A how-to guide for a precision medicine approach to the diagnosis and treatment of Alzheimer's disease.

Article purpose: The clinical approach to Alzheimer's disease (AD) is challenging, particularly in high-functioning individuals. Accurate diagnosis is crucial, especially given the significant side effects, including brain hemorrhage, of newer monoclonal antibodies approved for treating earlier stages of Alzheimer's. Although early treatment is more effective, early diagnosis is also more difficult. Several clinical mimickers of AD exist either separately, or in conjunction with AD pathology, adding to the diagnostic complexity. To illustrate the clinical decision-making process, this study includes de-identified cases and reviews of the underlying etiology and pathology of Alzheimer's and available therapies to exemplify diagnostic and treatment subtleties. Problem: The clinical presentation of Alzheimer's is complex and varied. Multiple other primary brain pathologies present with clinical phenotypes that can be difficult to distinguish from AD. Furthermore, Alzheimer's rarely exists in isolation, as almost all patients also show evidence of other primary brain pathologies, including Lewy body disease and argyrophilic grain disease. The phenotype and progression of AD can vary based on the brain regions affected by pathology, the coexistence and severity of other brain pathologies, the presence and severity of systemic comorbidities such as cardiac disease, the common co-occurrence with psychiatric diagnoses, and genetic risk factors. Additionally, symptoms and progression are influenced by an individual's brain reserve and cognitive reserve, as well as the timing of the diagnosis, which depends on the demographics of both the patient and the diagnosing physician, as well as the availability of biomarkers. Methods: The optimal clinical and biomarker strategy for accurately diagnosing AD, common neuropathologic co-morbidities and mimickers, and available medication and non-medication-based treatments are discussed. Real-life examples of cognitive loss illustrate the diagnostic and treatment decision-making process as well as illustrative treatment responses. Implications: AD is best considered a syndromic disorder, influenced by a multitude of patient and environmental characteristics. Additionally, AD existing alone is a unicorn, as there are nearly always coexisting other brain pathologies. Accurate diagnosis with biomarkers is essential. Treatment response is affected by the variables involved, and the effective treatment of Alzheimer's disease, as well as its prevention, requires an individualized, precision medicine strategy.

The tauopathies.

Tauopathies are a clinically and neuropathologically heterogeneous group of neurodegenerative disorders, characterized by abnormal tau aggregates. Tau, a microtubule-associated protein, is important for cytoskeletal structure and intracellular transport. Aberrant posttranslational modification of tau results in abnormal tau aggregates causing neurodegeneration. Tauopathies may be primary, or secondary, where a second protein, such as Aß, is necessary for pathology, for example, in Alzheimer's disease, the most common tauopathy. Primary tauopathies are classified based on tau isoform and cell types where pathology predominates. Primary tauopathies include Pick disease, corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain disease. Environmental tauopathies include chronic traumatic encephalopathy and geographically isolated tauopathies such as the Guam-Parkinsonian-dementia complex. The clinical presentation of tauopathies varies based on the brain areas affected, generally presenting with a combination of cognitive and motor symptoms either earlier or later in the disease course. As symptoms overlap and tauopathies such as Alzheimer's disease and argyrophilic grain disease often coexist, accurate clinical diagnosis is challenging when biomarkers are unavailable. Available treatments target cognitive, motor, and behavioral symptoms. Disease-modifying therapies have been the focus of drug development, particularly agents targeting Aß and tau pathology in Alzheimer's disease, although most of these trials have failed.

Cognitive Impairment in Aging Physicians: Current Challenges and Possible Solutions.

Aging physicians are at a higher risk of cognitive impairment, undermining patient safety and unraveling physicians' careers. Neurologists, occupational health physicians, and psychiatrists will participate in both health system policy decisions and individual patient evaluations. We address cognitive impairment in aging physicians and attendant risks and benefits. If significant cognitive impairment is found after an appropriate evaluation, precautions to confidentially support physicians' practicing safely for as long as possible should be instituted. Understanding that there is heterogeneity and variability in the course of cognitive disorders is crucial to supporting cognitively impaired, practicing physicians. Physicians who are no longer able to practice clinically have other meaningful options.

Antiviral Essential Oils Incorporated in Nanocarriers: Strategy for Prevention from COVID-19 and Future Infectious Pandemics.

