Cerebral Amyloid Angiopathy in Patients with Cognitive Impairment: Cerebrospinal Fluid Biomarkers.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is characterized by amyloid ß (Aß) deposition in brain vessels, leading to hemorrhagic phenomena and cognitive impairment. Magnetic resonance imaging (MRI)-based criteria allow a diagnosis of probable CAA in vivo, but such a diagnosis cannot predict the eventual development of CAA. METHODS: We conducted a retrospective cohort study of 464 patients with cognitive disorders whose data were included in a brain health biobank. De-identified parameters including sex, age, cognitive score, APOE status, and cerebrospinal fluid (CSF) levels of Aß 1-40, Aß 1-42, phosphorylated tau, and total tau were assessed in those with and without CAA. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined. RESULTS: CAA was present in 53 of 464 (11.5%) patients. P-tau level was significantly higher in those with CAA (115 vs. 84.3 pg/mL p = 0.038). In univariate analyses, the risk of developing CAA was higher with increased age (OR, 1.036; 95% CI: 1.008, 1.064; p = 0.011) and decreased CSF level of Aß 1-40 (OR, 0.685; 95% CI: 0.534, 0.878; p = 0.003). In multivariate analyses, the risk of CAA remained higher with a decreased CSF level of Aß 1-40 (OR, 0.681; 95% CI: 0.531, 0.874; p = 0.003). CONCLUSION: These findings suggest that Aß 1-40 levels in the CSF might be a useful molecular biomarker of CAA in patients with dementia.

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. HIGHLIGHTS: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

Exploratory Transcriptomic Profiling Reveals the Role of Gut Microbiota in Vascular Dementia.

Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (Il-1ß), chemokines (C-X-C motif chemokine ligand 10 (Cxcl10), chemokine ligand 2 (Ccl2)), and immune system genes (S100 calcium binding protein 8 (S100a8), lipocalin-2 (Lcn2)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (Hcrt), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (Npas4), GATA binding protein 3 (Gata3), and paired box 7 (Pax7) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.

IPA and WPA-SOAP position statement on deprivation of liberty of older persons with mental health conditions.

In recognition of the challenges faced by older persons deprived of their liberty, a call was made for input into the 2022 report to the United Nations Human Rights Council (HRC) on older persons. This Position Statement outlines the views of two global organizations, the International Psychogeriatric Association (IPA) and the World Psychiatric Association Section of Old Age Psychiatry (WPA-SOAP), working together to provide rights and dignity-based mental health services to older persons and it was sent to the Independent Expert on the enjoyment of all human rights by older persons at HRC.

Neuropsychological presentation of colpocephaly and porencephaly with symptom onset in adulthood.

Colpocephaly is a form of congenital ventriculomegaly while porencephaly describes any full-thickness defect within the brain which usually presents as a cystic structure. Postulated aetologies include intrauterine/perinatal injuries, genetic disorders, and morphogenesis error. Colopocephaly and porencephaly is typically diagnosed in infancy while diagnosis in adulthood is exceptionally rare. We report a case of co-existence of colpocephaly with porencephaly diagnosed incidentally in a 54-year-old male presenting with subtle cognitive and neurologic abnormalities. Neuropsychological assessment revealed weaknesses in executive functions, processing speed, and language.To our knowledge, this is the only reported case of dual incidental findings of porencephaly and colpocephaly in an adult.

Advances in Management of Neuropsychiatric Syndromes in Neurodegenerative Diseases.

PURPOSE OF REVIEW: Neuropsychiatric syndromes (NPS) are common in neurodegenerative disorders (NDD). This review describes the role of NPS in the diagnosis of NDD, criteria for the diagnosis of NPS, management of NPS, and agents in clinical trials for NPS. RECENT FINDINGS: NPS play an increasingly important role in the diagnosis of NDD. Consensus diagnostic criteria have evolved for psychosis, depression, agitation, and apathy in NDD. With one exception-pimavanserin is approved for the treatment of hallucinations and delusions in Parkinson's disease-there are no drugs approved by the FDA for treatment of NPS in NDD. Trials show that atypical antipsychotics reduce psychosis in AD and in Parkinson's disease, although side effect concerns have constrained their use. Antidepressants show benefit in treatment of Parkinson's disease with depression. Several agents are in clinical trials for treatment of NPS in NDD. Neuropsychiatric syndromes play a major role in NDD diagnosis. Clinical criteria allow recognition of NPS in NDD. Psychotropic medications are often useful in the treatment of NPS in NDD; efficacious, safe, and approved agents are needed.

