Meningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.

This paper describes the effects of the gut microbiota on the pathogenesis of Alzheimer's pathology by evaluating the current original key findings and identifying gaps in the knowledge required for validation. The diversity of the gut microbiota declines in the elderly and in patients with Alzheimer's disease (AD). Restoring the diversity with probiotic treatment alleviates the psychiatric and histopathological findings. This presents a problem: How does gut microbiota interact with the pathogenesis of AD? The starting point of this comprehensive review is addressing the role of bacterial metabolites and neurotransmitters in the brain under various conditions, ranging from a healthy state to ageing and disease. In the light of current literature, we describe three different linkages between the present gut microbiome hypothesis and the other major theories for the pathogenesis of AD as follows: bacterial metabolites and amyloids can trigger central nervous system inflammation and cerebrovascular degeneration; impaired gut microbiome flora inhibits the autophagy‐mediated protein clearance process; and gut microbiomes can change the neurotransmitter levels in the brain through the vagal afferent fibres.

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Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2) has been shown to invade brain tissue. Based on the evolutionary similarity with SARS-CoV, researchers propose that SARS-CoV-2 can invade the olfactory bulb and gastrointestinal (GI) system through angiotensin-converting enzyme 2. However, how SARS-CoV-2 causes neurological or GI symptoms is not clear. Many suggested intestinal and neural inflammations, caused by viral invasion, as the most likely reason for the GI and neurological symptoms; however, the patients with coronavirus disease 2019 (COVID-19) without neurological or GI symptoms indicate that this is not the case. The gut-brain axis could explain the reason for why some with COVID-19 do not have these symptoms. COVID-19 patients mostly show respiratory distress first, then diarrhea, anorexia, stroke, or loss of consciousness comes into view. Obviously, GI invasion is a mechanical process that begins with oral invasion and, therefore, most probably exists before the brain invasion, as indicated in case reports. However, when the GI tract is invaded, the virus may enter the central nervous system through vascular and lymphatic systems or the vagal nerve. SARS-CoV-2 can infect leukocytes and migrate with them into the brain, or the viral particles can be directly transported across the blood-brain barrier to the brain. Also, more recent research has revealed that SARS-CoV-2 can invade the peripheral lymphatic vessels connecting with the glymphatic system of the brain. The temporal correlation between neurological and gastrointestinal symptoms suggests the lymph vessels around the GI tract, the vascular system, or the gut-brain axis (enteric nervous system) as the most likely entry route for SARS-CoV-2 to the brain.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus infectious disease 2019 (COVID-19), which was first reported in Wuhan, China, in late December, 2019. Despite the tremendous efforts to control the disease, SARS-CoV-2 has infected 1,5 million people and caused the death of more than a hundred thousand people across the globe as of writing. Recently, Mao et al. [1] investigated the penetration potential of SARS-CoV-2 into the central nervous system in 214 patients. They reported that 36.4% of the patients had some neurologic findings which are ranged from nonspecific manifestations, e.g., dizziness, headache, and seizure, to specific manifestations, e.g., loss of sense of smell or taste, and stroke. Whether these common symptoms in their patients are related to SARS-CoV-2 infection is not known. However, it is important to mention here that dramatic neurologic symptoms, i.e., depressed level of consciousness, seizure, and stroke, are common in the patients at the late stage of the disease, accounting for increased mortality rate in severely affected patients. Nevertheless, to objectively delve into the direct relation between the neurologic symptoms and COVID-19, medical comorbidities of patients should also be considered [2]. Further studies are needed because we are in the midst of an ongoing pandemic of COVID-19, and neurologists may be confronted with new-onset neurologic symptoms owing to COVID-19. SARS-CoV-2 penetrates via human angiotensin-converting enzyme-2 receptor (ACE-2) that was also utilized by severe acute respiratory syndrome coronavirus (SARS CoV) [3]. Glial cells and neurons have been reported to express ACE-2 receptors, which make them a potential target of COVID-19. It was indicated that SARS CoV causes neuronal death by invading the brain via olfactory epithelium [4]. The electron microscopy, immunohistochemistry, and real-time reverse transcription- PCR findings have corroborated the presence of SARS-CoV in the brain tissue [4] and cerebrospinal fluid [5]. Together, it can be speculated that SARS-CoV-2 can affect the brain by penetrating the brain via the cribriform plate, which can account for the early findings of the COVID-19 like altered sense of smell or hyposmia. Because SARS-CoV-2 causes severe respiratory symptoms in people aged 60 years and older, it has important implications for patients with Alzheimer’s disease (AD) [6]. Therefore, in the countries that have taken action to the virus, clinic studies of AD have been stopped to protect the patients. However, rigorous quarantine of elders has aborted clinic trials and experimental studies conducted with transgenic animals. Transgenic models are quite expensive; the loss of these animals has costly consequences. There is no doubt that this storm will stop, but its catastrophic effects on dementia research will continue for a time. Thus, dementia researchers and pharmaceutical companies should determine an emergency action plan to exit the chaos of this pandemic. Here, we listed some challenges in dementia research during the COVID-19 outbreak and table some suggestions. All countries try to control SARS-CoV-2 by social distancing. Therefore, neurology clinics were closed, and routine examination of Alzheimer’s patients was stopped. However, the lockdown of patients with AD caused clinical studies to stop. which has severely affected dementia research. Additionally, the arrest of experimental studies due to the closing of universities in two hundred countries also deprives experimental achievements. The closing of universities may lead to data loss, death of expensive transgenic animals, international researchers to be faced with visa problems, and be lost the laboratory staff whose contract has expired [7]. It is impossible that forecasting when this COVID-19 pandemic will end is impossible and thus, it is essential that a solution be developed to continue dementia studies on Alzheimer’s patients. Remote monitoring of the patients with the use of technology is in the lead of possible solutions. Clinicians can continue to follow their patients by telemedicine [8], but extended lockdown of patients may cause depression in both patients and their caregivers [9]. It is also known that movement restriction exacerbates AD symptoms [10]. The monitorization of the patient in this condition with telemedicine would not provide objective data. In addition, when patients living in rural areas are considered, it will not be a surprise that reaching equally all patients is impossible. Therefore, a collective action plan protecting dementia research during the COVID-19 outbreak should be prepared by a consortium of pharmaceutical companies, researchers, clinicians, and patients. Data loss is in the lead of expected problems during the COVID-19 outbreak. For example, the planned ending dates of phase 2/3 trials of gantenerumab (Roche) and solanezumab (Lilly) were missed [11]. It is highly essential that patients be monitored from their homes with telemedicine to protect them. Nonetheless, it is not sufficient for the continuation of clinical trials and experimental studies. We suggest that patients of phase trails should be isolated in fully-equipped nursing homes managed by qualified personnel. In this way, the patients can be more effectively protected from SARS-CoV-2 and the depression caused by the lockdown.Young family members going out for basic needs could infect older family members. Also, patients with AD pay less attention to hand hygiene, which makes them more susceptible to SARS-CoV-2. Moreover, cats have recently been shown to be infected by SARS-CoV-2 [12]. Patients with AD may not follow directions of neurologists on telemedicine and thus, the interaction of Alzheimer’s patients with pets can cause a dangerous scenario. Consequently, the lockdown of patients with dementia in their homes might not be an appropriate exit strategy for the future of dementia research. On the other hand, it is important to mention here that the nursing home capacity of the United States may not be sufficient for 5,8 million Alzheimer’s patients aged 65 years and older [13]. Thus, we highlight that only the patients involved in the clinic trails should be followed in the nursing homes. The other patients can be monitored with telemedicine from their homes. The data will hardly be lost in patients isolated in nursing homes. In this strategy, secondary risk factors affecting the clinic trails like depression are also removed. The motivations of clinicians and researchers is as important as the patients in the catastrophic atmosphere of the outbreak. Governments, media, and funders can support the motivations of clinicians and researchers. For example, research funders and pharmaceutical companies can extend project deadlines and provide an additional promotion to the researchers who have completed their clinic trails. Consequently, a global action plan should be prepared to block SARS-CoV-2 penetration to dementia research. At first glance, it may be thought that the most appropriate strategy for patients with dementia is social isolation in their homes during the outbreak as in healthy young people and elders. However, we suggest that isolating patients with dementia in fully-equipped nursing homes can be a more appropriate exit strategy for the protection of dementia patients and research.

How are memories stored and retrieved? It was one of the most discussed questions in the past century by neuroscientists. Leading studies of the period brought two different explanations to this question: The first statement considers memory as a physiological change in the brain and suggest that the retrieval of memory is only occurred by the same physiologic changes observed during the memory formation, while the second suggests that memory is a psychic mood stored in mind and the retrieval of memory is occurred by mystical energy fluctuations. Although the exact reason and the pathogenesis of Alzheimer's disease have not yet been fully understood, the approaches that centered the retrieval strategy of lost memory constitutes the basis of the treatment strategies in Alzheimer's disease today. The majority of treatment studies has based on the manipulation of the cholinergic system; however, although serotonin has mnemonic effects, its role in the pathogenesis of Alzheimer's disease has not been investigated as much as the cholinergic system. Here we show how serotonin affects the pathogenesis of Alzheimer's disease in a comprehensive perspective and we suggest that the optogenetics manipulation of serotonin nuclei retrieve the lost memory by closing the inward-rectifier potassium channel Kir2 on the memory engram cells. Also, we raise the possible effects of serotonin on the memory engram cells and the interactions between the amyloid-centric hypothesis of Alzheimer's disease and the memory engram hypothesis to explain the pathophysiology of memory loss in Alzheimer's disease.

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