Predicting amyloid-PET and clinical conversion in apolipoprotein E ε3/ε3 non-demented individuals with multidimensional factors.

The apolipoprotein E (APOE) ε4 is a well-established risk factor of amyloid-ß (Aß) in Alzheimer's disease (AD). However, because of the high prevalence of APOE ε3, there may be a large number of people with APOE ε3/ε3 who are non-demented and have Aß pathology. There are limited studies on assessing Aß status and clinical conversion in the APOE ε3/ε3 non-demented population. Two hundred and ninety-three non-demented individuals with APOE ε3/ε3 from ADNI database were divided into Aß-positron emission tomography (Aß-PET) positivity (+) and Aß-PET negativity (-) groups using cut-off value of >1.11. Stepwise regression searched for a single or multidimensional clinical variables for predicting Aß-PET (+), and the receiver operating characteristic curve (ROC) assessed the accuracy of the predictive models. The Cox regression model explored the risk factors associated with clinical conversion to mild cognitive impairment (MCI) or AD. The results showed that the combination of sex, education, ventricle and white matter hyperintensity (WMH) volume can accurately predict Aß-PET status in cognitively normal (CN), and the combination of everyday cognition study partner total (EcogSPTotal) score, age, plasma p-tau 181 and WMH can accurately predict Aß-PET status in MCI individuals. EcogSPTotal score were independent predictors of clinical conversion to MCI or AD. The findings may provide a non-invasive and effective tool to improve the efficiency of screening Aß-PET (+), accelerate and reduce costs of AD trial recruitment in future secondary prevention trials or help to select patients at high risk of disease progression in clinical trials.

Neurofilament light as a biomarker of axonal degeneration in patients with mild cognitive impairment and Alzheimer's disease.

Cerebrospinal fluid neurofilament light and plasma neurofilament light concentrations are elevated in patients with mild cognitive impairment and Alzheimer's disease. We investigated the clinical relevance of increased neurofilament light concentrations in mild cognitive impairment and Alzheimer's disease patients. In this study, 244 subjects were divided into cognitively normal control (n = 67), stable mild cognitive impairment (n = 52), progressive mild cognitive impairment (n = 68), and Alzheimer's disease (n = 57). Linear regression examined the relationships between neurofilament light levels in cerebrospinal fluid or plasma and the diagnostic group. The relationships between neurofilament light and other biomarkers were assessed by Spearman correlation. Linear mixed-effects models were used to test cerebrospinal fluid and plasma neurofilament light as predictors of Alzheimer's disease characteristics, including cognition, cortical glucose metabolism, and brain structure. Cerebrospinal fluid and plasma neurofilament light levels were significantly elevated in Alzheimer's disease. Still, the correlations between neurofilament light and other cerebrospinal fluid biomarkers within the diagnostic groups were often not statistically significant. In addition, the diagnostic accuracy of cerebrospinal fluid and plasma neurofilament light for progressive mild cognitive impairment and Alzheimer's disease was almost the same as that of cerebrospinal fluid total tau (T-tau). It is phosphorylated tau (P-tau) and high cerebrospinal fluid. Neurofilament light predicted conversion from mild cognitive impairment to Alzheimer's disease. A high neurofilament light is related to poor cognition, low cerebral metabolism, hippocampal atrophy, and ventricular enlargement caused by Alzheimer's disease. Our work further identifies cerebrospinal fluid neurofilament light and plasma neurofilament light as biomarkers of axonal degeneration in patients with mild cognitive impairment and Alzheimer's disease.

Landmark-based spherical quasi-conformal mapping for hippocampal surface registration.

