Hippocampus and basal forebrain volumes modulate effects of anticholinergic treatment on delayed recall in healthy older adults.

"Introduction Volumes of hippocampus and cholinergic basal forebrain are associated with delayed recall performance and may modulate the effect of a muscarinic receptor antagonist on delayed recall in healthy volunteers Methods We studied 15 older adults before and after the oral administration of a single dose of 1 or 2 mg of the preferential M1 muscarinic receptor antagonist trihexyphenidyl (Artane™) or placebo in a double-blind randomized cross-over design. Hippocampus and basal forebrain volumes were measured using magnetic resonance imaging. Results We found a significant interaction between treatment and hippocampus volume and a trend level effect between treatment and anterior basal forebrain volume on task performance, with an attenuation of the association between volume size and performance with trihexyphenidyl. Discussion These findings suggest a reduction of delayed recall performance with increasing doses of the muscarinic antagonist that is related to an uncoupling of the association of task performance with cholinergic basal forebrain and hippocampus volumes.

Type 2 Diabetes Mellitus, Platelet Activation and Alzheimer's Disease: A Possible Connection

: Type 2 diabetes mellitus DM (T2DM) is associated with a 70% increased risk for dementia, including Alzheimer's disease (AD). Insulin resistance has been proposed to play a pivotal role in both T2DM and AD and the concept of "brain insulin resistance" has been suggested as an interpretation to the growing literature regarding cognitive impairment and T2DM. Subjects with T2DM present an abnormal platelet reactivity that together with insulin resistance, hyperglycaemia and dyslipidaemia effect the vascular wall by a series of events including endothelial dysfunction, oxidative stress and low-grade inflammation. Activated platelets directly contribute to cerebral amyloid angiopathy (CAA) by promoting the formation of β-amyloid (Aβ) aggregates and that Aβ, in turn, activates platelets, creating a feed-forward loop suggesting the involvement of platelets in the AD pathogenesis. Moreover, islet amyloid polypeptide deposition, co-localized with Aβ deposits, is a common finding in the brain of patients with T2DM. These observations raise the intriguing prospect that traditional or novel antiplatelet therapeutic strategies may alleviate fibril formation and could be used in the prevention or treatment of AD subjects with diabetes

Adverse performance effects of acute lorazepam administration in elderly long-term users: pharmacokinetic and clinical predictors.

BACKGROUND: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. METHODS: Cognitively intact elderly individuals (n=37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25-3.00 mg) or placebo on different days, approximately 1 week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. RESULTS: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. CONCLUSIONS: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population

Plasma Amyloid-β dynamics in late-life major depression: a longitudinal study

Depressed individuals are twice as likely to develop Alzheimer’s disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β1-40 (Aβ40) and amyloid-β1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, Aβ42/Aβ40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aβ42/Aβ40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aβ42/Aβ40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aβ42/Aβ40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD

Output order and variability in free recall are linked to cognitive ability and hippocampal volume in elderly individuals.

Adapted from the work of Kahana and colleagues (e.g., Kahana, 1996), we present two measures of order of recall in neuropsychological free recall tests. These are the position on the study list of the first recalled item, and the degree of variability in the order in which items are reported at test (i.e., the temporal distance across the first four recalled items). We tested two hypotheses in separate experiments: (1) whether these measures predicted generalized cognitive ability, and (2) whether they predicted gray matter hippocampal volume. To test hypothesis 1, we conducted ordinal regression analyses on data from a group of 452 participants, aged 60 or above. Memory performance was measured with Rey's AVLT and generalized cognitive ability was measured with the MMSE test. To test hypothesis 2, we conducted a linear regression analysis on data from a sample of 79 cognitively intact individuals aged 60 or over. Memory was measured with the BSRT and hippocampal volume was extracted from MRI images. Results of Experiment 1 showed that the position of the first item recalled and the degree of output order variability correlated with MMSE scores only in the delayed test, but not in the immediate test. In Experiment 2, the degree of variability in the recall sequence of the delayed trial correlated (negatively) with hippocampal size. These findings confirm the importance of delayed primacy as a marker of cognitive ability, and are consistent with the idea that the hippocampus is involved in coding the temporal context of learned episodes

A study on the specificity of the association between hippocampal volume and delayed primacy performance in cognitively intact elderly individuals.