Cognitive functions, apolipoprotein E genotype and hormonal replacement therapy of postmenopausal women.

OBJECTIVE: The results of many studies revealed that estrogen plus progestogen therapy (EPT) may modify dementia development risk in relation to the apolipoprotein E gene (APOE) polymorphisms. However, the mechanism and subsequently clinical importance of such an effect are still unexplained. The objective of this study was to explore the influence of EPT on cognitive functioning of women in their postmenopausal life in relation to APOE polymorphism. METHODS: The group of 214 women was recruited (106 out of this group with EPT) to the study. The inclusion criteria were: minimum two years after the last menstruation, FSH concentration over 30 U/ml and no dementia signs on Montreal Cognitive Assessment (MoCA). Computerized battery of Central Nervous System Vital Signs (CNS VS) test was used to diagnostic cognitive functions. APOE genotype was performed by multiplex PCR. Statistical analysis was performed using two-way analysis of variance in STATISTICA software. RESULTS & CONCLUSION: The women after menopause have reduced neurocognitive index (NCI) and cognitive functions. NCI and all studied cognitive functions of the patients depended significantly on APOE polymorphisms. The presence of APOE4 corresponded with decreased cognitive functions as opposed to APOE2 which was present in women with better level of cognitive functions. Constantly using EPT correlated with three cognitive functions: memory, verbal memory and processing speed, which were significantly worse for women taking EPT than not taking ones. The interaction between APOE polymorphisms and EPT application was significant only for processing speed. EPT applying women with ε2/ε3 and ε4 obtained better scores in processing speed than women not taking EPT with these APOE polymorphisms. The opposite situation concerned women with ε3/ε3, women taking EPT achieved worse processing scores in comparison with those not taking EPT. It should be noted that APOE polymorphism assessment may be a factor in predicting the effect of EPT on cognitive functioning in postmenopausal period.

Pimavanserin Treatment for Psychosis in Patients with Dementia with Lewy Bodies: A Case Series.

BACKGROUND Many patients with dementia with Lewy bodies (DLB) experience cholinesterase inhibitor- and antipsychotic-resistant psychosis. The new second-generation antipsychotic pimavanserin has been used with some success in the treatment of psychosis in other forms of dementia, including Alzheimer disease and Parkinson disease dementia. It is possible that pimavanserin may also be useful in the treatment of psychosis in DLB. We sought to describe the disease course and treatment of psychosis in 4 patients with DLB who were prescribed pimavanserin after other medications failed to reduce the frequency or severity of hallucinations and delusions. CASE REPORT This is a case series of 4 male patients (ages 56 to 74 at the beginning of the reports) who developed DLB and psychosis (eg, visual illusions, visual and olfactory hallucinations, and paranoid delusions). All 4 patients were prescribed cholinesterase inhibitors (eg, donepezil or rivastigmine) prior to pimavanserin, and only 1 patient experienced improved psychosis while on cholinesterase inhibitors. All 3 patients who were prescribed first-generation antipsychotics (eg, haloperidol) or traditional second-generation antipsychotics (eg, olanzapine, risperidone, or quetiapine) experienced initial or lasting side effects with no improvement of psychosis. Conversely, all 4 patients tolerated pimavanserin well, and 3 of the 4 patients experienced significant improvement of psychosis (eg, fewer hallucinations, fewer delusions, reduced paranoia, and/or reduced distress or agitation related to hallucinations and delusions) when prescribed pimavanserin. CONCLUSIONS This case series suggests that pimavanserin is tolerable in older males with DLB and that it may be useful for the reduction of distressful hallucinations, delusions, and paranoia in patients with DLB.

