[18F]THK-5351 PET Patterns in Patients With Alzheimer’s Disease and Negative Amyloid PET Findings

Background and PurposeAlzheimer’s disease (AD) does not always mean amyloid positivity. [¹⁸F]THK-5351 has been shown to be able to detect reactive astrogliosis as well as tau accompanied by neurodegenerative changes. We evaluated the [¹⁸F]THK-5351 retention patterns in positron-emission tomography (PET) and the clinical characteristics of patients clinically diagnosed with AD dementia who had negative amyloid PET findings.MethodsWe performed 3.0-T magnetic resonance imaging, [¹⁸F]THK-5351 PET, and amyloid PET in 164 patients with AD dementia. Amyloid PET was visually scored as positive or negative. [¹⁸F]THK-5351 PET were visually classified as having an intratemporal or extratemporal spread pattern.ResultsThe 164 patients included 23 (14.0%) who were amyloid-negative (age 74.9±8.3 years, mean±standard deviation; 9 males, 14 females). Amyloid-negative patients were older, had a higher prevalence of diabetes mellitus, and had better visuospatial and memory functions. The frequency of the apolipoprotein E ε4 allele was higher and the hippocampal volume was smaller in amyloid-positive patients. [¹⁸F]THK-5351 uptake patterns of the amyloid-negative patients were classified into intratemporal spread (n=10) and extratemporal spread (n=13). Neuropsychological test results did not differ significantly between these two groups. The standardized uptake value ratio of [¹⁸F]THK-5351 was higher in the extratemporal spread group (2.01±0.26 vs. 1.61±0.15, p=0.001). After 1 year, Mini Mental State Examination (MMSE) scores decreased significantly in the extratemporal spread group (-3.5±3.2, p=0.006) but not in the intratemporal spread group (-0.5±2.8, p=0.916). The diagnosis remained as AD (n=5, 50%) or changed to other diagnoses (n=5, 50%) in the intratemporal group, whereas it remained as AD (n=8, 61.5%) or changed to frontotemporal dementia (n=4, 30.8%) and other diagnoses (n=1, 7.7%) in the extratemporal spread group.ConclusionsApproximately 70% of the patients with amyloid-negative AD showed abnormal [¹⁸F]THK-5351 retention. MMSE scores deteriorated rapidly in the patients with an extratemporal spread pattern.     

Automated Classification to Predict the Progression of Alzheimer's Disease Using Whole-Brain Volumetry and DTI

Objective

This study proposes an automated diagnostic method to classify patients with Alzheimer''s disease (AD) of degenerative etiology using magnetic resonance imaging (MRI) markers.

Methods

Twenty-seven patients with subjective memory impairment (SMI), 18 patients with mild cognitive impairment (MCI), and 27 patients with AD participated. MRI protocols included three dimensional brain structural imaging and diffusion tensor imaging to assess the cortical thickness, subcortical volume and white matter integrity. Recursive feature elimination based on support vector machine (SVM) was conducted to determine the most relevant features for classifying abnormal regions and imaging parameters, and then a factor analysis for the top-ranked factors was performed. Subjects were classified using nonlinear SVM.

Results

Medial temporal regions in AD patients were dominantly detected with cortical thinning and volume atrophy compared with SMI and MCI patients. Damage to white matter integrity was also accredited with decreased fractional anisotropy and increased mean diffusivity (MD) across the three groups. The microscopic damage in the subcortical gray matter was reflected in increased MD. Classification accuracy between pairs of groups (SMI vs. MCI, MCI vs. AD, SMI vs. AD) and among all three groups were 84.4% (±13.8), 86.9% (±10.5), 96.3% (±4.6), and 70.5% (±11.5), respectively.

Conclusion

This proposed method may be a potential tool to diagnose AD pathology with the current clinical criteria.     