Delayed recall at the primacy position (first few items on a list) has been shown to predict cognitive decline in cognitively intact elderly participants, with poorer delayed primacy performance associated with more pronounced generalized cognitive decline during follow-up. We have previously suggested that this association is due to delayed primacy performance indexing memory consolidation, which in turn is thought to depend upon hippocampal function. Here, we test the hypothesis that hippocampal size is associated with delayed primacy performance in cognitively intact elderly individuals. Data were analyzed from a group (N=81) of cognitively intact participants, aged 60 or above. Serial position performance was measured with the Buschke selective reminding test (BSRT). Hippocampal size was automatically measured via MRI, and unbiased voxel-based analyses were also conducted to explore further regional specificity of memory performance. We conducted regression analyses of hippocampus volumes on serial position performance; other predictors included age, family history of Alzheimer's disease (AD), APOE ε4 status, education, and total intracranial volume. Our results collectively suggest that there is a preferential association between hippocampal volume and delayed primacy performance. These findings are consistent with the hypothesis that delayed primacy consolidation is associated with hippocampal size, and shed light on the relationship between delayed primacy performance and generalized cognitive decline in cognitively intact individuals, suggesting that delayed primacy consolidation may serve as a sensitive marker of hippocampal health in these individuals

Cross-sectional associations of CSF tau levels with Rey's AVLT: A recency ratio study

OBJECTIVE: The preeminent in vivo cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are amyloid β 1-42 (Aβ42), phosphorylated Tau (p-tau), and total Tau (t-tau). The goal of this study was to examine how well traditional (total and delayed recall) and process-based (recency ratio [Rr]) measures derived from Rey's Auditory Verbal Learning test (AVLT) were associated with these biomarkers. METHOD: Data from 235 participants (Mage = 65.5, SD = 6.9), who ranged from cognitively unimpaired to mild cognitive impairment, and for whom CSF values were available, were extracted from the Wisconsin Registry for Alzheimer's Prevention. Bayesian regression analyses were carried out using CSF scores as outcomes, AVLT scores as predictors, and controlling for demographic data and diagnosis. RESULTS: We found moderate evidence that Rr was associated with both CSF p-tau (Bayesian factor [BFM] = 5.55) and t-tau (BFM = 7.28), above and beyond the control variables, while it did not correlate with CSF Aβ42 levels. In contrast, total and delayed recall scores were not linked with any of the AD biomarkers, in separate analyses. When comparing all memory predictors in a single regression, Rr remained the strongest predictor of CSF t-tau levels (BFM = 3.57). CONCLUSIONS: Our findings suggest that Rr may be a better cognitive measure than commonly used AVLT scores to assess CSF levels of p-tau and t-tau in nondemented individuals. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

A review of the relationship between proinflammatory cytokines and major depressive disorder.

BACKGROUND: Determining etiological factors and reviewing advances in diagnostic modalities sensitive and specific to Major Depressive Disorder (MDD) is of importance in its evaluation and treatment. The inflammatory hypothesis is one of the most prevalent topics concerning MDD and may provide insight into the pathogenesis of depression, development of biomarkers, and ultimately production of more effective depression therapies. METHOD: We reviewed several studies to evaluate contemporary concepts concerning proinflammatory cytokines and their relationship to various depressive disorders, the use of anti-inflammatory therapies in MDD treatment, and the application of neuroimaging in conjunction with cytokine profiles from both plasma and CSF as possible diagnostic tools. RESULTS: Proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of depressive disorders in different populations. Studies have shown elevated serum levels of IL-1, IL-6, TNF-α, CRP, and MCP-1 in depressed patients, but have presented mixed results with IL-8 serum levels, and with IL-6 and MCP-1 CSF levels. Anti-inflammatory treatment of MDD may have adjuvant properties with current depression medications. MRI and NIRS neuroimaging confirm neurological abnormalities in the presence of elevated proinflammatory cytokines in depressed or stressed patients. LIMITATIONS: Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis. CONCLUSION: There is significant evidence that inflammatory processes influence the development and progression of MDD. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific modes of diagnostics in determining MDD etiology and provide guidance in individual therapies

Association of latent factors of neuroinflammation with Alzheimer's disease pathology and longitudinal cognitive decline

INTRODUCTION: We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum.METHODS: We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid.RESULTS: We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline.DISCUSSION: Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline.</p

Plasma BDNF Levels Vary in Relation to Body Weight in Females

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression as well as neuropsychiatric and neurodegenerative disorders. Recent studies show a role of BDNF in energy metabolism and body weight regulation. We examined BDNF levels in plasma and cerebrospinal fluid (CSF) samples from age matched elderly depressed and control subjects. Also, the association of BDNF levels with age, gender, body weight, body mass index (BMI), and cognitive performance was evaluated. We did not find any significant differences in plasma and CSF BDNF levels between depressed and control subjects. Plasma BDNF levels were negatively correlated with age (but not with BMI and body weight), when analyses were performed including both depressed and control subjects. A significant reduction in plasma BDNF levels was observed in females as compared to male subjects, and the change in BDNF levels were significantly and positively related to body weight in females. Furthermore, significant increases in Total Recall and Delayed Recall values were found in females as compared to males. In conclusion, the lower BDNF levels observed in females suggest that changes in peripheral BDNF levels are likely secondary to an altered energy balance. However, further studies using larger sample size are warranted