Characterization of the fine motor problems in patients with cognitive dysfunction – A computerized handwriting analysis

Objective Volume reduction and structural abnormality is the most replicated finding in neuroimaging studies of Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) is the early stage of AD development. Thus, it is necessary to investigate the link between atrophy of regions of interest (ROIs) in medial temporal lobe, the variation trend of ROI densities and volumes among patients with cognitive impairment, and the distribution characteristics of ROIs in the aMCI group, Alzheimer's disease (AD) group, and normal control (NC) group. Methods 30 patients with aMCI, 16 patients with AD, and 30 NC are recruited; magnetic resonance imaging (MRI) brain scans are conducted. Voxel-based morphometry was employed to conduct the quantitative measurement of gray matter densities of the hippocampus, amygdala, entorhinal cortex, and mammillary body (MB). FreeSurfer was utilized to automatically segment the hippocampus into 21 subregions and the amygdala into 9 subregions. Then, their subregion volumes and total volume were calculated. Finally, the ANOVA and multiple comparisons were performed on the above-mentioned data from these three groups. Results AD had lower GM densities than MCI, and MCI had lower GM densities than NC, but not all of the differences were statistically significant. In the comparisons of AD-aMCI-NC, AD-aMCI, and AD-NC, the hippocampus, amygdala, and entorhinal cortex showed differences in the gray matter densities (p < 0.05); the differences of mammillary body densities were not significant in the random comparison between these three groups (p > 0.05). The hippocampus densities and volumes of the subjects from the aMCI group and the AD group were bilaterally symmetric. The gray matter densities of the right side of the entorhinal cortex inside each group and the hippocampus from the NC group were higher than those of the left side (p < 0.05), and the gray matter densities of the amygdala and mammillary body were bilaterally symmetric in the three groups (p > 0.05). There were no gender differences of four ROIs in the AD, aMCI, and NC groups (p > 0.05). The volume differences of the hippocampus presubiculum-body and parasubiculum manifest no statistical significance (p > 0.05) in the random comparison between these three groups. Volume differences of the left amygdala basal nucleus, the left lateral nucleus, the left cortical amygdala transitional area, the left paravamnion nucleus, and bilateral hippocampal amygdala transition area (HATA) had statistical differences only between the AD group and the NC group (p < 0.05). Conclusion Structural defects of medial temporal lobe subfields were revealed in the aMCI and AD groups. Decreased gray matter densities of the hippocampus, entorhinal cortex, and amygdala could distinguish patients with early stage of AD between aMCI and NC. Volume decline of the hippocampus and amygdala subfields could only distinguish AD between NC.

Objective: To explore the relationship between apolipoprotein E (ApoE) gene polymorphism and hydrogen proton magnetic resonance spectroscopy ((1)H-MRS) in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment(aMCI). Methods: The cognitive function of 35 AD patients (AD group), 35 aMCI patients (aMCI group) and 36 normal controls (NC group) were evaluated by neuropsychological scales, including Mini-mental State Examination (MMSE) and Cambridge Cognitive Examination-Chinese version (CAMCOG-C). The genotypes of ApoE were analyzed by high-resolution melting assay. Brain regional metabolites were measured via (1)H-MRS technique with the regions of interest (ROIs) located in the left frontal lobe and left hippocampus. Results: The CAMCOG-C (NC group 94.00 (8.50);aMCI group 86.00(8.00);AD group 61.00(18.0)) and MMSE (NC group 29.00 (2.00);aMCI group 26.00(2.00);AD group 13.00(9.5)) scores in AD and aMCI group were significantly lower in comparison with that in NC group (P<0.05). There was multi-domain cognitive impairment both in AD and aMCI. The CAMCOG-C (ε4 carriers 76.00(28.00);no-ε4 carriers 89.00 (17.00)) and MMSE (ε4 carriers 23.00(16.00);no-ε4 carriers (27.00 (6.00))scores in ε4 carriers were significantly lower than those in no-ε4 carriers (P<0.05). The AD and aMCI groups showed decreased NAA/Cr ratio in the left hippocampus as well as elevated Cho/Cr ratio and MI/Cr in the left frontal lobe compared to the NC group (P<0.05). This change was even more pronounced in AD group when compared to aMCI group. The NAA/Cr ratio and Cho/Cr ratio in the left hippocampus in ε4 carriers were lower, the MI/Cr ratio in left frontal lobe in ε4 carriers was higher (P<0.05). Conclusions: ApoE gene polymorphism affects the alteration of (1)H-MRS in AD and aMCI patients. The combination of ApoE gene polymorphism and (1)H-MRS may be more useful to differentiate and diagnose AD and aMCI early.

