Alzheimer's Disease In Clinical Practice Research Articles

Biomarkers associated with the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive degenerative neurological illness with insidious onset. Due to the complexity of the pathogenesis of AD and different pathological changes, the clinical phenotypes of dementia are diverse, and these pathological changes also interact with each other. Therefore, it is of great significance to search for biomarkers that can diagnose these pathological changes to improve the ability to monitor the course of disease and treat the disease. The pathological mechanism hypothesis with high recognition of AD mainly includes the accumulation of β-amyloid (Aβ) around neurons and hyperphosphorylation of tau protein, which results in the development of neuronal fiber tangles (NFTs) and mitochondrial dysfunction. AD is an irreversible disease; currently, there is no clinical cure or delay in the disease process of drugs, and there is a lack of effective early clinical diagnosis methods. AD patients, often in the dementia stages and moderate cognitive impairment, will seek medical treatment. Biomarkers can help diagnose the presence or absence of specific diseases and their pathological processes, so early screening and diagnosis are crucial for the prevention and therapy of AD in clinical practice. β-amyloid deposition (A), tau pathology (T), and neurodegeneration/neuronal damage (N), also known as the AT (N) biomarkers system, are widely validated core humoral markers for the diagnosis of AD. In this paper, the pathogenesis of AD related to AT (N) and the current research status of cerebrospinal fluid (CSF) and blood related biomarkers were reviewed. At the same time, the limitations of humoral markers in the diagnosis of AD were also discussed, and the future development of humoral markers for AD was prospected. In addition, the contents related to mitochondrial dysfunction, prion virology and intestinal microbiome related to AD are also described, so as to understand the pathogenesis of AD in many aspects and dimensions, so as to evaluate the pathological changes related to AD more comprehensively and accurately.

Placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease and healthy participants.

The role of placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease (AD) is largely unknown, with only few studies in the area. Therefore, this study aims to investigate to which extent placebo analgesia and nocebo hyperalgesia effects are present in patients experiencing mild-to-moderate AD. Twenty-one patients with AD (test population) and 26 healthy participants (HP; design validation) were exposed to thermal pain stimulation on 3 test days: Lidocaine condition (open/hidden lidocaine administration), capsaicin condition (open/hidden capsaicin administration), and natural history (no treatment), in a randomized, within-subject design. Open lidocaine and open capsaicin were accompanied by verbal suggestions for pain relief and pain increase, respectively. Expected pain and actual pain intensity were measured on a numerical rating scale (0-10). Placebo and nocebo effects were calculated as pain differences in open-hidden lidocaine and capsaicin, respectively, controlled for no treatment. Healthy participants obtained a placebo effect ( P = 0.01) and a trend for a nocebo effect ( P = 0.07). Patients with AD did not obtain a placebo effect ( P = 0.44) nor a significant nocebo effect ( P = 0.86). Healthy participants expected lower and higher pain with open vs hidden lidocaine and capsaicin, respectively ( P < 0.001). The same expectation effects were seen in patients with AD (open vs hidden lidocaine, P = 0.008; open vs hidden capsaicin, P < 0.001). With a well-controlled experimental setting, this study suggests that patients with AD may not experience placebo analgesia effects. Nocebo hyperalgesia effects in patients with AD needs further research. These findings may have implications for the conduction of clinical trials and the treatment of patients with AD in clinical practice.

Neuropsychological predictors of conversion from mild cognitive impairment to dementia at different timepoints.

Impairment of episodic memory is largely considered the main cognitive marker of prodromic Alzheimer's disease (AD). Nevertheless, the neuropathological process in AD starts several years before and, apart from biomarkers well defined in the Amyloid (A), Tauopathy (T), Neurodegeneration (N) framework, early clinical and neuropsychological markers able to detect mild cognitive impairment (MCI) due to AD before the appearance of memory disorders are lacking in clinical practice. Investigations on semantic memory have shown promising results in providing an earlier marker of dementia in MCI patients. A total of 253 MCI subjects were followed up every 6months for 6years-186 converted to dementia and 67 remained stable at the sixth year of follow-up. Twenty-seven patients progressed in the first 2years (fast converters), 107 in the third to fourth year (intermediate converters), and 51 after the fourth year of follow-up (slow converters). Stable MCI subjects performed better than fast decliners in Mini-Mental State Examination (MMSE), several long-term memory scores, and category verbal fluency test (CFT); stable and intermediate converters differ only in MMSE and CFT tests; and stable and slow converters differ only in MMSE and phonological/semantic discrepancy score. Early impairment of semantic memory could predict the evolution to AD before the onset of episodic memory disorders, and the discrepancy between phonological and semantic verbal fluency could be able to detect this impairment in advance in respect of simple CFT tests. The assessment of different aspects of semantic memory and its degradation could represent an early cognitive marker to intercept MCI due to AD in clinical practice.

