Impact of AP@LZ in the daily life of three persons with Alzheimer's disease: long-term use and further exploration of its effectiveness.

AP@LZ is an electronic organiser that was designed to support the day-to-day activities of persons with Alzheimer's disease. To assess the potential of this technology, three participants (NI, JB, RD) were approached to take part in the study. They benefited from a structured cognitive intervention to learn how to operate AP@LZ; the intervention included the following learning stages: Acquisition, Application and Adaptation. Pre- and post-intervention measures were collected. NI, for whom a longitudinal study was conducted, still continued to use AP@LZ 24 months post-intervention. JB and RD also showed a gradual improvement in their performance throughout the intervention phase (sessions 1 to 19 for JB: performance increased from 50 to 100%; sessions 1 to 25 for RD: from 56 to 89%). The results of the use of AP@LZ in activities of daily living suggest that the application was beneficial for three persons with Alzheimer's disease whose profiles differed notably (age, cognitive and social profiles). Thus, results indicate that they were all able to learn how to operate AP@LZ's functions and to use them in their activities of daily living. Cognitive intervention appears to play an important role for the promotion of learning and adoption of such technology.

Viruses - a major cause of amyloid deposition in the brain.

INTRODUCTION: Clinically, Alzheimer's disease (AD) is a syndrome with a spectrum of various cognitive disorders. There is a complete dissociation between the pathology and the clinical presentation. Therefore, we need a disruptive new approach to be able to prevent and treat AD. AREAS COVERED: In this review, the authors extensively discuss the evidence why the amyloid beta is not the pathological cause of AD which makes therefore the amyloid hypothesis not sustainable anymore. They review the experimental evidence underlying the role of microbes, especially that of viruses, as a trigger/cause for the production of amyloid beta leading to the establishment of a chronic neuroinflammation as the mediator manifesting decades later by AD as a clinical spectrum. In this context, the emergence and consequences of the infection/antimicrobial protection hypothesis are described. The epidemiological and clinical data supporting this hypothesis are also analyzed. EXPERT OPINION: For decades, we have known that viruses are involved in the pathogenesis of AD. This discovery was ignored and discarded for a long time. Now we should accept this fact, which is not a hypothesis anymore, and stimulate the research community to come up with new ideas, new treatments, and new concepts.

Immunosenescence and Altered Vaccine Efficiency in Older Subjects: A Myth Difficult to Change.

Organismal ageing is associated with many physiological changes, including differences in the immune system of most animals. These differences are often considered to be a key cause of age-associated diseases as well as decreased vaccine responses in humans. The most often cited vaccine failure is seasonal influenza, but, while it is usually the case that the efficiency of this vaccine is lower in older than younger adults, this is not always true, and the reasons for the differential responses are manifold. Undoubtedly, changes in the innate and adaptive immune response with ageing are associated with failure to respond to the influenza vaccine, but the cause is unclear. Moreover, recent advances in vaccine formulations and adjuvants, as well as in our understanding of immune changes with ageing, have contributed to the development of vaccines, such as those against herpes zoster and SARS-CoV-2, that can protect against serious disease in older adults just as well as in younger people. In the present article, we discuss the reasons why it is a myth that vaccines inevitably protect less well in older individuals, and that vaccines represent one of the most powerful means to protect the health and ensure the quality of life of older adults.

CCCDTD5: research diagnostic criteria for Alzheimer's Disease.

The CCCDTD5 reviewed the research diagnostic criteria for Alzheimer's disease proposed in the NIA-AA Research Framework and supports their use in research but not in clinical practice.

Enhancing patient care via a pharmacist-managed rural anticoagulation clinic.

Integrating specialized pharmacist services and follow-up with the laboratory, home care nursing, retail pharmacy and physicians can ensure optimal outcomes for patients receiving anticoagulation, or "blood thinner," therapy. Improved patient education and discharge care planning can bridge disconnects, enable patients to better manage their care and ensure better patient outcomes and more effective use of health system resources. Specially trained pharmacists can provide safe and effective management of a high-alert medication to help prevent potentially life-threatening clots or bleeding. With advanced prescribing authorization, the pharmacist can seamlessly provide this service both locally in a community and via Telehealth to surrounding areas, potentially for any Albertan. Warfarin therapy may be lifelong or short-term (three to six months), but all patients require regular monitoring with blood tests. Many variables, both lifestyle and medication related, can impact therapy, and through extensive education and access via telephone to an "expert" for questions and follow-up of blood tests, patients are empowered to better regulate their anticoagulants. Anticoagulation pharmacists, as part of an AMS (anticoagulation management service), can provide a continuum of care for patients while in hospital, when discharged home, as an outpatient in the community or as a resident of a long-term care facility or seniors' home.

Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer's Disease?

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aß) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aß is the major cause of AD. Clinical trials targeting Aß in the brain have mostly failed, whether they attempted to decrease Aß production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aß is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aß as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aß decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aß to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aß - AD and discuss future possible treatments based on this paradigm.

Orthostatic hypotension associated with executive dysfunction in mild cognitive impairment.

INTRODUCTION: Midlife hypertension is associated with dementia in longitudinal studies while chronic hypotension in the elderly is associated with dementia onset. Orthostatic hypotension could influence cognitive performance in the elderly. The objective of this study was to assess the relationship between orthostatic hypotension and cognitive functions. METHODS: Consecutive participants with complete neuropsychological evaluation from a Memory Clinic were included. Orthostatic hypotension (OH) was defined by a fall≥20/10mmHg systolic/diastolic pressure. Participants were classified into one of 3 groups: 1) subjective cognitive impairment (SCI), 2) mild cognitive impairment (MCI), and 3) dementia. Neuropsychological tests were analyzed for patients with and without OH. RESULTS: One hundred and twenty participants were included, of which 16 (13%) were classified as SCI, 42 (35%) as MCI, and 63 (52%) with dementia. Prevalence of OH was 0% for the SCI group, 26% (n=11) for the MCI group, and 38% (n=24) for the dementia group. Age, sex, education, and brief cognitive test scores (MMSE & MoCA) were not different between groups with or without OH. In the MCI group, OH was associated with lower cognitive performance in several executive functions tests: visual working memory (p<0.001), processing speed (p=0.006), Stroop flexibility (p=0.030) and Trail-Making Test part B (p=0.024). There was no difference in episodic memory performance. OH was associated with a diagnosis of hypertension and the use of antihypertensive medication. No differences were observed in vascular brain injury between groups with and without OH. CONCLUSIONS: This study found that orthostatic hypotension prevalence is correlated to severity of cognitive deficits in a Memory Clinic. In MCI, OH is associated with lower performance in executive functions. OH could represent an under-recognized correlate of cognitive performance.

Multicenter Validation of an MMSE-MoCA Conversion Table.

BACKGROUND: Accumulating evidence points to the superiority of the MoCA over the MMSE as a cognitive screening tool. To facilitate the transition from the MMSE to the MoCA in clinical and research settings, authors have developed MMSE-MoCA conversion tables. However, it is unknown whether a conversion table generated from Alzheimer's disease (AD) patients would apply to patients with other dementia subtypes like vascular dementia or frontotemporal dementia. Furthermore, the reliability and accuracy of MMSE-MoCA conversion tables has not been properly evaluated. METHOD: We retrospectively examined the MMSE-MoCA relationship in a large multicenter sample gathered from 3 Memory Clinics in Quebec, Canada (1492 patients). We produced an MMSE-MoCA conversion table using the equi-percentile method with log-linear smoothing. We then cross-validated our conversion table with the ADNI dataset (1202 patients) and evaluated its accuracy for future predictions. RESULTS: The MMSE-MoCA conversion table is consistent with previously published tables and has an intra-class correlation of 0.633 with the ADNI sample. However, we found that the MMSE-MoCA relationship is significantly modified by diagnosis (P < .01), with dementia subtypes associated with a dysexecutive syndrome showing a trend towards higher MMSE than other dementia syndromes for a given MoCA score. The large width of 95% confidence interval (CI) for a new prediction suggests questionable reliability for clinical use. CONCLUSION: In this study, we validated a conversion table between MMSE and MoCA using a large multicenter sample. Our results suggest caution in interpreting the tables in heterogeneous clinical populations, as the MMSE-MoCA relationship may be different across dementia subtypes.

A 3-Month Aerobic Training Program Improves Brain Energy Metabolism in Mild Alzheimer's Disease: Preliminary Results from a Neuroimaging Study.

