Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aß42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Spinal cord stimulation may improve gait and cognition in hereditary spastic paraplegia with mental retardation: a case report.

BACKGROUND: Hereditary spastic paraplegia (HSP) include various sporadic and hereditary neurodegenerative disorders, characterized by progressive spasticity and weakness of lower limbs, possibly associated to additional features. CASE PRESENTATION: We report a male HPS patient in his 40 s, showing mental retardation associated with language impairment, dysarthria, and increased urinary frequency. Three months after treatment with electric chronic high-frequency cervical spinal cord stimulation (HF-SCS), he showed an amelioration of motor symptoms (lower limbs spasticity and gait), dysarthria, cognitive functioning (language and constructive praxic abilities), and urinary symptoms (decreased urinary frequency). Single-photon emission computed tomography (SPECT) showed a postoperative increase of cerebral perfusion in right frontal cortex and temporal cortex bilaterally. CONCLUSION: In our patient, HF-SCS might have induced an activation of ascending neural pathways, resulting in changes in activity in various cortical areas (including sensory-motor cortical areas), which may give rise to a modulation of activity in spared descending motor pathways and in neural networks involved in cognitive functions, including language. Although further studies in patients with HPS are needed to clarify whether HF-SCS can be a suitable treatment option in HSP, our observation suggests that HF-SCS, a minimally invasive neurosurgical procedure, might induce beneficial effects of on various symptoms of such orphan disease.

Biopsychosocial frailty and mild cognitive impairment subtypes: Findings from the Italian project on the epidemiology of Alzheimer's disease (IPREA).

INTRODUCTION: Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial phenotypes. We operationalized a biopsychosocial frailty construct, estimating its association with mild cognitive impairment (MCI) and its subtypes. METHODS: In 1980, older individuals from the population-based Italian PRoject on the Epidemiology of Alzheimer's disease (IPREA), we investigated cross-sectional associations among biopsychosocial frailty, MCI, and its subtypes. RESULTS: Participants with biopsychosocial frailty showed an increased odds ratio (OR) of MCI [OR: 4.36; 95% confidence interval (CI): 2.60-7.29; Fisher's exact p < 0.01], particularly for nonamnestic MCI single domain (naMCI-SD, OR:3.28; 95% CI: 1.35-7.97; Fisher's exact p = 0.02) and for nonamnestic MCI multiple domain (naMCI-MD, OR:6.92; 95% CI: 3.37-14.21; Fisher's exact p < 0.01). No statistically significant associations between amnestic MCI single or multiple domain and biopsychosocial frailty were observed. DISCUSSION: In a large, older Italian cohort, a biopsychosocial frailty phenotype was associated with MCI, in particular, could be associated with some of its subtypes, that is, naMCI-SD, and naMCI-MD.

Does the imbalance in the apolipoprotein E isoforms underlie the pathophysiological process of sporadic Alzheimer's disease?

Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood-brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aß) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE-Aß interaction inhibitors produced positive results in transgenic AD mouse models.

The impact of the COVID-19 pandemic on oncological disease extent at FDG PET/CT staging: the ONCOVIPET study.

PURPOSE: To investigate whether the COVID-19 pandemic and national lockdown had an impact on the extent of cancer disease at FDG PET/CT staging as surrogate marker. METHODS: Retrospective observational study including cancer patients submitted to FDG PET/CT staging from June 1 to October 31, 2020, and June 1 to October 31, 2019, respectively. Data regarding primary tumour, nodal (N) status and number of involved nodal stations, and presence and number of distant metastases (M) were collected. Each scan was classified in limited vs advanced status. Data were aggregated across the study population and tumour type. Bi-weekly frequencies of the observed events were analysed. RESULTS: Six hundred eleven patients were included (240 in 2019 vs 371 in 2020, respectively). A significant increase of advanced disease patients (rate 1.56, P < 0.001), N + or M + patients (rate 1.84 and 2.09, respectively, P < 0.001), and patients with a greater number of involved N stations or M (rate 2.01 and 2.06, respectively, P < 0.001) were found in 2020 compared with data of 2019. Analysis by tumour type showed a significant increase of advanced disease in lymphoma and lung cancer in 2020 compared with 2019 (P < 0.001). In addition, a significant increase of nodal involvement was found in lung, gastro-intestinal, and breast cancers, as well as in lymphoma patients (P < 0.02). A significant increase of distant metastases was found in lung cancers (P = 0.002). CONCLUSION: Cancer patients with advanced disease at FDG PET/CT staging increased in 2020 compared with 2019, following the national lockdown due to the COVID-19 pandemic, 1.5-fold with a significant increase of patients with N or M involvement. Targeted health interventions are needed to mitigate the effects of the pandemic on patient outcome.

