White Matter Alt in PD w/ Cognition /Grey Matter At

The analysis of original, un-flipped data demonstrated elevated axial diffusivity (p<0.01) in the superior and anterior corona radiata, internal capsule, and external capsule in the left hemisphere of PD relative to HC, while higher mean and radial diffusivity were discovered in the right (p<0.02 and p<0.03, respectively) and left (p<0.02 and p<0.02, respectively) in the fronto-temporal WM utilizing flipped data. 

1) cortical/subcortical GM alterations are not found or are only found in limited extents in PD-NCI; and 2) widespread WM alterations are found in PD-NCI.

Demyelination Polyneuropathies/Cognitive deficits/ CSF/BBB/D

CADP patients exhibiting BBBd at the time of first diagnosis failed in more neuropsychological tests than patients with intact integrity of the BBB (p < 0.05). When compared directly with the HC group, CADP patients performed worse than HC in tests measuring information processing ability and speed as well as phonemic verbal fluency after adjusting for confounding covariates.

The results of the CSF analysis of one of the patients were not available. Eight from the remaining 15 CADP patients (53%) exhibited BBBd at the time of first CADP diagnosis (mean range between CSF analysis and current neuropsychological testing 4.1 years, SD 3.1 years) but none exhibited CSF pleocytosis or immunoglobulin synthesis. Artificial blood contamination of the CSF was present in only two patients: one patient had only 1 erythrocyte/μl and a dysfunctional BBB, while another had 132 erythrocytes/μl and an intact BBB. 

 Just as a note, due to positive current events, these postings will be infrequent for the time being. Looking forward to a semi regular schedule in the near future. 

Posterior Cortical Atrophy/Novel Mutation in the Presenilin 1 Gene

Only the residues discussed are depicted and colored: I211 and Q223 in orange other residues in cyan. Hydrogen bonds are visualized as dashed yellow cylinders. 

Mutations in the presenilin 1 gene, affecting the function of γ-secretase, PCA usually display the same cerebrospinal fluid (CSF) biomarker including elevated levels of total tau (t-tau) and phosphorylated tau (p-tau) and dereased levels of amyloid-β (Aβ) consisting of 42 amino acids (Aβ42).  Mutation in prion protein gene (PRNP), or PSEN1 gene (Q223R) were associated with PCA phenotype.

Marked cortical and subcortical atrophy within both occipital and parietal lobes bilaterally. The atrophy was greater in the former. The right parietal lobe was more atrophic than the left one, with no asymmetry in the occipital lobes.

Intronic primers were used to amplify and sequence exons 3–12 of PSEN1, exons 16 and 17 of APP, exons 1–12 of PSEN2, and PRNP 

PCA, harboring a novel ATT>ATG mutation at codon 211 (I211M, g.44652T>G) of PSEN1 was identified. I211M mutation could be causative,Q223R mutation was identified.

Typical CSF biomarkers presentation should not exclude the possibility of causative link between PCA and AD

Infarction /CC

Out of 1,629 cases, 59 patients (3.6%) with corpus callosum infarctions were identified by diffusion weighted imaging, including 7 patients who had ischemic lesions restricted to the corpus callosum territory. Thirty six patients had lesions in the splenium (61.0%). Corpus callosum infarction patients suffered from a broad spectrum of symptoms. A classical callosal disconnection syndrome was found in 2 out of all patients with corpus callosum infarctions. Statistical differences in the risk factor and infarct pattern between the genu and/or body group and splenium group were revealed. Corpus callosum infarction and the callosal disconnection syndrome were generally rare. The most susceptible location of ischemic corpus callosum lesion was the splenium. Splenium infarctions were often associated with bilateral cerebral hemisphere involvement (46.2%).

Damage to the CC usually produces disturbance of higher brain function. Giroud and Dumas described two classic symptoms of the CC infarction: (1) callosal disconnection syndrome including apraxia, agraphia, tactile anomia of the left hand, and alien hand syndrome (AHS) as well as (2) frontal type gait disorders including a wide base, shuffling gait with short. Based on common anatomical understanding, three CC parts were discriminated: the genu, the body and the splenium, steps and loss of concomitant arm swing as the result of lacunar lesions in the anterior CC portion.

