Moderate Alzheimer's Disease Research Articles

Rivastigmine nasal spray for the treatment of Alzheimer’s Disease: Olfactory deposition and brain delivery

Alzheimer’s disease (AD) is characterized by a gradual decline in cognitive function and memory impairment, significantly impacting the daily lives of patients. Rivastigmine (RHT), a cholinesterase inhibitor, is used to treat mild to moderate AD via oral administration. However, oral administration is associated with slow absorption rate and severe systemic side effects. RHT nasal spray (RHT-ns), as a nose-to-brain delivery system, is more promising for AD management due to its efficient brain delivery and reduced peripheral exposure. This study constructed RHT-ns for enhancing AD treatment efficacy, and meanwhile the correlation between drug olfactory deposition and drug entering into the brain was explored. A 3D-printed nasal cast was employed to quantify the drug olfactory deposition. Brain delivery of RHT-ns was quantified using fluorescence tracking and Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) analysis, which showed a good correlation to the olfactory deposition. F2 (containing 1% (w/v) viscosity modifier Avicel® RC-591) with high olfactory deposition and drug brain delivery was further investigated for pharmacodynamics study. F2 exhibited superiority in AD treatment over the commercially available oral formulation. In summary, the present study showed the successful development of RHT-ns with improved olfactory deposition and enhanced brain delivery. It might provide new insight into the design and development of nose-to-brain systems for the treatment of AD.

Mental states in caregivers toward people with Alzheimer's disease at different stages.

Caring for people with Alzheimer's disease (AD) is burdensome, especially when family members act as caregivers. This multicenter survey first aimed to investigate caregivers' mental states as well as its influencing factors in caring for people with different severities of AD in China. People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for caregivers' mental states and living conditions, as well as caregivers' attitudes toward treatment and caring. Logistic regression was used to explore the factors that influence the positive and negative states of caregivers who care for people with different stages of AD. A total of 1,966 valid questionnaires were analyzed (mild AD: 795, moderate AD: 521, severe AD: 650). A total of 73.6% of caregivers maintained normal states (mild group: 71.9%, moderate group: 73.9%, severe group: 75.2%; X2 = 2.023, p = 0.364), and the proportions of caregivers with positive and negative states were 26.3% (mild group: 38.4%, moderate group: 24.6%, severe group: 13.1%; X2 = 119.000, p < 0.001) and 36.5% (mild group: 25.2%, moderate group: 36.9%, severe group: 50.2%; X2 = 96.417, p < 0.001), respectively. The major factors that both influenced caregivers' positive and negative states were the severity of AD, perceived efficacy of treatment, safety issues after AD dementia diagnosis and perceived social support (p < 0.005), while neuropsychiatric symptoms causing stress in caregivers (p < 0.001) only affected the negative states of caregivers. The results of further analysis according to disease severity showed that safety issues after AD dementia diagnosis (p < 0.005) only made significant differences in the mild-to-moderate group. To reduce negative states and promote positive states among caregivers, flexible and sensitive caregiving support could be built on caregivers' demands in caring for people with different stages of AD. The support of emotion, social functioning and nursing skills is one of the significant ways for health workers to enhance caregivers' competency.

Visual function changes along the continuum of Alzheimer's disease

Aims/Purpose: The progression of Alzheimer's disease (AD) is manifested by a gradual transition from a preclinical phase, characterized by asymptomatic pathological alterations, to an advanced phase of AD accompanied by cognitive impairment. The aim of this study was to explore visual function along the entire AD continuum.Methods: Each participant underwent a comprehensive visual examination, with only visually healthy individuals being selected for the study. The study comprised the following groups: controls (n = 53), positive family history of AD (FH+) (n = 13), mild cognitive impairment (MCI) (n = 23), mild AD (n = 25), and moderate AD (n = 21). The study analysed the results of visual acuity (VA) and contrast sensitivity (CS).Results: A significant reduction in VA was identified between the control group and the MCI, mild AD and moderate AD groups. CS showed significant changes in all cognitive impairment groups compared to the control group and the FH+ group at spatial frequencies of 12 and 18 cpd. In contrast, significant differences were only observed at spatial frequencies of 3 and 6 cpd between the cognitively impaired groups, starting from moderate AD, with no detectable decrease in CS during the MCI phase. No differences were detected between the control group and the FH+ group. The tests showed a positive correlation with the Mini Mental State Examination score and exhibited a favourable predictive ability in the presence of memory impairment, with higher predictive performance observed in the advance stages of AD.Conclusions: The presence of alterations in VA and CS can be observed as early as the MCI stage in individuals with AD. Recognizing the continuum of AD holds significant significance in early detection, with visual examination offering a straightforward and cost‐effective diagnostic tool for AD. Healthcare professionals can leverage this knowledge to gain a better understanding of the progressive nature of the disease.