Processed meat consumption and the risk of incident late-onset depression: a 12-year follow-up of the Salus in Apulia Study.

BACKGROUND: the possible relationship between dietary habits and the incidence of late-onset depression (LOD), defined as first depression onset at later age, is unclear. OBJECTIVE: to investigate the relationship between consumption of different food groups and incident LOD. DESIGN: longitudinal population-based study with a 12-year follow-up. SETTING: Castellana Grotte, Bari, Italy. SUBJECTS: five hundred and forty-six older subjects from the Salus in Apulia Study. METHODS: baseline data were recorded in 2003-06, and diagnostic data were recorded in 2013-18 at follow-up. Dietary intake was assessed with a food frequency questionnaire. Depressive disorders were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders. Subjects who already suffered from depression or other psychiatric disorders at baseline were excluded from the analysis. The association between LOD and single dietary determinants was examined by Cox regression analysis and then applying the hazard ratio (HR). RESULTS: subjects with incident LOD (n = 34) had lower global cognition and total cholesterol levels and a higher body mass index (BMI) at baseline. Only processed meat significantly increased the risk of incident LOD of about 10% by 5 g/day intake (HR adjusted for age, sex, education, multimorbidity and BMI: 1.13, 95% confidence intervals: 1.04-1.22). A similar relationship was found for single foods in the processed meat food group such as sausages, salami and mortadella and baked ham, but not for raw ham. CONCLUSIONS: in midlife, a higher intake of processed meat was not only associated with an increased risk of cardiovascular- and metabolic-related chronic diseases in older age but also with an increased risk of developing LOD.

18F-Fluoroethylcholine PET/CT Radiomic Analysis for Newly Diagnosed Prostate Cancer Patients: A Monocentric Study.

AIM: The aim of this study is to assess whether there are some correlations between radiomics and baseline clinical-biological data of prostate cancer (PC) patients using Fluorine-18 Fluoroethylcholine (18F-FECh) PET/CT. METHODS: Digital rectal examination results (DRE), Prostate-Specific Antigen (PSA) serum levels, and bioptical-Gleason Score (GS) were retrospectively collected in newly diagnosed PC patients and considered as outcomes of PC. Thereafter, Volumes of interest (VOI) encompassing the prostate of each patient were drawn to extract conventional and radiomic PET features. Radiomic bivariate models were set up using the most statistically relevant features and then trained/tested with a cross-fold validation test. The best bivariate models were expressed by mean and standard deviation to the normal area under the receiver operating characteristic curves (mAUC, sdAUC). RESULTS: Semiquantitative and radiomic analyses were performed on 67 consecutive patients. tSUVmean and tSkewness were significant DRE predictors at univariate analysis (OR 1.52 [1.01; 2.29], p = 0.047; OR 0.21 [0.07; 0.65], p = 0.007, respectively); moreover, tKurtosis was an independent DRE predictor at multivariate analysis (OR 0.64 [0.42; 0.96], p = 0.03) Among the most relevant bivariate models, szm_2.5D.z.entr + cm.clust.tend was a predictor of PSA levels (mAUC 0.83 ± 0.19); stat.kurt + stat.entropy predicted DRE (mAUC 0.79 ± 0.10); cm.info.corr.1 + szm_2.5D.szhge predicted GS (mAUC 0.78 ± 0.16). CONCLUSIONS: tSUVmean, tSkewness, and tKurtosis were predictors of DRE results only, while none of the PET parameters predicted PSA or GS significantly; 18F-FECh PET/CT radiomic models should be tested in larger cohort studies of newly diagnosed PC patients.

Anti-amyloid-ß protein agents for the treatment of Alzheimer's disease: an update on emerging drugs.