BACKGROUND: Aerobic training has some benefits for delaying the onset or progression of Alzheimer's disease (AD). Little is known about the implication of the brain's two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits. OBJECTIVE: To determine whether aerobic exercise training modifies brain energy metabolism in mild AD. METHODS: In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu) and acetoacetate (CMRacac) using neuroimaging and cognitive testing were done before and after the Walking program. RESULTS: Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 µmol/100 g/min; p = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2-3-fold (all p≤0.03). CMRglu was unchanged after Walking (28.0±0.1 µmol/100 g/min; p = 0.96). There was a tendency toward improvement in the Stroop-color naming test (-10% completion time, p = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p≤0.01). CONCLUSION: In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement.

Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia.

BACKGROUND: The cerebral metabolic rate of glucose (CMRg) is lower in specific brain regions in Alzheimer's disease (AD). The ketones, acetoacetate and ß-hydroxybutyrate, are the brain's main alternative energy substrates to glucose. OBJECTIVE: To gain insight into brain fuel metabolism in mild AD dementia by determining whether the regional CMR and the rate constant of acetoacetate (CMRa and Ka, respectively) reflect the same metabolic deficit reported for cerebral glucose uptake (CMRg and Kg). METHODS: Mild AD dementia (Mild AD; n = 10, age 76 y) patients were compared with gender- and age-matched cognitively normal older adults (Controls; n = 29, age 75 y) using a PET/MRI protocol and analyzed with both ROI- and voxel-based methods. RESULTS: ROI-based analysis showed 13% lower global CMRg in the gray matter of mild AD dementia versus Controls (34.2 ± 5.0 versus 38.3 ± 4.7 µmol/100 g/min, respectively; p = 0.015), with CMRg and Kg in the parietal cortex, posterior cingulate, and thalamus being the most affected (p ≤ 0.022). Neither global nor regional CMRa or Ka differed between the two groups (all p ≥ 0.188). Voxel-based analysis showed a similar metabolic pattern to ROI-based analysis with seven clusters of significantly lower CMRg in the mild AD dementia group (uncorrected p ≤ 0.005) but with no difference in CMRa. CONCLUSION: Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones.

Elusive Alzheimer's disease: can immune signatures help our understanding of this challenging disease? Part 1: clinical and historical background.

Alzheimer's disease (AD) is the most common form of dementia. Its most important pathological hallmarks are profound neuronal loss, presence of intracellular neurofibrillary tangles, and extracellular deposition of beta-amyloid protein (Aß) as beta-amyloid plaques. These latter aggregations result in neuronal degeneration in brain regions important not only for memory, but also for other cognitive functions. One of the most important risk factors for AD is age and with the increase of life-expectancy AD has thus become the most common form of dementia. It is now formally recognized by several new diagnostic criteria that AD is not a homogeneous disease. The current "Holy Grail" is to be able to diagnose variants of AD before they manifest clinically and before irreparable brain damage is done. To achieve this goal, robust and reliable biomarkers that reflect the pathogenesis of AD have to be implemented. This is of paramount importance because such biomarkers may provide clues to pathways that can be targeted for interventions aimed at disease prevention or improvement. Although much attention has focused on Aß as a major component of AD, Aß may be a less attractive target since an increasing amount of data has raised concerns about its causative role in AD. This review will be in two parts, this first part will deal with the current clinical knowledge and the questions raised by the Aß cascade hypothesis in the pathogenesis of AD and the second part will aim to synthesize our current knowledge and to discuss new data that suggest how immune alterations may contribute to the development of AD and may therefore provide beneficial targets in novel approaches for the treatment of AD.

Elusive Alzheimer's disease: can immune signatures help our understanding of this challenging disease? Part 2: new immune paradigm.

Alzheimer's disease (AD) is the most common form of dementia. Its most important pathological hallmarks are profound neuronal loss, presence of intracellular neurofibrillary tangles, and extracellular deposition of beta-amyloid protein (Aß) as beta-amyloid plaques. One of the most important risk factors for AD is age and with the increase of life-expectancy AD has become the most common form of dementia. The current "Holy Grail" is to be able to diagnose variants of AD before they manifest clinically and before irreparable brain damage is done. To be able to do so, we need robust and reliable biomarkers which reflect the pathogenesis of AD. This is essential because such biomarkers might indicate pathways that could be targeted for interventions aiming at disease prevention or amelioration. Although much attention has been focused on Aß in this respect, it may not be as attractive a target as thought if current doubts concerning its causative role are substantiated. This review will be in two parts, the first part dealt with the current clinical knowledge and the questions raised by the Aß cascade hypothesis in the pathogenesis of AD and this second part aims to synthesize our current knowledge and new data suggesting how immunity may contribute to the development of AD and may itself be targeted in future treatments.