BACKGROUND: Coronavirus has become a life-threatening disease and it is caused by severe acute respiratory syndrome (SARS). This new strain of coronavirus is not completely understood and to date, there is no treatment for coronavirus. Traditional ayurvedic medicines, mainly essential oils and Chinese herbs, have always played a vital role in the prevention and treatment of several epidemics and pandemics. In the meantime, guidelines of the ministry of AYUSH (Ayurveda, yoga, unani, siddha and homoepathy) include a traditional medicinal treatment for flu and fever and also recommended to boost immunity to prevent the spread of coronavirus. It is not possible to find which essential oil will offer the best level of protection. However, it is likely to assume that some essential oils are likely to offer a measurable level of defense in the same way they do with many other known viruses. METHODS: Literature relevant to various essential oils having antiviral activity has been collected and compiled. Various nanocarriers of essential oils have also been stated. The database was collected using various search engines such as J-Gate, Google Scholar, Sci-Hub, PubMed, ScienceDirect, etc. Results: Essential oils contain active constituents such as phenolic compounds, terpenoids, alkaloids, phenyl propanoids, etc., which are responsible for their biological properties such as antiviral, antibacterial, antimicrobial, antioxidant activities and many more. However, the use of essential oils has always been limited due to poor solubility, solvent toxicity, volatility and low solubility. Many nanotechnology based carriers especially, liposomes, dendrimers, nanoparticles, nanoemulsion and microemulsion, etc. have been evidenced to overcome limitations associated with essential oils. CONCLUSION: Several essential oils possess potent antiviral activity and are characterized by fewer side effects and are safe for human use. The nanocarrier systems of these oils have proved the potential to treat viral and bacterial infections. Lay Summary: Current COVID-19 era demands traditional treatment for immunity boost up as support therapy. Traditional ayurvedic medicines, mainly essential oils and Chinese herbs, have always played a vital role in the prevention and treatment of several epidemics and pandemics. Therefore, authors have summarized various essential oils having antiviral activity in current manuscript. Various nanocarriers of essential oils have been reported. Essential oils contain active constituents such as phenolic compounds, terpenoids, alkaloids, phenyl propanoids, etc., which are responsible for their biological properties such as antiviral, antibacterial, antimicrobial, antioxidant activity. However, the use of essential oils has always been limited due to poor solubility, solvent toxicity, volatility and low solubility. Many nanotechnology based carriers especially, liposomes, dendrimers, nanoparticles, nanoemulsion and microemulsion, etc. have been evidenced to overcome limitations associated with essential oils. The nanocarrier systems of these oils have proved the potential to treat viral and bacterial infections.

Heterogeneity of Alzheimer's disease: consequence for drug trials?

BACKGROUND: Alzheimer's disease is a heterogenous disorder with multiple phenotypes and genotypes, although they eventually converge to a final common clinicopathological endpoint. However, Alzheimer's disease drug trials do not account for the heterogeneity of the disease in trial design, impeding development of effective drugs. DISCUSSION: Alzheimer's disease drug trials commonly have wide inclusion criteria that subsume multiple subtypes of the condition, with varying genotypes, phenotypes, and clinical courses. The outcome variables used in many trials may not be sensitive for the particular disease subtype and trials may not follow patients for the appropriate length of time necessary for the subtype of disease. Methods of stratifying treatment trial design to account for disease heterogeneity using algorithms incorporating demographics, neuroimaging, genetics, and clinical phenotypes, as well as more tailored outcome measures, are proposed to allow for personalized, precision medicine in Alzheimer's disease therapeutics development. Approaching Alzheimer's disease as a heterogenous disorder will likely improve yield in the search for effective treatments for the condition.

Menopause-Related Cognitive Impairment.

BACKGROUND: Identifying the cognitive changes associated with the menopausal transition prevents misattribution of symptoms to more ominous causes such as neurodegenerative disease. CASE: Two women with cognitive loss and objective evidence of menopause-related cognitive impairment are presented, misattributed to Alzheimer disease in one case and frontotemporal dementia in the other. Neurocognitive testing, neuroimaging, and laboratory findings are reviewed. Both women were diagnosed with menopause-related cognitive impairment and were stable in follow-up over 4 or more years. CONCLUSIONS: Recognizing the cognitive changes associated with menopause and distinguishing from cognitive impairment resulting from other etiologies-including neurodegenerative diseases such as Alzheimer disease-has important clinical implications both for treatment and for prognosis.

CD151-A Striking Marker for Cancer Therapy.

