Advanced Alzheimer's Disease Patients Research Articles

Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.

In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.

Inter-Hospital Advanced and Mild Alzheimer's Disease Classification Based on Electroencephalogram Measurements via Classical Machine Learning Algorithms.

In pursuit of diagnostic tools capable of targeting distinct stages of Alzheimer's disease (AD), this study explores the potential of electroencephalography (EEG) combined with machine learning (ML) algorithms to identify patients with mild or moderate AD (ADM) and advanced AD (ADA). This study aims to assess the classification accuracy of six classical ML algorithms using a dataset of 668 patients from multiple hospitals. The dataset comprised measurements obtained from 668 patients, distributed among control, ADM, and ADA groups, collected from five distinct hospitals between 2011 and 2022. For classification purposes, six classical ML algorithms were employed: support vector machine, Bayesian linear discriminant analysis, decision tree, Gaussian Naïve Bayes, K-nearest neighbor and random forest. The RF algorithm exhibited outstanding performance, achieving a remarkable balanced accuracy of 93.55% for ADA classification and 93.25% for ADM classification. The consistent reliability in distinguishing ADA and ADM patients underscores the potential of the EEG-based approach for AD diagnosis. By leveraging a dataset sourced from multiple hospitals and encompassing a substantial patient cohort, coupled with the straightforwardness of the implemented models, it is feasible to attain notably robust results in AD classification.

Changes in arginine metabolism in advanced Alzheimer's patients: Experimental and theoretical analyses

Limited data obtained in studies conducted in recent years suggest that changes in arginine metabolism may be associated with the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms of this pathway's effects on the disease are not clear and there are conflicting data. Therefore, in this study, we aimed to determine the levels of l-arginine and its important metabolites and enzymes involved in the pathway in advanced AD patients to examine the change in l-arginine metabolism as inclusively as possible.Serum and plasma samples were obtained from 51 patients diagnosed with advanced AD and 30 volunteer controls. Arginase, Ornithine Decarboxylase (ODC), Arginine Decarboxylase (ADC), and Agmatinase levels in serum samples were determined by enzyme-linked immunosorbent assay (ELISA) and, l-arginine, Ornithine and nitric oxide (NO) levels were determined by colorimetric method. Agmatine levels were measured by high-performance liquid chromatography in the plasma samples of the study groups. Furthermore, in silico molecular docking studies were performed to get preliminary knowledge about the binding interactions of the agmatine with various targets such as AChE, butyrylcholinesterase (BuChE), BACE-1 and tau protein kinase 1 which play an important role in AD pathogenesis.Agmatine and l-arginine levels were found to be significantly lower in the patient group than in the control group. Milder but not statistically significant reductions were observed in all other parameters we measured involved in l-arginine metabolism. Furthermore, NO levels were found to be significantly lower in men with advanced AD patients than in control men. It has been analyzed that agmatine ligand interacts effectively with the studied proteins which play an important role in AD pathogenesis; these interactions were significant and, based on the docking score, occurred in the following order: butyrylcholinesterase (PDB id: 1P0I) > Human acetylcholinesterase > Human tau-protein kinase I.In conclusion, in advanced AD patients, the activity of the l-arginine pathway decreased in general, especially agmatine formation, and this may be due to the decrease in l-arginine levels. Therefore, arginine de novo synthesis may be decreased in advanced AD patients. Furthermore, according to the MolDock binding score, agmatine ligand has a high binding affinity for proteins involved in AD management and/or pathogenesis. Therefore, agmatine may play a role in the pathogenesis of AD by inhibiting the activity of these proteins. However, additional comprehensive studies are needed to clarify these thoughts.

Plasma lncRNA profiling identified BC200 and NEAT1 lncRNAs as potential blood-based biomarkers for late-onset Alzheimer's disease.

