Relationship between finger movement characteristics and brain voxel-based morphometry.

Alzheimer's disease is the most common form of neurodegenerative disorder and early detection is of great importance if new therapies are to be effectively administered. We have investigated whether the discrimination between early Alzheimer's disease (AD) and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI) measures. In this study 30 AD patients and 36 control subjects were included. High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images.1H MRS was acquired from the hippocampus and LCModel was used for metabolic quantification. Altogether, this yielded 58 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis to distinguish between subjects with AD and Healthy controls. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 87%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 6 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The method shows strong potential for discriminating between Alzheimer's disease and controls.

Objective: Consistent with Uittenhove and Lemaire (2012), we expected that strategy execution would be slower following execution of a difficult strategy than after an easy strategy (strategy sequential difficulty, SSD, effects). Moreover, we expected larger SSD effects in older adults than in young adults, and especially in Alzheimer's disease (AD) patients, a population with marked cognitive impairments. Method: A total of 25 young and older (41 AD and 25 healthy) adults were asked to execute rounding strategies to solve arithmetic problems (e.g., solving 43 + 68 by rounding operands down or up, e.g., 40 + 70 = 110). We measured solution latencies and percentage errors with a strategy as a function of the difficulty of the just-executed strategy. Results: Solution latencies were significantly shorter following the easier rounding-down strategy than following the harder rounding-up strategy, F(2, 156) = 35.8. Moreover, this effect was significantly larger in AD patients, F(1, 78) = 117.4. Conclusions: We found comparable SSD effects in young and healthy older adults but dramatically increased SSD effects in AD patients. This has implications to further our understanding of strategic aspects underlying decreased cognitive functioning in AD patients.

BackgroundIn a previous study, we demonstrated that the enzyme plasminogen activator inhibitor‐1 (PAI‐1), which inhibits plasmin synthesis in the central nervous system (CNS), is increased in the serum of patients with Alzheimer’s disease (AD). In addition to reducing the accumulation of Ab, plasmin in the CNS regulates the synthesis of the trophic factor brain‐derived neurotrophic factor (BDNF) which appears to be altered in the brain of patients with AD. We investigated whether BDNF serum levels in AD and amnestic mild cognitive impairment (aMCI) patients are altered compared to cognitively healthy controls. Moreover, we examined the PAI‐1/BDNF ratio in these patient groups and correlated with cognitive scores as measured by Mini‐Mental State Examination (MMSE).Method40 AD, 40 aMCI and 10 healthy controls were recruited. Venous blood was collected and BDNF serum concentration were quantified by sandwich ELISAs. Comparisons among the experimental groups (AD dementia, aMCI patients, and cognitively healthy controls) on BDNF serum levels were performed using univariate analyses of variance (ANOVA). Pearson correlation coefficients were calculated to explore relationships between biochemical and clinical data. The level of statistical significance was set at p<0.05.ResultThe results showed that BDNF serum levels are decreased in AD as compared to aMCI patients (p < .05). In addition, there was a positive correlation between PAI‐1 and BDNF serum levels (r = .190, p < .05). Furthermore, PAI‐1/BDNF ratio was significantly increased in AD patients as compared to aMCI (p < .001) and controls (p < .001). Lastly, PAI‐1/BDNF ratio negatively correlated with MMSE score (r = ‐.508, p < .001).ConclusionThese data suggest that in AD a reduction of plasmin caused by PAI‐1 may negatively affect the production of BDNF and promote disease progression. Our results also demonstrate that the PAI‐1/BDNF ratio is increased in AD patients compared with aMCI and controls. They also suggest that this ratio could be used as a marker of AD in a state of overt cognitive impairment, as supported by the strong negative correlation between PAI‐1/BDNF ratio and MMSE.

