A change of PD-1/PD-L1 expression on peripheral T cell subsets correlates with the different stages of Alzheimer's Disease

Editorial: New drugs for Alzheimer's disease in Japan

Intrinsic Connectivity Identifies the Hippocampus as a Main Crossroad between Alzheimer’s and Semantic Dementia-Targeted Networks

Calculation deficits are a common early manifestation of Alzheimer disease (AD). To investigate oral and written calculation skills in AD patients using quantitative and qualitative methods. Comparison among controls, patients with mild AD, and patients with moderate AD on measures of arithmetic skill. Tertiary care university medical center. Twenty patients with AD (11 with mild AD, 9 with moderate AD) and 23 elderly controls. Tests of oral arithmetic (Wechsler Adult Intelligence Scale-Third Edition [WAIS-III] Arithmetic subtest) and written arithmetic (Wide Range Achievement Test-3 [WRAT-3] Arithmetic subtest) were administered, and overall group differences were examined. Errors on selected WRAT-3 problems were qualitatively analyzed across groups using a set of error codes. Patients with mild and moderate AD performed significantly below controls on both oral and written arithmetic tasks (P<.001). Patients with moderate AD performed worse than those with mild AD on written arithmetic (P<.002) but not on oral arithmetic tasks. On selected WRAT-3 problems, single- and multiple-digit addition and subtraction operations and single-digit division operations were preserved in patients with mild AD. In contrast, only single-digit addition was preserved in patients with moderate AD. Errors of operation substitution and number position were the most common error types observed in AD patients. Patients with moderate AD displayed multiple error types and high incidence rates compared with controls, while patients with mild AD exhibited error types and incidence rates intermediate to controls and patients with moderate AD. A decline in calculation abilities is one of the hallmark cognitive features of AD. Patients with mild AD maintain relative preservation of simple written calculation skills but demonstrate marked impairment as task complexity increases. Patients with moderate AD demonstrate global impairments extending to the simplest arithmetic skills. These findings suggest that loss of calculation abilities in AD is both hierarchical (by arithmetic operation) and a function of disease severity.

CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease.