Exact pathophysiological cascades leading to CC infarction require further detailed investigation which, due to the aforementioned overall low incidence and potential life style differences.

Modulation of Habit Formation by Levodopa in PD

Average reaction times are displayed per group over blocks of 40 presentations, exemplified by the responses to non-target cues in the NoGo task version with the highest number of responses (no difference was obtained between task versions). Since conditioning-deconditioning sequences comprised 120 presentations during conditioning followed by 40 presentations during deconditioning, block 1 to 3 (labelled C1, C2 and C3) reflect performance during conditioning, whereas block 4 (labelled D) equates to deconditioning. The error bars indicate the standard error of the mean. Note that reaction times increased significantly during deconditioning compared to any of the conditioning blocks (indicated by asterisks) over all groups.

AD Risk Polymorphisms Regulate Gene Expression ZCWPW1 & CELF1 Loci

SNPs in LD with rs1476679 produce eQTL with PILRB in control brains (GSE15745)

eQTLs of IGAP GWAS SNPs in control brains (UKBEC).

SNPs in LD with rs1476679 produce eQTL with PILRB in control brains (GSE15745).

Expression of IGAP GWAS loci is associated with disease status in GSE5281.

Correlation between expression of genes within the CELF1 locus is lost in AD brains.

Expression of MTCH2, NDUFS3, PTPMT1, PSMC3, and NUP160 are highly correlated in laser micro-dissected neurons. Correlation is lost in AD brains. Gene expression in all brain samples (A, D, G, J, M, P, S). Control only (B, E, H, K, N, Q, T). AD only (C, F, I, L, O, R, U). 

APOEε4 is the strongest genetic risk factor for LOAD: carrying one copy of APOEε4 increases AD risk by 3 fold and carrying two copies of APOEε4 increases AD risk by 8–10 fold. However, only 50% of LOAD cases carry an APOEε4 allele, suggesting that other genetic factors contribute to risk for LOAD.

These significant eQTLs and expression differences in LOAD brains were observed in genes that occur within the IGAP GWAS loci but not the named IGAP GWAS gene. Together, our findings demonstrate that several LOAD risk variants modify expression of nearby genes and may contribute to LOAD risk.

A recent IGAP GWAS in 74,046 individuals revealed 21 loci that are significantly associated with altered AD risk, 12 of which are novel: ABCA7, APOE, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, CR1, EPHA1, FERMT2, HLA-DRB5/DRB1, INPP5D, MEF2C, MS4A6A, NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1.

Does HT influence the onset of HD

Evaluate the contribution of AHT to the AO of HD. HD patients with CAGexp ranging between 40 and 50, with known AHT status (86 hypertensives vs. 544 normotensives) and with AHT onset mAO in HD patients with AHT was manifested on average 7 years later than in normotensives (52.5 vs. 45 years, P<0.0001), suggesting that AHT is associated with the appearance of motor symptoms at a later onset HD patient is more likely to be recorded with a history of AHT.

Variance in mAO for each CAGexp allele (40–44 range) in normotensives and in pre-HD AHT patients

Numbers above the square brackets are the difference in median years between Pre-HD AHT and normotensives for each CAGexp allele. 

Mitochondrial influence PD in the Cypriot population

 

Inconsistent findings concerning mitochondrial haplogroups and their association to PD.

Mitochondrial haplogroup U was associated with a reduced PD risk in the Cypriot population. PD cases belonging to UKJT and R (xH, xUKJT) haplogroup, the odds of having a later age of onset of PD were 13 and 15 times respectively higher than the odds for cases with an H haplogroup. Midbrain dopaminergic neurons have a high rate of metabolic activity and are therefore dependent on the energy (ATP) released by oxidative phosphorylation in mitochondria. Mitochondrial dysfunction caused by genetic variants in both mitochondrial and nuclear DNA, can adversely affect neuronal function and lead to neurodegenerative diseases, such as Alzheimer’s disease (AD) and PD. Mitochondrial haplogroup K, which has been previously linked to lower PD risk, is particularly common in the Cypriot.

 Polymerase chain reaction was used to amplify the entire mitochondrial DNA (mtDNA) Hypervariable Region 1 (HVR 1).