Background: The cognitive decline induced by Alzheimer's disease (AD) is closely related to changes in hippocampal structure captured by magnetic resonance imaging (MRI). To accurately analyze the morphological changes of the hippocampus induced by AD, it is necessary to establish a one-to-one surface correspondence to compare the morphological measurements across different hippocampal surfaces. However, most existing landmark-based registration methods cannot satisfy both landmark matching and diffeomorphism under large deformations. To address these challenges, we propose a landmark-based spherical registration method via quasi-conformal mapping to establish a one-to-one correspondence between different hippocampal surfaces. Methods: In our approach, we use the eigen-graph of the hippocampal surface to extract the intrinsic and unified landmarks of all the hippocampal surfaces and then realize the parameterization process from the hippocampal surface to a unit sphere according to the barycentric coordinate theory and the triangular mesh optimization algorithm. Finally, through the local stereographic projection, the alignment of the landmarks is achieved based on the quasi-conformal mapping on a two-dimensional (2D) plane under the constraints of Beltrami coefficients which can effectively control the topology distortion. Results: We verified the proposed registration method on real hippocampus data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and created AD and normal control (NC) groups. Our registration algorithm achieved an area distortion index (ADI) of 0.4362e-4±0.7800e-5 in the AD group and 0.5671e-4±0.602e-5 in the NC group, and it achieved an angle distortion index (Eangle) of 0.6407±0.0258 in the AD group and 0.6271±0.0194 in the NC group. The accuracy of support vector machine (SVM) classification for the AD vs. NC groups based on the morphological features extracted from the registered hippocampal surfaces reached 94.2%. Conclusions: This landmark-based spherical quasi-conformal mapping for hippocampal surface registration algorithm can maintain precise alignment of the landmarks and bijectivity in the presence of large deformation.

Hippocampal volume maximally modulates the relationship between subsyndromal symptomatic depression and cognitive impairment in non-demented older adults.

BACKGROUND: Subsyndromal symptomatic depression (SSD) is associated with an elevated risk of cognitive impairment in non-demented older adults. Given that hippocampal and middle temporal gyrus atrophy have been shown to cause SSD, our study aimed to investigate the effect of hippocampal volume on the association between SSD and cognitive impairment. METHODS: 338 non-demented older adults from the ADNI (Alzheimer's Disease Neuroimaging Initiative) cohort who underwent cognitive assessments, questionnaires on depressive symptoms and MRI brain were studied. SSD group is defined as a score of 1-5 based on Geriatric Depression Scale scores. We conducted causal mediation analyses to investigate the effect of hippocampal volume on cognitive performance cross-sectionally. RESULTS: The SSD group displayed lower left and right hippocampal volume (p<0.01) than the non-SSD group. SSD was linked to poorer cognition and smaller hippocampal volume. We found that hippocampal volume partially mediated the effect of SSD on cognitive performance including the global cognition and the cognitive section of Alzheimer's Disease Assessment Scale, with mediation percentages ranging from 6.45 % to 30.46 %. In addition, we found that the thickness of the left middle temporal, right entorhinal and right fusiform gyrus, brain regions linked to AD, mediate the relationship between SSD and cognition with mediation percentages ranging from 8.67 % to 21.44 %. LIMITATIONS: Our article didn't differentiate between mild cognitive impairment and normal population. CONCLUSION: The associations of SSD and cognitive impairment are linked to alterations in Alzheimer's Disease related brain regions.

Detection of Tau-PET Positivity in Clinically Diagnosed Mild Cognitive Impairment with Multidimensional Features.

BACKGROUND: The way to evaluate brain tau pathology in vivo is tau positron emission tomography (tau-PET) or cerebrospinal fluid (CSF) analysis. In the clinically diagnosed mild cognitive impairment (MCI), a proportion of tau-PET are negative. Interest in less expensive and convenient ways to detect tau pathology in Alzheimer's disease has increased due to the high cost of tau-PET and the invasiveness of lumbar puncture, which typically slows down the cost and enrollment of clinical trials. OBJECTIVE: We aimed to investigate one simple and effective method in predicting tau-PET status in MCI individuals. METHODS: The sample included 154 individuals which were dichotomized into tau-PET (+) and tau-PET (-) using a cut-off of >1.33. We used stepwise regression to select the unitary or combination of variables that best predicted tau-PET. The receiver operating characteristic curve was used to assess the accuracy of single and multiple clinical markers. RESULTS: The combined performance of three variables [Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13), Mini-Mental State Examination (MMSE), ADNI-Memory summary score (ADNI-MEM)] in neurocognitive measures demonstrated good predictive accuracy of tau-PET status [accuracy = 85.7%, area under the curve (AUC) = 0.879]. The combination of clinical markers model (APOEɛ4, neurocognitive measures and structural MRI imaging of middle temporal) had the best discriminative power (AUC = 0.946). CONCLUSION: As a noninvasive test, the combination of APOEɛ4, neurocognitive measures and structural MRI imaging of middle temporal accurately predicts tau-PET status. The finding may provide a non-invasive, cost-effective tool for clinical application in predicting tau pathology among MCI individuals.