An Open-Label, Pilot Study of Daratumumab SC in Mild to Moderate Alzheimer's Disease.

We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer's disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures.

Changes in colour perception in Alzheimer's disease continuum

Aims/Purpose: The progression of Alzheimer's disease (AD) manifests from a preclinical stage, characterized by asymptomatic pathological alterations, to an advanced stage of AD accompanied by cognitive impairment. The aim of this study was to explore visual function along the entire AD continuum, from individuals with a high genetic predisposition to those in the moderate phase of the disease.Methods: All participants underwent a visual examination and had to be visually healthy to be included. The study contained five groups: controls (n = 53), individuals with a positive family history of AD (HF+) (n = 13), mild cognitive impairment (MCI) (n = 23), mild AD (n = 25) and moderate AD (n = 21). The study analysed the results of errors in colour perception.Results: A significant increase in the total number of errors was observed between the control group and the moderate AD group. And also when comparing the FH+ group with the MCI group, the mild AD group and the moderate AD group. Significant differences were found on the tritan axis between the control group and the mild AD group, as well as in the moderate AD group. Significant differences were observed between the FH+ group and the mild AD group, as well as in the moderate AD group. A significant increase in the number of errors on the deutan axis was observed between the control group and both the mild and moderate AD groups. In addition, a statistically significant increase was observed when comparing the FH+ group with the moderate AD group. The test correlated with the MMSE score and also showed good predictive value when memory impairment was present.Conclusions: Understanding the importance of changes in colour perception in AD continuum can aid in the early detection and treatment of AD, potentially improving patient outcomes and facilitating targeted interventions.

Verification of the Physiological Therapeutic Effects of Harvesting Activities in a Patient with Moderate Alzheimer&amp;#8217;s Disease with Long-Term Agricultural Experience

Verification of the Physiological Therapeutic Effects of Harvesting Activities in a Patient with Moderate Alzheimer&amp;#8217;s Disease with Long-Term Agricultural Experience

The Association Between Brain Metabolic Biomarkers Using 18F-FDG and Cognition and Vascular Risk Factors, as well as Its Usefulness in the Diagnosis and Staging of Alzheimer's Disease.

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is valuable in Alzheimer's disease (AD) workup. To explore the effectiveness of 18F-FDG PET in differentiating and staging AD and associations between brain glucose metabolism and cognitive functions and vascular risk factors. 107 participates including 19 mild cognitive impairment (MCI), 38 mild AD, 24 moderate AD, 15 moderate-severe AD, and 11 frontotemporal dementia (FTD) were enrolled. Visual and voxel-based analysis procedures were utilized. Cognitive conditions, including 6 cognitive function scores and 7 single-domain cognitive performances, and vascular risk factors linked to hypertension, hyperlipidemia, diabetes, and obesity were correlated with glucose metabolism in AD dementia using age as a covariate. 18F-FDG PET effectively differentiated AD from FTD and also differentiated MCI from AD subtypes with significantly different hypometabolism (except for mild AD) (height threshold p < 0.001, all puncorr < 0.05, the same below). The cognitive function scores, notably Mini-Mental State Examination and Montreal Cognitive Assessment, correlated significantly with regional glucose metabolism in AD participants (all p < 0.05), whereas the single-domain cognitive performance and vascular risk factors were significantly associated with regional glucose metabolism in MCI patients (all p < 0.05). This study underlines the vital role of 18F-FDG PET in identifying and staging AD. Brain glucose metabolism is associated with cognitive status in AD dementia and vascular risk factors in MCI, indicating that 18F-FDG PET might be promising for predicting cognitive decline and serve as a visual framework for investigating underlying mechanism of vascular risk factors influencing the conversion from MCI to AD.

Transcranial blood-brain barrier opening in Alzheimer's disease patients using a portable focused ultrasound system with real-time 2-D cavitation mapping.

