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IntroductionBehavioral and Psychological Symptoms of Dementia (BPSD) are a heterogeneous set of psychological reactions and abnormal behaviors in people with dementia (PwD). Current assessment tools, like the Neuropsychiatric Inventory (NPI), only rely on caregiver assessment of BPSD and are therefore prone to bias.Materials and methodsA multidisciplinary team developed the BPSD-SINDEM scale as a three-part instrument, with two questionnaires administered to the caregiver (evaluating BPSD extent and caregiver distress) and a clinician-rated observational scale. This first instrument was tested on a sample of 33 dyads of PwD and their caregivers, and the results were qualitatively appraised in order to revise the tool through a modified Delphi method. During this phase, the wording of the questions was slightly changed, and the distress scale was changed into a coping scale based on the high correlation between extent and distress (r = 0.94). The final version consisted of three 17-item subscales, evaluating BPSD extent and caregiver coping, and the unchanged clinician-rated observational scale.ResultsThis tool was quantitatively validated in a sample of 208 dyads. It demonstrated good concurrent validity, with the extent subscale correlating positively with NPI scores (r = 0.64, p

Background: Neuropsychiatric symptoms (NPSs) are a distressful aspect of dementia and the knowledge of structural correlates of NPSs is limited. We aimed to identify associations of fronto-limbic circuit with specific NPSs in patients with various types of cognitive impairment. Methods: Of 84 participants, 27 were diagnosed with mild cognitive impairment (MCI), 41 with Alzheimer's disease (AD) dementia and 16 with non-AD dementia. In all patients we assessed regional brain morphometry using a region of interest (ROI)-based analysis. The mean cortical thickness (CT) of 20 cortical regions and the volume (V) of 4 subcortical areas of the fronto-limbic system were extracted. NPSs were rated with the Neuropsychiatric Inventory (NPI). We used multiple linear regression models adjusted for age and disease duration to identify significant associations between scores of NPI sub-domains and MRI measures of brain morphometry. Results: All significant associations found were negative, except those between irritability and the fronto-opercular regions in MCI patients (corresponding to a 40-50% increase in CT) and between delusions and hippocampus and anterior cingulate gyrus (with a 40-60% increase). Apathy showed predominant involvement of the inferior frontal regions in AD group (a 30% decrease in CT) and of the cingulate cortex in non-AD group (a 50-60% decrease in CT). Anxiety correlated in MCI patients with the cingulate gyrus and caudate, with a CT and V decrease of about 40%, while hallucinations were associated with left enthorinal gyrus and right amygdala and temporal pole. Agitation showed associations in the AD group with the frontal regions and the temporal pole, corresponding to a 30-40% decrease in CT. Euphoria, disinhibition and eating abnormalities were associated in the MCI group with the entorhinal, para-hippocampal and fusiform gyri, the temporal pole and the amygdala (with a 40-70% decrease in CT and V). Finally, aberrant motor behavior reported a significant association with frontal and cingulate regions with a 50% decrease in CT. Conclusion: Our findings indicate that specific NPSs are associated with the structural involvement of the fronto-limbic circuit across different types of neurocognitive disorders. Factors, such as age and disease duration, can partly account for the variability of the associations observed. [ABSTRACT FROM AUTHOR]

Objective: Dementias and mild cognitive impairment (MCI) are associated with variously combined changes in the neurotransmitter system and signaling, from neurotransmitter synthesis to synaptic binding. The study tested the hypothesis that different dementia subtypes and MCI may share similar reductions of brain availability in amino acid precursors (AAPs) of neurotransmitter synthesis and concomitant similar impairment in energy production and increase of oxidative stress, i.e., two important metabolic alterations that impact neurotransmission. Materials and methods: Sixty-five demented patients (Alzheimer's disease, AD, n = 44; frontotemporal disease, FTD, n = 13; vascular disease, VaD, n = 8), 10 subjects with MCI and 15 control subjects (CTRL) were recruited for this study. Cerebrospinal fluid (CSF) and plasma levels of AAPs, energy substrates (lactate, pyruvate), and an oxidative stress marker (malondialdehyde, MDA) were measured in all participants. Results: Demented patients and subjects with MCI were similar for age, anthropometric parameters, biohumoral variables, insulin resistance (HOMA index model), and CSF neuropathology markers. Compared to age-matched CTRL, both demented patients and MCI subjects showed low CSF AAP tyrosine (precursor of dopamine and catecholamines), tryptophan (precursor of serotonin), methionine (precursor of acetylcholine) limited to AD and FTD, and phenylalanine (an essential amino acid largely used for protein synthesis) (p = 0.03 to <0.0001). No significant differences were found among dementia subtypes or between each dementia subtype and MCI subjects. In addition, demented patients and MCI subjects, compared to CTRL, had similar increases in CSF and plasma levels of pyruvate (CSF: p = 0.023 to <0.0001; plasma: p < 0.002 to <0.0001) and MDA (CSF: p < 0.035 to 0.002; plasma: p < 0.0001). Only in AD patients was the CSF level of lactate higher than in CTRL (p = 0.003). Lactate/pyruvate ratios were lower in all experimental groups than in CTRL. Conclusion: AD, FTD, and VaD dementia patients and MCI subjects may share similar deficits in AAPs, partly in energy substrates, and similar increases in oxidative stress. These metabolic alterations may be due to AAP overconsumption following high brain protein turnover (leading to phenylalanine reductions), altered mitochondrial structure and function, and an excess of free radical production. All these metabolic alterations may have a negative impact on synaptic plasticity and activity. [ABSTRACT FROM AUTHOR]

