Reduced monoaminergic nuclei MRI signal detectable in pre-symptomatic older adults with future memory decline

Evidence from murine models and human post-mortem studies indicates that monoaminergic nuclei undergo degeneration at the pre-symptomatic stage of Alzheimer’s disease (AD). Analysing 129 datasets from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and relying on the Clinical Dementia Rating as group-defining instrument, we hypothesised that the MRI signal of monoaminergic nuclei would be a statistically significant predictor of memory decline in participants initially recruited in ADNI as healthy adults. As opposed to a group of cognitively stable participants, participants developing memory decline had reduced signal in the ventral tegmental area at baseline, before any evidence of functional decline emerged. These findings indicate that monoaminergic degeneration predates the onset of memory decline in an AD-centred initiative, with a crucial involvement of very-early changes of a dopaminergic region. This translates into potential informative avenues for pharmacological treatment of pre-symptomatic AD

The network substrate of confabulatory tendencies in Alzheimer's disease

Confabulatory phenomena are rare in the early stage of Alzheimer's disease (AD), are often provoked and are triggered by questions or in response to neuropsychological testing. In this retrospective study functional connectivity alterations were investigated for the first time in a group of patients with early AD who had shown evidence of verbal and non-verbal confabulatory tendencies. Resting-state functional magnetic resonance imaging (fMRI) scans of 18 confabulating patients were compared with those of 18 non confabulators. The finding showed that confabulators had decreased connectivity between a seed region in the right inferolateral frontal cortex and right mediotemporal and insular regions, and increased connectivity with frontal areas and a homologous region on the left. The seed control region in the left inferolateral frontal cortex showed increased connectivity with midline frontal and anterior cingulate regions, while a decrease was found in temporal areas. Confabulatory tendencies appear in early AD as a result of disconnection between crucial computational hubs in frontal and mediotemporal regions. This disconnection is coupled with the presence of up-regulation of frontal activity, and especially of midline and anterior cingulate regions, which might disrupt efficient output monitoring in confabulators

Sex differences in olfactory cortex neuronal loss in aging

Introduction: Aging plays a major role in neurodegenerative disorders such as Alzheimer’s disease, and impacts neuronal loss. Olfactory dysfunction can be an early alteration heralding the presence of a neurodegenerative disorder in aging. Studying alterations in olfaction-related brain regions might help detection of neurodegenerative diseases at an earlier stage as well as protect individuals from any danger caused by loss of sense of smell. Objective: To assess the effect of age and sex on olfactory cortex volume in cognitively healthy participants. Method: Neurologically healthy participants were divided in three groups based on their age: young (20–35 years; n = 53), middle-aged (36–65 years; n = 66) and older (66–85 years; n = 95). T1-weighted MRI scans acquired at 1.5 T were processed using SPM12. Smoothed images were used to extract the volume of olfactory cortex regions. Results: ANCOVA analyses showed significant differences in volume between age groups in the olfactory cortex (p ≤ 0.0001). In women, neuronal loss started earlier than in men (in the 4th decade of life), while in men more substantial neuronal loss in olfactory cortex regions was detected only later in life. Conclusion: Data indicate that age-related reduction in the volume of the olfactory cortex starts earlier in women than in men. The findings suggest that volume changes in olfaction-related brain regions in the aging population deserve further attention as potential proxies of increased risk of neurodegenerative diseases.MMA was funded by a scholarship by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

Glycometabolic Alterations in Secondary Adrenal Insufficiency: Does Replacement Therapy Play a Role?

Secondary adrenal insufficiency (SAI) is a potentially life-threatening endocrine disorder due to an impairment of corticotropin (ACTH) secretion from any process affecting the hypothalamus or pituitary gland. ACTH deficit can be isolated or associated with other pituitary failures (hypopituitarism). An increased mortality due to cardiovascular, metabolic, and infectious diseases has been described in both primary and secondary adrenal insufficiency. However, few studies have provided compelling evidences on the underlying mechanism in SAI, because of the heterogeneity of the condition. Recently, some studies suggested that inappropriate glucocorticoid (GCs) replacement therapy, as for dose and/or timing of administration, may play a role. Hypertension, insulin resistance, weight gain, visceral obesity, increased body mass index, metabolic syndrome, impaired glucose tolerance, diabetes mellitus, dyslipidemia have all been associated with GC excess. These conditions are particularly significant when SAI coexists with other pituitary alterations, such as growth hormone deficiency, hypogonadism, and residual tumor. Novel regimen schemes and GC preparations have been introduced to improve compliance and better mimick endogenous cortisol rhythm. The controlled trials on the improved replacement therapies, albeit in the short-term, show some beneficial effects on cardiovascular risk, glucose metabolism, and quality of life. This review examines the current evidence from the available clinical trials investigating the association between different glucocorticoid replacement therapies (type, dose, frequency, and timing of treatment) and glycometabolic alterations in SAI

Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer's Disease in Humans

Background: There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimer’s disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans. Objective: We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls. Methods: Structural and resting state functional MRI scans, and neuropsychological scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested. Results: VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD. Conclusion: Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration

Distinctive neuropsychological profiles differentiate patients with functional memory disorder from patients with amnestic-mild cognitive impairment