The emerging double-edged sword role of exosomes in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive loss of memory and cognitive dysfunction. The primary pathological hallmarks of AD are senile plaques formed by deposition of amyloid β (Aβ) protein, intracellular neurofibrillary tangles resulting from hyperphosphorylation of microtubule-associated protein tau, and loss of neurons. At present, although the exact pathogenesis of AD is still unclear and there is a lack of effective treatment for AD in clinical practice, researchers have never stopped exploring the pathogenic mechanism of AD. In recent years, with the rise of the research of extracellular vesicles (EVs), people gradually realize that EVs also play important roles in neurodegenerative diseases. Exosomes, as a member of the small EVs, are regarded as carriers for information exchange and material transport between cells. Many cells of the central nervous system can release exosomes in both physiological and pathological conditions. Exosomes derived from damaged nerve cells can not only participate in Aβ production and oligomerization, but also disseminate the toxic proteins of Aβ and tau to neighboring neurons, thereby acting as "seeds" to amplify the toxic effects of misfolded proteins. Furthermore, exosomes may also be involved in the degradation and clearance process of Aβ. There is increasing evidence to suggest that exosomes play multiple roles in AD. Just like a double-edged sword, exosomes can participate in AD pathology in a direct or indirect way, causing neuronal loss, and can also participate in alleviating the pathological progression of AD. In this review, we summarize and discuss the current reported research findings on this double-edged role of exosomes in AD.

Electrochemical impedance-based biosensor for label-free determination of plasma P-tau181 levels for clinically accurate diagnosis of mild cognitive impairment and Alzheimer's disease

Plasma phosphorylated-tau threonine 181 (p-tau181) is a promising biomarker for predicting Alzheimer's disease (AD) and mild cognitive impairment (MCI), which is the symptomatic pre-dementia stage of AD. To date, there are limitations in the current diagnosis and classification of the two stages of MCI and AD in clinical practice remain a dilemma. In this study, we aimed to discriminate and diagnose patients with MCI, AD, and healthy participants based on the accurate, label-free, and ultrasensitive detection of p-tau181 levels in human clinical plasma samples using our developed electrochemical impedance-based biosensor, which allows to detect p-tau181 at a very low concentration of 0.92 fg mL−1. Human plasma samples were collected from 20 patients with AD, 20 patients with MCI, and 20 individuals with healthy control. The change in charge-transfer resistance of the developed impedance-based biosensor caused by capturing p-tau181 in plasma samples was recorded to evaluate the determination of plasma p-tau181 levels in human clinical samples for discrimination and diagnosis of AD, MCI, and healthy control individuals, respectively. Receiver operating characteristic (ROC) curve, a standard analysis to judge the clinically diagnostic capability of our biosensor platform based on the estimated levels of plasma p-tau181, resulted a sensitivity of 95%, a specificity of 85%, the area under the ROC curve (AUC) value of 0.94 of the accuracy for discriminating AD patients from healthy controls; a sensitivity of 70%, a specificity of 70%, the AUC of 0.75 to discriminate MCI patients from healthy controls. Statistical analysis (one-way analysis of variance (ANOVA)) was used to compare the estimated plasma p-tau181 levels in clinical samples, indicated significantly higher for AD patients with healthy controls (***p ≤ 0.001), AD with MCI patients (***p ≤ 0.001), and MCI patients with healthy controls (*p ≤ 0.05), respectively. In addition, we compared our sensor to the global cognitive function scales and discovered that it performed noticeably improvement in diagnosing the stages of AD. These results demonstrated the good application of our developed electrochemical impedance-based biosensor in the identification of clinical disease stages. Moreover, in this study, a small dissociation constant (KD) of 0.533 pM was first determined to evaluate the high binding affinity between the p-tau181 biomarker and its antibody, providing a reference parameter for future studies of the p-tau181 biomarker and AD.