Alzheimer's disease (AD) is a chronic neurodegenerative disease that has been characterized by progressive development of long onset early disease with complicated etiology and may cause memory loss, cognitive impairment, and behavioral changes. Physical exercise may play a preventive role in AD. In the present study, we investigated the impact of longer-term physical exercise on the finger tapping of AD patients by comparing the finger tapping of AD patients and healthy controls. In this study, 140 subjects aged ≥ 60 years were enrolled. Group A consisted of 70 subjects (27 males and 43 females) without exercise habits who were selected from Yangpu District (Shanghai, China). Group B consisted of 70 subjects (27 males and 43 females) who were selected from Minxing District (Shanghai, China). All the subjects were right-handed as well. The subjects' data, including subjects' age, weight, height, Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and finger tapping frequency, were measured. The subjects were matched in age, weight, and height. The AD subjects' MoCA and MMSE scores were noticeably lower than healthy subjects' scores (P<0.001); besides, AD patients with exercise had significantly lower MoCA and MMSE scores than healthy controls with exercise (P<0.001). The finger tapping of AD subjects' left hands was significantly lower than that of healthy subjects without AD (P<0.01), and AD subjects with exercise tapped significantly slower with their left hand than healthy subjects with exercise (P<0.01). Meanwhile, AD subjects with exercise tapped significantly faster with the left hand than AD subjects (P<0.05). The right hands of AD subjects tapped remarkably less than healthy subjects (P<0.01) with or without exercise. Meanwhile, subjects with exercise tapped significantly faster with their right hand than healthy subjects (P<0.05), and AD subjects with exercise tapped significantly faster with their right hand than AD subjects (P<0.05). Long-term physical exercises can improve finger tapping frequency, especially in patients with AD. Finger tapping frequency may be used as an index to monitor the cognitive decline in ageing AD patients.

BackgroundThe Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to explore which tests and their measures are able to detect cognitive change after a single dose of donepezil in Alzheimer disease (AD) patients. The aim of this study was to establish the ability of CANTAB tests and their measures to detect cognitive change after a single 5-mg dose of donepezil in treatment-naïve AD patients.Material/MethodsWe enrolled 62 treatment-naïve AD patients and 30 healthy controls in this prospective, randomized, rater-blinded study. AD patients were randomized to 2 groups: the AD+ group received donepezil after the first CANTAB testing and the AD− group remained treatment-naïve at second testing. The time period between repeated testing was 4 hours. Parallel versions of CRT, SOC, PAL, SWM, and PRM tests were used.ResultsAll groups did not differ according to age, education, gender, or depression (p>0.05). AD+ and AD− groups did not differ according to MMSE. SOC, PAL, PRM, and SWM tests distinguished AD from controls. Eight measures of PAL and PRM had a strong correlation with MMSE (r>0.7). Repeated-measures ANOVA with Bonferroni post-hoc test showed the difference of change in AD+ and AD− groups between first and second CANTAB testing in 7 PAL measures. AD+ and AD− groups differed in the second testing by 7 PAL measures. Four PAL measures differed in first and second testing within the AD+ group.ConclusionsThe CANTAB PAL test measures, able to detect cognitive change after a single dose of donepezil in AD patients, are: PAL mean trials to success, total errors (adjusted), total errors (6 shapes, adjusted), and total trials (adjusted).

