Novel Targets and Interventions for Cognitive Complications of Diabetes

Diabetes and cognitive dysfunction, ranging from mild cognitive impairment to dementia, often coexist in individuals over 65 years of age. Vascular contributions to cognitive impairment/dementia (VCID) are the second leading cause of dementias under the umbrella of Alzheimer’s disease and related dementias (ADRD). Over half of dementia patients have VCID either as a single pathology or a mixed dementia with AD. While the prevalence of type 2 diabetes in individuals with dementia can be as high as 39% and diabetes increases the risk of cerebrovascular disease and stroke, VCID remains to be one of the less understood and less studied complications of diabetes. We have identified cerebrovascular dysfunction and compromised endothelial integrity leading to decreased cerebral blood flow and iron deposition into the brain, respectively, as targets for intervention for the prevention of VCID in diabetes. This review will focus on targeted therapies that improve endothelial function or remove iron without systemic effects, such as agents delivered intranasally, that may result in actionable and disease-modifying novel treatments in the high-risk diabetic population.

An Overview of Combination Treatment with Citicoline in Dementia

Introduction: The present article reports an overview of the studies about combination treatment with citicoline of Alzheimer’s (AD) and mixed dementia (MD). Methods: A Medline search was carried out by using the keywords Alzheimer’s dementia, mixed dementia, older people, treatment with citicoline, memantine, and acetylcholinesterase inhibitors (AchEIs). Results: Six studies were found to match the combination treatment of citicoline with AcheIs and/or memantine. The CITIRIVAD and CITICHOLINAGE studies were the first to report the potential benefits of adding citicoline to acetylcholinesterase inhibitors (AchEIs). Then, we added citicoline to memantine in the CITIMEM study, and finally, we demonstrated benefits in terms of delay in cognitive worsening with the triple therapy (citicoline + AchEIs + memantine). Other authors also reinforced our hypothesis through two further studies. Conclusions: Open, prospective studies are advised to confirm the utility of combination therapy with citicoline for the treatment of AD and MD.

Behavioral Interventions in Long-Term Care Facilities during the COVID-19 Pandemic: A Case Study

During the COVID-19 pandemic, long-term care (LTC) centers have adopted a series of measures that have affected the physical and cognitive health of patients. The routines of the patients, as well as the interventions of professionals, have been altered. In the case presented here, our aim was to explain the effect that the strong confinement due to the spread of the first COVID-19 wave in Spain had on a 75-year-old resident in an LTC center, with cognitive and behavioral symptomatology compatible with a diagnosis of mixed dementia, as well as the measures that the center adopted to manage the lockdown situation in the best possible way, including personalized attention protocols and a video call program. Different nosological hypotheses are also raised using a semiological analysis, including the analysis of the initial and continuation diagnostic protocols, as well as the therapeutic options.

High fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner.

Approximately 70% of Alzheimer's disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3x more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet for 3 months prior to behavior assessment. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, HF diet caused greater accumulation of amyloid beta in MxD females compared to MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. In conclusion, high fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women.

Reliability of Addenbrooke's Cognitive Examination III in differentiating between dementia, mild cognitive impairment and older adults who have not reported cognitive problems

Diagnosing dementia can be challenging for clinicians, given the array of factors that contribute to changes in cognitive function. The Addenbrooke’s Cognitive Examination III (ACE-III) is commonly used in dementia assessments, covering the domains of attention, memory, fluency, visuospatial and language. This study aims to (1) assess the reliability of ACE-III to differentiate between dementia, mild cognitive impairment (MCI) and controls and (2) establish whether the ACE-III is useful for diagnosing dementia subtypes. Client records from the Northern Health and Social Care Trust (NHSCT) Memory Service (n = 2,331, 2013–2019) were used in the analysis including people diagnosed with Alzheimer’s disease (n = 637), vascular dementia (n = 252), mixed dementia (n = 490), MCI (n = 920) and controls (n = 32). There were significant differences in total ACE-III and subdomain scores between people with dementia, MCI and controls (p < 0.05 for all), with little overlap between distribution of total ACE-III scores (< 39%) between groups. The distribution of total ACE-III and subdomain scores across all dementias were similar. There were significant differences in scores for attention, memory and fluency between Alzheimer’s disease and mixed dementia, and for visuospatial and language between Alzheimer’s disease–vascular dementia (p < 0.05 for all). However, despite the significant differences across these subdomains, there was a high degree of overlap between these scores (> 73%) and thus the differences are not clinically relevant. The results suggest that ACE-III is a useful tool for discriminating between dementia, MCI and controls, but it is not reliable for discriminating between dementia subtypes. Nonetheless, the ACE-III is still a reliable tool for clinicians that can assist in making a dementia diagnosis in combination with other factors at assessment.

Inflammatory Biomarkers Aid in Diagnosis of Dementia

Dual pathology of Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) commonly are found together at autopsy, but mixed dementia (MX) is difficult to diagnose during life. Biological criteria to diagnose AD have been defined, but are not available for vascular disease. We used the biological criteria for AD and white matter injury based on MRI to diagnose MX. Then we measured multiple biomarkers in CSF and blood with multiplex biomarker kits for proteases, angiogenic factors, and cytokines to explore pathophysiology in each group. Finally, we used machine learning with the Random forest algorithm to select the biomarkers of maximal importance; that analysis identified three proteases, matrix metalloproteinase-10 (MMP-10), MMP-3 and MMP-1; three angiogenic factors, VEGF-C, Tie-2 and PLGF, and three cytokines interleukin-2 (IL-2), IL-6, IL-13. To confirm the clinical importance of the variables, we showed that they correlated with results of neuropsychological testing.