Multiplexed femtomolar detection of Alzheimer's disease biomarkers in biofluids using a reduced graphene oxide field-effect transistor

Alzheimer's disease (AD) is a neurodegenerative disease that accounts for 70% of all dementia. Early stage diagnosis of AD is essential as there is no certain treatment after the lesion has progressed in the late stage. Nevertheless, there are still limitations of early diagnosis of AD using neuroimaging and psychological memory assessments. Here, we demonstrate ultrasensitive and multiplexed detection of pivotal AD biomarkers (Aβ1-42 and t-Tau) in biofluids using a reduced graphene oxide field-effect transistor (gFET). The proposed approach provides a wide logarithmically linear range of detection from 10−1–105 pg mL−1 and a femtomolar-level limit of detection in biofluids (human plasma and artificial cerebrospinal fluid) as well as phosphate-buffered saline (PBS). Furthermore, as these core biomarkers have different surface charges in physiological conditions based on the isoelectric point (pI), we achieved a distinctive output signal for each biomarker. The gFET biosensor platform presented in this paper has great potential and can be used for early diagnosis of AD in clinical practice as well as accurate analysis based on the surface charge of the analytes.

Alzheimer's "Prevention" vs. "Risk Reduction": Transcending Semantics for Clinical Practice.

The terms “prevention” and “risk reduction” are often used interchangeably in medicine. There is considerable debate, however, over the use of these terms in describing interventions that aim to preserve cognitive health and/or delay disease progression of Alzheimer's disease (AD) for patients seeking clinical care. Furthermore, it is important to distinguish between Alzheimer's disease prevention and Alzheimer's dementia prevention when using these terms. While prior studies have codified research-based criteria for the progressive stages of AD, there are no clear clinical consensus criteria to guide the use of these terms for physicians in practice. A clear understanding of the implications of each term will help guide clinical practice and clinical research. The authors explore the semantics and appropriate use of the terms “prevention” and “risk reduction” as they relate to AD in clinical practice.

Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer's Disease: A 7-Year Follow-Up Study.

Although molecular positron emission tomography imaging of amyloid and tau proteins can facilitate the detection of preclinical Alzheimer’s disease (AD) pathology, it is not useful in clinical practice. More practical surrogate markers for preclinical AD would provide valuable tools. Thus, we sought to validate the utility of conventional magnetic resonance spectroscopy (MRS) as a screening method for preclinical AD. A total of 289 older participants who were cognitively normal at baseline were clinically followed up for analysis of MRS metabolites, including N-acetyl aspartate (NAA) and myo-inositol (MI) in the posterior cingulate cortex (PCC) for 7 years. The 289 participants were retrospectively divided into five groups 7 years after baseline: 200 (69%) remained cognitively normal; 53 (18%) developed mild cognitive impairment (MCI); 21 (7%) developed AD; eight (2%) developed Parkinson’s disease with normal cognition, and seven (2%) developed dementia with Lewy bodies (DLB). The NAA/MI ratios of the PCC in the AD, MCI, and DLB groups were significantly decreased compared with participants who maintained normal cognition from baseline to 7 years after baseline. MMSE scores 7 years after baseline were significantly correlated with MI/Cr and NAA/MI ratios in the PCC. These results suggest that cognitively normal elderly subjects with low NAA/MI ratios in the PCC might be at risk of progression to clinical AD. Thus, the NAA/MI ratio in the PCC measured with conventional 1H MRS should be reconsidered as a possible adjunctive screening marker of preclinical AD in clinical practice.

123I-MIBG myocardial scintigraphy and neurocirculatory abnormalities in patients with dementia with Lewy bodies and Alzheimer's disease

BackgroundAlthough adoption of new clinical criteria for dementia with Lewy bodies (DLB) leads to an increase in the proportion of patients diagnosed with probable DLB, the sensitivity of clinical diagnostic criteria of DLB is low, and there are no generally accepted clinical or imaging biomarkers to distinguish DLB from other types of dementia. In this study, we investigated whether neurocirculatory abnormalities and cardiac sympathetic denervation differed in controls and patients with subjective memory impairment (SMI), mild cognitive impairment (MCI), Alzheimer's disease (AD), and DLB. We also assessed whether spontaneous features of Parkinsonism might be related to the neurocirculatory abnormalities and cardiac sympathetic denervation found in DLB. MethodsTwenty-two consecutive patients with probable DLB were enrolled in this study; 25 age-matched controls, 14 SMI, 24 MCI, and 37 AD patients were also evaluated. Metaiodobenzylguanidine (MIBG) uptake was assessed using the ratio of the heart to the upper mediastinum (H/M ratio), and orthostatic vital signs and ambulatory 24-hour blood pressure monitoring values were recorded. ResultsThe mean H/M ratio was significantly lower and the proportion of orthostatic hypotension was higher in patients with DLB than in controls, SMI, MCI and AD patients. In patients with DLB, spontaneous Parkinsonism was not related to the degree of cardiac sympathetic denervation nor did it influence neurocirculatory abnormalities. ConclusionOur results suggest that MIBG scintigraphy and autonomic function tests may be useful for distinguishing between DLB and AD in clinical practice. Myocardial postganglionic sympathetic denervation and autonomic dysfunctions are present in patients with DLB regardless of spontaneous Parkinsonism.