Lecanemab is a humanized murine IgG1 antibody. Recent Phase 3 clinical trials have demonstrated its ability to reduce brain amyloid-β (Aβ) load and slow cognitive decline in patients with early Alzheimer's disease (AD). However, since its approval, reports on adverse effects (AEs) associated with lecanemab have been limited. To better understand the AEs related to lecanemab and provide guidance for future clinical use, we analyzed lecanemab-associated AEs using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). We extracted all AEs reports from the FAERS database for the period from the first quarter of 2023 to the third quarter of 2024. Using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms, we conducted a comprehensive analysis of lecanemab-related AEs, restricting the analysis to AEs with the role code of primary suspect (PS). A total of 811 AEs reports related to lecanemab used in AD patients and 506 AEs in Non-AD patients were included. The preferred terms (PTs) identified as positive across all four algorithms included headache, Amyloid Related Imaging Abnormalities-oedema/effusion (ARIA-E), chills, Amyloid Related Imaging Abnormalities-haemosiderosis/microhaemorrhage (ARIA-H), fatigue, infusion-related reaction, nausea, pyrexia, pain, influenza like illness, and so on. Among these, ARIA-E, ARIA-H, brain oedema and status epilepticus were associated with Important Medical Events (IMEs) for AD patients, and brain oedema, cerebral haemorrhage, cerebral microhaemorrhage, subdural haematoma, ischaemic stroke, cerebral infarction were associated with IMEs for Non-AD patients. At the system organ class (SOC) level, the highest signal detection for lecanemab was observed in nervous system disorders among AD and Non-AD patients [ROR for AD: 2.42 (2.2-2.65); ROR for Non-AD: 6.97 (6.12-7.95)]. The median time to the occurrence of these AEs was 44 days after administration in AD patients and 30 days for Non-AD patients. This study utilized the FAERS database to evaluate lecanemab-associated AEs in AD and non-AD patients, along with their temporal patterns post-marketing authorization, thereby establishing a foundation for subsequent clinical pharmacovigilance. A biweekly 10mg/kg was identified as the optimal therapeutic dosage. ARIA emerged as frequent treatment-related AEs, with APOEɛ4 carriers demonstrating heightened susceptibility. This necessitates serial brain MRI surveillance for all patients during treatment, aimed not only at early ARIA detection but also vigilant monitoring of IMEs including cerebral haemorrhage, cerebral microhaemorrhages, subdural haematoma, cerebral edema, ischaemic stroke, and cerebral infarction. While AD patients predominantly exhibited non-specific clinical manifestations, non-AD cohorts showed elevated risks of stroke-related complications. Consequently, dynamic neurological deficit monitoring is indispensable for non-AD populations receiving lecanemab to mitigate adverse outcomes. Finally, comprehensive reassessment of anticoagulant or antiplatelet therapy indications is warranted in both AD and non-AD patients to reduce hemorrhagic risks.

In this study, we evaluated the response of different human skin fibroblast cultures obtained from eight probable Alzheimer's disease patients and eight non-Alzheimer's disease subjects to an acute oxidative injury elicited by H(2)O(2). This treatment generates reactive oxygen species, which are responsible for DNA damage and apoptosis. To compare the sensitivity of fibroblasts from Alzheimer's disease or non-Alzheimer's disease patients to H(2)O(2) exposure, we evaluated different parameters, including cell viability, the extension of DNA damage and the ability of the cells to arrest proliferation and to activate an apoptotic program. We found that fibroblasts from Alzheimer's disease patients were more resistant that those from control subjects to H(2)O(2) treatment, although the extent of DNA damage induced by the oxidative injury was similar in both experimental groups. The protective mechanism of Alzheimer's disease fibroblasts was related to an impairment of H(2)O(2)-induced cell cycle arrest and characterized by an accelerated re-entry into the cell cycle and a diminished induction of apoptosis. Fibroblasts from Alzheimer's disease patients also have a profound impairment in the H(2)O(2)-activated, p53-dependent pathway, which results in a lack of activation of p53 or p53-target genes, including p21, GADD45 and bax. This study demonstrates a specific alteration of an intracellular pathway involved in sensing and repairing DNA damage in peripheral cells from Alzheimer's disease patients.

Several studies have reported changes in the corpus callosum (CC) in Alzheimer's disease. However, the involved region differed according to the study population and study group. Using deep learning technology, we ensured accurate analysis of the CC in Alzheimer's disease. We used the Open Access Series of Imaging Studies (OASIS) dataset to investigate changes in the CC. The individuals were divided into three groups using the Clinical Dementia Rating (CDR); 94 normal controls (NC) were not demented (NC group, CDR = 0), 56 individuals had very mild dementia (VMD group, CDR = 0.5), and 17 individuals were defined as having mild and moderate dementia (MD group, CDR = 1 or 2). Deep learning technology using a convolutional neural network organized in a U-net architecture was used to segment the CC in the midsagittal plane. Total CC length and regional magnetic resonance imaging (MRI) measurements of the CC were made. The total CC length was negatively associated with cognitive function. (beta = -0.139, p = 0.022) Among MRI measurements of the CC, the height of the anterior third (beta = 0.038, p <0.0001) and width of the body (beta = 0.077, p = 0.001) and the height (beta = 0.065, p = 0.001) and area of the splenium (beta = 0.059, p = 0.027) were associated with cognitive function. To distinguish MD from NC and VMD, the receiver operating characteristic analyses of these MRI measurements showed areas under the curves of 0.65-0.74. (total CC length = 0.705, height of the anterior third = 0.735, width of the body = 0.714, height of the splenium = 0.703, area of the splenium = 0.649). Among MRI measurements, total CC length, the height of the anterior third and width of the body, and the height and area of the splenium were associated with cognitive decline. They had fair diagnostic validity in distinguishing MD from NC and VMD.