Long non-coding RNAs (lncRNA) play critical roles in pathogenesis of neurodegenerative diseases. Human plasma carries lncRNAs that are stable in the blood, and their disease-specific profile have made them valuable biomarkers for some diseases. This study reports screening of the plasma levels of 90 lncRNAs in patients with Alzheimer disease (AD) to find out plasma-based AD biomarkers. Total RNA was isolated from plasma samples of 50 AD and 50 matched healthy controls. The plasma samples of 10 advanced AD patients and 10 matched healthy controls were screened for expression levels of 90 lncRNAs using Human LncRNA Profiler qPCR Array Kit (SBI). Based on the profiling results, lncRNAs BC200, NDM29, NEAT1, FAS-AS1 and GAS5-AS1 were selected for further analysis in all samples and their biomarker potency was evaluated by ROC curve analysis. We further surveyed RNAseq data by in silico analysis. We found that the NEAT1 and BC200 levels in the plasma of the AD patients were significantly higher compared with the control group (P=0.0021, p= 0.02, respectively). ROC curve analysis showed that the plasma level of NEAT1 and BC200 discriminated AD patients from healthy controls with sensitivity of 72 % and 60 %, and specificity of 84 % and 91 % respectively. Moreover, NEAT1 discriminated MCI (60 % sensitivity and 91 % specificity) and advanced-AD patients from healthy controls (73 % sensitivity and 71 % specificity). Besides, plasma level of BC200 discriminated the pre-clinical subjects from healthy controls with 83 % sensitivity and 66 % specificity. A positive correlation was also observed between plasma levels of BC200 with the age patients (r = 0.34, p=0.02). In silico RNAseq data analysis showed that a total of 33 lncRNAs were up-regulated but 13 lncRNAs were down-regulated significantly in AD patients compared with the healthy controls. In conclusion, this study elucidated that the plasma levels of lncRNAs NEAT1 and BC200 might be considered as potential blood-based biomarkers for AD development and progression.

Long-Term Inhalation of Hydrogen Gas for Patients with Advanced Alzheimer's Disease: A Case Report Showing Improvement in Fecal Incontinence

Introduction: Molecular hydrogen (H2) has emerged as a therapeutic medical gas that exerts multiple functions. H2 inhalation has been approved as safe, and some clinical studies showed that it effectively improved conditions of patients with a variety of disorders such as stroke, heart infarction, chronic obstructive pulmonary disease, cancer, and COVID-19. Urinary and fecal incontinences are unavoidable symptoms of advanced Alzheimer's disease (AD) dementia. In particular, fecal incontinence increases the level of confusion for patients and caretakers suffer from increased workloads. Materials and Methods: To assess the integrity of the neurons related to AD, the bundles of neurons passing through the hippocampus were visualized by modified diffusion tensor imaging (DTI) technology using advanced magnetic resonance imaging (MRI) Results: A 79-year-old woman with advanced AD continued to inhale 3% H2 gas containing 21% oxygen twice daily for 1 hour and maintained clinical observations for 2 years. After the long period of inhalation of H2 gas, the patient went to the bathroom by herself for adequate excretion. She remained to be able to go to the bathroom for her bowel movements in time, afterwards. After the long-term inhalation of H2 gas, her MRI of the brain to generate DTI images with an anisotropic (FA) value of 0.2 (FA = 0.2) showed improved integrity of the hippocampal neurons along with these clinical improvements. Conclusion: This case report casts the question on the current understanding that the advanced and severe AD patients will never improve.

Circadian Rhythm Disruption and Alzheimer's Disease: The Dynamics of a Vicious Cycle.