Medial temporal lobe atrophy scores translated to clinical practice: Editorial comment on ‘Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut‐offs'

Medial temporal lobe atrophy scores translated to clinical practice: Editorial comment on ‘Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut‐offs'

Frequency power and coherence of electroencephalography are correlated with the severity of Alzheimer's disease: A multicenter analysis in Taiwan

Slowing of average electroencephalography (EEG) frequency in Alzheimer's disease (AD) is well established, but whether EEG changes are able to reflect the severity of AD is uncertain. We attempt to establish quantitative EEG parameters that are suitable for evaluating AD in clinical practice. Ninety-five patients with newly diagnosed AD at different stages from four neurologic institutes were enrolled for the study. Standard scalp resting EEG data were collected for quantitative analysis. Global band power ratio and interhemispheric alpha band coherence were calculated. Patients with advanced AD had a greater slow-to-fast wave power ratio. Among several power ratio parameters, global theta and delta to alpha and beta band power ratio showed the best correlation with stages of AD (p < 0.05 between any two patient groups). Patients with advanced AD had decreased coherence in multiple brain regions. The phenomenon was most prominent in the centroparietal region (p < 0.05 between any two patient groups). Increased global slow-to-fast power ratio and decreased centroparietal interhemispheric alpha band coherence are strongly correlated with disease progress in AD patients. These two quantitative EEG parameters may help evaluate AD patients in daily clinical practice. Global power ratio changes may suggest a shift of dominant frequency, and decreased interhemispheric alpha band coherence may suggest functional disconnection and corpus callosum abnormalities in AD patients.

Using blood markers for Alzheimer disease in clinical practice?

Until recently, the notion of having blood markers of Alzheimer disease (AD) available for clinical use was more likely to be seen in an episode of a TV medical drama or a science fiction movie than in a peer-reviewed scientific journal. The search for biomarkers suffered from serious obstacles, including, but not limited to, inadequate diagnostic accuracy, and an inability to replicate findings across samples between laboratories or even within individual laboratories. However, the serious scientific world took notice when, in 2007, Ray et al.1 published a plasma-based screening tool that utilized advanced proteomic and bioinformatics methods to create a blood profile that was highly accurate in identifying persons with AD as well as those who were most likely to progress from mild cognitive impairment (MCI) to AD dementia. Enthusiasm diminished, …

Rivastigmine patch for treatment of Alzheimer's disease in clinical practice in Thailand

Rivastigmine is a cholinesterase inhibitor for treatment of mild to moderate Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The new patch formulation was recently made available. We assessed the safety, tolerability, and cognitive outcome of rivastigmine patch in treatment of mild to moderate AD in clinical practice in Thailand. A multicentre, hospital-based, prospective observational study was conducted in nine hospitals across Thailand. Patients with probable mild to moderate AD who received the rivastigmine patch were enrolled. Data were collected data at baseline, weeks 4-8 and after week16. A total of 116 AD patients were screened, and three were excluded. Of 113 patients, 62.8% were women with a mean age of 73.3 ± 9.2 years; 79.7% were newly diagnosed. One-third of all patients had been using antipsychotic or antidepressant medication. Common comorbidities were hypertension and dyslipidemia. The Thai Mental State Examination score significantly increased from 18.6 to 20.3 (weeks 4-8) and 20.4 (week 16+) (P < 0.001). Scores based on physicians' (Clinical Global Impression) and caregivers' (Patients' Caregiver Global Impression of Change) impressions of improvement suggested minimal improvement. Because of adverse events, seven patients's dosages were reduced 10 cm(2) to 5 cm(2) or from 5 cm(2) to nothing. Itching was the most common adverse symptom. During the first 16 weeks after initiation of rivastigmine patch therapy, patients with probable mild to moderate AD had statistically significant improvement in cognitive function, but clinically marginal benefit. Rivastigmine was safe and well tolerated.