The role of vascular dementia associated genes in patients with Alzheimer's disease: A large case–control study in the Chinese population

AimThe role of vascular dementia (VaD)‐associated genes in Alzheimer''s disease (AD) remains elusive despite similar clinical and pathological features. We aimed to explore the relationship between these genes and AD in the Chinese population.MethodsEight VaD‐associated genes were screened by a targeted sequencing panel in a sample of 3604 individuals comprising 1192 AD patients and 2412 cognitively normal controls. Variants were categorized into common variants and rare variants according to minor allele frequency (MAF). Common variant (MAF ≥ 0.01)‐based association analysis was conducted by PLINK 1.9. Rare variant (MAF < 0.01) association study and gene‐based aggregation testing of rare variants were performed by PLINK 1.9 and Sequence Kernel Association Test‐Optimal (SKAT‐O test), respectively. Age at onset (AAO) and Mini‐Mental State Examination (MMSE) association studies were performed with PLINK 1.9. Analyses were adjusted for age, gender, and APOE ε4 status.ResultsFour common COL4A1 variants, including rs874203, rs874204, rs16975492, and rs1373744, exhibited suggestive associations with AD. Five rare variants, NOTCH3 rs201436750, COL4A1 rs747972545, COL4A1 rs201481886, CST3 rs765692764, and CST3 rs140837441, showed nominal association with AD risk. Gene‐based aggregation testing revealed that HTRA1 was nominally associated with AD. In the AAO and MMSE association studies, variants in GSN, ITM2B, and COL4A1 reached suggestive significance.ConclusionCommon variants in COL4A1 and rare variants in HTRA1, NOTCH3, COL4A1, and CST3 may be implicated in AD pathogenesis. Besides, GSN, ITM2B, and COL4A1 are probably involved in the development of AD endophenotypes.     

Genome-wide association study identifies multiple novel loci associated with disease progression in subjects with mild cognitive impairment

Alzheimer''s disease (AD) is the leading cause of dementia among the elderly population; however, knowledge about genetic risk factors involved in disease progression is limited. We conducted a genome-wide association study (GWAS) using clinical decline as measured by changes in the Clinical Dementia Rating-sum of boxes as a quantitative trait to test for single-nucleotide polymorphisms (SNPs) that were associated with the rate of progression in 822 Caucasian subjects of amnestic mild cognitive impairment (MCI). There was no significant association with disease progress for any of the recently identified disease susceptibility variants in CLU, CR1, PICALM, BIN1, EPHA1, MS4A6A, MS4A4E or CD33 following multiple testing correction. We did, however, identify multiple novel loci that reached genome-wide significance at the 0.01 level. These top variants (rs7840202 at chr8 in UBR5: P=4.27 × 10⁻¹⁴; rs11637611 with a cluster of SNPs at chr15q23 close to the Tay–Sachs disease locus: P=1.07 × 10⁻¹⁵; and rs12752888 at chr1: P=3.08 × 10⁻¹¹) were also associated with a significant decline in cognition as well as the conversion of subjects with MCI to a diagnosis of AD. Taken together, these variants define approximately 16.6% of the MCI sub-population with a faster rate of decline independent of the other known disease risk factors. In addition to providing new insights into protein pathways that may be involved with the progress to AD in MCI subjects, these variants if further validated may enable the identification of a more homogeneous population of subjects at an earlier stage of disease for testing novel hypotheses and/or therapies in the clinical setting.     

Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss

BackgroundA blood-based biomarker of Alzheimer's disease (AD) would be superior to cerebrospinal fluid (CSF) and neuroimaging measures in terms of cost, invasiveness, and feasibility for repeated measures. We previously reported that blood ceramides varied in relation to timing of memory impairment in a population-based study. The present objective was to examine whether plasma ceramides varied by AD severity in a well-characterized clinic sample and were associated with cognitive decline and hippocampal volume loss over 1 year.MethodsParticipants included 25 normal controls (NC), 17 amnestic Mild Cognitive Impairment (MCI), and 21 early probable AD. A thorough neuropsychological battery and neuroimaging with hippocampal volume determination were conducted at baseline and 1 year later. Plasma ceramides were assayed at baseline using high performance liquid chromatography coupled electrospray ionization tandem mass spectrometry.ResultsAlthough all saturated ceramides were lower in MCI compared with AD at baseline, ceramides C22:0 and C24:0 were significantly lower in the MCI group compared with both NC and AD groups (P < .01). Ceramide levels did not differ (P > .05) in AD versus NC. There were no cross-sectional associations between ceramides C22:0 and C24:0 and either cognitive performance or hippocampal volume among any group. However, among the MCI group, higher baseline ceramide C22:0 and C24:0 levels were predictive of cognitive decline and hippocampal volume loss 1 year later.ConclusionResults suggest that very long-chain plasma ceramides C22:0 and C24:0 are altered in MCI and predict memory loss and right hippocampal volume loss among subjects with MCI. These plasma ceramides may be early indicators of AD progression.     

Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia

Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer''s disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL=18, 69.9±6.7 years) and subjects with mild cognitive impairment (MCI=15, 74.9±8.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL=17, MCI=7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (ρ=−0.41, P=0.049) and global cortical (ρ=−0.46, P=0.02) vasoreactivity to hypercapnia (VR_h). The FCRP–VR_h relationships were most pronounced in the MCI group: hippocampus (ρ=−0.77, P=0.04); global cortex (ρ=−0.83, P=0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR_h was lower in MCI than in NL subjects (Z=−2.0, P=0.047). This difference persisted after age and FCRP correction (F_[3,20]=4.6, P=0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR_h is more sensitive to vascular burden than either resting CBF or brain volume.     

The Effect of Cognitive Training in Patients with Mild Cognitive Impairment and Early Alzheimer's Disease: A Preliminary Study

Background and Purpose

The objective of this study was to determine the benefits of cognitive training in patients with amnestic mild cognitive impairment (aMCI) and those with early Alzheimer''s disease (AD).

Methods

Eleven patients with aMCI and nine with early AD (stage 4 on the Global Deterioration Scale) participated in this study. Six participants with aMCI and six with AD were allocated to the cognitive training group, while five participants with aMCI and three with AD were allocated to a wait-list control group. Multicomponent cognitive training was administered in 18 weekly, individual sessions. Outcome measures were undertaken at baseline, and at 2 weeks and 3 months of follow-up.

Results

In the trained MCI group, there were significant improvements in the delayed-recall scores on the Seoul Verbal Learning Test at both the 2-week and 3-month follow-ups compared with baseline (baseline, 1.6±1.5; 2 weeks, 4.4±1.5, p=0.04; 3 months, 4.6±2.3, p=0.04). The phonemic fluency scores (1.0±0.8 vs. 5.0±1.8, p=0.07) and Korean Mini-Mental State Examination scores (18.8±0.5 vs. 23.8±2.2, p=0.07) also showed a tendency toward improvement at the 2-week follow-up compared to baseline in the trained AD group.

Conclusions

This study provides evidence of the effectiveness of cognitive training in aMCI and early AD. The efficacy of cognitive training programs remains to be verified in studies with larger samples and a randomized design.     

The Association of Blood-Based Inflammatory Factors IL-1β, TGF-β and CRP with Cognitive Function in Alzheimer’s Disease and Mild Cognitive Impairment

Objective Many patients suffer from dementia in its most common form, Alzheimer’s disease (AD). In this study, the levels of IL-1β, TGF-β and CRP, which are involved in the inflammatory response in Alzheimer’s disease and its mild cognitive impairment (MCI), were measured and analyzed. Methods Seventy nine subjects participated in this study (mean age: 75.56 years, female: 54.3%, AD: 26, MCI: 28, normal: 25). The overall cognitive function of the subjects and the severity of the disease stage were assessed using the Mini-Mental State Examination (MMSE-K), the Clinical Dementia Rating (CDR), the Global Deterioration Scale (GDS) and the Geriatric Depression Scale-Korean (GDS-K). Results It was observed that patients with AD had significantly higher levels of IL-1β and TGF-β than the patients with MCI and normal controls. In addition, the MCI group showed a statistically significantly higher TGF-β concentration than the normal group. Conclusion These results suggest that IL-1β and TGF-β may be useful biological markers for patients with Alzheimer’s disease.     

Plasma Total Homocysteine Levels are not Associated with Medial Temporal Lobe Atrophy, but with White Matter Changes in Alzheimer's Disease

Background and purpose

Elevated plasma total homocysteine (tHcy) levels are reported to be associated with an increased risk of Alzheimer''s disease (AD). However, the mechanism by which homocysteine contributes to the pathogenesis of AD is as yet unknown. The aim of this study was to elucidate the relationship between white matter changes (WMC) and medial temporal lobe atrophy (MTA) on brain magnetic resonance imaging (MRI), and plasma levels of tHcy in AD patients.