Background : Focused ultrasound (FUS) in combination with microbubbles has recently shown great promise in facilitating blood-brain barrier (BBB) opening for drug delivery and immunotherapy in Alzheimer's disease (AD). However, it is currently limited to systems integrated within the MRI suites or requiring post-surgical implants, thus restricting its widespread clinical adoption. In this pilot study, we investigate the clinical safety and feasibility of a portable, non-invasive neuronavigation-guided FUS (NgFUS) system with integrated real-time 2-D microbubble cavitation mapping. Methods : A phase 1 clinical study with mild to moderate AD patients (N = 6) underwent a single session of microbubble-mediated NgFUS to induce transient BBB opening (BBBO). Microbubble activity under FUS was monitored with real-time 2-D cavitation maps and dosing to ensure the efficacy and safety of the NgFUS treatment. Post-operative MRI was used for BBB opening and closure confirmation as well as safety assessment. Changes in AD biomarker levels in both blood serum and extracellular vesicles (EVs) were evaluated, while changes in amyloid-beta (Aβ) load in the brain were assessed through 18F-florbetapir PET. Results : BBBO was achieved in 5 out of 6 subjects with an average volume of 983 ± 626 mm3 following FUS at the right frontal lobe both in white and gray matter regions. The outpatient treatment was completed within 34.8 ± 10.7 min. Cavitation dose significantly correlated with the BBBO volume (R 2 > 0.9, N = 4), demonstrating the portable NgFUS system's capability of predicting opening volumes. The cavitation maps co-localized closely with the BBBO location, representing the first report of real-time transcranial 2-D cavitation mapping in the human brain. Larger opening volumes correlated with increased levels of AD biomarkers, including Aβ42 (R 2 = 0.74), Tau (R 2 = 0.95), and P-Tau181 (R 2 = 0.86), assayed in serum-derived EVs sampled 3 days after FUS (N = 5). From PET scans, subjects showed a lower Aβ load increase in the treated frontal lobe region compared to the contralateral region. Reduction in asymmetry standardized uptake value ratios (SUVR) correlated with the cavitation dose (R 2 > 0.9, N = 3). Clinical changes in the mini-mental state examination over 6 months were within the expected range of cognitive decline with no additional changes observed as a result of FUS. Conclusion : We showed the safety and feasibility of this cost-effective and time-efficient portable NgFUS treatment for BBBO in AD patients with the first demonstration of real-time 2-D cavitation mapping. The cavitation dose correlated with BBBO volume, a slowed increase in pathology, and serum detection of AD proteins. Our study highlights the potential for accessible FUS treatment in AD, with or without drug delivery.

Difficulties in Assessing the Economic Burden of Alzheimer's Disease

Background. Age-related changes associated with the decrease in health and autonomy drastically increase the cost of medical care, maintenance and treatment. Late detection of ilnesses is the root cause of escalating the economic weight from age-related diseases, causing a surge in costs for the recovery, treatment and care of those needing outside assistance. One of the age-associated diseases is Alzheimer's disease. Alzheimer's disease is one of the many manifestations of age-related dementia, accompanied by a violation of human cognitive abilities. This cluster of diseases does not affect other systems (cardiovascular, musculoskeletal, digestive), and they can operate normally. An important effect of this disease for society is the impossibility of conducting a full-fledged work activity, as memory, attention, etc. are disturbed. That is, with absolutely normally functioning body systems, a person cannot perform the simplest operations. Another important feature is the lack of an effective way to treat this disease. The pathogenesis is so complex that today there is no method of treatment aimed at all links. Also of great importance is the timeliness of detection of this disease. Due to the fact that recently there were test systems and express diagnostics for the early detection of Alzheimer's disease, it became possible to start treatment earlier, which increased the chances of recovery and reduced treatment costs in case of diagnosing moderate and severe Alzheimer's disease gravity. Aim. Revealing the difficulties of assessing the economic burden of Alzheimer's Disease. Materials and methods. To identify the difficulties of assessing the economic burden, free sources, publications on Alzheimer's disease, data from clinical guidelines, the standard for providing medical care to elderly and senile patients with cognitive disorders, information on maximum selling prices registered and included in the State Register of Vital and Essential Drugs Prices, statistical data, compulsory health insurance tariffs. Results. The main problematic issues of the difficulty of assessing the economic burden of Alzheimer's disease are identified. Conclusion. Diseases of the nervous system are of particular importance for the health of the patient, since disorders affecting this system do not allow the patient to fully and fully fulfill their labor duties. In this regard, the development of a method for assessing the cost-effectiveness of Alzheimer's disease, as one of the most common disorders of cognitive functions, is an extremely important social task aimed at optimizing the treatment process, early detection and effective treatment aimed at recovery.

Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease

We report the case of a 79-year-old woman with Alzheimer’s disease who participated in a Phase III randomized controlled trial called CLARITY-AD testing the experimental drug lecanemab. She was randomized to the placebo group and subsequently enrolled in an open-label extension which guaranteed she received the active drug. After the third biweekly infusion, she suffered a seizure characterized by speech arrest and a generalized convulsion. Magnetic resonance imaging revealed she had multifocal swelling and a marked increase in the number of cerebral microhemorrhages. She was treated with an antiepileptic regimen and high-dose intravenous corticosteroids but continued to worsen and died after 5 days. Post-mortem MRI confirmed extensive microhemorrhages in the temporal, parietal and occipital lobes. The autopsy confirmed the presence of two copies of APOE4, a gene associated with a higher risk of Alzheimer’s disease, and neuropathological features of moderate severity Alzheimer’s disease and severe cerebral amyloid angiopathy with perivascular lymphocytic infiltrates, reactive macrophages and fibrinoid degeneration of vessel walls. There were deposits of β-amyloid in meningeal vessels and penetrating arterioles with numerous microaneurysms. We conclude that the patient likely died as a result of severe cerebral amyloid-related inflammation.

Evidences and therapeutic advantages of donanemab in the treatment of early Alzheimer's disease.

The humanised monoclonal antibody donanemab is being developed to treat early onset Alzheimer's disease (AD). This drug targets N-truncated pyroglutamate amyloid-peptide at position 3 (N3pG), a modified form of deposited amyloid-peptide. The symptoms of Alzheimer's disease include gradual memory loss and other cognitive impairments. This disease is characterized by amyloid plaques, which are formed as a result of an accumulation of amyloid-(A-β) peptides. Despite granting donanemab breakthrough therapy designation in June 2021, the FDA rejected donanemab's accelerated approval application in January 2023, due to inadequate safety data. According to the baseline amyloid level, the time to achieve plaque clearance (amyloid plaque level <24.1 centiloids) varied. Patients with higher baseline levels were more likely to achieve amyloid clearance. The safety of the drug was demonstrated by amyloid-related imaging abnormalities (ARIA), which ranged from 26.1 to 30.5 % in the studies. Clinical trial results have shown that donanemab delays cognitive and functional deterioration in patients with mild to moderate AD. However, it is not yet known whether donenameb offers therapeutic benefits that can change and improve the clinical condition of AD patients. To achieve significant clinical benefits in AD patients with cognitive impairment, further studies may be needed to investigate the interaction between A-β plaque reduction and toxic tau levels.

Affective theory of mind in people with mild and moderate Alzheimer's disease.

This study compared the affective theory of mind (ToM) of people with mild and moderate Alzheimer's disease (AD) and healthy older adults and also investigated the relationship between affective ToM and cognitive and clinical functioning in AD people. This cross-sectional study included 156 older adults with AD and 40 healthy older adults. We used an experimental task involving reasoning processes in different contextual situations. The affective ToM was impaired in AD groups compared with healthy group, with moderate AD group showing lower performance than mild AD group. The affective ToM task of mild AD group was significantly correlated with the Mini-Mental State Examination (MMSE) and education years. Linear regression showed only education years as a predictor of ToM task performance. The neuropsychiatric symptoms and functionality were not correlated with the affective ToM. Our findings demonstrated that people with mild and moderate AD presented impairments in affective ToM that can be explained by the difficulties to infer emotion from reasoning processes. In addition, the education years variable proved to be an affective ToM performance's predictor for the mild AD group, but not for the moderate AD group, indicating that ToM abilities are affected differently in different stages of AD. Neuropsychiatric symptoms and functionality seem to have no influence on affective ToM impairments in people with AD.