Memantine in Moderately-Severe-to-Severe Alzheimerʼs Disease

Postmarketing surveillance studies (PMS) are an important tool for evaluating a drug's effectiveness and safety in clinical practice. To our knowledge, no PMS on memantine monotherapy for moderately-severe-to-severe Alzheimer's disease (AD) according to National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association criteria has been conducted to date. The Lombardy Health Office, Italy, promoted this PMS to evaluate the effectiveness and safety of memantine in the treatment of moderately-severe-to-severe AD in clinical practice. A total of 451 patients with moderately-severe-to-severe AD (mean age 77 +/- 7 years; 72% female), free of cholinergic medication, received memantine (standard titration to 10 mg twice daily). After 6 months of therapy, treatment effectiveness was evaluated according to two definitions of response ('no deterioration' and 'improvement'), as measured by changes in baseline scores on the Clinical Global Impression of Change, Mini-Mental State Examination, Neuropsychiatric Inventory and Activities of Daily Living scales. The safety measure was the frequency of adverse events (AEs). At 6-month assessment, 26.8% of subjects showed no deterioration and 3.8% showed improvement. In those showing no deterioration, response to treatment at the 3-month assessment was associated with a greater probability of a response at 6 months (adjusted odds ratio = 8.54; 95% CI 4.54, 16.05). Seventy patients (15.5%) experienced at least one AE and 39 (8.6%) discontinued treatment prematurely because of an AE. Of those who experienced an AE, 27 (38.6%) manifested behavioural and psychological symptoms of dementia. The proportion of responders to memantine treatment in this PMS was similar to that reported in a previous randomized clinical trial (26.8% vs 29%, respectively). The proportion of patients who discontinued treatment prematurely because of an AE (8.6%) was similar to that reported in two previous randomized clinical trials (10% and 12.4%). This PMS provides additional evidence that both the effectiveness and the tolerability of memantine may be transferred into real world medicine, where AD patients receiving treatment are not selected according to strict criteria.

Fully automatic differential diagnosis system for dementia with Lewy bodies and Alzheimer’s disease using FDG-PET and 3D-SSP

To evaluate a fully automatic computer-assisted diagnostic system for mild dementia with Lewy bodies (DLB), permitting distinction from mild Alzheimer's disease (AD). Using 18F-fluorodeoxyglucose and positron emission tomography (FDG-PET), glucose metabolic images were obtained from mild DLB and mild AD patients. Two groups consisting of 16 mild DLB patients and 21 mild AD patients were recruited for diagnostic evaluation between mild DLB and mild AD. The mean age+/-SD of the mild DLB group and the mild AD group was 74.3+/-4.9 and 71.7+/-2.1 years, respectively, and the mean scores of the MMSE for the mild DLB and the mild AD group were 21.7+/-1.9 and 23.1+/-2.1, respectively. A receiver operating characteristic (ROC) analysis was performed to compare the diagnostic performance, in terms of discrimination between DLB and AD, of conventional axial FDG-PET images inspected visually by experts and beginners with that of our fully automatic diagnosis system using the statistical brain mapping method and Z scores obtained with the DLB template. The diagnostic performance of the automatic system was comparable to that of visual inspection by experts. The area under the ROC curve for the automatic diagnosis system was 0.77. The mean area under the ROC curve for visual inspection by experts and beginners was 0.76 and 0.65, respectively. The fully automatic differential diagnosis system for distinction between mild DLB and AD showed a similar diagnostic accuracy to visual inspection by experts. It would be a useful diagnostic tool to distinguish mild DLB from mild AD in clinical practice.

Risk Factors for Alzheimer's Disease: An Overview for Clinical Practitioners

To review current information on various risk factors of Alzheimer's disease (AD) for clinicians so that they may educate patients or their families in a clinical setting. Published medical literature and research articles from MEDLINE. Reviews and articles from 1985 to 2003 concerning risk factors associated with AD. Data on risk factors ranging from possible or controversial to well established. AD is an irreversible, progressive neurodegenerative disorder. AD is currently known to be the most common cause of dementia in the United States. Over the last several decades, different levels of risk factors associated with AD have been identified. With more information available to the public via various resources, there is greater need for clinical practitioners to provide up-to-date information on risk factors in a meaningful way. This article discusses advanced age, family history, gender, low education, apolipoprotein E e4, head injury, cardiovascular conditions, and aluminum. Since there currently is no cure or preventive measure for AD, it is important to educate patients and their families about risk factors of AD in clinical practice.