Methods

Seventy-two patients with a clinical diagnosis of probable AD were recruited to the study. Plasma tHcy levels, vascular risk factors, and WMC and MTA on brain MRI were evaluated in all patients. The AD patients were classified into two groups: those with no or minimal WMC (69.2±8.8 years, mean±SD, n=36) and those with moderate-to-severe WMC (74.6±4.6 years, n=36) on brain MRI.

Results

In a univariate logistic regression analysis, the risk of moderate-to-severe WMC in AD was significantly associated with increasing age, female gender, lower education level, hypertension, high plasma tHcy levels, and lower Mini-Mental State Examination (MMSE) score. Multivariate logistic regression analysis revealed only high plasma tHcy as the independent and significant risk factor for moderate-to-severe WMC [odds ratio (OR; adjusted for age, gender, education level, MMSE score, and hypertension comparing the top tertile - tHcy levels ≥12.9 µmol/L - with the bottom tertile - tHcy levels ≤9.4 µmol/L)=7.35; 95% confidence interval, confidence interval=1.36-39.84; p=0.02], and age as a borderline significant risk factor (OR=1.08, 95% CI=0.99-1.19, p=0.09) in AD patients. Plasma tHcy levels were not correlated significantly with either right or left MTA.

Conclusions

Our results suggest that the vascular pathway mediates the association between elevated plasma tHcy levels and AD.     

Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([¹⁸F]DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [¹⁸F]DPA-714 binding in healthy subjects and Alzheimer''s disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250±10 MBq [¹⁸F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [¹⁸F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (V_T). Simplified reference tissue model (SRTM)-derived binding potential (BP_ND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [¹⁸F]DPA-714 cannot be used for separating individual AD patients from heathy subjects, but further studies including TSPO binding status are needed to substantiate these findings.     

Amyloid‐β protein and MicroRNA‐384 in NCAM‐Labeled exosomes from peripheral blood are potential diagnostic markers for Alzheimer's disease

ObjectiveWe aimed to establish a method to determine whether amyloid‐β (Aβ) protein and miR‐384 in peripheral blood neural cell adhesion molecule (NCAM)/ATP‐binding cassette transporter A1 (ABCA1) dual‐labeled exosomes may serve as diagnostic markers for the diagnosis of Alzheimer''s disease (AD).MethodsThis was a multicenter study using a two‐stage design. The subjects included 45 subjective cognitive decline (SCD) patients, 50 amnesic mild cognitive impairment (aMCI) patients, 40 AD patients, and 30 controls in the discovery stage. The results were validated in the verification stage in 47 SCD patients, 45 aMCI patients, 45 AD patients, and 30 controls. NCAM single‐labeled and NCAM/ABCA1 double‐labeled exosomes in the peripheral blood were captured and detected by immunoassay.ResultsThe Aβ42, Aβ_42/40, Tau, P‐T181‐tau, and miR‐384 levels in NCAM single‐labeled and NCAM/ABCA1 double‐labeled exosomes of the aMCI and AD groups were significantly higher than those of the SCD, control, and vascular dementia (VaD) groups (all p < 0.05). The Aβ42 and miR‐384 levels in NCAM/ABCA1 dual‐labeled exosomes of the aMCI and AD groups were higher than those of the control and VaD groups (all p < 0.05). The exosomal Aβ42, Aβ_42/40, Tau, P‐T181‐tau, and miR‐384 levels in peripheral blood were correlated with those in cerebrospinal fluid (all p < 0.05).ConclusionThis study, for the first time, established a method that sorts specific surface marker exosomes using a two‐step immune capture technology. The plasma NCAM/ABCA1 dual‐labeled exosomal Aβ_42/40 and miR‐384 had potential advantages in the diagnosis of SCD.     

Neuropsychiatric co-morbidities in non-demented Parkinson's disease

Objective:

To evaluate neuropsychiatric co-morbidities (depression, psychosis and anxiety) in non-demented patients with Parkinson''s disease (PD).

Background:

Non-motor symptoms like neuropsychiatric co-morbidities are common in Parkinson''s disease and may predate motor symptoms. Currently there is scarcity of data regarding neuropsychiatry manifestations in Indian patients with PD.