Exercise and cardiorespiratory (CR) fitness may moderate age-related regional brain changes in nondemented (ND) older adults. The relationship of fitness to Alzheimer disease (AD)-related brain change is understudied, particularly in the hippocampus, which is disproportionately affected in early AD. The role of apolipoprotein E4 (apoE4) genotype in modulating this relationship is also unknown. ND (n=56) and early-stage AD patients (n=61) over the age of 65 years had magnetic resonance imaging and CR fitness assessments. Voxel-based morphometry techniques were used to identify AD-related atrophy. We analyzed the relationship of CR fitness with white and gray matter within groups, assessed fitness-related brain volume change in areas most affected by AD-related atrophy, and then analyzed differential fitness-brain relationships between apoE4 carriers. Atrophy was present in the medial temporal, temporal, and parietal cortices in patients with mild AD. There was a significant positive correlation of CR fitness with parietal and medial temporal volume in AD patients. ND patients did not have a significant relationship between brain volume and CR fitness in the global or small volume correction analyses. There was not a significant interaction for fitness x apoE4 genotype in either group. In early-stage AD, CR fitness is associated with regional brain volumes in the medial-temporal and parietal cortices suggesting that maintaining CR fitness may modify AD-related brain atrophy.

A leaky gut contributes to postural dysfunction in patients with Alzheimer's disease

Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that can estimate the directionality of fibers and the microstructural of white matter in human brain. DTI researches have demonstrated that demyelinations existed in white matter of Alzheimer's disease (AD) patients mainly by fractional anisotropy (FA) and apparent diffusion constant (ADC). FA or ADC is usually used to reveal different structural properties at the independent voxel while they cannot tell us the connective relationship among voxels. In this study, we took propagation speed generated by fast marching method (FMM) as connectivity values. The significant differences of connectivity values between AD patients and elderly normal controls (NC) show that the structural connection of some regions has changed in AD patients. DTI data was acquired from 10 NC and 10 AD patients. After preprocessing, we chose the seed points in corpus callosum where FA values evidently changed by group analysis. From the seed point, we tracked all connected voxels using FMM, and then compared connectivity values of these voxels between Ad and NC statistically. The results reveal that AD patients have significant decline of connectivity values in some regions of corpus callosum where we also found significant decline of FA values in. It means that the structural connections of AD patients changed and this phenomenon may help us to explain the decreased functional activity in AD.

Thermodynamic and kinetic origins of Alzheimer's and related diseases: A chemical engineer's perspective