All mammalian cells exhibit circadian rhythm in cellular metabolism and energetics. Autonomous cellular clocks are modulated by various pathways that are essential for robust time keeping. In addition to the canonical transcriptional translational feedback loop, several new pathways of circadian timekeeping - non-transcriptional oscillations, post-translational modifications, epigenetics and cellular signaling in the circadian clock - have been identified. The physiology of circadian rhythm is expansive, and its link to the neurodegeneration is multifactorial. Circadian rhythm disruption is prevelant in contamporary society where light-noise, shift-work, and transmeridian travel are commonplace, and is also reported from the early stages of Alzheimer's disease (AD). Circadian alignment by bright light therapy in conjunction with chronobiotics is beneficial for treating sundowning syndrome and other cognitive symptoms in advanced AD patients. We performed a comprehensive analysis of the clinical and translational reports to review the physiology of the circadian clock, delineate its dysfunction in AD, and unravel the dynamics of the vicious cycle between two pathologies. The review delineates the role of putative targets like clock proteins PER, CLOCK, BMAL1, ROR, and clock-controlled proteins like AVP, SIRT1, FOXO, and PK2 towards future approaches for management of AD. Furthermore, the role of circadian rhythm disruption in aging is delineated.

Cerebrolysin in the therapy of mild cognitive impairment and dementia due to Alzheimer's disease: 30 years of clinical use.

Alzheimer's disease (AD) is the most common neurocognitive disorder and a global health problem. The prevalence of AD is growing dramatically, especially in low- and middle-income countries, and will reach 131.5 million cases worldwide by 2050. Therefore, developing a disease-modifying therapy capable of delaying or even preventing the onset and progression of AD has become a world priority, and is an unmet need. The pathogenesis of AD, considered as the result of an imbalance between resilience and risk factors, begins many years before the typical clinical picture develops and involves multiple pathophysiological mechanisms. Since the pathophysiology of AD is multifactorial, it is not surprising that all attempts done to modify the disease course with drugs directed towards a single therapeutic target have been unsuccessful. Thus, combined modality therapy, using multiple drugs with a single mechanism of action or multi-target drugs, appears as the most promising strategy for both effective AD therapy and prevention. Cerebrolysin, acting as a multitarget peptidergic drug with a neurotrophic mode of action, exerts long-lasting therapeutic effects on AD that could reflect its potential utility for disease modification. Clinical trials demonstrated that Cerebrolysin is safe and efficacious in the treatment of AD, and may enhance and prolong the efficacy of cholinergic drugs, particularly in moderate to advanced AD patients. In this review, we summarize advances of therapeutic relevance in the pathogenesis and the biomarkers of AD, paying special attention to neurotrophic factors, and present results of preclinical and clinical investigations with Cerebrolysin in AD.

In Vivo Assessment of Tau Deposition in Alzheimer Disease and Assessing Its Relationship to Regional Brain Glucose Metabolism and Cognition.

In this study, we investigated the relationship of cerebral tau deposition (F-tau-AD-ML 104 PET/CT) with glucose metabolism (F-FDG PET/CT) and cognitive function in patients with Alzheimer disease (AD). Seventy subjects (Mini Mental State Examination [MMSE] score <18 = 37 [AD]; MMSE score, 18-24 = 16 [early AD]) and 17 controls were included in this study. All participants underwent detailed neurological and neuropsychological evaluation, followed by F-tau-AD-ML 104 and F-FDG PET/CT imaging. Region-wise SUVmax ratios at 50 to 60 minutes postinjection were calculated for F-tau-AD-ML 104 and F-FDG, using the cerebellar cortex as the reference region. Linear models were used to investigate the association of regional F-tau-AD-ML 104 retention with F-FDG uptake and cognition (MMSE scores). F-Tau-AD-ML 104 retention was observed in the parietal lobe, temporal lobe, hippocampus, parahippocampus, frontal lobe, anterior and posterior cingulate, and precuneus in advanced and early AD patient as compared with normal controls with regional hypometabolism in overlapping regions on F-FDG PET. Significant negative association was found between F-tau-AD-ML 104 regional retention and glucose metabolism in the parietal lobe, temporal lobe, hippocampus, parahippocampus, frontal lobe, anterior and posterior cingulate, and precuneus among patients with advanced and early AD. In advanced and early AD patients, a negative association was found between F-tau-AD-ML 104 regional retention (precuneus) and cognition (MMSE score), whereas a positive association was observed between F-FDG regional uptake (precuneus) and cognition (MMSE score). Tau pathology overlapped with areas of hypometabolism on FDG PET in the brains of AD patients. Tau deposition was found to have negative association with cognitive scores in these patients.