Successful management of cerebral venous sinus thrombosis due to adenomyosis: Case reports and literature review.

OBJECTIVES: Cerebral venous sinus thrombosis (CVST) due to adenomyosis, though rare, threaten women with severe morbidity. Adenomyosis is easily overlooked in the etiological assessment of CVST. Etiological under-recognization has considerable prognostic, and therapeutic implications. The current study reports two cases of successful management of cerebral venous sinus thrombosis due to adenomyosis. MATERIALS AND METHODS: We present two young women with cerebral venous sinus thrombosis due to adenomyosis. We additionally review the literature to identify previously reported cases of stroke associated with adenomyosis. RESULTS: Except for this report, a total of 25 cases of stroke related to adenomyosis have been reported in the literature, of which only three cases are related to CVST. Through their diagnosis and treatment, we believe that early diagnosis and treatment are important for these patients with long-term illnesses. In addition, through literature review, for female stroke patients with heavy menstruation combined with anemia or carbohydrate antigen (CA) 125 elevation, the existence of adenomyosis should be vigilant and the etiological treatment should be timely targeted. CONCLUSION: Our cases illustrate the significance of the etiological identification of CVST for women with adenomyosis and serve to increase clinicians' awareness of this disabling, but sometimes treatable, condition. In CVST due to adenomyosis associated with iron deficiency anemia and/or high serum CA125 level, antithrombotic therapy and treatment for the anemia may improve the hypercoagulable state. The long-term monitoring of D-dimer levels is required.

Studying APOE ɛ4 Allele Dose Effects with a Univariate Morphometry Biomarker.

BACKGROUND: A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. OBJECTIVE: We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N = 30), heterozygotes (HT, N = 49) and non-carriers (NC, N = 61). METHODS: Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-ß (Aß) positive AD patients and Aß negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. RESULTS: The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. CONCLUSION: The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals.

GluR1 phosphorylation and persistent expression of levodopa-induced motor response alterations in the Hemi-Parkinsonian rat.

The phosphorylation of glutamate receptor 1 (GluR1) has been increasingly implicated in the formation and maintenance of plastic responses. To investigate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa treatment of parkinsonian patients, we evaluated the time course of these changes in relation to the phosphorylation of GluR1 in 6-hydroxydopamine (6-OHDA) lesioned animals. Three weeks of twice-daily levodopa administration to rats shortened the duration of the rotational responses and increased the peak turning responses, which lasted at least 7 days after withdrawal of chronic levodopa treatment. The shortened response duration and increased peak turning, resembling human wearing-off fluctuations and dyskinesia, were associated with a marked increase in Ser-845 phosphorylated GluR1 (pGluR1S845) immunoreactivity in lesioned striatum in response to levodopa treatment. The time course of changes in GluR1 phosphorylation correlated with the time course of changes in motor behavior after withdrawal of chronic levodopa therapy. Our immunostaining data showed that these changes were confined to parvalbumin-positive neurons where GluR1 are exclusively expressed. Both the altered motor response and the degree of pGluR1S845 were attenuated by the intrastriatal administration of protein kinase A (PKA) inhibitor Rp-cAMPS or GluR1 antisense oligonucleotides. The results suggest that Ser-845 GluR1 phosphorylation within parvalbumin-positive neurons contributes to the persistence of the motor response alterations produced by chronic intermittent dopaminergic stimulation.

The Effects of CSF Neurogranin and APOE ε4 on Cognition and Neuropathology in Mild Cognitive Impairment and Alzheimer's Disease.