Neuropsycho‐linguistic study of agraphia and aphasia in Moroccan Arabic in patients with Alzheimer’s disease

AbstractBackgroundAgraphia and aphasia are common symptoms of neurodegenerative diseases such as Alzheimer’s disease (AD). While most studies were carried out in English, to our knowledge no study has been conducted in Arabic, to characterize these neuro‐psycholinguistic impairments in AD.MethodOur sample included 14 patients (4 with mild and 10 with moderate AD). They met the clinical criteria for AD (McKhann, 2011). The average age is 68.2 years (SD 6; 57‐77). The average number of years of education is 13 years (SD 2.9; 6‐16). The average duration of the disease is 4.2 years (SD 1.97; 1‐8) . The neurolinguistic assessment was used with Mini‐Linguistic State Examination test (MLSE, Patel et al., 2020; Taiebine et al, 2021) for the screening of language disorders. Furthermore, an exhaustive neuropsychological assessment has been carried out (global cognitive functions, memory, attention, verbal fluency, executive, praxis, and visuo‐constructional functions). The writing samples were analyzed using the MMSE sentence writing and MLSE writing subtests.ResultStatistical analysis showed that MLSE scores were influenced by disease severity and duration, whereas education level and age had no effect. As AD progresses, additional impairments become apparent in other cognitive domains. However, the marked syntactic deterioration in MLSE, compared to other linguistic domains, is an atypical pattern, whereas syntax is generally preserved in AD. (Taiebine et al, 2021). Neurolinguistic assessment showed impairment at the macro‐ and micro‐linguistic levels in terms of functional words, verbs, cohesion, and coherence. The analysis of paragraphias showed that the most frequent errors were literal omissions with missing diacritics (36%), followed by graphomotor errors (30%) and allographic errors (10%). The allographic errors are mainly graphemic simplifications that share visuospatial similarities with target letters.ConclusionThis study offers a new perspective on the linguistic characterization of AD. Moreover, it confirms the hierarchical decline in language. The pattern of post‐graphemic disorders found in our patients was consistent with the impairment of peripheral writing buffers in Arabic: graphemic, graphomotor, and allographic.

Subclinical mesial temporal lobe activity in Alzheimer’s Disease

AbstractBackgroundAnimal and human studies of Alzheimer’s disease (AD) demonstrated that aberrant network activity with neuronal hyperexcitability plays a role in disease pathogenesis and cognitive functioning. Suppressing network hyperexcitability with levetiracetam improved cognitive functioning in familial AD mice and executive functioning in patients with AD and epileptiform activity. Manifestations of network hyperexcitability are unsensitive biomarkers since they are mostly subclinical and not visible on scalp EEG. (Lam et al. 2019, Vossel et al. 2021, Sanchez et al. 2012). Our purpose was to identify subclinical epileptiform activity in two patients with mild cognitive impairment (MCI) and one patient with moderate AD, with a suspicion of network hyperexcitability based on either spikes on 24‐h scalp EEG or a history suspect for seizures without epileptiform discharges on scalp EEG.MethodThree patients were implanted with bilateral foramen ovale (FO) electrodes to obtain more direct measures of mesial temporal lobe epileptiform activity. Scalp EEG according to the 10‐20 system and polysomnography were simultaneously recorded in all subjects for three to five consecutive days. Polysomnography was scored according to the AASM scoring rules. Persyst 14 software was used for automatic spike detection.ResultInvasive recordings showed interictal epileptic activity in all three patients, which was occasional during wakefulness and abundant during sleep. In one patient two nocturnal unilateral mesiotemporal seizures, characterized by arousal, were recorded during N1 sleep, while at the same time no epileptiform activity was visible on scalp EEG.ConclusionIn patients with AD subclinical mesial temporal epileptiform activity can be present with a normal scalp EEG. Epileptic activity is predominantly found during sleep. Our findings suggest an important role for network hyperexcitability in AD disease pathogenesis.

Low circulating choline levels correlate with Alzheimer’s disease pathology severity and cognitive impairment