Objective To study the changes of fractional anisotropy (FA) value of white matter of brain and temporal stem in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients as well as normal cognitive (NC) aged people with diffusion tensor imaging (DTI), and explore the damage mechanism of temporal stem and its diagnostic value on AD and aMCI. Methods Ten patients with AD, 10 patients with aMCI and 10 NC volunteers as control group were scanned by routine MRI and DTI. FA values were calculated by post-processing software (DTIstudio) in temporal stem (including anterior commissure, uncinate fasciculus and inferior occipitofrontal fasciculus), and white matter in anterior frontal, temperal, parietal and occipital lobes. The data were analyzed by SPSS 13.0. If bilateral differences of FA values were not statistically significant (P > 0.05), the average values of bilateral FA were selected and compared among 3 groups. If bilateral differences of FA values were statistically significant (P 0.05, for all). 2) There was significant difference of FA values in anterior commissure, uncinate fasciculus and inferior occipitofrontal fasciculus between AD and aMCI groups (P 0.05, for all). Conclusions The significant difference of FA values in temporal stem among AD, aMCI and NC groups suggests that temporal stem fiber bundles are of great significance in the white matter damage of AD, and DTI is helpful for the differential diagnosis of AD, aMCI and NC. The abnormal changes of FA values in anterior commissure, uncinate fasciculus, inferior occipitofrontal fasciculus, anterior frontal and parietal lobes are of great diagnostic value in AD. doi: 10.3969/j.issn.1672-6731.2014.03.011

Alzheimer's disease (AD) is characterized by amyloid-beta plaques, tau tangles, and neuroinflammation. C-X3-C motif chemokine ligand 1 (CX3CL1, also known as fractalkine), a neuroimmune chemokine implicated in AD pathogenesis, shows inconsistent alterations in plasma/serum across studies. Specifically examining age-dependency and diagnostic utility, we investigated plasma CX3CL1 levels across the cognitive continuum (cognitively normal [CN], amnestic mild cognitive impairment [aMCI], AD) in a Chinese cohort. A total of 443 participants, including 130 patients with AD, 72 patients with aMCI, and 99 age-and sex-matched CN controls, as well as a cohort of 142 CN subjects of different ages, were enrolled from Chongqing General Hospital. Plasma CX3CL1 levels were determined using Enzyme-Linked Immunosorbent Assay (ELISA). Apolipoprotein E genotypes (APOE) were performed. The correlations between Plasma CX3CL1 levels and cognition test scores or age were analyzed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis. Plasma CX3CL1 levels significantly increased with age in CN individuals. No significant sex difference was found. Plasma CX3CL1 levels did not differ significantly between APOE ε4 carriers and non-carriers. Stepwise elevation across continuum: CX3CL1 levels showed a significant stepwise increase: CN controls (1.73 ± 0.51 ng/mL) < aMCI (2.40 ± 1.06 ng/mL) < AD (4.15 ± 1.24 ng/mL) (p < 0.001 between all groups). This pattern persisted in both male and female subgroups, between the AD group and the aMCI group, between the AD group and the CN control group (p < 0.001), between the aMCI group and the CN control group, and between the male and female subgroups (p < 0.05). CX3CL1 levels negatively correlated with Mini-Mental State Examination (MMSE) scores and positively correlated with age. Plasma CX3CL1 levels exhibit a significant age-dependent increase in cognitively normal individuals, peak in midlife (40-49 years), and demonstrate a stepwise elevation across the AD continuum (CN → aMCI → AD). Strong inverse correlations with cognitive scores in disease groups and high diagnostic accuracy for AD, particularly against CN, support its role as a biomarker reflecting both physiological aging and AD-related pathological decline. Its regulation appears independent of APOE ε4 status. The midlife peak suggests potential relevance for preclinical processes, warranting further investigation of CX3CL1 as a biomarker and therapeutic target.