Introduction: Neural circuit alterations lay at the core of brain physiopathology, and yet are hard to unveil in living subjects. The Virtual Brain (TVB) modeling, by exploiting structural and functional magnetic resonance imaging (MRI), yields mesoscopic parameters of connectivity and synaptic transmission. Methods: We used TVB to simulate brain networks, which are key for human brain function, in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) patients, whose connectivity and synaptic parameters remain largely unknown; we then compared them to healthy controls, to reveal novel in vivo pathological hallmarks. Results: The pattern of simulated parameter differed between AD and FTD, shedding light on disease-specific alterations in brain networks. Individual subjects displayed subtle differences in network parameter patterns that significantly correlated with their individual neuropsychological, clinical, and pharmacological profiles. Discussion: These TVB simulations, by informing about a new personalized set of networks parameters, open new perspectives for understanding dementias mechanisms and design personalized therapeutic approaches. [ABSTRACT FROM AUTHOR]

Brain pathologies are characterized by microscopic changes in neurons and synapses that reverberate into large scale networks altering brain dynamics and functional states. An important yet unresolved issue concerns the impact of patients' excitation/inhibition profiles on neurodegenerative diseases including Alzheimer's Disease, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis. In this work, we used The Virtual Brain (TVB) simulation platform to simulate brain dynamics in healthy and neurodegenerative conditions and to extract information about the excitatory/inhibitory balance in single subjects. The brain structural and functional connectomes were extracted from 3T-MRI (Magnetic Resonance Imaging) scans and TVB nodes were represented by a Wong-Wang neural mass model endowing an explicit representation of the excitatory/inhibitory balance. Simulations were performed including both cerebral and cerebellar nodes and their structural connections to explore cerebellar impact on brain dynamics generation. The potential for clinical translation of TVB derived biophysical parameters was assessed by exploring their association with patients' cognitive performance and testing their discriminative power between clinical conditions. Our results showed that TVB biophysical parameters differed between clinical phenotypes, predicting higher global coupling and inhibition in Alzheimer's Disease and stronger N-methyl-D-aspartate (NMDA) receptor-dependent excitation in Amyotrophic Lateral Sclerosis. These physio-pathological parameters allowed us to perform an advanced analysis of patients' conditions. In backward regressions, TVB-derived parameters significantly contributed to explain the variation of neuropsychological scores and, in discriminant analysis, the combination of TVB parameters and neuropsychological scores significantly improved the discriminative power between clinical conditions. Moreover, cluster analysis provided a unique description of the excitatory/inhibitory balance in individual patients. Importantly, the integration of cerebro-cerebellar loops in simulations improved TVB predictive power, i.e., the correlation between experimental and simulated functional connectivity in all pathological conditions supporting the cerebellar role in brain function disrupted by neurodegeneration. Overall, TVB simulations reveal differences in the excitatory/inhibitory balance of individual patients that, combined with cognitive assessment, can promote the personalized diagnosis and therapy of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: CSF and imaging biomarkers are needed for the etiological diagnosis of neurocognitive disorders, but evidence is incomplete on their rational use in the clinic. Since October 2020, a European task force has been defining an evidence‐based diagnostic workflow, where incomplete evidence is filled by the opinion of experts. Herein, we report the preliminary results through January 2022. Method: A Delphi method was used to reach consensus. Eleven pertinent European scientific societies delegated two panelists each to join Delphi rounds and voting. Consensus was set at 70% of consistent responses. Result: In the 5 voting rounds completed so far, panelists defined clinical setting (specialist outpatient service) and stage of application (prodromal and mild dementia) of the workflow, patients' age window of biomarkers use (strongly encouraged below 70 years and of limited usefulness over 85). Workflow is configurated to be patient‐centered and structured on three levels of assessment (W): W1, definition of clinical profiles based on the combined results of MRI, neuropsychology, blood tests; W2, choice of first‐line biomarkers according to the main clinical suspicion (i.e., FDG‐PET for frontotemporal lobar degeneration and motor tauopathies, dopamine SPECT/PET for Lewy body spectrum disorders, and CSF biomarkers either for Alzheimer's disease or in cases with inconclusive neuropsychological and/or MRI findings, whereas no biomarker was indicated in suspected vascular cognitive impairment); W3, selection of a second‐line biomarker when results of first‐line biomarkers are inconsistent with diagnostic hypothesis (i.e., not typical FDG‐PET pattern) or uninformative (i.e., borderline CSF amyloid results) or not sufficient to rule out other etiologies (i.e., amyloid‐positive and tau‐negative CSF results) or when a diagnosis remains possible despite a negative first‐line biomarker (e.g., normal dopamine SPECT/PET in suspected prodromal dementia with Lewy bodies). Conclusion: The task force is currently defining the second‐line biomarkers of W3 and the project it set to deliver the final algorithm by June 2022. The workflow will promote consistency in diagnosing neurocognitive disorders across countries, and rational use of resources. The initiative has an impact in preparing clinicians to work in the upcoming clinical space where etiological disease‐modifying drugs are expected to be available. [ABSTRACT FROM AUTHOR]