AbstractBackgroundModifiable environmental risk factors may help reduce Alzheimer’s disease (AD) incidence. Choline plays key roles in healthy body and brain function (Blusztajn, 1998) and supplementation above the adequate daily intake (ADI) reduces AD pathology (Velazquez et al., 2019). Choline deficiency increases AD risk and pathology (Dave et al., 2023; Yuan et al., 2022). Notably, recent reports estimate that ∼90% of Americans do not reach the ADI for dietary choline (Zeisel, 2017), making it imperative to better understand the link between choline and AD risk.MethodWe obtained serum samples from severe AD (AD‐Sev; Braak stage VI), moderate AD (AD‐Mod; Braak stage IV), and healthy control (CON; &lt; Braak stage III) subjects (n = 12/group; balanced for sex) from the Banner Sun Health Research Institute’s Brain and Body Donation Program. Cognitive test scores (Mini‐Mental State Examination (MMSE)), plaque burden, and Braak stage was characterized by Banner Sun Health. We assessed free choline, acetylcholine (ACh), and TNFα levels. Gas‐chromatography‐mass spectrometry was used to profile aqueous metabolites and short‐chain fatty acids.ResultThere were no significant group differences for post‐mortem interval (M = 3.79). We found disease associated differences, where AD‐Sev and AD‐Mod patients had lower levels of free choline and ACh, and higher levels of pro‐inflammatory cytokine TNFα, than CON. AD‐Mod showed a significant difference in all these measurements compared to AD‐Sev. Free choline and ACh were positively correlated to MMSE scores, whereas free choline and ACh levels were negatively correlated with total plaque and Braak Stage. Free choline and ACh were negatively correlated with TNFα. Metabolomics analysis revealed significant differences (p &lt; 0.05) in the metabolisms of beta‐alanine, linoleic acid, and of taurine and hypotaurine.ConclusionCollectively, as free choline and ACh levels decreased, AD pathology increased. Free choline was also associated with MMSE score. Increased TNFα was observed in cases with lower choline, illustrating increased inflammation. Together, this data expands on our recent (Dave et al., 2023) and others (Yuan et al., 2022) publications, highlighting links between low choline and AD risk.

Functional connectivity changes of the Locus Coeruleus in Alzheimer’s Disease

AbstractBackgroundGrowing evidence indicates neurone loss in the Locus Coeruleus(LC) in patients with Alzheimer’s Disease(AD). The widespread projection and rich connectivity of the LC with multiple brain regions and its interaction with different neural networks suggests the importance of investigating the functional connectivity of the LC, an area of research which has been less studied. Aims: The primary aim of this study was to test for differences in functional connectivity of the LC between AD subjects and matched controls using neuromelanin‐sensitive MRI(NM‐MRI). The secondary aim of this study was to test for the effects of AD on the resting state networks.MethodPre‐processing of the fMRI and structural MRI data from 23 AD subjects and 23 controls was completed using the FMRIB Software Library(FSL). The images were skull‐stripped, registered, and normalised to the MNI152_t1_2mm_brain template. LC masks were created from the NM‐MRI scans also using FSL. The subsequent data was processed using the CONN toolbox. Seed‐to‐voxel and ROI‐ROI analysis were used to produce connectivity maps and comparisons were conducted between AD and controls, left and right LC, mild and moderate AD, and resting state networks.ResultAD subjects had connections from the LC to only 43 brain regions, compared to 80 brain regions in the controls. In comparison to controls, AD subjects had reduced LC connectivity in the subcallosal cortex(p‐FDR = 0.016417), increased LC connectivity in the right supramarginal and postcentral gyri(p‐FDR = 0.000002), and reduced connectivity in the default mode network(p‐FDR = 0.000286) and sensorimotor network(p‐FDR = 0.027524). The left LC in the AD subjects had significant connections to only 56 brain regions compared to 81 brain regions in the right LC. In particular, the left LC had decreased number of significant connections to the amygdala and vermis, compared to the right LC. The number of significant LC connections decreased with progression from controls to mild AD to moderate AD.ConclusionThis study provides new evidence of reduced LC functional connectivity in AD patients and asymmetrical reduction in the LC skewed towards the left LC. LC connectivity reduction could indicate pathogenesis and progression of AD, aiding prediction of disease progression and development of novel intervention targets.

Effect of tetrahydrocannabinol and melatonin combination on suicide ideation and behavior in dementia due to Alzheimer’s disease