INTRODUCTION: Currently available Alzheimer's disease (AD) therapeutics are only symptomatic, targeting cholinergic and glutamatergic neurotransmissions. Several putative disease-modifying drugs in late-stage clinical development target amyloid-ß (Aß) peptide and tau protein, the principal neurophatological hallmarks of the disease. AREAS COVERED: Phase III randomized clinical trials of anti-Aß drugs for AD treatment were searched in US and EU clinical trial registries and principal biomedical databases until May 2020. EXPERT OPINION: At present, compounds in Phase III clinical development for AD include four  anti-Ab monoclonal antibodies (solanezumab, gantenerumab, aducanumab, BAN2401), the combination of cromolyn sodium and ibuprofen (ALZT-OP1), and two small molecules (levetiracetam, GV-971). These drugs are mainly being tested in subjects during early AD phases or at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD. The actual results support the hypothesis that elevated Aß represents an early stage in the AD continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials to slow cognitive decline during the AD preclinical stages. However, a series of clinical failures may question further development of Aß-targeting drugs and the findings from current ongoing Phase III trials will hopefully give light to this critical issue.

The Challenge of Antidepressant Therapeutics in Alzheimer's Disease.

The link between depression and Alzheimer's disease (AD) is controversial, because it is not clear if depression is an independent risk factor for the disease or a prodromal symptom in the older population. Cerebral amyloid-ß (Aß) peptide deposition is associated with both cognitive symptoms and neuropsychiatric symptoms (NPS), which may be a biological mechanism of compensation. Despite the widespread use of antidepressant therapeutics (30-50% of patients with AD/dementia are on antidepressants), there is mixed evidence regarding the benefits from their use in AD depression. Monoaminergic antidepressant drugs have shown only modest or no clinical benefits. Therefore, it is important to understand the reason of this drug-resistance and the relationship between antidepressant drugs and the Aß peptide. The goal of the present review is to highlight the etiology of depression in patients affected by AD in comparison to depressive disorders without AD, and to speculate on more appropriate and alternative therapeutics.

Prognostic significance of normalized FDG-PET parameters in patients with multiple myeloma undergoing induction chemotherapy and autologous hematopoietic stem cell transplantation: a retrospective single-center evaluation.

PURPOSE: The purpose of this study was to determine retrospectively, through a single-center evaluation, whether FDG PET-CT normalized semi-quantitative parameters may predict response to induction chemotherapy (iChT) and hematopoietic stem cell transplantation (HSCT), as well as disease progression and progression-free survival in multiple myeloma (MM) patients, thus becoming a tool of personalized medicine. METHODS: Patients undergoing iChT and HSCT with baseline and post-treatment FDG PET-CTs from January 2008 to July 2015 were included. The following baseline and post-treatment parameters were obtained: SUVmax, SUVmean, SUVpeak, MTVsum, TLGsum, rPET (lesion SUVmax/liver SUVmax) and qPET (lesion SUVpeak/liver SUVmean). Baseline-to-post-treatment changes (Δ) were also calculated. Metabolic and clinical laboratory progression or response at follow-up were noted; time-to-metabolic-progression (TMP) was defined as the interval from post-treatment scan to eventual progression at follow-up FDG PET-CTs. Possible association between each functional parameter and metabolic/clinical-laboratory progression or response was determined. Kaplan-Meier curves allowed to depict the TMP trend according to FDG PET-CT parameters. RESULTS: Twenty-eight patients were included. Significantly higher ΔrPET and ΔqPET values were observed in ten patients with "metabolic response", with respect to 18 patients having "metabolic progression" (median 0.62 [IQR 0.32 - 1.34] vs median 0.00 [IQR -0.25 - 0.49] for ΔrPET; P = 0.045; median 0.51 [IQR 0.32 - 1.13] vs median 0.00 [IQR -0.31 - 0.67] for ΔqPET; P = 0.035). Neither normalized nor non normalized parameters differed significantly between the 20 patients with "clinical-laboratory response" and the eight patients with "clinical-laboratory progression". ΔrPET value lower than 0.38 and ΔqPET value lower than 0.27 predicted a significantly shorter TMP (P = 0.003 and P = 0.005, respectively). CONCLUSIONS: Normalized semi-quantitative parameters are effective in predicting persistent response to treatment and shorter TMP in patients with MM undergoing iChT and HSCT.

The Role of Biomarkers in Psychiatry.

Psychiatric illnesses are cognitive and behavioral disorders of the brain. At present, psychiatric diagnosis is based on DSM-5 criteria. Even if endophenotype specificity for psychiatric disorders is discussed, it is difficult to study and identify psychiatric biomarkers to support diagnosis, prognosis, or clinical response to treatment. This chapter investigates the innovative biomarkers of psychiatric diseases for diagnosis and personalized treatment, in particular post-genomic data and proteomic analyses.