Cerebrospinal fluid (CSF) measurements of neurogranin (Ng) have emerged as a promising biomarker for cognitive decline in mild cognitive impairment (MCI) and Alzheimer's disease (AD). The apolipoprotein E ε4 (APOE ε4) allele is by far the most consistent genetic risk factor for AD. However, it is not known whether the pathophysiological roles of Ng in MCI or AD are related to APOEε4. We stratified 250 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN) ε4 negative (CN ε4-), CN ε4 positive (CN ε4+), MCI ε4 negative (MCI ε4-), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4-), and AD ε4 positive (AD ε4+). CSF Ng levels were significantly increased in APOE ε4 carriers compared to APOE ε4 non-carriers with MCI. In addition, CSF Ng identified MCI ε4+ versus CN ε4-, but not MCI ε4- versus CN ε4-. Similarly, CSF Ng negatively correlated with Mini-Mental State Examination (MMSE) scores at baseline in the MCI ε4+ group. Our findings support the use of CSF Ng as a biomarker of synaptic pathology for AD. We propose that the roles of CSF Ng in the pathophysiology of MCI may be related to APOE ε4.

Amyloid and tau positive mild cognitive impairment: clinical and biomarker characteristics of dementia progression.

BACKGROUND: According to the amyloid, tau, neurodegeneration research framework classification, amyloid and tau positive (A+T+) mild cognitive impairment (MCI) individuals are defined as prodromal Alzheimer disease. This study was designed to compare the clinical and biomarker features between A+T+MCI individuals who progressed to progressive MCI (pMCI) and those who remained stable MCI (sMCI), and to identify relevant baseline clinical biomarker and features that could be used to predict progression to dementia within 2 years. METHODS: We stratified 197 A+T+MCI individuals into pMCI (n = 64) and sMCI (n = 133) over 2 years. Demographics and cognitive assessment scores, cerebrospinal fluid (CSF), and neuroimaging biomarkers (18F-florbetapir positron emission tomography mean standardized uptake value ratios [SUVR] and structural magnetic resonance imaging [MRI]) were compared between pMCI and sMCI at baseline, 12- and 24-month follow-up. Logistic regression models then were used to evaluate clinical baseline and biomarker features that predicted dementia progression in A+T+MCI. RESULTS: pMCI individuals had higher mean 18F-florbetapir SUVR, CSF total-tau (t-tau), and p-tau181P than those in sMCI individuals. pMCI individuals performed poorer in cognitive assessments, both global and domain specific (memory, executive, language, attention, and visuospatial skills) than sMCI. At baseline, there were significant differences in regions of interest of structural MRI between the two groups, including bilateral amygdala, hippocampus and entorhinal, bilateral inferior lateral ventricle, left superior and middle temporal, left posterior and caudal anterior cingulate (P < 0.05). Baseline CSF t-tau levels and cognitive scores of Montreal cognitive assessment, functional assessment questionnaire, and everyday cognition by the patient's study partner language domain could predict progression to dementia in A+T+MCI within 2 years. CONCLUSIONS: In future clinical trials, specific CSF and cognitive measures that predict dementia progression in A+T+MCI might be useful risk factors for assessing the risk of dementia progression.

The effect of ApoE ε 4 on clinical and structural MRI markers in prodromal Alzheimer's disease.