The frequency of the independent variable was increased and accordingly the study power. The clusters created were L (xM, xN), M, N (including N, W, X and I) (xR), R (R*, R0), HV (HV, V), JT and U (including K) and the superclusters were LMN (including L, M, N, W, X and I), UKJT (including U, K, J and T) and R (including R*, R0, HV and V) (xH, xUKJT).

NP on I AD

The model shows that even modest neuroprotective effects on basic cognitive units can lead to dramatic reductions in the number of AD's deterioration. From a functional viewpoint, normal cognition depends on the contribution of a number of basic cognitive units (BCU), which may represent neurons, synapses or cerebral circuits (biological units). The cognitive reserve refers to the number of BCU an individual has to lose before developing dementia symptoms.  Consequently, reported incidence rates of AD's can be used to model and ‘visualize’ the effect of aging on BCU counts.  

Mathematical model offers a unique method to estimate the effect of neuroprotection on AD incidence. Several observations support the model: 1) Virtually the entire population has AD-related pathology (amyloid plaques and neurofibrillary tangles) by age 90 years.

 (p) of failure in cognition at any given age, age-specific z-scores can be directly obtained from these p values. Re-arranging the formula of the z-score, the following equation is obtained: E(y|x) = c−z-score×SD(y|x), where c represents the symptom threshold, E(y|x) is the expected BCU count (y) at any given age (x), and SD(y|x) is the corresponding standard deviation. Regression analyses of previous post-mortem analysis also suggest that SD(y|x) = 0.1 is the most likely value for the standard deviation. Consequently, the final equation is E(y|x) = BCU| age = 0.5−0.1×z-score.  Results could only be obtained if such "hypothetical" neuroprotective treatment were universally applied to the general population.

iScore for Ischemic and ICH for Intracerebral

Functional outcome (modified Rankin scale (mRS)), and quality of life (visual analogue scale (VAS)) at six months in major disabling stroke who had a Barthel Index ≤6 (of 20) at day four. Unfavorable functional outcome was defined as mRS >3, non-satisfactory quality of life as VAS <60. Followed-up at six months after stroke.

60 were included, with a mean age of 72 years. Of 15 who were predicted to worsen, one actually survived at six months (positive predictive value (PPV), 0.93; 95% CI, 0.66–0.99). Of thirty who survived, one was predicted to end (false positive rate (FPR), 0.03; 95%CI 0.00–0.20). Of forty-six who were predicted to have an unfavorable outcome, four had a favorable outcome (PPV, 0.93; 95% CI, 0.81–0.98; FPR, 0.30; 95% CI; 0.08–0.65). Prediction of non-satisfactory quality of life was less accurate (PPV, 0.63; 95% CI, 0.26–0.90; FPR, 0.18; 95% CI 0.05–0.44).

Included in the Advance Directive And Proxy opinions in acute sTroke (ADAPT) cohort, a prospective, two-center cohort study. Consecutive admits at the stroke unit with major disability, defined as Barthel Index (BI) ≤6 (out of 20) at day four after ischemic stroke or intracerebral hemorrhage were eligible for participation. This population is the only one under evaluation because these are the only ones in whom treatment restrictions are most often considered.

The frequently used iScore for ischemic stroke and ICH score for intracerebral hemorrhage have areas under the curve for prognosis end case at 30 days of 0.79 and 0.88, respectively, in validation studies. This means that both prognostic models and prognostic estimates lack the accuracy to serve as sole base for decisions. The predictive accuracy might increase when using a combination of ‘mathematical’ prediction models and prognostic estimates.

Preventive Antibacterial Therapy in Acute Ischemic Stroke/ Moxifloxacin

Pneumonia is a major risk factor of death after acute stroke. Preventive antibacterial therapy with Moxifloxacin not only prevents the development of post-stroke infections, it also reduces mortality, and improves neurological outcome significantly.

Randomized, double-blind, placebo-controlled trial in 80 with severe, non-lacunar, ischemic stroke (NIHSS>11) in the middle cerebral artery (MCA) territory. Injections received were either intravenous moxifloxacin (400 mg daily) or placebo for 5 days starting within 36 hours after stroke onset. Preventive administration of moxifloxacin is superior in reducing infections after severe non-lacunar ischemic stroke compared to placebo. In addition, the results emphasize the pivotal role of immunodepression in developing post-stroke infections.