High Activities of BACE1 in Brains with Mild Cognitive Impairment

Moving Beyond Amyloid in Alzheimer's Therapeutics

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

Objective: To analyze the correlation of muscle strength with cognitive function and medial temporal lobe atrophy (MTA) in patients with mild to moderate Alzheimer's disease (AD). Methods: General information, sarcopenia-related indicators, neuropsychological tests and MTA score were collected in 80 confirmed AD patients (41 mild and 39 moderate patients) and 43 normal controls (NC) from the Memory Disorders Clinic of Department Of Neurology in the Second Affiliated Hospital of Soochow University between January and December 2021. Appendicular skeletal muscle mass index (ASMI), grip strength and 5-times sit-to-stand time and 6-m gait speed were used for assessing muscle mass, muscle strength and physical function, respectively. Cognitive function was assessed by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment scale (MoCA), Memory and Executive Screening Scale (MES), Digit Symbol Substitution Test (DSST), Digital Span Test (DST) and Verbal Fluency Task (VFT), respectively. DST included Forward Digit Span Test (FDST) and Backward Digit Span Test (BDST). All the subjects underwent 3.0T coronal three-dimensional gradient echo sequence MRI. MTA scale was performed to evaluate the degree of medial temporal lobe atrophy. The differences in the sarcopenia-related indicators, cognitive score and MTA score were analyzed among the three groups, and the partial correlation analysis was performed between the inter-groups. Results: Eighty AD patients (24 males and 56 females) were included, aged (72±7) years old, with 41 mild and 39 moderate patients. Meanwhile, 43 NC included 19 males and 24 females, with a mean age of (70±6) years old. The disease duration in moderate AD patients was longer than that of mild AD patients [34.0 (25.0, 43.5) months vs 24.0 (11.0, 34.0) months, P<0.001]. The differences of sarcopenia-related indicators and MTA score among the three groups were statistically significant (all P<0.001), including 5-times sit-to-stand time [(13.6±1.8) s vs (11.5±1.7) s vs (10.3±1.9) s, P<0.001] and MTA score [2.0 (2.0, 3.0) vs 1.0 (1.0, 2.0) vs 0 (0, 0), P<0.001]. In neuropsychological tests, compared to the NC group, MMSE, MoCA, MES and VFT scores in mild and moderate AD groups were lower (all P<0.001); meanwhile, compared to the mild AD group, the moderate group had lower MMSE, MoCA, MES, DSST and VFT scores (all P<0.001). In sarcopenia-related indicators, muscle strength in particular was correlated with widespread cognitive functioning domains and MTA score in AD patients. Grip strength was positively correlated with MMSE, MoCA , MES, FDST (r=0.387, 0.418, 0.522 and 0.484, respectively, all P<0.001), DSST (r=0.327, P=0.006) and VFT score (r=0.354, P=0.003), and negatively correlated with MTA score (r=-0.631, P<0.001). 5-times sit-to-stand time was negatively correlated with MMSE, MoCA, MES, DSST, FDST, VFT score (r=-0.583, -0.587, -0.814, -0.591, -0.552 and -0.485, respectively, all P<0.001), and BDST (r=-0.355, P=0.003) strongly positively correlated with MTA score (r=0.836, P<0.001). ASMI was positively correlated with MMSE, MoCA, MES, DSST, FDST score (r=0.257, 0.238, 0.428, 0.282 and 0.364, respectively, all P<0.05), and negatively correlated with MTA score (r=-0.377, P=0.001). 6-m gait speed was positively correlated with MMSE, MoCA, MES, DSST, FDST score (r=0.419, 0.486, 0.699, 0.559 and 0.500, respectively, all P<0.001), BDST and VFT score (r=0.384、0.377, respectively, both P=0.001), and strongly negatively correlated with MTA score (r=-0.803, P<0.001). Conclusions: Patients with mild to moderate AD have widespread cognitive impairment. Muscle mass, muscle strength and physical function are all significantly impaired. Compared to muscle mass and physical function, decreased muscle strength is significantly associated with widespread cognitive decline and increased degree of medial temporal lobe atrophy.

Donepezil provides greater benefits in mild compared to moderate Alzheimer's disease: Implications for early diagnosis and treatment

This study aimed to investigate the changes and deterioration in lexical processing caused by Alzheimer's disease (AD). It analyzed the differences in lexical processing between individuals with healthy controls, mild AD, and moderate AD as well as how these groups processed varying lexical aspects. A total of 180 older adults participated in the experiment, including 60 healthy controls, 60 with mild AD, and 60 with moderate AD. Each group was further divided into two subgroups, with each subgroup assigned to one of two different experiments. The experiments assessed the speed and accuracy of lexical processing in both orthography and meaning using compound words. Individuals with mild and moderate AD showed significant differences in the speed and accuracy of lexical processing, both in orthography and meaning, compared to healthy controls. When the prime character shared character-level units with the target word, it enhanced the accuracy of lexical processing in AD patients. Mild AD patients demonstrated a significant advantage in both the speed and accuracy of processing high-frequency words in terms of orthography and meaning, while moderate AD patients only showed a significant advantage in orthographic processing accuracy. The AD group showed no significant differences in the speed and accuracy of processing high- and low-transparency words in terms of orthographic and meaning processing. Lexical processing significantly deteriorated in individuals with AD, with a greater decline observed in those with moderate AD. Differences in lexical processing between mild and moderate AD patients highlighted the varying impact of the disease's severity.