BACKGROUND: Apolipoprotein E (ApoE) ε 4 has been identified as the strongest genetic risk factor for Alzheimer's disease (AD). However, the importance of ApoE ε 4 on clinical and biological heterogeneity of AD is still to be determined, particularly at the prodromal stage. Here, we evaluate the association of ApoE ε 4 with clinical cognition and neuroimaging regions in mild cognitive impairment (MCI) participants based on the AT (N) system, which is increasingly essential for developing a precise assessment of AD. METHODS: We stratified 178 A+T+MCI participants (prodromal AD) into ApoE ε 4 (+) and ApoE ε 4 (-) according to ApoE genotype from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We determined Aß-positivity (A+) by the standardized uptake values ratios (SUVR) means of florbetapir-PET-AV45 (the cut-off value of 1.1) and fibrillar tau-positivity (T+) by cerebrospinal fluid (CSF) phosphorylated-tau at threonine 181 position (p-Tau) (cut-off value of 23 pg/mL). We evaluated the effect of ApoE ε 4 status on cognitive conditions and brain atrophy from structural magnetic resonance imaging (MRI) scans. A multivariate analysis of variance was used to compare the differences of cognitive scores and brain atrophy from structural MRI regions of interest (ROIs) between both groups. Furthermore, we performed a linear regression model to assess the correlation between signature ROIs of structural MRI and cognitive scores in the prodromal AD participants. RESULTS: ApoE ε 4 (+) prodromal AD participants had lower levels of CSF Aß 1-42, higher levels of t-Tau, more memory and global cognitive impairment, and faster decline of global cognition, compared to ApoE ε 4 (-) prodromal AD. ApoE ε 4 (+) prodromal AD participants had a thinner cortical thickness of bilateral entorhinal, smaller subcortical volume of the left amygdala, bilateral hippocampus, and left ventral diencephalon (DC) relative to ApoE ε 4 (-) prodromal AD. Furthermore, the cortical thickness average of bilateral entorhinal was highly correlated with memory and global cognition. CONCLUSIONS: ApoE ε 4 status in prodromal AD participants has an important effect on clinical cognitive domains. After ascertaining the ApoE ε 4 status, specific MRI regions can be correlated to the cognitive domain and will be helpful for precise assessment in prodromal AD.

Comparative effects of acute or chronic administration of levodopa to 6-OHDA-lesioned rats on the expression and phosphorylation of N-methyl-D-aspartate receptor NR1 subunits in the striatum.

N-methyl-D-aspartate receptor (NMDA) has been increasingly implicated in the formation and maintenance of various forms of behavioral and synaptic plasticity. Recent evidence has linked striatal NMDA function to the adverse effects of long-term dopaminergic treatment in Parkinson's disease. The subcellular distribution and phosphorylation of NMDA subunit, NR1, reflects NMDA receptor activity. To elucidate molecular mechanisms that underlie the persisting alterations in motor response occurring with levodopa treatment of parkinsonian patients, we evaluated the effects of unilateral nigrostriatal depletion with 6-hydroxydopamine and subsequent levodopa treatment on motor responses and NR1 alterations. Three weeks of levodopa administration to rats shortened the rotational duration and increased the peak turning responses, which lasted after withdrawal of chronic levodopa treatment. We found a significant reduction in the abundance of both phosphorylated NR1 on serine residues 890 and 896 (pNR1S890 and pNR1S896) and NR1 in the cell plasma membrane of lesioned striatum. Chronic treatment of lesioned rats with levodopa markedly upregulated pNR1S890, pNR1S896, and pNR1S897 in lesioned striatum with a concomitant normalization of the plasma membrane NR1 abundance. The magnitude of increased pNR1S890, pNR1S896, and pNR1S897 is dependent on the number of levodopa injections and is paralleled by a sensitization of the rotational response. Our data indicate that glutamate signaling is triggered during the levodopa administration. Activated NMDA receptor NR1-mediated mechanisms are involved in the persistent expression of the motor response alterations that appear during chronic levodopa therapy of parkinsonian rats and continue after treatment withdrawal.

PMS777, a new cholinesterase inhibitor with anti-platelet activated factor activity, regulates amyloid precursor protein processing in vitro.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive impairment of memory and cognition. Previous data have shown that beta-amyloid (Abeta) cascade plays a central role in AD pathophysiology and thus drugs regulate amyloid precursor protein (APP) metabolism may have therapeutic potential. Here the effects of PMS777, a new cholinesterase inhibitor with anti-platelet activated factor activity, on APP processing were investigated. Using SH-SY5Y(APP695) cells, it showed that PMS777 treatment caused significant decreased secretion of sAPPalpha into the conditioned media without affecting cellular holoAPP synthesis. When PC12 cells were incubated with PMS777, the same effect was observed. The data also indicated that 10 muM PMS777 incubation decreased the release of Abeta42 into the cell media as compared with vehicle group in SH-SY5Y(APP695) cells. Pretreatment of cells with M-receptor scopolamine antagonized the decreased secretion of sAPPalpha induced by PMS777, but N-receptor alpha-bungarotoxin pretreatment did not have such an effect. These results indicated that PMS777 could modulate APP processing in vitro and that decreasing Abeta generation might demonstrate its therapeutic potential in AD.

