Madia Lozupone

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance

Background Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer’s Disease

The failure of several Phase II/III clinical trials in Alzheimers disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

Progresses in treating agitation: a major clinical challenge in Alzheimer’s disease

Introduction: Treatment of neuropsychiatric symptoms (NPS) represents a major clinical challenge in Alzheimer’s disease (AD). Agitation and aggression are frequently seen during institutionalization and increase patient morbidity and mortality and caregiver burden. Off-label use of atypical antipsychotics for treating agitation in AD showed only modest clinical benefits, with high side-effect burden and risk of mortality. Non-pharmacological treatment approaches have become the preferred first-line option. When such treatment fails, pharmacological options are often used. Therefore, there is an urgent need to identify effective and safe pharmacological treatments for efficiently treating agitation and aggression in AD and dementia. Areas covered: Emerging evidence on the neurobiological substrates of agitation in AD has led to several recent clinical trials of repositioned and novel therapeutics for these NPS in dementia as an alternative to antipsychotics. We operated a comprehensive literature search for published articles evaluating pharmacological interventions for agitation in AD, with a review of recent clinical trials on mibampator, dextromethorphan/quinidine, cannabinoids, and citalopram. Expert opinion: Notwithstanding the renewed interest for the pharmacological treatment of agitation in AD, progresses have been limited. A small number and, sometimes methodologically questionable, randomized controlled trials (RCTs) have produced disappointing results. However, recently completed RCTs on novel or repositioned drugs (mibampator, dextromethorphan/quinidine, cannabinoids, and citalopram) showed some promise in treating agitation in AD, but still with safety concerns. Further evidence will come from ongoing Phase II and III trials on promising novel drugs for treating these distressing symptoms in patients with AD and dementia.

Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer's Disease and Late-Life Cognitive Disorders: A Systematic Review

In the last decade, the association between diet and cognitive function or dementia has been largely investigated. In the present article, we systematically reviewed observational studies published in the last three years (2014-2016) on the relationship among dietary factors and late-life cognitive disorders at different levels of investigation (i.e., dietary patterns, foods and food-groups, and dietary micro- and macronutrients), and possible underlying mechanisms of the proposed associations. From the reviewed evidence, the National Institute on Aging-Alzheimers Association guidelines for Alzheimers disease (AD) and cognitive decline due to AD pathology introduced some evidence suggesting a direct relation between diet and changes in the brain structure and activity. There was also accumulating evidence that combinations of foods and nutrients into certain patterns may act synergistically to provide stronger health effects than those conferred by their individual dietary components. In particular, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline. Moreover, also other emerging healthy dietary patterns such as the Dietary Approach to Stop Hypertension (DASH) and the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diets were associated with slower rates of cognitive decline and significant reduction of AD rate. Furthermore, some foods or food groups traditionally considered harmful such as eggs and red meat have been partially rehabilitated, while there is still a negative correlation of cognitive functions with saturated fatty acids and a protective effect against cognitive decline of elevated fish consumption, high intake of monounsaturated fatty acids and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA.

Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy.

Pharmacological manipulation of tau protein in Alzheimers disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimers disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued.

Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients

ABSTRACT Introduction: Currently available drugs against Alzheimer’s disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target β-amyloid (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aβ drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016. Expert opinion: Drugs in Phase III clinical development for AD include one inhibitor of the β-secretase cleaving enzyme (BACE) (verubecestat), three anti-Aβ monoclonal antibodies (solanezumab, gantenerumab, and aducanumab), an inhibitor of receptor for advanced glycation end products (RAGE) (azeliragon) and the combination of cromolyn sodium and ibuprofen (ALZT-OP1). These drugs are mainly being tested in subjects during early phases of AD or in subjects at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD. The hope is to intervene in the disease process when it is not too late. However, previous clinical failures with anti-Aβ drugs and the lack of fully understanding of the pathophysiological role of Aβ in the development of AD, put the new drugs at substantial risk of failure.