Cognition in advanced normal pressure hydrocephalus: A pilot study from South India.

Literature on cognition in normal pressure hydrocephalus (NPH) is sparse and more so on cognition in advanced NPH. To study the cognitive profile in a hospital-based cohort of cognitively-advanced NPH. This was a prospective cross-sectional study. The patients included those availing dementia care service from three different tertiary care centres during a period of 5 years from 2010 to 2014. Patients were considered to have cognitively-advanced NPH if the Addenbrooke's Cognitive Examination(ACE) score was 50 or less. In addition to ACE, the patients underwent a battery of other neuropsychologic tests including the digit forward test, Trail A and Trail B, Rey auditory verbal learning test, Cambridge behaviour inventory, hospital anxiety and depression scale, informant questionnaire for cognitive decline in the elderly, and scale for activities of daily living. Data analysis was done using the Statistical Package for the Social Sciences. Dementia was confirmed in 326 cases, 193 (59.2%) with NPH, 77 (23.6%) with Alzheimer's disease (AD), 29 (8.9%) with frontotemporal dementia (FTD), and 27 (8.3%) with vascular dementia based on the commonly used criteria. Detailed neuropsychologic assessment could be done in 23 patients with NPH and 15 patients with AD. The mean age was 72.06 ± 9.62 years. Thirteen (56.5%) of the patients were males, and the mean duration of education was for 7.74 ± 3.21 years; the mean duration of illness was for 2.73 ± 2.72 years. The mean mini-mental state examination score was 11.6 ± 5.2 and the mean ACE score was 27.26 ± 1.3. The most severely impaired factor was memory (mean score 6.7 ± 4; percentage of maximum score [PMS] 19.41 ± 11.58) and the least affected was language (mean score 15.56 ± 8.25; PMS 37.06 ± 19.63. No significant difference was seen between ACE total score or subscores when the 15 advanced AD patients were compared. The cognitive profile of NPH at an advanced stage was similar to that seen in advanced AD. As advanced NPH shows cognition similar to cortical dementia, the pathologic correlate in NPH may not be hydrocephalus alone.

Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness.

Memantine is approved for the treatment of advanced Alzheimer's disease (AD) and reduces glutamate-mediated neuronal excitotoxicity by antagonism of N-methyl-D-aspartate receptors. In the pathophysiology of AD immune responses deviate and infectious side effects are observed during memantine therapy. However, the particular effects of memantine on human T lymphocytes are unresolved. Here, we provide evidence that memantine blocks Kv1.3 potassium channels, inhibits CD3-antibody- and alloantigen-induced proliferation and suppresses chemokine-induced migration of peripheral blood T cells of healthy donors. Concurrent with the in vitro data, CD4+ T cells from AD patients receiving therapeutic doses of memantine show a transient decline of Kv1.3 channel activity and a long-lasting reduced proliferative response to alloantigens in mixed lymphocyte reactions. Furthermore, memantine treatment provokes a profound depletion of peripheral blood memory CD45RO+ CD4+ T cells. Thus, standard doses of memantine profoundly reduce T cell responses in treated patients through blockade of Kv1.3 channels. This may normalize deviant immunopathology in AD and contribute to the beneficial effects of memantine, but may also account for the enhanced infection rate.

Dual-tasks and walking fast: Relationship to extra-pyramidal signs in advanced Alzheimer disease