AbstractBackgroundSuicide ideation in young adults increases with regular use of marijuana. Separately, prevalence of suicide and dementia also increases with age, and Alzheimer’s disease (AD) is associated with a moderate risk of suicide. The Columbia‐Suicide Severity Scale (C‐SSRS) has been used since the FDA guidance in 2012, however, it has not been validated. Studies show its effectiveness in mild to moderate dementia, but not in severe dementia. Here, we present preliminary data on the application of C‐SSRS in a Phase 1 trial on AD patients using IGC‐AD1, a combination of tetrahydrocannabinol (THC) and melatonin (IGC‐AD1).MethodTwelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5 ± 5.5yrs, 69.2% women) participated in a three Cohort Phase‐1, MAD, safety, and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts 2 and 3, one ml BID and TID were administered respectively with a minimum of 4‐days washout between Cohorts. Daily, solicited, and non‐solicited adverse events (AEs) were monitored along with vital signs.For all three Cohorts the C‐SSRS was administered at baseline and again on days 5,10, EOT and EOT+2 by a neuropsychologist. In addition, suicidal ideation was included as a solicited adverse event (AE) that was reported daily.ResultIn 420 man‐days (10 patients on active * 14 days * 3‐Cohorts) of dosing there was one day on which a participant on active medication self‐reported suicidal ideation as part of the solicited AEs. It self‐resolved the next day. All 150 administrations of C‐SSRS to the participants on active medication, across all three Cohorts, showed no suicide ideation or behavior. Likewise, across 30 administrations in the placebo group there were no suicide ideations or behaviors. No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were reported.ConclusionTHC and melatonin in IGC‐AD1 did not increase the risk of developing suicidal ideation or behavior as assessed by the C‐SSRS in the mild to moderate AD trial population. The preliminary results also show that IGC‐AD1 was well tolerated and safe.

Efficacy of benfotiamine plus donepezil treatment for patients with mild‐to‐moderate Alzheimer’s disease: multicenter, randomized, phase II clinical trial

AbstractBackgroundTo assess the efficacy of benfotiamine plus donepezil treating mild‐to‐moderate Alzheimer’s disease (AD).MethodDesign: Multicenter, randomised, double‐blind, phase II clinical trial. Setting: 21 cognitive clinics of tertiary hospitals affiliated Medical Colleges or Universities in China. Participants: 434 patients who took donepezil (5 mg daily) continuously for more than 6 months (inclusive) were screened. Intervention: 302 patients entered this study and were randomly assigned (1:1:1 allocation) to high‐dose benfotiamine (600 mg daily, n = 99) plus donepezil (5 mg daily, the same below), low‐dose benfotiamine (300 mg daily, n = 104) plus donepezil or the only donepezil (n = 99) groups. Main outcomes measures: The primary efficacy outcome was the change of Assessment Scale‐Cognitive Subscale 11(ADAS‐cog) score at week 52 from baseline.ResultIn the overall population, the primary efficacy outcome did not reach significant difference, but tended to be beneficial to benfotiamine plus donepezil treatment with a dose‐effect relationship. Post hoc analyses showed that for the moderate AD subgroup in the full analysis set, the increases of ADAS‐cog scores at week 52 from baseline were the least in high‐dose benfotiamine plus donepezil (‐3.07, p = 0.027) and the second least in low‐dose benfotiamine plus donepezil (‐1.49, p &gt; 0.05) as compared with that in only donepezil. There were no significant differences in the primary efficacy outcome among three subgroups of mild cases.ConclusionCompared to only donepezil, benfotiamine plus donepezil treatment tends to have beneficial effects on delaying cognitive decline of mild to moderate AD. Post hoc analyses showed that the efficacy of benfotiamine plus donepezil treatment with a dose‐effect relationship is better than that of only donepezil treatment for moderate AD, but not for mild AD. The current proof of concept study showed that the combination treatment of correcting TDP reduction with acetylcholinesterase inhibitor is an effective therapeutic way for AD. Future studies should further expand the sample to verify these results.

Effect of the combination of tetrahydrocannabinol and melatonin (IGC‐AD1) on blood pressure variability in patients with mild to moderate Alzheimer’s Disease