Objectives: Self awareness is progressively vanishing in Alzheimer's disease (AD) patients, while insight of amnesia seemingly stays longer than self awareness. It is clinically informative to prove that the residual learning ability of the patients exists, though defective, to help construct a better individualized rehabilitative strategy. Methods: Eighty-one patients (M:F=28:53), aged 59~102, with AD dementia were divided into four groups by mini-mental status examination (MMSE) scores (early: ＞/=21, n=16; mild: 16-20, n= 19; moderate: 11-15, n=30; severe: ＜/=10, n=16). Each group was tested for 1) self awareness by asking each individual name, age, birthday and children number, 2) visual confrontation naming of 3 presented objects, namely pencil, comb, and key, and 3) insight of amnesia by asking whether or not they have memory problems. Only completing right answers to all items in each test was counted as correct response (CR). Numbers of CR in each test were collected for analysis. Results: A concordant trend was noted between the severity of AD and test results. In mild and moderate AD patients whose self awareness were vanishing (CR=42%→0%), the insight of amnesia remained to a significant degree (CR=84%→60%). In early AD, four patients denied memory problems. The test result of confrontation naming was closer to that of insight of amnesia in mild and moderate AD patients, as compared to that of self awareness. Conclusions: While self awareness is vanishing in mild and moderate AD patients, their insight of amnesia remained to a significant degree, suggesting a learning effect. The learned insight of amnesia, through daily interaction, stays longer and stronger than self awareness in mild to severe AD patients. The four patients in their early AD denying memory problems did not learn from environmental feedbacks. The closer test results of insight of amnesia with confrontation naming in mild and moderate AD patients suggest a cortical language learning process. The potential of learning in AD patients sheds guiding light on rehabilitative strategy in mild and moderate AD.

To validate the value of whole-brain computed tomography perfusion (CTP) and CT angiography (CTA) in the diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Whole-brain CTP and four-dimensional CT angiography (4D-CTA) images were acquired in 30 MCI, 35 mild AD patients, 35 moderate AD patients, 30 severe AD patients and 50 normal controls (NC). Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and correlation between CTP and 4D-CTA were analysed. Elevated CBF in the left frontal and temporal cortex was found in MCI compared with the NC group. However, TTP was increased in the left hippocampus in mild AD patients compared with NC. In moderate and severe AD patients, hypoperfusion was found in multiple brain areas compared with NC. Finally, we found that the extent of arterial stenosis was negatively correlated with CBF in partial cerebral cortex and hippocampus, and positively correlated with TTP in these areas of AD and MCI patients. Our findings suggest that whole-brain CTP and 4D-CTA could serve as a diagnostic modality in distinguishing MCI and AD, and predicting conversion from MCI based on TTP of left hippocampus. • Whole-brain perfusion using the full 160-mm width of 320 detector rows • Provide clinical experience of 320-row CT in cerebrovascular disorders of Alzheimer's disease • Initial combined 4D CTA-CTP data analysed perfusion and correlated with CT angiography • Whole-brain CTP and 4D-CTA have high value for monitoring MCI to AD progression • TTP in the left hippocampus may predict the transition from MCI to AD.

CSF markers in Alzheimer disease patients are not related to the different degree of cognitive impairment

Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

Whilst there is evidence implicating small vessel cerebrovascular disease in the pathogenesis of Alzheimer's disease (AD), its specific contribution to the pathophysiology of AD remains unclear. The burden of small vessel cerebrovascular disease visualized as white matter hyperintensity (WMH) and its association with medial temporal atrophy (MTA) at different stages of AD was studied. One hundred and sixty-five cognitively normal (CN) community controls, 103 mild cognitive impairment (MCI) patients, 141 mild AD patients and 68 moderate-severe AD patients were studied. Clinical, cognitive and risk factor data were collected, and WMH and MTA were quantified by trained raters. The Jonckheere-Terpstra test for ordered alternatives was used to study the association between WMH and MTA in different stages of AD. The burden of total WMH increased significantly with increasing severity of AD, even after correcting for confounders. The proportion of CN, MCI, mild AD and moderate-severe AD subjects with severe burden of WMH was 6.7%, 9.7%, 28.4%, and 39.7%, respectively. A strong positive association between WMH severity and MTA was evident amongst MCI (P = 0.011) and mild AD (P = 0.003) subjects, but not in CN (P = 0.953) and moderate-severe AD subjects (P = 0.301). The burden of WMH increased significantly from the stage of CN to MCI to AD. The association between WMH and MTA was greatest at the stage of MCI and mild AD. This has implications on the strategy to slow the progression of AD, where measures to reduce WMH, including control of vascular risk factors, need to be optimized at the stage of MCI and mild AD.