Extra-pyramidal signs (EPS) and cadence predicted falls risk in patients with advanced Alzheimer disease (AD). Dual task performance predicts falls with variable success. Dual-task performance and walking fast were examined in advanced AD patients with EPS (EPS+, > 3 modified Unified Parkinson's Disease Rating Scale [UPDRS] signs) or without EPS (EPS−, three or less UPDRS signs). Demographics, mental and functional status, behavioral impairment, EPS, and quantitative gait measures (GaitRite) were determined. The effects of an automatic dual-task (simple counting) and of walking fast on spatial and temporal gait characteristics were compared between EPS+ and EPS− subjects using a repeated measures design. Cadence decreased, while stride time, swing time and variability in swing time increased with the dual task. Results were insignificant after adjusting for secondary task performance. With walking fast, speed, cadence and stride length increased while stride time, swing time and double support time decreased. Although EPS+ subjects were slower and had decreased stride length, dual task and walking fast effects did not differ from EPS− subjects. Patient characteristics, the type of secondary task and the specific gait measures examined vary in the literature. In this moderately to severely demented population, EPS did not affect “unconscious” (dual task) or “conscious” (walking fast) gait modulation. Given their high falls risk, and retained ability to modulate walking, EPS+ AD patients may be ideal candidates for interventions aimed at preventing falls.

Daytime sleepiness in mild and moderate Alzheimer's disease and its relationship with cognitive impairment

The increased tendency to fall asleep during the daytime together with increased wakefulness during the night has been demonstrated in patients with advanced Alzheimer's disease (AD). The aim of this study was to assess daytime sleep propensity in a cohort of patients with mild/moderate AD and to correlate it with cognitive impairment. Twenty drug-free AD patients meeting the NINCDS-ADRDA criteria for probable AD were evaluated. According to their Clinical Dementia Rating scores, subjects were classified into mild (CDR1; n=11) and moderate (CDR2; n=9) dementia patients. A group of 12 healthy subjects was taken as controls. The subjects were evaluated by the multiple sleep latency test (MSLT) after their nocturnal sleep pattern had been assessed by a polysomnographic recording throughout the night before. Both groups of AD patients showed a higher level of daytime sleepiness, which was statistically significant for mean daytime sleep latency (MDSL) (controls versus CDR1 and versus CDR2, CDR1 versus CDR2) and for 10:00 and 12:00 hour naps (controls versus CDR1, controls versus CDR2). In the entire group of AD patients, MDSL was significantly related with MMSE, De Renzi's Token test, verbal fluency, verbal digit span, story recall, Raven's Progressive Matrices, Weigl test and Benton's three-dimensional test. These data indicate that an increased sleep propensity during daytime occurs also in patients with mild/moderate AD detected by objective neurophysiological techniques.

Soluble interleukin-1 receptor type II, IL-18 and caspase-1 in mild cognitive impairment and severe Alzheimer's disease

In the present study, we have determined levels of soluble interleukin-1 (IL-1) receptor type II (sIL-1RII), interleukin-18 (IL-18) and caspase-1 in cerebrospinal fluid and serum from mild cognitive impairment patients that later progressed to Alzheimer's disease (AD) and severe AD patients. Previous studies have shown that a chronic local inflammatory process is a part of AD neuropathology. In this process, activated microglial production of IL-1 seems to play an important role. In a previous study, we have shown increased levels of sIL-1RII in CSF from AD patients in a mild-moderate disease stage. In the present study, we found no significant differences in CSF or serum levels of sIL-1RII in either mild cognitive impairment or advanced AD patients as compared to control subjects. Likewise, there was no significant difference between mild cognitive impairment and severe AD patients. The same was true for caspase-1 and IL-18 serum levels, whereas CSF levels of caspase-1 and IL-18 were below detection limits. Our data indicate that the IL-1 system is relatively intact in the early and late stages of AD.

Hospice use for the patient with advanced Alzheimer's disease: the role of the geriatric psychiatrist.

Advanced Alzheimer's disease (AD) can place an immense burden on caregivers as they struggle to provide end-of-life (EOL) care for the patient. Palliative care, as delivered by hospice, provides a viable solution. Hospice maintains the patient's quality of life (QOL) and helps the family during the grieving process. However, many providers are not familiar with hospice and its care for advanced AD patients. Geriatric psychiatrists can be central in implementing hospice, and they can remain an important part of the care once it is in place. A principal clinical challenge is establishing the six-month prognosis for such patients, which is a prerequisite for initiating hospice admission.