Tat-Src reduced NR2B tyrosine phosphorylation and its interaction with NR2B in levodopa-induced dyskinetic rats model.

Augmented function of N-methyl-d-aspartate receptor subunit 2B (NR2B) and Src protein tyrosine kinase have been demonstrated to get involved in the pathological mechanisms of dyskinesia. In view of functional interactions between NR2B and Src, we investigated the effects of uncoupling NR2B and Src interactions on dyskinesia by using the Src-derived interfering peptide (Tat-Src). In the present study, valid 6-hydroxydopamine-lesioned parkinsonian rats were treated with levodopa intraperitoneally for 22 days to induce dyskinetic rats model. On day 23, dyskinetic rats received either Tat-Src or Tat-sSrc or vehicle with each levodopa dose. The data showed that in dyskinetic rats model intraperitoneal microinjection of Tat-Src improved dyskinetic behaviors and decreased NR2B tyrosine phosphorylation and the interactions of Src with NR2B induced by chronic levodopa treatment. Besides, Tat-Src also attenuated S-nitrosylation (SNO-Src) and the autophosphorylation (p-Src) of Src, which catalyzed NR2B phosphorylation. These findings suggest that targeting NR2B/Src complexes can be one potential treatment for dyskinesia in Parkinson's disease.

Headache Secondary to Isolated Sphenoid Sinus Fungus Ball: Retrospective Analysis of 6 Cases First Diagnosed in the Neurology Department.

Fungal sphenoid sinusitis is easily misdiagnosed in clinic, particularly for patients with normal immunological status. Due to the anatomic characteristics of sphenoid sinus, patients presented with various nonspecific symptoms and complications. Headache is the most common presentation, but location of headache is not fixed. We intended to analyze 6 cases of headache secondary to the isolated sphenoid sinus fungus ball (SSFB) which were first diagnosed in the Neurology Department. There was significant female predominance with mean ages of 55 years. They had repeatedly headache history from months to years. The headache was unilateral and usually on the side of lesions. Medication of pain relievers worked well in the beginning of SSFB, but not in the late stage of disease. Notably, all patients did not present positive nervous systemic signs. A preoperative computed tomography (CT) scan or magnetic resonance imaging (MRI) demonstrated the inflammation in sphenoid sinus. Some cases showed calcification in soft tissue or bone lesions of sinus wall. All of 6 patients undertook transnasal endoscopic sphenoidotomy without antifungal therapy after operation. Characteristic fungus ball (FB) was detected after histopathological examination. No headache recurrence was found after average 15.5 months follow-up. Our results suggested that transnasal endoscopic sphenoidotomy is the treatment of choice to remove the FB in sphenoid sinus with a low rate of morbidity and recurrence.

CSF Aß1-42 level is associated with cognitive decline in early Parkinson's disease with rapid eye movement sleep behavior disorder.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) is associated with cognitive decline in early Parkinson's disease (PD). However, the underlyling basis for this association remains unclear. METHODS: Parkinson's Progression Marker's Initiative (PPMI) subjects underwent baseline RBD testing with RBD sleep questionnaire (RBDSQ). Serial assessments included measures of motor symptoms, non-motor symptoms (NMS), neuropsychological assessment, blood and cerebrospinal fluid (CSF) biomarkers. Up to three years follow-up data were included. We stratified early PD subjects into PD with RBD (RBDSQ score > 5) and PD without RBD groups. Then, we evaluated baseline biomarkers in each group as a predictor of cognitive decline using Montreal Cognitive Assessment (MoCA) score changes over three years in regression models. RESULTS: Four hundred twenty-three PD subjects were enrolled at baseline, and a total of 350 PD subjects had completed 3 years of study follow-up with completely serial assessments. We found that at baseline, only CSF ß-amyloid 1-42 (Aß1-42) was significantly lower in PD subjects with RBD. On three years follow-up analysis, PD subjects with RBD were more likely to develop incident mild cognitive impairment (MCI) and presented greater cognitive decline in MoCA score. Lower baseline CSF Aß1-42 predicted cognitive decline over 3 years only in PD subjects with RBD (ß = - 0.03, P = 0.003). A significant interaction between Aß1-42 and the 2 groups confirmed that this effect was indeed higher in PD with RBD than the other individual (ß = - 2.85, P = 0.014). CONCLUSION: These findings indicate that CSF Aß1-42 level is associated with global cognitive decline in early PD with RBD. The addition of CSF Aß1-42 to RBD testing increase the likelihood of identifying those at high risk for cognitive decline in early PD.