The Association Between Decline in Physical Functioning and Atrophy of Medial Temporal Areas in Community-Dwelling Older Adults With Amnestic and Nonamnestic Mild Cognitive Impairment

Plasma neurofilament light chain levels in Alzheimer’s disease

[18F]FDG-PET and [11C]PIB-PET are validated as neurodegeneration and amyloid biomarkers of Alzheimer's disease (AD). We used a PET staging system based on the 2018 NIA-AA research framework to compare the proportion of amyloid positivity (A+) and hypometabolism ((N)+) in cases of mild probable AD, amnestic mild cognitive impairment (aMCI), and healthy controls, incorporating an additional classification of abnormal [18F]FDG-PET patterns and investigating the co-occurrence of such with A+, exploring [18F]FDG-PET to generate hypotheses in cases presenting with clinical-biomarker "mismatches." Elderly individuals (N = 108) clinically classified as controls (N = 27), aMCI (N = 43) or mild probable AD (N = 38) were included. Authors assessed their A(N) profiles and classified [18F]FDG-PET neurodegenerative patterns as typical or non-typical of AD, performing re-assessments of images whenever clinical classification was in disagreement with the PET staging (clinical-biomarker "mismatches"). We also investigated associations between "mismatches" and sociodemographic and educational characteristics. AD presented with higher rates of A+ and (N)+. There was also a higher proportion of A+ and (N)+ individuals in the aMCI group in comparison to controls, however without statistical significance regarding the A staging. There was a significant association between amyloid positivity and AD (N)+ hypometabolic patterns typical of AD. Non-AD (N)+ hypometabolism was seen in all A- (N)+ cases in the mild probable AD and control groups and [18F]FDG-PET patterns classified such individuals as "SNAP" and one as probable frontotemporal lobar degeneration. All A- (N)- cases in the probable AD group had less than 4years of formal education and lower socioeconomic status (SES). The PET-based staging system unveiled significant A(N) differences between AD and the other groups, whereas aMCI and controls had different (N) staging, explaining the cognitive impairment in aMCI. [18F]FDG-PET could be used beyond simple (N) staging, since it provided alternative hypotheses to cases with clinical-biomarker "mismatches." An AD hypometabolic pattern correlated with amyloid positivity. Low education and SES were related to dementia in the absence of biomarker changes.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

To evaluate hippocampal volume in patients with AD and aMCI, and correlate its atrophy with verbal episodic memory performance.MethodsWe studied 42 individuals older than 50 years, including 14 with amnestic mild cognitive impairment (aMCI), 14 with mild Alzheimer’s disease (AD) and 14 normal controls. All individuals were submitted to the Rey auditory verbal learning test (RAVLT) to evaluate episodic memory. They were also submitted to the forward (FDS) and backward digit span (BDS) subtest of WAIS-R to evaluate working memory and attention, and to the Mini Mental State Examination (MMSE). Hippocampal volumetric measurements were performed according to anatomic guidelines from a standard protocol using high-resolution T1-inversion recovery 3-mm coronal MRI slices. Hippocampal volumes (HV) were corrected for the variation in total intracranial volume. There was no significant difference between the three groups concerning age and education.ResultsOn RAVLT, there was a continuum between the three groups, with AD recalling less words, controls more, and aMCI subjects showing an intermediate performance on all sub-items. We found an asymmetry between HVs, with smaller mean left HV for all groups. ANOVA and post hoc Tukey’s test for comparisons of HV showed a significant difference among groups, with difference between controls and both AD and aMCI, although there was no significant difference between AD and aMCI groups.ConclusionsThere was a significant correlation between hippocampal volumes and scores on RAVLT, confirming that medial temporal structures are closely associated with memory performance in normal ageing as well as in aMCI and AD.