Association of Variation in Behavioral Symptoms With Initial Cognitive Phenotype in Adults With Dementia Confirmed by Neuropathology.

IMPORTANCE: Behavioral and psychological symptoms of dementia (BPSDs) in association with amnestic and nonamnestic cognitive phenotypes have not been evaluated across diagnoses of Alzheimer disease pathology (ADP), Lewy body-related pathology (LRP), and mixed pathology (ADP-LRP). OBJECTIVES: To determine the clinical phenotypes at the initial visit that are associated with the nature and severity of BPSDs in patients with ADP, LRP, and ADP-LRP. DESIGN, SETTING, AND PARTICIPANTS: This retrospective longitudinal cohort study included 2422 participants with neuropathologically confirmed ADP, LRP, or mixed ADP-LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019. Participants had a mean (SD) interval of 5.5 (2.8) years from initial visit to autopsy. MAIN OUTCOMES AND MEASURES: Clinician-determined diagnosis of change across 10 BPSDs (agitation, apathy, depression, delusions, disinhibition, auditory hallucinations, visual hallucinations, irritability, personality change, and rapid eye movement [REM] sleep behavior) and the highest severity score for behavioral change on the Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: A total of 2422 participants (1187 with ADP, 904 with ADP-LRP, and 331 with LRP) were included in the analysis (1446 men [59.7%]; mean [SD] age, 74.4 [10.1] years). Compared with initial amnestic symptoms, executive symptoms were associated with a higher risk for 7 of the 10 BPSDs (hazard ratio [HR] range, 1.28-2.45), and visuospatial symptoms were associated with a higher risk for 2 of the 10 BPSDs (HR range, 1.91-2.51), but neither were associated with a low risk for any BPSD. Language symptoms were associated with a low risk of onset for 3 of 10 BPSDs (HR range, 0.43-0.79) and a high risk for 1 BPSD (personality change) (HR, 1.42 [95% CI, 1.10-1.83]). Participants with LRP had a lower risk for agitation (HR, 0.74 [95% CI, 0.60-0.92]), disinhibition (HR, 0.78 [95% CI, 0.62-0.99]), and irritability (HR, 0.81 [95% CI, 0.68-0.96]) and a higher risk for apathy (HR, 1.19 [95% CI, 1.02-1.38]), depression (HR, 1.32 [95% CI, 1.12-1.55]), auditory (HR, 2.00 [95% CI, 1.37-2.93]) and visual (HR, 2.78 [95% CI, 2.21-3.49]) hallucinations, and REM sleep behavior changes (HR, 4.77 [95% CI, 3.61-6.31]) compared with the ADP group. The ADP-LRP group had a higher risk for delusions (HR, 1.27 [95% CI, 1.08-1.48]), auditory (HR, 1.62 [95% CI, 1.21-2.15]) and visual (HR, 1.57 [95% CI, 1.30-1.89]) hallucinations, and REM sleep behavior changes (HR, 2.10 [95% CI, 1.63-2.70]) than the ADP group and a lower risk for visual hallucinations (HR, 0.56 [95% CI, 0.45-0.71]) and REM sleep behavior changes (HR, 0.44 [95% CI, 0.34-0.57) than the LRP group. Overall, women showed a lower risk of agitation (HR, 0.86 [95% CI, 0.75-0.98]), apathy (HR, 0.79 [95% CI, 0.71-0.87]), visual hallucinations (HR, 0.76 [95% CI, 0.64-0.90]), irritability (HR, 0.77 [95% CI, 0.69-0.86]), and REM sleep behavior change (HR, 0.45 [95% CI, 0.35-0.58]) and a higher risk of depression (HR, 1.26 [95% CI, 1.13-1.41]). Older age was associated with a lower risk of most BPSDs (HR range, 0.98-0.99) except delusions (HR, 1.00 [95% CI, 1.00-1.01]) and auditory hallucinations (HR, 0.99 [95% CI, 0.97-1.00]) and a low NPI-Q composite score (ß = -0.07 [95% CI, -0.08 to -0.05]; P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that the risks of BPSDs differ with respect to the initial cognitive phenotype, underlying neuropathology, age, and sex. Awareness of these associations could be helpful in dementia management.