Biopsychosocial frailty and the risk of incident dementia: The Italian longitudinal study on aging.

INTRODUCTION: Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial domains/phenotypes. We operationalized a new biopsychosocial frailty (BF) construct, estimating its impact on the risk of incident dementia and its subtypes. METHODS: In 2171 older individuals from the population-based Italian Longitudinal Study on Aging (ILSA), we identified by latent class procedures the BF construct as the physical frail status plus at least one of the two items of the 30-item Geriatric Depression Scale impaired (items 3/10). RESULTS: Over a 3.5-year follow-up, participants with BF showed an increased risk of overall dementia (hazard ratio [HR]: 2.16, 95% confidence interval [CI]:1.07-4.37), particularly vascular dementia (VaD) (HR: 3.21, 95% CI: 1.05-9.75). Similarly, over a 7-year follow-up, an increased risk of overall dementia (HR: 1.84, 95% CI: 1.06-3.20), particularly VaD (HR: 2.53, 95% CI: 1.08-5.91), was also observed. DISCUSSION: In a large cohort of Italian older individuals without cognitive impairment at baseline, a BF model was a short- and long-term predictor of overall dementia, particularly VaD.

Innovative biomarkers in psychiatric disorders: a major clinical challenge in psychiatry.

INTRODUCTION: Currently, the diagnosis of psychiatric illnesses is based upon DSM-5 criteria. Although endophenotype-specificity for a particular disorder is discussed, the identification of objective biomarkers is ongoing for aiding diagnosis, prognosis, or clinical response to treatment. We need to improve the understanding of the biological abnormalities in psychiatric illnesses across conventional diagnostic boundaries. The present review investigates the innovative post-genomic knowledge used for psychiatric illness diagnostics and treatment response, with a particular focus on proteomics. Areas covered: This review underlines the contribution that psychiatric innovative biomarkers have reached in relation to diagnosis and theragnosis of psychiatric illnesses. Furthermore, it encompasses a reliable representation of their involvement in disease through proteomics, metabolomics/pharmacometabolomics and lipidomics techniques, including the possible role that gut microbiota and CYP2D6 polimorphisms may play in psychiatric illnesses. Expert opinion: Etiologic heterogeneity, variable expressivity, and epigenetics may impact clinical manifestations, making it difficult for a single measurement to be pathognomonic for multifaceted psychiatric disorders. Academic, industry, or government's partnerships may successfully identify and validate new biomarkers so that unfailing clinical tests can be developed. Proteomics, metabolomics, and lipidomics techniques are considered to be helpful tools beyond neuroimaging and neuropsychology for the phenotypic characterization of brain diseases.

Additive Role of a Potentially Reversible Cognitive Frailty Model and Inflammatory State on the Risk of Disability: The Italian Longitudinal Study on Aging.

OBJECTIVE: Cognitive frailty is a condition recently defined by operationalized criteria describing the simultaneous presence of physical frailty and mild cognitive impairment (MCI). Two subtypes for this clinical construct have been proposed: "potentially reversible" cognitive frailty (physical frailty plus MCI) and "reversible" cognitive frailty (physical frailty plus pre-MCI subjective cognitive decline). Here the prevalence of a potentially reversible cognitive frailty model was estimated. It was also evaluated if introducing a diagnosis of MCI in older subjects with physical frailty could have an additive role on the risk of dementia, disability, and all-cause mortality in comparison with frailty state or MCI condition alone, with analyses separately performed for inflammatory state. METHODS: In 2,373 individuals from the population-based Italian Longitudinal Study on Aging with a 3.5-year-follow-up, we operationally categorized older individuals without dementia into four groups: non-frail/non-MCI, non-frail/MCI, frail/non-MCI, and frail/MCI. RESULTS: The prevalence of potentially reversible cognitive frailty was 1%, increasing with age and more represented in women than in men, and all groups were associated with significant increased incident rate ratios of dementia, disability, and mortality. A significant difference in rates of disability has been found between the MCI and non-MCI groups (contrasts of adjusted predictions: 0.461; 95% confidence interval: 0.187-0.735) in frail individuals with high inflammatory states (fibrinogen >339 mg/dL). CONCLUSION: In older individuals without dementia and with elevated inflammation, a potentially reversible cognitive frailty model could have a significant additional predictive effect on the risk of disability than the single conditions of frailty or MCI.