Communication within the brain is highly dynamic. Alzheimer's disease (AD) exhibits dynamic progression corresponding to a decline in memory and cognition. However, little is known of whether brain dynamics are disrupted in AD and its prodromal stage, mild cognitive impairment (MCI). For our study, we acquired high sampling rate functional near-infrared spectroscopy imaging data at rest from the entire cortex of 23 patients with AD dementia, 25 patients with amnestic mild cognitive impairment (aMCI), and 30 age-matched healthy controls (HCs). Sliding-window correlation and k-means clustering analyses were used to construct dynamic functional connectivity (FC) maps for each participant. We discovered that the brain's dynamic FC variability strength ( ) significantly increased in both aMCI and AD group as compared to HCs. Using the value as a measurement, the classification performance exhibited a good power in differentiating aMCI [area under the curve ( )] or AD ( ) from HCs. Furthermore, we identified two abnormal brain FC states in the AD group, of which the occurrence frequency ( ) exhibited a significant decrease for the first-level FC state (state 1) and a significant increase for the second-level FC state (state 2). We also found that the abnormal in these two states significantly correlated with the cognitive impairment in patients. These findings provide the first evidence to demonstrate the disruptions of dynamic brain connectivity in aMCI and AD and extend the traditional static (i.e., time-averaged) FC findings in the disease (i.e., disconnection syndrome) and thus provide insights into understanding the pathophysiological mechanisms occurring in aMCI and AD.

Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) are characterized by abnormal functional connectivity (FC) of default-mode network (DMN), salience network (SN), and central executive network (CEN). Static FC (sFC) and dynamic FC (dFC) combined with triple network model can better study the dynamic and static changes of brain networks, and improve its potential diagnostic value in the diagnosis of AD spectrum disorders. Differences in sFC values and dFC variability patterns among the three brain networks of the three groups (53 AD patients, 40 aMCI patients, and 40 NCs) were computed by ANOVA using Gaussian Random Field theory (GRF) correction. The correlation between FC values (sFC values and dFC variability) in the three networks and cognitive scores (MMSE and MoCA) in AD and aMCI groups was analyzed separately. Within the DMN network, there were significant differences of sFC values in right/left medial superior frontal gyrus and dFC variability in left opercular part inferior frontal gyrus and right dorsolateral superior frontal gyrus among the three groups. Within the CEN network, there were significant differences of sFC values in left superior parietal gyrus. Within the SN network, there were significant differences of dFC variability in right Cerebelum_7b and left opercular part inferior frontal gyrus. In addition, there was a significant negative correlation between FC values (sFC values of CEN and dFC variability of SN) and MMSE and MoCA scores. It suggests that sFC, dFC combined with triple network model can be considered as potential biomarkers for AD and aMCI.

Background: The three words - three shapes (3W3S) test enables differentiation between aspects of learning and memory, characterizing incidental recall (IR), delayed recall (DR), and recognition (REC), thereby allowing assessment of both verbal and non-verbal memory. The test’s simplicity and its form of assessment can be useful in diagnosing amnestic and non-amnestic mild cognitive impairment (a/naMCI), and Alzheimer’s disease (AD). Objective: To verify the applicability and discriminatory capacity of the 3W3S test in patients with aMCI, naMCI and AD within a Brazilian population. Methods: We evaluated 107 elderly individuals divided into four diagnostic groups: normal control; (n=33), aMCI (n=20), naMCI (n=42), and mild AD (n=12) and their performance throughout different stages of the 3W3S test were compared. Results: In the non-verbal task, the AD group exhibited the poorest performance across all stages; in IR, the naMCI group surpassed the AD group; both MCI groups (except by AD) were able to match controls after learning and in recognition memory; the MCI group performed worse than the controls in DR (all p-values &lt;0.001). In the verbal task, the AD group demonstrated the worst performance in all stages; the aMCI group performed better than naMCI in IR (all p-values &lt;0.001). Patients with aMCI and naMCI achieved similar scores in all stages of the tasks (all p-values &gt;0.005). Conclusion: The 3W3S test demonstrated effectiveness in clinical diagnosis between AD, MCI, and normal controls, revealing score discrepancies. There was no significant difference in scores between the naMCI and aMCI groups.