Advances in Management of Psychosis in Neurodegenerative Diseases.

PURPOSE OF THE REVIEW: Psychosis is broadly defined as a disengagement from reality. It describes syndromes that impair both thought content and thought process. Psychosis negatively impacts an individual's quality of life, in addition to the families caring for them. Psychosis with different types of hallucinations and delusions occurs in the context of delirium. Neuropsychiatric symptoms (NPS) are almost universal in the course of common neurodegenerative disorders (NDD) like Alzheimer's disease (AD) or Parkinson's disease (PD). In this paper, the authors took an effort to characterize AD and PD psychosis with a special focus on the most diagnostically reliable features. Effectiveness and limitations of pharmacological interventions are discussed. RECENT FINDINGS: Consensus diagnostic criteria have evolved for psychosis secondary to AD as well as psychosis in PD. Psychotropic medications can be effective in the treatment of NPS in NDD; however, clinicians must be mindful of the side effects. There is a consensus on benefit of initiating any acetylcholinesterase inhibitor (ACHI: donepezil, rivastigmine, and galantamine) as a first line of treatment for psychosis in AD, as it may reduce and/or avoid the need for the use antipsychotics. Pimavanserin, a selective-serotonin inverse agonist that preferentially targets 5-HT2A receptors, while avoiding activity at dopamine and other receptors commonly targeted by antipsychotics had recently been approved by FDA to treat hallucinations and delusions in PD. Quetiapine is widely prescribed for the treatment of psychosis in different NDD, but the data remains equivocal. Psychosis with different types of hallucinations and delusions may occur in the context of delirium and is almost universal as a neuropsychiatric symptom in the course of PD and AD. Currently, pimavanserin remains the only pharmacologic agent approved for treatment of psychosis in PD. In cases of other NPS in other than Parkinson's diseases, atypical antipsychotics are commonly used off-label. More research is greatly needed to advance this field and address NPS especially psychosis in geriatric population.

Postmenopausal cognitive changes and androgen levels in the context of apolipoprotein E polymorphism.

INTRODUCTION: The focus of this study was to assess cognitive functions in relation to androgens and specifically testosterone and dehydroepiandrosterone in postmenopausal women as well as the correlation between cognitive functions and these two androgens according to polymorphism of the apolipoprotein E gene (APOE). MATERIAL AND METHODS: A group of 402 women was recruited to the study (minimum 2 years after the last menstruation, follicle-stimulating hormone (FSH) more than 30 U/ml and no dementia signs on Montreal Cognitive Assessment). The computerized battery of the Central Nervous System Vital Signs test was used to diagnose cognitive functions. APOE genotyping was performed by multiplex polymerase chain reaction (PCR). Testosterone (TTE) and dehydroepiandrosterone (DHEA) in the blood serum were assessed for further statistical correlations analysis. RESULTS: In the group of postmenopausal women, higher testosterone concentration was associated with lower scores for Neurocognition Index (NCI) (p = 0.028), memory (p = 0.008) and psychomotor speed (p < 0.001). Presence of at least one APOE ε4 allele potentiated testosterone's negative influence on cognitive functions (p < 0.05). Woman with a high normal level of DHEA scored significantly better in verbal (p = 0.027) and visual memory (p < 0.001) than other participants. APOE polymorphism did not modify the relationship between DHEA concentration and scores for cognitive functions. CONCLUSIONS: Hormonal balance variations after menopause may influence brain processes concerned with cognition, especially memory and psychomotor speed. The observed effects may be related to androgens' influence on higher cortical functions in the changed hormonal dynamics of the postmenopausal period.