Measurements of both hippocampal blood flow and hippocampal gray matter volume in the same individuals with Alzheimer's disease.

We evaluated both hippocampal blood flow and hippocampal gray matter volume using single photon emission tomography and magnetic resonance imaging in the same individuals with Alzheimer's disease (AD) and in age-matched controls. The hippocampal blood flow was not significantly lower in mild AD patients (n = 21, Mini-Mental State Examination (MMSE) 23.3+/-2.1) than in controls (n = 16) with a 57% overlap. The hippocampal blood flow was significantly lower in advanced AD patients (n = 22, MMSE 15.4+/-3.2) than in controls. The hippocampal gray matter volume was significantly smaller in mild AD patients than in controls, although a 43% overlap was present. There was no significant difference in the hippocampal gray matter volume between the mild and advanced AD patients. The combination of measurements of hippocampal blood flow and gray matter volume discriminated 71% of mild AD patients from controls. These results suggest the usefulness of a combined analysis of hippocampal blood flow and gray matter volume for the early diagnosis of AD.

Preserved blood pressure and heart rate circadian rhythm in early stage Alzheimer's disease.

This study investigated the blood pressure (BP) values over the day-night period in 11 noninstitutionalized patients affected by probable Alzheimer's disease (AD) in its early stage. The scientific aim was to detect whether the BP circadian rhythm (CR) was preserved, given the fact that CR disruption was observed in advanced or institutionalized AD patients. The BP within-day values were gathered via noninvasive ambulatory monitoring. The BP time series were analyzed according to the chronobiological procedure, called Cosinor method with three harmonic components. The biometric analysis was able to document that BP changes over the 24-h scale in AD patients as a function of a significant CR. Such a preserved circadian regulation is, however, compromised in the second and third harmonic component, suggesting that the BP within-day variability is desynchronized by the environmental clues that act as synchronizers during the diurnal part of the day. The preservation of the BP CR in the early stage of AD suggests using such a finding as a clinical tool for confirming the recent onset of the disease. As a matter of fact, it is presumed that the disease is not evolved enough to reach the suprachiasmatic nuclei, wherein is located the BP circadian pacemaker. The abolition of the ultradian components is another precocious sign that, in turn, indicates early-stage AD patients to be particularly compromised in their synchronization to diurnal cues, such as social routines, meal timing schedule, psycho-physical activity, and occupational schemes.

Brain endothelial cell enzymes cleave platelet-retained amyloid precursor protein

We have previously demonstrated that thrombin-activated platelets from patients with advanced Alzheimer's disease (AD) retain significantly more surface membrane-bound amyloid precursor protein (mAPP) than, platelets from non-demented age-matched individuals (AM). We have studied interactions between these platelets and the cerebrovascular endothelium to which activated platelets adhere in a model system, investigating their involvement in the formation of amyloid β peptide (Aβ) deposits in AD patients. We report here that there appear to be α and β secretase-like activities in primary human blood brain barrier endothelial cell (BEC) cultures from both AD patients and AM control subjects (AD-BEC and AMBEC, respectively) as well as a γ secretase-like activity that appears only in ADBEC. No such activities were observed in human umbilical vein endothelial cells (HUVECs). Furthermore, there is more penetration of the platelet-released products platelet factor 4 and soluble APP through the BEC layer grown from AD patients than that grown from AM individuals, whereas none penetrate through a HUVEC layer. Thus the interaction between platelets, the APP they have retained or released, and cerebral vascular endothelial cells may be at least partially responsible for amyloidogenic deposits around the cerebral vasculature of AD patients.