The structural MRI markers and cognitive decline in prodromal Alzheimer's disease: a 2-year longitudinal study.

BACKGROUND: Being clinically diagnosed with a mild cognitive impairment (MCI) due to Alzheimer's disease (AD) is widely studied. Yet, the clinical and structural neuroimaging characteristics for prodromal AD, which are defined as A+T+MCI based on the AT (N) system are still highly desirable. This study evaluates the differences of the cognitive assessments and structural magnetic resonance imaging (MRI) between the early MCI (EMCI) and late MCI (LMCI) participants based on the AT (N) system. The potential clinical value of the structural MRI as a predictor of cognitive decline during follow-up in prodromal AD is further investigated. METHODS: A total of 406 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were chosen and dichotomized into EMCI and LMCI groups according to the Second Edition (Logical Memory II) Wechsler Memory Scale. Multiple markers' data was collected, including age, sex, years of education, ApoE4 status, cerebrospinal fluid (CSF) biomarkers, standardized uptake values ratios (SUVR) means of florbetapir-PET-AV45, cognitive measures, and structural MRI. We chose 197 A+T+MCI participants (prodromal AD) with positive biomarkers of Aß plaques (labeled "A") and fibrillar tau (labeled "T"). We diagnosed Aß plaques positive by the SUVR means of florbetapir-PET-AV45 (cut-off >1.1) and fibrillar tau positive by CSF phosphorylated-tau at threonine 181 (p-tau) (cut-off >23 pg/mL). The differences of cognitive assessments and regions of interest (ROIs) defined on the MRI template between EMCI and LMCI were compared. Furthermore, the potential clinical utility of the MRI as the predictor of cognitive decline in prodromal AD was evaluated by investigating the relationship between baseline MRI markers and cognition decline at the follow-up period, through a linear regression model. RESULTS: The LMCI participants had a significantly more amyloid burden and CSF levels of total t-tau than the EMCI participants. The LMCI participants scored a lower result than the EMCI group in the global cognition scales and subscales which included tests for memory, delayed recall memory, executive function, language, attention and visuospatial skills. The cognition levels declined faster in the LMCI participants during the 12- and 24-month follow-up. There were significant differences in ROIs on the structural MRI between the two groups, including a bilateral entorhinal, a bilateral hippocampus, a bilateral amygdala, a bilateral lateral ventricle and cingulate, a corpus callosum, and a left temporal. The thickness average of the left entorhinal, the left middle temporal, the left superior temporal, and the right isthmus cingulate was a main contributor to the decreased global cognition levels. The thickness average of the left superior temporal and bilateral entorhinal played a key role in the memory domain decline. The thickness average of the left middle temporal, and the right isthmus cingulate was significantly associated with an executive function decline. CONCLUSIONS: Based on the AT (N) system, surely, both the EMCI and LMCI diagnoses presented significant differences in multiple cognition domains. Signature ROIs from the structural MRI tests had correlated a cognitive decline, and could act as one potential predictive marker.

Characterizing biomarker features of cognitively normal individuals with ventriculomegaly.