Linking Orders in Electronic Medical Records Can Improve the Frequency With Which Recommended Treatments Are Ordered as Illustrated in the Treatment of Alcohol Withdrawal.

OBJECTIVE: The purpose of this study was to collect objective data concerning the prescription of vitamin supplementation treatment in hospitalized patients at risk for alcohol withdrawal. METHODS: This study compared the total number of orders for folate, thiamine, and multivitamins with assessments ordered using the revised Clinical Institute Withdrawal Assessment of Alcohol (CIWA-Ar) during 2 congruent time periods in a hospital system before and after these orders were linked to determine the effectiveness of the link. Frequency counts of the order sets containing CIWA-Ar with and without doses of folate, thiamine, and multivitamins were extracted from the electronic medical record. One set of frequencies was collected between January 1, 2012, and June 15, 2012. The second set was collected between January 1, 2013, and June 15, 2013, after the intervention in which these orders were linked. Percentages were calculated from the frequency counts. RESULTS: Results of the study showed that before the intervention linking these orders, thiamine was ordered only 41 times, folate 42 times, and multivitamin 42 times, whereas CIWA-Ar was ordered 1228 times within the same time parameters (3.34%, 3.42%, and 3.42%, respectively), for a total average rate of 10.18%. After orders for thiamine, folate, and multivitamins were linked to the CIWA-Ar, the average rate of these vitamins being ordered with CIWA-Ar reached 77.94%. CONCLUSION: This study found that linking CIWA-Ar and vitamin supplementation orders within the electronic medical record increases the likelihood of them being ordered together. We propose that this can be applied to other treatments that are commonly ordered together and that such orders should be linked to improve the standards of care for all patients.

The Innate Immunity in Alzheimer Disease- Relevance to Pathogenesis and Therapy.

The genetic, cellular, and molecular changes associated with Alzheimer disease provide evidence of immune and inflammatory processes involvement in its pathogenesis. These are supported by epidemiological studies, which show some benefit of long-term use of NSAID. The hypothesis that AD is in fact an immunologically mediated and even inflammatory pathological process may be in fact scientifically intriguing. There are several obstacles that suggest the need for more complex view, in the process of targeting inflammation and immunity in AD. In our previous studies we proposed a reliable methodology to assess innate immunity in Alzheimer patients and controls. The methodology is based on the phenomenon of human leukocytes being resistant to viral infection. The unspecific character of the resistance, dependent on interferons and tumor necrosis factor, and occurrence in cells ex vivo indicate that an in vivo mechanism of innate immunity may be involved. The above mentioned resistance could be estimated in a test based on peripheral blood leukocytes infection by vesicular stomachs virus.

Retinoids for treatment of Alzheimer's disease.

Retinoids are Vitamin A derivatives involved in cellular regulatory processes including cell differentiation, neurite outgrowth and defense against oxidative stress. Retinoids may also influence Amyloid beta processing upregulation of alpha secretase via ADAM10. Vitamin A and other retinoids also directly inhibit formation of Amyloid fibrils in vivo. These properties of retinoids are relevant to theories of Alzheimer's disease pathogenesis. Retinoids are already used in treatment of acne vulgaris, psoriasis, neuroblastoma and acute promyelocytic leukemia. Clinical studies involving in cognitively impaired older adults with Alzheimer's disease are beginning with a variety of retinoids. These studies need to address safety issues of retinoids in older populations, and hold hope for demonstrating efficacy in translating these basic mechanisms to treatment of a widespread dementing illness.

Frontiers in Alzheimer's disease therapeutics.

Alzheimer disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cognitive domain. Because of the exponential increase in the incidence of AD with age, the aging population across the world has seen a congruous increase AD, emphasizing the importance of disease altering therapy. Current therapeutics on the market, including cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, provide symptomatic relief but do not alter progression of the disease. Therefore, progress in the areas of prevention and disease modification may be of critical interest. In this review, we summarize novel AD therapeutics that are currently being explored, and also mechanisms of action of specific drugs within the context of current knowledge of AD pathologic pathways.