Tau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium

ABSTRACT Small molecular weight compounds able to inhibit formation of tau oligomers and fibrils have already been tested for Alzheimer’s disease (AD) treatment. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (also known as methylene blue) was investigated in a 24-week Phase II study in 321 mild-to-moderate AD patients at the doses of 69, 138, and 228 mg/day. This trial failed to show significant positive effects of MT in the overall patient population. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected patients and cerebral blood flow in mildly affected patients. A follow-up compound (TRx0237) claimed to be more bioavailable and less toxic than MT, is now being developed. Phase III clinical trials on this novel TAI in AD and in the behavioral variant of frontotemporal dementia are underway.

Cognitive frailty: a potential target for secondary prevention of dementia

Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy; Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy; Department of Clinical Research in Neurology, University of Bari Aldo Moro, “Pia Fondazione Cardinale G. Panico”, Tricase, Italy; Geriatric Medicine-Memory Unit and Rare Disease Centre, University of Bari ‘Aldo Moro’, Bari, Italy; Psychiatric Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy

Emerging biomarkers and screening for cognitive frailty

Physical frailty and cognitive frailty are two important targets of secondary intervention in aging research to narrow the gap between life and health span. The objective of the present narrative review was to examine clinical and epidemiological studies investigating the recently proposed construct of cognitive frailty and its subtypes, with a focus on operational definitions, clinical criteria, and emerging biomarkers potentially useful for the screening of this novel entity. Both physical frailty and frailty indexes with a multidimensional nature were associated with late-life cognitive impairment/decline, incident dementia, Alzheimer’s disease (AD), mild cognitive impairment, vascular dementia, non-AD dementias, and AD pathology proposing cognitive frailty as a clinical entity with cognitive impairment related to physical causes with a potential reversibility. The new clinical and research AD criteria established by the National Institute on Aging–Alzheimer’s Association and the American Psychiatric Association could improve the differential diagnosis of cognitive impairment within the cognitive frailty construct. The emerging biomarkers of sarcopenia, physical frailty, and cognitive impairment will provide the basis to establish more reliable clinical and research criteria for cognitive frailty, using different operational definitions for frailty and cognitive impairment and useful clinical, biological, and imaging markers for this novel clinical construct.

Metabolic Syndrome: Differences between Psychiatric and Internal Medicine Patients

Objectives: The existence of specific features of Metabolic Syndrome (MetS) in psychiatric population in comparison to not psychiatric patients has not been systematically investigated. The purpose of this study is to evaluate the differences of MetS among a group of psychiatric patients and a group of internal medicine patients in terms of anthropometric measurements, biochemical variables, and cardiovascular risk. Methods: We enrolled 83 psychiatric inpatients under pharmacological treatment (schizophrenia n = 24, bipolar disorder n = 27, major depression n = 14, other n = 18) and 77 internal medicine patients visited for supposed MetS as affected by overweight or arterial hypertension. Results: Psychiatric patients differed from control subjects by age (yrs) (47 ± 9 vs. 52 ± 8.6, p = 0.001), waist circumference (cm) (111.9 ± 10.9 vs. 106 ± 12.6,p= 0.02), HDL cholesterol (mg/dl) (36.8 ± 7 vs. 48 ± 11.3, p = 0.001), serum insulin (µU/ml) (26 ± 12.5 vs. 16.4 ± 8.8, p = 0.001), triglyceride/HDL cholesterol ratio (4.8 ± 2.7 vs. 3.3 ± 2.2, p = 0.01). Female psychiatric patients had higher levels of triglycerides (mg) (178 + 86 vs. 115 + 53, p = 0.002) and of HOMA index (7.8 + 5 vs. 3.8 + 3.3, p = 0.005). Triglycerides and triglycerides/HDL ratio levels were higher in Unipolar Depression. A positive association was found between antidepressant drug treatment with triglycerides and triglycerides/HDL ratio levels, neuroleptic treatment with the HOMA index, and antipsychotics drugs with the Framingham index. Limitations: Psychiatric study population numerosity and duration of psychiatric illness and drug treatment. Conclusions: Specific features of MetS in psychiatric population are mainly represented by young age of onset, hyperinsulinemia, increased abdominal adiposity, and low HDL cholesterol whose common denominator may be insulin-resistance.