Accelerated Long-Term Forgetting Limited to the Recollection Component of Recognition Memory in a Temporal Lobe Epileptic Patient.

Accelerated long-term forgetting (ALF) is a frequent finding in patients with temporal lobe epilepsy (TLE). Here we report the case of a TLE patient who complained of marked difficulties in remembering personal events and information even though repeated neuropsychological assessments had failed to detect any deficit on common laboratory memory tests. The patient underwent an experimental investigation that involved estimating recollection and familiarity processes in the performance on verbal and visual recognition tests, over intervals ranging from 10 minutes to 7 days. Results showed accelerated forgetting confined to the recollection component only, which was particularly evident in the verbal test.

Emerging drugs to reduce abnormal ß-amyloid protein in Alzheimer's disease patients.

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 ß-amyloid (Aß) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aß 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 ß-secretase cleaving enzyme (BACE) (verubecestat), three anti-Aß 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-Aß drugs and the lack of fully understanding of the pathophysiological role of Aß in the development of AD, put the new drugs at substantial risk of failure.

Evaluation of swallowing function after supracricoid laryngectomy as a primary or salvage procedure.

The primary functional issues following conservative therapy for advanced laryngeal cancer concern swallowing. Here, we evaluated the recovery of swallowing after supracricoid partial laryngectomy (SCL) in patients with primary or recurrent laryngeal cancer. We evaluated the swallowing recovery in 27 SCL patients through oropharyngoesophageal scintigraphy, and we evaluated their quality of life using EORTC questionnaires. Four patients underwent total laryngectomy during follow-up. Patients who retained their larynges were able to feed without nutritional support and without tracheostoma. The only significantly different parameter between the primary and salvage cases was the time elapsed to the removal of nasogastric/PEG tubes, which was longer in salvage cases. SCL has been demonstrated as a valuable option for primary and recurrent laryngeal cancer patients. The present data demonstrate good functional results, particularly in terms of swallowing after previous treatments and in primary settings. The combination of oropharyngoesophageal scintigraphy and questionnaires appears to be an adequate, standardizable approach to assessing swallowing function after SCL.

How can we manage progressive supranuclear palsy syndrome with pharmacotherapy?

INTRODUCTION: Tauopathies are a spectrum of clinicopathological neurodegenerative disorders with increased aggregates included in glia and/or neurons of hyperphosphorylated insoluble tau protein, a microtubule-associated protein. Progressive supranuclear palsy (PSP) is an atypical dopaminergic-resistant parkinsonian syndrome, considered as a primary tauopathy with possible alteration of tau isoform ratio, and tau accumulations characterized by 4 R tau species as the main neuropathological lesions. AREAS COVERED: In the present review article, we analyzed and discussed viable disease-modifying and some symptomatic pharmacological therapeutics for PSP syndrome (PSPS). EXPERT OPINION: Pharmacological therapy for PSPS may interfere with the aggregation process or promote the clearance of abnormal tau aggregates. A variety of past and ongoing disease-modifying therapies targeting tau in PSPS included genetic, microtubule-stabilizing compounds, anti-phosphorylation, and acetylation agents, antiaggregant, protein removal, antioxidant neuronal and synaptic growth promotion therapies. New pharmacological gene-based approaches may open alternative prevention pathways for the deposition of abnormal tau in PSPS such as antisense oligonucleotide (ASO)-based drugs. Moreover, kinases and ubiquitin-proteasome systems could also be viable targets.

Social Dysfunction and Apathy: Transdiagnostic Domains in Late-Life Cognitive Disorders.

Social dysfunction is a maladaptive process of coping, problem solving, and achieving one's goals. A new definition of apathy was cross-linked to social dysfunction, with a reduced goal-directed behavior and social interaction as a separate dimension. We hypothesized that these two neuropsychiatric symptoms may be included in the mild behavioral impairment diagnostic framework, operationalizing and standardizing late-life neuropsychiatric symptom assessment, to improve risk determination of dementia. Social dysfunction and apathy were transdiagnostic and prodromic for late-life cognitive disorders. A transdiagnostic approach could provide a useful mean for a better understanding of apathy and related conditions such as social behavior.