The Severe Impairment Battery

Measurement of cognitive dysfunction in the early stages of Alzheimer's disease (AD) has been well studied and there are many objective tests in use for this purpose. However, with the exception of clinical rating scales, such as the Clinical Dementia Rating Scale, Global Deterioration Scale, and Functional Assessment Staging, there are few objective measures of cognition in the more advanced stages of AD. Given a renewed interest in potential AD therapies, objective measures of mental functioning are needed to adequately assess change in more advanced AD patients. As part of an effort by the NIA-Alzheimer's Disease Cooperative Study to evaluate new measures of efficacy for their utility in treatment studies, the Severe Impairment Battery (SIB) was examined in a 1-year evaluation of change across a wide range of AD severity. The data suggest that the SIB is a reliable and valid measure of progression, particularly in persons with moderate to severe AD. The SIB may therefore be a useful outcome measure in clinical trials that include patients with more advanced stages of AD.

Blunted adrenocorticotropin and increased adrenal steroid response to human corticotropin-releasing hormone in Alzheimer's disease

Previous studies suggest disturbances in the central regulation of the hypothalamic-pituitary-adrenocortical axis (HPA) in advanced Alzheimer's disease (AD). In this study the reactivity of the HPA axis was evaluated by stimulation with corticotropin-releasing hormone (CRH) of patients with mild to moderate AD. Twenty-three patients with AD (aged 61-88 yr) and 19 healthy elderly (aged 62-84 yr) received an intravenous bolus injection of human CRH (1 microgram/kg) at 3:00 PM. CRH-stimulated plasma ACTH levels were significantly lower in AD patients, while serum cortisol, dehydroepiandrosterone, and androstenedione responses relative to the amount of ACTH released were higher in AD patients. Significant correlations were found between low basal plasma ACTH levels and temporal lobe atrophy (p=0.02) and between peak plasma ACTH levels and hippocampal atrophy (p = 0.01). These findings suggest abnormalities at several levels of HPA axis in AD.

Toward a neurologic model of competency: Cognitive predictors of capacity to consent in Alzheimer's disease using three different legal standards.

To identify cognitive predictors of competency performance and status in Alzheimer's disease (AD) using three differentially stringent legal standards for capacity to consent. Univariate and multivariate analyses of independent neuropsychological test measures with three dependent measures of competency to consent to treatment. University medical center. 15 normal older controls and 29 patients with probably AD (15 mild and 14 moderate). Subjects were administered a batter of neuropsychological measures theoretically linked to competency function, as well as two clinical vignettes testing capacity to consent to medical treatment under five legal standards (LSs). The present study focused on three differentially stringent LSs: the capacity simply to "evidence a treatment of choice" (LS1), which is a minimal standard; the capacity to "appreciate the consequences" of a treatment of choice (LS3), a moderately stringent standard; and the capacity to "understand the treatment situation and choices" (LS5), the most stringent standard. Control subject and AD patient neuropsychological test scores were correlated with scores on the three LSs. The resulting univariate correlates were than analyzed using stepwise regression and discriminant function to identify key multivariate predictors of competency performance and status under each LS. No neuropsychological measures predicted control group performance on the LSs. For the AD group, a measure of simple auditory comprehension predicted LS1 performance (r(2)=0.44, p < 0.0001), a word fluency measure predicted LS3 performance (r(2)=0.58, p < 0.0001), and measures of conceptualization and confrontation naming together predicted LS5 performance (r(2)=0.81, p < 0.0001). Under discriminant function analysis, confrontation naming was the best single predictor of LS1 competency status for all subjects, correctly classifying 96% of cases (42/44). Measures of visumotor tracking and confrontation naming were the best single predictors, respectively, of competency status under LS3 (91% [39/43]) and LS5 (98% [43/44]). Multiple cognitive functions are associated with loss of competency in AD. Deficits in conceptualization, semantic memory, and probably verbal recall are associated with the declining capacity of mild AD patients to understand a treatment situation and choices (LS5); executive dysfunction with the declining capacity of mild to moderate AD patients to identify the consequences of treatment choice (LS3); and receptive aphasia and severe dysnomia with the declining capacity of advanced AD patients to evidence a simple treatment choice (LS1). The results offer insight into the relationship between different legal thresholds of competency and the progressive cognitive changes characteristic of AD, and represent an initial step toward a neurologic model of competency.