Methods:

In this cross-sectional study consecutive 126 non-demented patients with PD (MMSE ≥25) were enrolled. They were assessed using Unified Parkinson''s disease rating scale (UPDRS), Hoehn & Yahr (H&Y) stage, Schwab and England (S&E) scale of activity of daily life. Mini-international neuropsychiatric interview (MINI) was used for diagnosis of depression, psychosis and anxiety. Beck''s depression inventory (BDI), Brief psychiatric rating scale (BSRS) and Hamilton rating scale for anxiety (HAM-A) scales were used for assessment of severity of depression, psychosis and anxiety respectively.

Results:

Mean age and duration of disease was 57.9 ± 10.9 years and 7.3 ± 3.6 years respectively. At least one of the neuropsychiatric co-morbidity was present in 64% patients. Depression, suicidal risk, psychosis and anxiety were present in 43.7%, 31%, 23.8% and 35.7% respectively. Visual hallucinations (20.6%) were most frequent, followed by tactile (13.5%), auditory (7.2%) and olfactory hallucinations (1.6%). Patients with depression had higher motor disability (UPDRS-motor score 33.1 ± 14.0 vs 27.3 ± 13.3; and UPDRS-total 50.7 ± 21.8 vs 41.0 ± 20.3, all p values <0.05). Patients with psychosis were older (63.6 ± 8.0 years vs 56.1 ± 11.1 years, p < 0.05) and had longer duration of illness (8.6 ± 3.4 years vs 6.9 ± 3.5, p < 0.05).

Conclusions:

About two third patients with Parkinson''s disease have associated neuropsychiatric co-morbidities. Depression was more frequent in patients with higher disability and psychosis with longer duration of disease and older age. These co-morbidities need to be addressed during management of patients with PD.     

Improvement of Screening Accuracy of Mini-Mental State Examination for Mild Cognitive Impairment and Non-Alzheimer's Disease Dementia by Supplementation of Verbal Fluency Performance

Objective

This study aimed to investigate whether the supplementation of Verbal Fluency: Animal category test (VF) performance can improve the screening ability of Mini-Mental State Examination (MMSE) for mild cognitive impairment (MCI), dementia and their major subtypes.

Methods

Six hundred fifty-five cognitively normal (CN), 366 MCI [282 amnestic MCI (aMCI); 84 non-amnestic MCI (naMCI)] and 494 dementia [346 Alzheimer''s disease (AD); and 148 non-Alzheimer''s disease dementia (NAD)] individuals living in the community were included (all aged 50 years and older) in the study.

Results

The VF-supplemented MMSE (MMSE+VF) score had a significantly better screening ability for MCI, dementia and overall cognitive impairment (MCI plus dementia) than the MMSE raw score alone. MMSE+VF showed a significantly better ability than MMSE for both MCI subtypes, i.e., aMCI and naMCI. In the case of dementia subtypes, MMSE+VF was better than the MMSE alone for NAD screening, but not for AD screening.

Conclusion

The results support the usefulness of VF-supplementation to improve the screening performance of MMSE for MCI and NAD.     

The impact of transfer learning on 3D deep learning convolutional neural network segmentation of the hippocampus in mild cognitive impairment and Alzheimer disease subjects

Research on segmentation of the hippocampus in magnetic resonance images through deep learning convolutional neural networks (CNNs) shows promising results, suggesting that these methods can identify small structural abnormalities of the hippocampus, which are among the earliest and most frequent brain changes associated with Alzheimer disease (AD). However, CNNs typically achieve the highest accuracy on datasets acquired from the same domain as the training dataset. Transfer learning allows domain adaptation through further training on a limited dataset. In this study, we applied transfer learning on a network called spatial warping network segmentation (SWANS), developed and trained in a previous study. We used MR images of patients with clinical diagnoses of mild cognitive impairment (MCI) and AD, segmented by two different raters. By using transfer learning techniques, we developed four new models, using different training methods. Testing was performed using 26% of the original dataset, which was excluded from training as a hold‐out test set. In addition, 10% of the overall training dataset was used as a hold‐out validation set. Results showed that all the new models achieved better hippocampal segmentation quality than the baseline SWANS model (p _s < .001), with high similarity to the manual segmentations (mean dice [best model] = 0.878 ± 0.003). The best model was chosen based on visual assessment and volume percentage error (VPE). The increased precision in estimating hippocampal volumes allows the detection of small hippocampal abnormalities already present in the MCI phase (SD = [3.9 ± 0.6]%), which may be crucial for early diagnosis.     

