with Parkinson's disease (PD) and multiple system atrophy (MSA). There was a significant positive correlation between cardiac MIBG uptake and the Cross-Cultural Smell Identification (CCSI) score in patients with PD (r = 0.56; P = 0.003) independent of the disease duration or clinical rating of motor status. However, patients with MSA did not show a significant correlation between cardiac MIBG uptake and the CCSI score. Our findings suggest that the functional losses of the olfactory and cardiac sympathetic systems are closely coupled in PD.

Isolated continuous rhythmic involuntary tongue movements following a pontine infarct.

Isolated involuntary tongue movements are rare and poorly understood. The anatomical substrate and pathogenesis underlying involuntary tongue movements remain elusive. We describe a patient who developed isolated continuous rhythmic involuntary tongue movements after pontine infarct without evidence of hypertrophy of inferior olivary nucleus on follow-up magnetic resonance image. We discuss the rhythmic involuntary tongue movements as a prototype of involuntary hyperkinetic movement released by a central pacemaker.

Predicting the Long-Term Outcome after Subacute Stroke within the Middle Cerebral Artery Territory.

BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) score is known to be effective in predicting the likelihood of recovery after stroke. However, the baseline NIHSS score predicts long-term outcomes rather crudely because early changes in stroke scores may influence the stroke outcomes. Therefore, a precise prognostic algorithm or a cutoff point for predicting long-term outcomes based on data from serial NIHSS scores is needed. METHODS: We serially assessed 437 patients with acute symptomatic ischemic stroke within the middle cerebral artery territory who presented with nonlacunar stroke and were followed-up for at least 6 months after symptom onset. The NIHSS score was serially checked at 0, 1, 3, 7, and 14 days after admission. In all patients, the Barthel index (BI) and the modified Rankin Scale (mRS) score were checked, with a poor outcome defined as any of the following endpoints: death, modified mRS score of >3, or BI of <60. RESULTS: A marked neurological improvement or worsening (i.e., a change in the NIHSS score of at least 4) was seen in 13.5% or 5.5% of the patients, respectively, during the first 7 days after admission. About 25% of the 437 patients had poor long-term outcomes. Analysis of receiver operating characteristic curves showed that the NIHSS score at day 7 after admission was better for predicting poor long-term outcomes than was the baseline score (P=0.003). In addition, we analyzed the cutoff point of the 7th-day NIHSS score for predicting a poor outcome at 6 months after symptom onset. An NIHSS score of at least 6 at day 7 after admission predicted poor long-term outcomes with a sensitivity of 84% [95% confidence interval (CI), 76-90%], a specificity of 92% (95% CI, 88-94%), and positive and negative predictive values of 77% and 95%, respectively. A logistic regression analysis revealed that age, diffusion-weighted imaging lesion volume, stroke history, and 7th-day NIHSS score were independently associated with poor outcome. However, no score used in addition to the 7th-day NIHSS score improved the prediction of a poor outcome. CONCLUSIONS: An NIHSS score of at least 6 on day 7 after admission accurately forecasts a poor long-term outcome after stroke. Our data may be helpful in predicting the long-term prognosis as well as in making decisions regarding novel therapeutic applications in subacute-stroke trials.

Non-cardioembolic Mechanisms in Cryptogenic Stroke: Clinical and Diffusion-weighted Imaging Features.

BACKGROUND: The role of several cardiogenic risk factors, including patent foramen ovale, in patients with cryptogenic stroke has been extensively studied. However, little attention has been paid to the role of non-cardioembolic causes of cryptogenic stroke. We therefore sought to identify the characteristics of cryptogenic stroke. METHODS: We studied 832 patients with acute infarction in the middle cerebral arterial territory. We divided the patients into four subtypes: 402 with large artery atherosclerosis (LAA), 133 with cardioembolism, 182 with small arterial occlusion (SAO), and 115 with cryptogenic stroke. We compared risk factors and lesion patterns observed by diffusion-weighted imaging (DWI) between patients with cryptogenic stroke and those with stroke of other subtypes. RESULTS: Both risk factors and DWI lesion patterns differed between the cryptogenic and cardioembolic groups (P<0.05). Risk factors for cryptogenic stroke were similar to those for the LAA and SAO groups. Similarly, DWI lesion patterns for cryptogenic stroke were similar to LAA patients. Large cortical infarcts on DWI were more common in the cardioembolic group than in the LAA or cryptogenic groups (P<0.001). In contrast, deep, non-lacunar (OR 5.02; 95% CI 2.68~9.40; P<0.001) and superficial perforator infarcts (OR 2.23; 95% CI 1.08~4.59; P=0.029) were independently associated with the cryptogenic group. CONCLUSIONS: Our results indicate that non-cardioembolic causes, such as macro- and microangiopathy, are important mechanisms in the pathogenesis of cryptogenic stroke.