CBF Levels of Neuron-Specific Enolase Severity/ Hypoxic-Ischemic / Hypothermia

Cerebrospinal fluid levels of neuron-specific enolase (CSF-NSE) during the first 72 hours correlate with other tools used to assess ongoing brain damage, including clinical grading of hypoxic-ischemic encephalopathy (HIE), abnormal patterns in amplitude integrated electroencephalography (aEEG) and (MRI)

The HIE group showed higher levels of CSF-NSE than the control group: median 70 ng/ml (29; 205) vs 10.6 ng/ml (7.7; 12.9); p <0.001. Median levels of CSF-NSE with severe, moderate, and mild HIE were 220.5 ng/ml (120.5; 368.8), 45.5 ng/ml (26, 75.3), and 26 ng/ml (18, 33), respectively. CSF-NSE levels correlated were significantly higher with seizures, abnormal aEEG, or abnormal MRI, compared to those without abnormalities. CSF-NSE concentrations for hypoxic-ischemic.

CSF-NSE levels in the control group were 10.6 (7.7; 12.9). CSF-NSE levels in 20, 12, and 11 with severe, moderate, and mild HIE, respectively, were 220.5 ng/ml (120.5; 368.8), 45.5 ng/ml (26, 75.3), and 26 ng/ml (18, 33). No statistically significant differences were found between any of the grades of HIE compared to controls or between any of the grades of HIE (analysis of variance after log-transformation of CSF-NSE values, with post hoc pairwise analysis); p<0.05. HIE: hypoxic-ischaemic encephalopathy; CSF-NSE: cerebrospinal fluid–neuron specific enolase. 

Risk factors for Deep & Lobar/ CTDR

Remote parenchymal hemorrhage (rPH) after intravenous thrombolysis is defined as hemorrhages that appear in brain regions without visible ischemic damage, remote from the area of ischemia causing the initial stroke.  934  (mean age 73.9±12.6 years). We observed rPH in 34  (3.6%); 9 (0.9%) were deep and 25 (2.7%) lobar. No hemorrhage was observed in 900 (96.6%). High blood pressure within the first 24 hours after intravenous thrombolysis is associated with deep rPH, whereas lobar rPH are associated with imaging markers of amyloid deposition. A positron emission tomography study found an association between those with CAA and IV-rtPA associated ICH.  With an acute ischemic stroke, speculate that deep rPH is the result of two concomitant processes (hypertensive episodes and IV-rtPA). Similarly, those with hypertension who are under treatment with anticoagulants have a high risk of a spontaneous deep ICH.

Medial Temporal Measures b/w BD & AD

A) Medial temporal lobe (MTL) atrophy in BD, and the differences in the atrophic patterns between BD and Alzheimer's disease (AD).The volumes of the hippocampus and amygdala, and morphologic parameters (volume, surface area, cortical thickness and mean curvature) of the entorhinal cortex (ERC) and perirhinal cortex (PRC) were calculated using an automated approach. Volume reduction of the hippocampus, amygdala and ERC, and disturbance of the PRC curvature was found in both AD & BD compared with the controls (p<0.05, uncorrected). There were no significant differences among all the structural measures between the AD & BD. Finally, partial correlation analyses revealed that cognitive decline could be attributed to ERC thinning in AD & volume reduction of PRC in BD.

B) Morphologic changes of MTL cortices and deep gray matter in AD and BD and determined their relationships with the cognitive impairments. There were three main findings: (1) Volume reduction in the amygdala and shape disturbance in the PRC was involved in both AD and BD . (2) There were no significant differences in all of the structural measures between AD and BD, although the atrophy of most structures was more significant in AD than in BD relative to the controls. (3) Cognitive impairments were determined by ERC thickness in AD and PRC volume in BD.

Seizures (SANAD)

Residual plots and incorporation of time-dependent covariate effects were used to investigate the proportional hazards assumption. The predictive accuracy of the models was assessed using the c-statistic. Analyses were performed using R version 3.2.3, and significance was set at the 5% level. Computer code for all analyses

1593 participants included in this analysis, 536 had a first breakthrough seizure with median time to first breakthrough seizure 0.7 years from starting treatment (interquartile range (IQR) 0.2–1.2 years). Additionally, the median follow-up time from achievement of remission to date of last follow-up was\(IQR 1.0–3.3 years).