Markers of Alzheimer's disease in a population attending a memory clinic

BackgroundNew marker-based criteria for the diagnosis of Alzheimer's disease (AD) were recently proposed. We describe their operational translation in 144 consecutive patients referred to our Memory Clinic.MethodsVisual ratings of hippocampal atrophy and of cortical glucose hypometabolism in magnetic resonance imaging and positron emission tomography, and concentrations of total tau and Aβ1-42 in cerebrospinal fluid were assessed in 12 patients with subjective memory complaints (SMCs) (Mini-Mental State Examination [MMSE] score, 28.0 ± 1.1 [mean ± SD]), 37 with mild cognitive impairment (MCI) (MMSE, 25.1 ± 3.6), 55 with AD (MMSE, 21.1 ± 3.5), and 40 with non-AD dementia (MMSE, 21.6 ± 5.5).ResultsThe sensitivity for AD of each individual biomarker was higher (65% to 87%) than for MCI (18% to 50%). Each biomarker's specificity for SMC and non-AD dementias was good to moderate (83% and 53%). Positivity for at least one marker increased the probability 38 times of belonging to the AD group (P < 0.0001).ConclusionThe new diagnostic criteria can be operationalized in clinical routines, but longitudinal studies of MCI patients will need to assess the criteria's prognostic value.     

The APOE ?4/?4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer's disease patients

Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer''s disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Aβ), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ɛ4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ɛ2 and ɛ3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ɛ4/ɛ4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.     

Regional hyperperfusion in older adults with objectively-defined subtle cognitive decline

Although cerebral blood flow (CBF) alterations are associated with Alzheimer’s disease (AD), CBF patterns across prodromal stages of AD remain unclear. Therefore, we investigated patterns of regional CBF in 162 Alzheimer’s Disease Neuroimaging Initiative participants characterized as cognitively unimpaired (CU; n = 80), objectively-defined subtle cognitive decline (Obj-SCD; n = 31), or mild cognitive impairment (MCI; n = 51). Arterial spin labeling MRI quantified regional CBF in a priori regions of interest: hippocampus, inferior temporal gyrus, inferior parietal lobe, medial orbitofrontal cortex, and rostral middle frontal gyrus. Obj-SCD participants had increased hippocampal and inferior parietal CBF relative to CU and MCI participants and increased inferior temporal CBF relative to MCI participants. CU and MCI groups did not differ in hippocampal or inferior parietal CBF, but CU participants had increased inferior temporal CBF relative to MCI participants. There were no CBF group differences in the two frontal regions. Thus, we found an inverted-U pattern of CBF signal across prodromal AD stages in regions susceptible to early AD pathology. Hippocampal and inferior parietal hyperperfusion in Obj-SCD may reflect early neurovascular dysregulation, whereby higher CBF is needed to maintain cognitive functioning relative to MCI participants, yet is also reflective of early cognitive inefficiencies that distinguish Obj-SCD from CU participants.     

Lithium attenuates blood–brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β‐catenin signaling‐dependent mechanism in mice