Cluster of differentiation 151 (CD151) is a member of the mammalian tetraspanin family, which is involved in diverse functions such as maintaining normal cellular integrity, cell-to-cell communication, wound healing, platelet aggregation, trafficking, cell motility and angiogenesis. CD151 also supports de novo carcinogenesis in human skin squamous cell carcinoma (SCC) and tumor metastasis. CD151 interacts with α3ß1 and α6ß4 integrins through palmitoylation where cysteine plays an important role in the association of CD151 with integrins and non-integrin proteins. Invasion and metastasis of cancer cells were diminished by decreasing CD151 association with integrins. CD151 functions at various stages of cancer, including metastatic cascade and primary tumor growth, thus reinforcing the importance of CD151 as a target in oncology. The present review highlights the role of CD151 in tumor metastasis and its importance in cancer therapy.

Open-label, short-term, repetitive transcranial magnetic stimulation in patients with Alzheimer's disease with functional imaging correlates and literature review.

BACKGROUND: Accumulating evidence suggests repetitive transcranial magnetic stimulation (rTMS) may be beneficial in ameliorating cognitive deficits in Alzheimer's disease (AD). METHODS: AD patients received four high-frequency rTMS sessions over the bilateral dorsolateral prefrontal cortex (DLPFC) over two weeks. Structured cognitive assessments were administered at baseline, at 2 weeks after completion of rTMS, and at 4 weeks post treatment. At these same times, tolerant patients underwent functional magnetic resonance imaging (fMRI) while performing structured motor and cognitive tasks. We also reviewed literature regarding the effects of rTMS on cognitive function in AD. RESULTS: A total of 12 patients were enrolled, eight of whom tolerated the fMRI. Improvement was seen in Boston Diagnostic Aphasia Examination tests of verbal and non-verbal agility 4 weeks post-treatment. The fMRI analysis showed trends for increased activation during cognitive performance tasks immediately after and at 4 weeks post-treatment. Our literature review revealed several double-blind, sham-controlled studies, all showing sustained improvement in cognition of AD patients with rTMS. CONCLUSIONS: There was improvement in aspects of language after four rTMS treatments, sustained a month after treatment cessation. Our results are consistent with other studies and standardization of treatment protocols using functional imaging may be of benefit.

Current attitudes on self-use and prescription of hormone therapy among New York City gynaecologists.

OBJECTIVE: The results of the Women's Health Initiative studies dramatically altered hormone therapy use around the world. In countries outside the United States, self-use in physicians remained unaltered while prescription use declined, implying that physicians may not concur with the findings. We wished to explore prevailing attitudes among American physicians by examining New York City obstetrician-gynaecologists' self-use and prescription use of hormone therapy. STUDY DESIGN: All board-certified obstetrician-gynaecologists in New York City were invited to complete and return a detailed, previously validated questionnaire concerning hormone therapy use. RESULTS: Two hundred and nine questionnaires were returned, for a response rate of 12% (209/1797). Gynaecologists agreed with the findings from the Women's Health Initiative studies regarding indications and contraindications to hormone therapy use. Even so, three-quarters of female gynaecologists and female partners of male gynaecologists (74%; 67/91) use or have previously used hormone therapy. However, only 27.3% (21/77) of male gynaecologists and 12.3% (14/114) of female gynaecologists recommend hormone therapy to all menopausal women regardless of contraindications. Gynaecologists remain divided in their attitude toward hormone therapy; 30% of gynaecologists felt that hormone therapy use generally prolonged women's lives, 36% felt it was not useful in prolonging women's lives, and 33% were unsure. CONCLUSION: Since the publication of the Women's Health Initiative findings, New York City gynaecologists prescribe hormone therapy to fewer patients. However, they continue to self-use hormone therapy at much higher rates, even as they seem to concur with Women's Health Initiative recommendations, contributing to the ongoing controversy surrounding the validity of the Women's Health Initiative findings.

Which presidents are most memorable?

BACKGROUND/RATIONALE: Episodic memory loss is a hall-mark of Alzheimer's disease (AD), with recall of recent events becoming progressively difficult. A commonly used tool, the recollection of US presidents, was assessed in evaluating episodic versus semantic memory loss among AD patients compared with spouse controls. METHODS: A total of 36 patients (12 men, 24 women) with possible or probable AD were asked to "give the names of 5 US presidents" and concurrently administered the Mini-Mental State Examination (MMSE). Twenty-three spouses (12 men, 11 women) were controls. The year 1980 demarcated "remote" versus "recent" presidents. RESULTS: Patients were older, had lower MMSE scores (P < .001), and recalled fewer presidents than controls (P < .005), after controlling for age. Among patients, men were more educated than women (P < .05) and recalled more presidents (P < .001). No gender differences were observed in controls. CONCLUSIONS: Patients with AD preferentially recalled remote presidents, supporting retention of semantic memory in this group. There were no gender differences between groups.