OBJECTIVES: Patients with functional memory disorder (FMD) report significant memory failures in everyday life. Differentiating these patients from those with memory difficulties due to early stage neurodegenerative conditions is clinically challenging. The current study explored whether distinctive neuropsychological profiles could be established, suitable to differentiate patients with FMD from healthy individuals and those experiencing amnestic mild cognitive impairment (a-MCI). METHODS: Patients with a clinical diagnosis of FMD were compared with patients with a-MCI, and healthy matched controls on several tests assessing different cognitive functions. Patients with clinically established mood disorders were excluded. Patients with FMD and a-MCI were broadly comparable on the level of their subjective memory complaints as assessed by clinical interview. RESULTS: The neuropsychological profile of the FMD patients, although they expressed subjective memory and attention concerns during their clinical interview was distinct from patients with a-MCI on tests of memory [semantic fluency, age of acquisition (AoA) analysis of semantic fluency, verbal and non-verbal memory]. FMD patients did not differ significantly from healthy controls, but their scores on the letter fluency and digit cancellation tasks were not significantly different from those of the a-MCI patients indicating a possible sub-threshold deficit on these tasks. CONCLUSION: Whilst subjective complaints are common within the FMD population, no objective impairment could be detected, even on a sensitive battery of tasks designed to detect subtle deficits caused by an early neurodegenerative brain disease. This study indicates that FMD patients can be successfully differentiated from patients with neurodegenerative memory decline by characterising their neuropsychological profile

Reduced monoaminergic nuclei MRI signal detectable in pre-symptomatic older adults with future memory decline

Supplementary information: Supplementary file1 (Microsft Word docx) available at https://static-content.springer.com/esm/art%3A10.1038%2Fs41598-020-71368-1/MediaObjects/41598_2020_71368_MOESM1_ESM.docxCopyright © The Author(s) 2020. Evidence from murine models and human post-mortem studies indicates that monoaminergic nuclei undergo degeneration at the pre-symptomatic stage of Alzheimer's disease (AD). Analysing 129 datasets from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and relying on the Clinical Dementia Rating as group-defining instrument, we hypothesised that the MRI signal of monoaminergic nuclei would be a statistically significant predictor of memory decline in participants initially recruited in ADNI as healthy adults. As opposed to a group of cognitively stable participants, participants developing memory decline had reduced signal in the ventral tegmental area at baseline, before any evidence of functional decline emerged. These findings indicate that monoaminergic degeneration predates the onset of memory decline in an AD-centred initiative, with a crucial involvement of very-early changes of a dopaminergic region. This translates into potential informative avenues for pharmacological treatment of pre-symptomatic AD.This manuscript is not associated with any sources of funding

Understanding the effect of cognitive/brain reserve and depression on regional atrophy in early Alzheimer’s disease

Introduction: Depression in patients with mild cognitive impairment (MCI) and dementia of the Alzheimer’s type (AD) is associated with worse prognosis. Indeed, depressed MCI patients have worse cognitive performance and greater loss of gray-matter volume in several brain areas. To date, knowledge of the factors that can mitigate this detrimental effect is still limited. The aim of the present study was to understand in what way cognitive reserve/brain reserve and depression interact and are linked to regional atrophy in early stage AD. Methods: Depression was evaluated with the Patient Health Questionnaire-9 in 90 patients with early AD, and a cutoff of ≥ 5 was used to separate depressed (n = 44) from non-depressed (n = 46) patients. Each group was further stratified into high/low cognitive reserve/brain reserve. Cognitive reserve was calculated using years of education as proxy, while normalized parenchymal volumes were used to estimate brain reserve. Voxel-based morphometry was carried out to extract and analyze gray-matter maps. 2 × 2 ANCOVAs were run to test the effect of the reserve-by-depression interaction on gray matter. Age and hippocampal ratio were used as covariates. Composite indices of major cognitive domains were also analyzed with comparable models. Results: No reserve-by-depression interaction was found in the analytical models of gray matter. Depression was associated with less gray matter volume in the cerebellum and parahippocampal gyrus. The brain reserve-by-depression interaction was a significant predictor of executive functioning. Among those with high brain reserve, depressed patients had poorer executive skills. No significant results were found in association with cognitive reserve. Conclusion: These findings suggest that brain reserve may modulate the association between neurodegeneration and depression in patients with MCI and dementia of the AD type, influencing in particular executive functioning

Cognitive stimulation of the default-mode network modulates functional connectivity in healthy aging

A cognitive-stimulation tool was created to regulate functional connectivity within the brain Default-Mode Network (DMN). Computerized exercises were designed based on the hypothesis that repeated task-dependent coactivation of multiple DMN regions would translate into regulation of resting-state network connectivity. Forty seniors (mean age: 65.90 years; SD: 8.53) were recruited and assigned either to an experimental group (n = 21) who received one month of intensive cognitive stimulation, or to a control group (n = 19) who maintained a regime of daily-life activities explicitly focused on social interactions. An MRI protocol and a battery of neuropsychological tests were administered at baseline and at the end of the study. Changes in the DMN (measured via functional connectivity of posterior-cingulate seeds), in brain volumes, and in cognitive performance were measured with mixed models assessing group-by-timepoint interactions. Moreover, regression models were run to test gray-matter correlates of the various stimulation tasks. Significant associations were found between task performance and gray-matter volume of multiple DMN core regions. Training-dependent up-regulation of functional connectivity was found in the posterior DMN component. This interaction was driven by a pattern of increased connectivity in the training group, while little or no up-regulation was seen in the control group. Minimal changes in brain volumes were found, but there was no change in cognitive performance. The training-dependent regulation of functional connectivity within the posterior DMN component suggests that this stimulation program might exert a beneficial impact in the prevention and treatment of early AD neurodegeneration, in which this neurofunctional pathway is progressively affected by the disease

Memory difficulties are not always a sign of incipient dementia: a review of the possible causes of loss of memory efficiency

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