BackgroundVasogenic cerebral edema resulting from blood–brain barrier (BBB) damage aggravates the devastating consequences of intracerebral hemorrhage (ICH). Although augmentation of endothelial Wnt/β‐catenin signaling substantially alleviates BBB breakdown in animals, no agents based on this mechanism are clinically available. Lithium is a medication used to treat bipolar mood disorders and can upregulate Wnt/β‐catenin signaling.MethodsWe evaluated the protective effect of lithium on the BBB in a mouse model of collagenase IV‐induced ICH. Furthermore, we assessed the effect and dependency of lithium on Wnt/β‐catenin signaling in mice with endothelial deletion of the Wnt7 coactivator Gpr124.ResultsLithium treatment (3 mmol/kg) significantly decreased the hematoma volume (11.15 ± 3.89 mm³ vs. 19.97 ± 3.20 mm³ in vehicle controls, p = 0.0016) and improved the neurological outcomes of mice following ICH. Importantly, lithium significantly increased the BBB integrity, as evidenced by reductions in the levels of brain edema (p = 0.0312), Evans blue leakage (p = 0.0261), and blood IgG extravasation (p = 0.0009) into brain tissue around the hematoma. Mechanistically, lithium upregulated the activity of endothelial Wnt/β‐catenin signaling in mice and increased the levels of tight junction proteins (occludin, claudin‐5 and ZO‐1). Furthermore, the protective effect of lithium on cerebral damage and BBB integrity was abolished in endothelial Gpr124 knockout mice, suggesting that its protective effect on BBB function was mainly dependent on Gpr124‐mediated endothelial Wnt/β‐catenin signaling.ConclusionOur findings indicate that lithium may serve as a therapeutic candidate for treating BBB breakdown and brain edema following ICH.     

Interactions between cigarette smoking and cognitive status on functional connectivity of the cortico‐striatal circuits in individuals without dementia: A resting‐state functional MRI study

AimsCigarette smoking is a modifiable risk factor for Alzheimer''s disease (AD), and controlling risk factors may curb the progression of AD. However, the underlying neural mechanisms of the effects of smoking on cognition remain largely unclear. Therefore, we aimed to explore the interaction effects of smoking × cognitive status on cortico‐striatal circuits, which play a crucial role in addiction and cognition, in individuals without dementia.MethodsWe enrolled 304 cognitively normal (CN) non‐smokers, 44 CN smokers, 130 mild cognitive impairment (MCI) non‐smokers, and 33 MCI smokers. The mixed‐effect analysis was performed to explore the interaction effects between smoking and cognitive status (CN vs. MCI) based on functional connectivity (FC) of the striatal subregions (caudate, putamen, and nucleus accumbens [NAc]).ResultsThe significant interaction effects of smoking × cognitive status on FC of the striatal subregions were detected in the left inferior parietal lobule (IPL), bilateral cuneus, and bilateral anterior cingulate cortex (ACC). Specifically, increased FC of right caudate to left IPL was found in CN smokers compared with non‐smokers. The MCI smokers showed decreased FC of right caudate to left IPL and of right putamen to bilateral cuneus and increased FC of bilateral NAc to bilateral ACC compared with CN smokers and MCI non‐smokers. Furthermore, a positive correlation between FC of the NAc to ACC with language and memory was detected in MCI smokers.ConclusionsCigarette smoking could affect the function of cortico‐striatal circuits in patients with MCI. Our findings suggest that quitting smoking in the prodromal stage of AD may have the potential to prevent disease progression.     

The Effects of Galantamine Treatment on Attention and Its Relationship with Cognition and Activities of Daily Living in Patients with Mild to Moderate Alzheimer's Disease

Background and Purpose

The positive effects of galantamine on cognition and activities of daily living (ADL) in Alzheimer''s disease (AD) are thought to be mediated via improvements in attention. The purpose of this study was to determine the effect of galantamine on attention in AD patients using a computerized attention test and to elucidate the relationship between improvements in attention and change in cognition and ADL.

Methods

In this multicenter, open-label, prospective study, patients with mild to moderate AD received galantamine and then submitted to computerized attention tests, the Alzheimer''s Disease Assessment Scale-cognitive subscale, and instrumental ADL (IADL) at baseline, 4 weeks, and 12 weeks. The differences in reaction time on computerized tests were explored relative to the changes in cognition and IADL.

Results

After 12 weeks of taking the trial medication there was a significant reduction from baseline levels in the choice reaction time (baseline, 5,216±3,650 sec; 12 weeks, 4,139±2,920 sec; p<0.01) and the simple reaction time (baseline, 1,089±782 sec; 12 weeks, 908±606 sec; p<0.01). Correlation analyses of changes in choice or simple reaction times relative to cognition and ADL measures yielded no significant associations. The improvement in attention observed at 4 weeks of galantamine treatment was not associated with any significant changes in outcome measures at the end of trial.

Conclusions

This study found no significant association between the improvement in attention after treatment with galantamine and changes in cognition and ADL in patients with mild to moderate AD, despite the significant improvement in attention over the course of the treatment.