INTRODUCTION: The clinical significance of ventriculomegaly in cognitively normal elderly individuals remains unclear. METHODS: We selected cognitively normal individuals (n = 425) from the Alzheimer's Disease Neuroimaging Initiative database and calculated Evans index (EI) based on the ratio of the frontal horn and skull diameter. We defined ventriculomegaly as EI ≥ 0.30, and the participants were stratified into EI ≥ 0.30 group and EI < 0.30 group. Neuropsychological, imaging, and fluid biomarker profiles between the two groups were then compared using regression models. RESULTS: A total of 96 (22.5%) individuals who had ventriculomegaly performed worse on the cognitive tests; showed smaller hippocampal volume but larger caudate, cingulate, and paracentral gyrus volumes; and displayed lower positron emission tomography [18F]fluorodeoxyglucose standardized uptake value ratio but higher amyloid burden represented by higher [18F]florbetapir standardized uptake value ratio and lower cerebrospinal fluid amyloid ß 1-42 levels compared to those without ventriculomegaly. DISCUSSION: Asymptomatic ventriculomegaly might be an early imaging signature of preclinical Alzheimer's disease and/or normal pressure hydrocephalus.

Mitogen activated protein kinase and protein kinase C activation mediate promotion of sAPPalpha secretion by deprenyl.

The beta amyloid cascade plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Therefore, drugs that regulate amyloid precursor protein (APP) processing toward the nonamyloidgenic pathway may have therapeutic potential. Many anti-dementia drugs can regulate APP processing in addition to their pharmacological properties. Deprenyl is a neuroprotective agent used to treat some neurodegenerative diseases, including AD. In the present study, the effects of deprenyl on APP processing were investigated. Using SK-N-SH and PC12 cells, it was demonstrated that deprenyl stimulated the release of the nonamyloidogenic alpha-secretase form of soluble APP (sAPPalpha) in a dose-dependent manner without affecting cellular APP expression. The increase of sAPPalpha secretion by deprenyl was blocked by the mitogen activated protein (MAP) kinase inhibitor U0126 and PD98059, and by the protein kinase C (PKC) inhibitor GF109203X and staurosporine, suggesting the involvement of these signal transduction pathways. Deprenyl induced phosphorylation of p42/44 MAP kinase, which was abolished by specific inhibitors of MAP kinase and PKC. Deprenyl also phosphorylated PKC and its major substrate, and myristoylated alanine-rich C kinase (MARCKS) at specific amino acid residues. The data also indicated that 10microM deprenyl successfully induced two PKC isoforms involved in the pathogenesis of AD, PKCalpha and PKCepsilon, to translocate from the cytosolic to the membrane fraction. This phenomenon was substantiated by immunocytochemistry staining. These data suggest a novel pharmacological mechanism in which deprenyl regulates the processing of APP via activation of the MAP kinase and PKC pathways, and that this mechanism may underlie the clinical efficacy of the drug in some AD patients.

Cellular and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications.

5-HT1A autoreceptor stimulation can act to attenuate supraphysiological swings in extracellular dopamine levels following long-term levodopa treatment and may be useful in the treatment and prevention of the motor complications. The purpose of this study was to investigate cellular and behavioral effects of 5-HT1A receptor agonist 8-OH-DPAT in a rat model of levodopa-induced motor complications. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg with benserazide 12.5 mg/kg, twice daily), intraperitoneally (i.p.) for 22 days. On day 23, animals received either 8-OH-DPAT (1 mg/kg, i.p.) or 8-OH-DPAT plus WAY-100635 (0.1 mg/kg, i.p) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg, i.p.) plus 8-OH-DPAT (1 mg/kg, i.p.) or levodopa (50 mg/kg, i.p.) plus vehicle, administered twice daily for 22 consecutive days. Our study showed that 8-OH-DPAT plus levodopa both prolonged the duration of the motor response and reduced peak turning. 8-OH-DPAT plus levodopa also decreased the frequency of failures to levodopa. Co-administration of WAY-100635, a 5-HT1A receptor antagonist, with 8-OH-DPAT eliminated the effect of 8-OH-DPAT on motor complications indicating that the observed 8-OH-DPAT responses were probably mediated at the 5-HT1A autoreceptor. Moreover, 8-OH-DPAT plus levodopa significantly reduced hyperphosphorylation of GluR1 at serine 845, which was closely associated with levodopa-induced motor complications.