BACKGROUNDThe role of cerebral microvascular dysfunction in early cognitive impairment and dementia has become increasingly recognized. Furthermore, pathological changes in both Alzheimer’s disease and vascular dementia are almost always associated with cerebral hemodynamic deficits.AIMTo investigate the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) assessment of the blood-brain barrier (BBB) in combination with relevant plasma biomarkers for mild cognitive impairment (MCI).METHODSThis study selected 50 patients with non-amnestic MCI (na-MCI group), 52 patients with amnestic MCI (a-MCI group), and 55 healthy elderly controls (control group). The Chinese version of the Montreal cognitive assessment (MoCA), auditory verbal learning test (AVLT), Hamilton anxiety/depression scale (HAMA/HAMD), and activity of daily living (ADL) scales were used to analyze the characteristics of mental and behavioral symptoms of patients with MCI. The DCE-MRI technique was used to assess the contrast enhancement kinetics. The Patlak model was utilized to analyze the BBB permeability (volume transfer constants). Further, fasting blood was was used to quantify plasma homocysteine (Hcy), β-amyloid protein (Aβ) 40, Aβ42, human phosphorylated tau-181 protein (p-tau181), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) levels, as well as serum neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) concentrations.RESULTSThe na-MCI and a-MCI groups demonstrated significantly lower MoCA and AVLT-Huashan version scores, and statistically higher HAMA, HAMD, and ADL scores compared to the control group. Moreover, the a-MCI group showed notably higher HAMA, HAMD, and ADL scores compared to the na-MCI group. Cranial MRI results revealed significant disparities in cerebral blood flow in the left and right frontal lobes, temporal lobes, hippocampi, cuneus, precuneus, parietal lobes, basal ganglia, and occipital lobes between the a-MCI and na-MCI groups. Compared to healthy controls, patients with MCI demonstrated a smaller amplitude of hippocampal contrast enhancement kinetics and a slower decay rate, indicating smaller vascular volume and increased BBB permeability. Further, Hcy, p-tau181, ICAM-1, VCAM-1, PAI-1, and NFL levels were substantially higher in the a-MCI group than in the na-MCI group, whereas the Aβ42 level was significantly lower. We did not observe any significant differences in Aβ40 and GFAP levels.CONCLUSIONPatients with MCI may have experienced cerebrovascular system changes in the hippocampal region. Disorders associated with changes in cerebral blood supply may begin before pathophysiological changes are visible by imaging, which provides references for the assessment and treatment of patients with cognitive disorders. Further, DCE-MRI provides a noninvasive approach to diagnose subtle BBB leakage associated with cerebrovascular pathology.

Regional cortical atrophy in depression and neurocognitive disorders.

BackgroundFirst‐degree relatives of individuals with late‐onset Alzheimer’s Disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. We sought to test how structural or functional abnormalities in the default mode network (DMN) during the brain’s “resting state” characterized individuals at risk for AD.MethodWe used MRI and fMRI to study cognitively healthy individuals (n=28) with and without AD family history (FH+ and FH‐, respecitvely), those with amnestic mild cognitive impairment (aMCI; n=31) and early‐stage AD (n=25). We tested connectivity within the DMN, as well as measures of volume and thickness within both the medial temporal cortex and in selected seed regions. Our primary hypothesis was that there would be a linear decline within the risk groups on all measures of AD risk (FH‐&gt;FH+&gt;aMCI&gt;AD).ResultAs expected, we identified significantly decreased medial temporal cortex volumes in the aMCI and AD groups compared to both nondemented groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH‐ and AD groups. This pattern emerged primarily in connectivity between the precuneus and frontal regions.ConclusionWe present distinct structural and functional brain imaging profiles for two AD‐risk groups; cognitively healthy, FH+ individuals, and individuals with aMCI. These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.