AbstractBackgroundBlood pressure (BP) variability (BPV) is a risk factor for Alzheimer’s disease (AD). Medications, such as atypical antipsychotics used to treat neuropsychiatric symptoms (NPS) common in AD, contribute to altering BP. Here we present preliminary data on the use of IGC‐AD1, a combination intervention of tetrahydrocannabinol (THC) and melatonin, on BP and BPV.MethodParticipants with hypertension (n = 12) and mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) were enrolled in a three‐Cohort Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, Cohort‐2 and Cohort‐3, one ml QD, BID, and TID of IGC‐AD1 were administered respectively for 14‐days with a minimum of 4‐days washout between Cohorts. For all Cohorts, BP was recorded daily. Coefficients of variation (CV), ∆DBP and ∆SBP (diastolic and systolic blood pressure) were calculated to assess SBP‐variability for each Cohort. A chi‐square was performed to verify whether the difference between controlled and uncontrolled SBP (&gt;140mmHg in more than 20% of values per participant) was related to IGC‐AD1. SBP‐CV difference among Cohorts was determined with a one‐way ANOVA. The difference between active and placebo for each Cohort was assessed with independent t‐tests (dplr R‐Studio). BP‐associated adverse events (AEs) were evaluated daily.ResultVariability measures fell within the normal range (∆DVP = 45.0±13.5 mmHg, ∆SBP = 66.44±22.9 mmHg, CV = 7.6±5.3 mmHg) for all three Cohorts. Cohort‐1 (mmHg): ∆SBP = 42.3±15.56, ∆DVP = 25.6±8.86, CV = 10.14±3.84; Cohort‐2 (mmHg): ∆SBP = 41.9±11.73, ∆DVP = 23±9.7, CV = 8.95±1.96; Cohort‐3 (mmHg): ∆SBP = 39.6±11.76, ∆DVP = 23.6±7.82, CV = 8.84±7.83. IGC‐AD1 had no statistically significant effect between controlled and uncontrolled SBP (X2(2) = 1.15, p = 0.562). There was no SBP‐CV mean‐difference among Cohorts (F (2,27) = 0.589, p = 0.562). No differences were detected between placebo and active (Cohort‐1: t(1.64) = 0.315, p = 0.788, Cohort‐2: t(1.31) = ‐0.225, p = 0.85, Cohort‐3: t(3.53) = 1.63, p = 0.188). While BP related AEs were reported, none were deemed, by the PI, to be associated with IGC‐AD1.ConclusionPreliminary data indicate that IGC‐AD1, a cannabis‐based formulation, in trials to treat NPS did not statistically affect BP or BPV in a MAD study indicating that it may not contribute as a risk factor for AD; warranting a larger placebo‐controlled trial.

Reduction of apathy and caregiver distress using a combination of tetrahydrocannabinol and melatonin in dementia due to Alzheimer’s disease

AbstractBackgroundApathy is one of the most frequent and long‐lasting neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD). Up to 78% of AD patients exhibit apathy, which is related to caregiver distress, decreased quality of life, and increased morbidity. While many medications and behavioral interventions are used to treat apathy, the effects are often limited and lack in‐depth research to support these approaches. We present preliminary data for improvement in NPI‐apathy (NPI‐ap) scores and NPI Caregiver Distress (NPI‐D) scores using IGC‐AD1, a tetrahydrocannabinol (THC) and melatonin combination.MethodTwelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort, Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts‐2 and 3, one ml BID and TID were administered respectively, with a minimum of 4‐days washout between Cohorts. Solicited and non‐solicited adverse events (AEs) were monitored daily.In each Cohort, seven participants (5‐active, 2‐placebo) had apathy at baseline, as rated by the NPI‐ap. They were administered the NPI‐ap at EOT and the Wilcoxon matched pairs signed‐rank test (R‐Studio, dplyr) was used to compare the difference in NPI‐ap scores between baseline and EOT. A similar analysis was carried out for NPI‐D.ResultIn Cohort‐1 mean NPI‐ap at baseline and EOT was 5.4 and 3 respectively (mean difference = ‐2.4, v = 6, p = 0.091). In Cohort‐2 mean NPI‐ap at baseline and EOT was 5.2 and 2.4 respectively (mean difference = ‐2.8, v = 6, p = 0.087). In Cohort‐3 mean NPI‐ap at baseline and EOT was 5.2 and 2.6 respectively (mean difference = ‐2.6, v = 6, p = 0.087). Results for NPI‐D: (Cohort‐1:mean difference = ‐0.6, 37.5%, v = 6, p = 0.075; Cohort‐2:mean difference = ‐1.8, 69.2%, v = 15, p = 0.028; Cohort‐3:mean difference = ‐0.2, 12.5%, v = 2, p = 0.5). No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were observed.ConclusionAs IGC‐AD1 contains THC, the results are intriguing because cannabis use has been associated with apathy but also increased empathy and sociality. In Cohort‐1, Cohort‐2, and Cohort‐3 NPI‐ap was reduced 44.44%, 53.85%, and 50% respectively. These results, while not statistically significant (p&gt;0.05), appear clinically significant (reduction≥30%). A larger placebo‐controlled study is warranted.