In the past, little or no attention was paid to cognitive disorders associated with depression (a condition sometimes termed pseudodementia). However, recent years have seen a growing interest in these changes, not only because of their high frequency in acute-stage depression, but also because they have been found to persist, as residual symptoms (in addition to affective and psychomotor ones), in many patients who respond well to antidepressant treatment. These cognitive symptoms seem to impact significantly not only on patients' functioning and quality of life, but also on the risk of recurrence of depression. Therefore, over the past decade, pharmacological research in this field has focused on the development of new agents able to counteract not only depressive symptoms, but also cognitive and functional ones. In this context, novel antidepressants with multimodal activity have emerged. This review considers the different issues, in terms of disease evolution, raised by the presence of cognitive disorders associated with depression and considers, particularly from the neurologist's perspective, the ways in which the clinical approach to cognitive symptoms, and their interpretation to diagnostic and therapeutic ends, have changed in recent years. Finally, after outlining the pharmacodynamics and pharmacokinetics of the first multimodal antidepressant, vortioxetine, it reports the main results obtained with the drug in depressed patients, also in consideration of the ever-increasing evidence on its different mechanisms of action in animal models. [ABSTRACT FROM AUTHOR]

Trigeminal autonomic cephalalgias (TACs) are primary headaches that include cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks (SUNHAs) with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA). Hemicrania continua (HC) is another form that has been ascribed to TACs for clinical and pathophysiologic reasons. Cluster headache is the most common of these syndromes, even if comparatively rare, with a lifetime prevalence of around 1 in 1,000. TACs share many aspects from a pathophysiologic standpoint (a hypothalamic activation may be involved in all forms initiating the attacks), but differences in attack duration and frequency and in extent of treatment response distinguish one from the other. This review focuses on the treatments currently available for these headaches according to the most recent guidelines. Due to the low frequency of most TACs, there are little data from randomized controlled trials; therefore, evidence from simple open studies in small case series or single-case observations are reported. Promising results have been recently obtained with novel modes of drug administration, invasive pericranial interventions, and different strategies such as neurostimulation. There are also some future treatments being studied at present. [ABSTRACT FROM AUTHOR]

Aim: To assess the effects of evening chronic administration of diazepam on 24-h blood pressure (BP) and heart rate (HR) in healthy young adults. Methods: This randomized double blind, cross-over study evaluated the effects of diazepam 5 mg or placebo, both ingested in the evening, on 24-h ambulatory BP and HR in healthy subjects aged 21-30. Results: A total of 30 subjects were included in the analysis. At the end of 4-week diazepam intake, an increase in 24-h HR mean values was found (+5.2 beats/min, p < 0.05). Analysis of subperiods showed that diazepam produced a 10.1% increase in night-time HR (+6.1 beats/min, p < 0.01) without affecting BP. A significant HR rise (+4.9 beats/min, p < 0.05) and SBP reduction (-3.8 mm Hg, p < 0.05) were observed in the morning hours. The HR increase persisted in day-time hours (+4.6 beats/min, p < 0.05), while BP values resulted unaffected. Conclusions: In healthy subjects, diazepam taken as a hypnotic agent induces a significant HR increase, possibly mediated mediated by a decrease in vagal tone. This effect might be of clinical relevance due to the role that HR plays as an independent cardiovascular risk factor. [ABSTRACT FROM AUTHOR]