IS THYROID ASSOCIATED WITH DEMENTIA? A CASE CONTROL STUDY

Objectives: The present study was undertaken with an objective to explore if thyroid is related to dementia among participants aged 45 years and above. Design: Participants aged more than 45 years of age, giving written informed consent and meeting the selection criteria were enrolled in the study. The participants were administered with a series of paper pencil tests. The data was further analyzed for any association using the Statistical Package for Social Sciences, version 22 (SPSS 22). Setting: Participants attending the Outpatient Department (OPD) at Institute of Human Behaviour and Allied sciences (IHBAS), a tertiary care neuropsychiatric hospital and normal elderly controls from local community. Participants: A sample size of at least 40 cases of Dementia of Alzheimer type and at least 40 cases of vascular/ mixed dementia and 60 normal controls were recruited. Measurements: Semi-structured Performa for demographic and clinical variables; Hindi mental status examination (HMSE) for cognitive functions was applied as screening tools for both case and control groups;Tools for patients with dementia: NINCDS-ADRDA criteria for Probable Alzheimer's disease (McKhann et al), NINDS /AIREN criteria for diagnosis of probable vascular dementia (VaD), NINDS-AIREN diagnostic criteria for “Alzheimer's disease with Cerebro-Vascular Disease” (mixed dementia), Clinical Dementia Rating Scale (Morris et al 1997), and 5 ml blood sample collection and analysis through vein puncture. Results: The results of the study indicate that subclinical hypothyroidism is associated with dementia of Alzheimer type. Conclusion: When considered in light with varied ndings of prior studies, it may be implied that subclinical thyroid dysfunction not especially hypo or hyperthyroidism is a risk for DAT.

Olfactory Bulb Proteomics Reveals Widespread Proteostatic Disturbances in Mixed Dementia and Guides for Potential Serum Biomarkers to Discriminate Alzheimer Disease and Mixed Dementia Phenotypes

The most common form of mixed dementia (MixD) is constituted by abnormal protein deposits associated with Alzheimer’s disease (AD) that coexist with vascular disease. Although olfactory dysfunction is considered a clinical sign of AD-related dementias, little is known about the impact of this sensorial impairment in MixD at the molecular level. To address this gap in knowledge, we assessed olfactory bulb (OB) proteome-wide expression in MixD subjects (n = 6) respect to neurologically intact controls (n = 7). Around 9% of the quantified proteins were differentially expressed, pinpointing aberrant proteostasis involved in synaptic transmission, nucleoside monophosphate and carbohydrate metabolism, and neuron projection regeneration. In addition, network-driven proteomics revealed a modulation in cell-survival related pathways such as ERK, AKT, and the PDK1-PKC axis. Part of the differential OB protein set was not specific of MixD, also being deregulated across different tauopathies, synucleinopathies, and tardopathies. However, the comparative functional analysis of OB proteome data between MixD and pure AD pathologies deciphered commonalities and differences between both related phenotypes. Finally, olfactory proteomics allowed to propose serum Prolow-density lipoprotein receptor-related protein 1 (LRP1) as a candidate marker to differentiate AD from MixD phenotypes.

Baseline ECGs done in memory clinics in Leicestershire

AimsTo ascertain the compliance of the Mental Health Service of Older People (MHSOP) memory clinics in obtaining ECGs, based on the agreed criteria.BackgroundCholinesterase inhibitors are a main pharmacological treatment for Alzheimer's dementia (AD). These drugs may worsen pre-existing cardiac conditions or cause significant cardiac side effects. A baseline ECG can be beneficial before starting patients on these medications. Previously in Leicestershire, all memory clinic patients were receiving routine ECGs. However, new standards were set based on the NICE guidelines and criteria outlined in other regions, to reduce the use of this time consuming and expensive investigation for patients who may not require it.MethodA total of 120 patients attending memory clinics in Leicestershire over a 6 month period (April to September 2019), were randomly selected and their electronic records retrospectively reviewed. The data collection tool was designed to encompass the key aspects of the criteria for obtaining an ECG for those attending the memory clinic. The information was analysed using Microsoft Excel.ResultOf the 120 patients, 23 (19.2%) were diagnosed with AD, 10 (8.33%) with mixed and 19 (15.8%) with vascular dementia. 68 (56.7%) had a diagnosis of “other” which included mild cognitive impairment or diagnosis still under investigation. 0 patients were diagnosed with Lewy Body Dementia or Parkinson's dementia. Of the total number of patients, only 10 had an ECG done, 2 with a diagnosis of AD, 1 with mixed dementia, 1 with vascular dementia and 6 “other”. The 10 ECGs done were all requested by nursing staff.Although 27 (22.5%) patients were identified to have a diagnosis of AD or mixed dementia, plus at least one of the criteria for an ECG, only 6 (22.2%) were discussed with the Multi-Disciplinary Team (MDT) following which only 3 of the 27 patients (11.1%) had an ECGConclusionDespite having clear criteria for requesting an ECG for those attending the memory clinic, compliance over the 6 month period was low. The following recommendations may be useful in improving compliance:Displaying the ECG algorithm in the memory service clinic rooms.Raise awareness amongst memory service clinicians of the criteria for requesting ECGs.