Inasmuch as Alzheimer's disease (AD) is difficult to diagnose, patients with suspected dementias are often given FDA approved medications, including donepezil, rivastigmine, memantine HCl, or a combination, prior to diagnosis, and some respond with improved cognition. The present study demonstrates how concentrations of a select group of serum protein biomarkers can provide the basis for sensitive and specific differential diagnosis of AD in drug treated patients. Optimization is addressed by taking into account whether the patients and controls have or do not have increased risk of AD die to the presence or absence of Apolipoprotein E4. For differential diagnosis of AD, prospectively collected newly drawn blood serum samples were obtained from drug treated Alzheimer's disease and Parkinson's disease patients from a first (39 drug treated DTAD, and 31 age matched normal controls) and second medical center (56 drug treated DTPD, 47 age-matched normal controls). Analytically validated quantitative 2D gel electrophoresis (%CV ≤ 20%; LOD ≥ 0.5 ng/spot, 300 μg/ml of blood serum) was employed with patient and control sera for differential diagnosis of AD. Protein quantitation was subjected to statistical analysis by single variable Dot, Box and Whiskers and Receiver Operator Characteristics (ROC) plots for individual biomarker performance, and multivariate linear discriminant analysis for joint performance of groups of biomarkers. Protein spots were identified and characterized by LC MS/MS of in-gel trypsin digests, amino acid sequence spans of the identified peptides, and the protein spot molecular weights and isoelectric points. The single variable statistical profiles of 58 individual protein biomarker concentrations of the DTAD patient group differed from those of the normal and/or the disease control groups. Multivariate linear discriminant analysis of blood serum concentrations of the 58 proteins distinguished drug treated Alzheimer's disease (DTAD) patients from drug treated Parkinson's disease (DTPD) patients and age matched normal controls (collectively not-DTAD, DTAD Sensitivity 87.2%, Not-DTAD Specificity 87.2). Moreover, when the patients and controls were stratified into carriers or non-carriers of Alzheimer's high risk Apolipoprotein E 4 allele and/or the Apolipoprotein E4 protein, the DTAD, DTPD and control Apo E4 (+) profiles were more divergent from one another than the corresponding Apo E4 (-) profiles. Multivariate stepwise linear discriminant analysis selected 17 of the 58 biomarkers as optimal and complimentary for distinguishing Apo E4 (+) DTAD patients from Apo E4 (+) DTPD and Apo E4 (+) controls (collectively Apo E4 (+) not-DTAD, DTAD Sensitivity 100%, not-DTAD Specificity 100%) and 22 of the 58 biomarkers for distinguishing Apo E4 (-) DTAD patients from Apo E4 (-) DTPD and Apo E4 (-) controls (collectively Apo E4 (-) not-DTAD, DTAD Sensitivity 94.4%, not- DTAD Specificity 94.4%). Only 6 of the selected proteins were common to both the Apo E4 (+) and the Apo E4 (-) discriminant functions. Recombining of the results of Apo E4 (+) and Apo E4 (-) discriminations provided overall sensitivity for total DTAD of 97.4% and specificity for total not-DTAD of 95.7%. These results can form the basis of a blood test for differential diagnosis of Alzheimer's disease patients already under treatment (DTAD) by anti dementia drugs, including donepezil, rivastigmine, memantine HCl, or a combination thereof. Also, the profile differences and the rise in specificity and sensitivity obtained by handling the Apo E4 (+) and Apo E4 (-) groups separately supports the concept that they are different patient and control populations in terms of the "normal" physiology, the pathophysiology of disease, and the response to drug treatment. Taking that into account enables increased sensitivity and specificity of differential diagnosis of Alzheimer's disease.

Sleep disruption, nightly restlessness, sundowning, and other circadian disturbances are frequently seen in Alzheimer's disease (AD) patients. Changes in the suprachiasmatic nucleus and pineal gland are thought to be the biological basis for these behavioral disturbances. Melatonin is the main endocrine message for circadian rhythmicity from the pineal. To determine whether melatonin production was affected in AD, melatonin levels were determined in the cerebrospinal fluid (CSF) of 85 patients with AD (mean age, 75 +/- 1.1 yr) and in 82 age-matched controls (mean age, 76 +/- 1.4 yr). Ventricular postmortem CSF was collected from clinically and neuropathologically well defined AD patients and from control subjects without primary neurological or psychiatric disease. In old control subjects (>80 yr of age), CSF melatonin levels were half of those in control subjects of 41-80 yr of age [176 +/- 58 (n = 29) and 330 +/- 66 (n = 53) pg/mL, respectively; P = 0.016]. We did not find a diurnal rhythm in CSF melatonin levels in control subjects. In AD patients the CSF melatonin levels were only one fifth (55 +/- 7 pg/mL) of those in control subjects (273 +/- 47 pg/mL; P = 0.0001). There was no difference in the CSF melatonin levels between the presenile (42 +/- 11 pg/mL; n = 21) and the senile (59 +/- 8 pg/mL; n = 64; P = 0.35) AD patients. The melatonin level in AD patients expressing apolipoprotein E-epsilon3/4 (71 +/- 11 pg/mL) was significantly higher than that in patients expressing apolipoprotein E-epsilon4/4 (32 +/- 8 pg/ml; P = 0.02). In the AD patients no significant correlation was observed between age of onset or duration of AD and CSF melatonin levels. In the present study, a dramatic decrease in the CSF melatonin levels was found in old control subjects and even more so in AD patients. Whether supplementation of melatonin may indeed improve behavioral disturbances in AD patients should be investigated.

A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients.APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis.We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p < 0.0001) and MCI patients (p < 0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p < 0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p < 0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p < 0.05) superoxide dismutase activity with respect to non-E4 carriers.This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor.