Modeling and Optimization of Single Photon Avalanche Photodiodes for X-Ray Detection

Avalanche Photodiodes (APDs) are electronic devices that transduce a photon flux into an electrical current and provide internal amplification of this current exploiting the impact ionization mechanism. APDs are used as receivers in optical fiber communication links as well as detectors in physics experiments and medical imaging. According to the needs of the target application, they can either be operated below (Linear mode) or above (Geiger mode) their breakdown voltage. For X-ray detection, APDs fabricated in III-V compound semiconductors, such as GaAs, offer an interesting alternative to SiAPDs, thanks to the short attenuation length at high energies offered by these materials. However, to improve the poor noise performance of APDs fabricated in III-V compounds given by similar electron\u2019s and hole\u2019s impact ionization coefficients, structures alternative to p-i-n APDs have to be employed. A possible solution is the use of staircase APDs, where heterojunctions between III-V compound semiconductors and their alloys with metals are exploited to enhance the electron to hole impact ionization probability by creating an artificial superlattice. This thesis aims at proposing models to compute the figures of merit of APDs fabricated in III-V compound semiconductors and operating in Linear mode for the detection of X-rays. Since accurate modeling of impact ionization is key to obtain reliable data from simulations, we present the development of a suite of simulations tools that includes finite difference and a Random Path Length algorithm implementation of a newly derived nonlocal history dependent impact ionization model and a Full Band Monte Carlo transport simulator. All these models have been validated against experimental results and are thus powerful tools in support of the interpretation of single photon APDs electrical measurements and for the optimization of their performance. These simulation tools have been used to compute the gain, the excess noise factor, the response time, the bandwidth and the jitter of different APD structures, including staircase APDs. In addition, the Full Band Monte Carlo transport simulator has been employed to assess the basic assumptions, identify the limitations and improve the calibration of nonlocal history dependent impact ionization models. We have found that, even though nonlocal history dependent models give results that are in a satisfactory agreement with experiments, they neglect that after an impact ionization event secondary carriers are generated with non null kinetic energy and that carrier-phonon scattering may lead to electrons and holes that travel for few free flights with velocities that are opposite to the direction of the electric fields. These aspects may become relevant and yield misleading results, in particular for short devices

CSF alpha-synuclein aggregates by seed amplification and clinical presentation of AD

Introduction: Accumulating evidence suggests that α-synuclein (αSyn) can modulate Alzheimer's disease (AD) pathology. The aim of this study was to evaluate the prevalence and clinical features associated with cerebrospinal fluid (CSF) αSyn detected by seed amplification assay (SAA) in AD. Methods: Eighty AD patients with CSF AT(N) biomarker positivity (mean age 70.3 ± 7.3 years) and 28 non-AD age-matched controls were included. All subjects underwent standardized clinical assessment; CSF αSyn aggregates were detected by SAA. Results: CSF was αSyn-SAA positive (αSyn+) in 36/80 AD patients (45%) and in 2/28 controls (7.1%). AD αSyn+ and αSyn- patients were comparable for age, disease severity, comorbidity profile, and CSF core biomarkers. AD αSyn+ presented a higher prevalence of atypical phenotypes and symptoms. Conclusions: Our findings demonstrate that concomitant CSF αSyn pathology is present in a significant proportion of AD patients starting in the early stages and can affect clinical presentation. Longitudinal studies are warranted to evaluate the significance for the disease course

Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria

Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction since birth has led to normal cognitive development. However, PKU patients can still develop cognitive or behavioral abnormalities and subtle neurological deficits. Despite the increasing evidence in the field, the assessment of neurocognitive, psychopathological, and neurological follow-up of PKU patients at different ages is still debated. The high interindividual variability in the cognitive outcome of PKU patients makes the specificity of the neurocognitive and behavioral assessment extremely challenging. In the present paper, a multidisciplinary panel of Italian PKU experts discussed different tools available for cognitive, psychopathological, and neurological assessment at different ages based on the existing literature and daily clinical practice. This study aims to provide evidence and a real-life-based framework for a specific clinical assessment of pediatric, adolescent, and adult patients affected by PKU

Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient

Background: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood–cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. Methods: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40–60 and 9.0 over 60 years. Results: 1209 subjects were included in the study. 718 females and 491 males (age: 15–88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease sub- groups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivari- able linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. Conclusions: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach

Unsupervised but not supervised gait parameters are related to fatigue in Parkinson’s disease: a pilot study

IntroductionFatigue is a common and disabling symptom in Parkinson’s disease (PD), also affecting gait. Detection of fatigue-associated changes of gait using mobile health technologies (MHT) could become increasingly effective.MethodsCognitively unimpaired PD patients without fluctuations (UPDRS IV < 1) underwent a standard neurological assessment including the PD-Fatigue scale (PFS-16). PD patients with (PD-F) and without fatigue (PD-N) were matched for age, sex, cognitive function and disease severity. Each participant underwent MHT gait assessment under supervised condition (SC) and unsupervised condition (UC).ResultsGait parameters of 21 PD-F and 21 PD-N did not significantly differ under SC. Under UC, PD-F showed higher step time, step time variability and asymmetry index compared to PD-N and the PFS-16 correlated with step time.ConclusionThis is the first MHT-based study with PD patients showing a correlation between fatigue and gait parameters. In addition, the data collected suggest that UC is clearly superior to SC in addressing this question

Metabolic connectivity of resting-state networks in alpha synucleinopathies, from prodromal to dementia phase

Previous evidence suggests that the derangement of large-scale brain networks reflects structural, molecular, and functional mechanisms underlying neurodegenerative diseases. Although the alterations of multiple large-scale brain networks in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are reported, a comprehensive study on connectivity reconfiguration starting from the preclinical phase is still lacking. We aimed to investigate shared and disease-specific changes in the large-scale networks across the Lewy Bodies (LB) disorders spectrum using a brain metabolic connectivity approach. We included 30 patients with isolated REM sleep behavior disorder (iRBD), 28 with stable PD, 30 with DLB, and 30 healthy controls for comparison. We applied seed-based interregional correlation analyses (IRCA) to evaluate the metabolic connectivity in the large-scale resting-state networks, as assessed by [18F]FDG-PET, in each clinical group compared to controls. We assessed metabolic connectivity changes by applying the IRCA and specific connectivity metrics, such as the weighted and unweighted Dice similarity coefficients (DC), for the topographical similarities. All the investigated large-scale brain resting-state networks showed metabolic connectivity alterations, supporting the widespread involvement of brain connectivity within the alpha-synuclein spectrum. Connectivity alterations were already evident in iRBD, severely affecting the posterior default mode, attentive and limbic networks. Strong similarities emerged in iRBD and DLB that showed comparable connectivity alterations in most large-scale networks, particularly in the posterior default mode and attentive networks. Contrarily, PD showed the main connectivity alterations limited to motor and somatosensory networks. The present findings reveal that metabolic connectivity alterations in the large-scale networks are already present in the early iRBD phase, resembling the DLB metabolic connectivity changes. This suggests and confirms iRBD as a risk condition for progression to the severe LB disease phenotype. Of note, the neurobiology of stable PD supports its more benign phenotype

Multidisciplinary lifestyle intervention to manage pancreatic cancer-related cachexia: a case report

Pancreatic cancer remains an aggressive disease, with a poor prognosis and a high risk of incurring into cachexia. Supportive care, such as exercise, nutritional and psychological support, may be effective in reducing functional loss, psychological distress and improving nutritional status. We report the effect of 12 weeks of multimodal lifestyle intervention in a 55-year-old female, diagnosed with unresectable body/tail pancreatic cancer and metastasis in the liver, bone, lymph node and lung, to counteract cachexia. The multimodal program resulted safe and feasible. Over 12 weeks, considerable improvements were found in body weight, health-related physical fitness, nutritional status, distress scores, anxiety and depression levels. These findings highlight the potential role of integrated supportive interventions to manage metastatic cancer and cancer-induced cachexia

Occipital atrophy signature in prodromal Lewy bodies disease

Introduction: Dementia with Lewy bodies (DLB) is typically characterized by parietal, temporal, and occipital atrophy, but less is known about the newly defined prodromal phases. The objective of this study was to evaluate structural brain alterations in prodromal DLB (p-DLB) as compared to healthy controls (HC) and full-blown dementia (DLB-DEM). Methods: The study included 42 DLB patients (n = 20 p-DLB; n = 22 DLB-DEM) and 27 HC with a standardized neurological assessment and 3-tesla magnetic resonance imaging. Voxel-wise analyses on gray-matter and cortical thickness were implemented to evaluate differences between p-DLB, DLB-DEM, and HC. Results: p-DLB and DLB-DEM exhibited reduced occipital and posterior parieto-temporal volume and thickness, extending from prodromal to dementia stages. Occipital atrophy was more sensitive than insular atrophy in differentiating p-DLB and HC. Occipital atrophy correlated to frontotemporal structural damage increasing from p-DLB to DLB-DEM. Discussion: Occipital and posterior-temporal structural alterations are an early signature of the DLB continuum and correlate with a long-distance pattern of atrophy

Effects of dopaminergic treatment on inhibitory control differ across Hoehn and Yahr stages of Parkinson's disease

: Motor inhibitory control, a core component of cognitive control, is impaired in Parkinson's disease, dramatically impacting patients' abilities to implement goal-oriented adaptive strategies. A progressive loss of the midbrain's dopamine neurons characterizes Parkinson's disease and causes motor features responsive to dopaminergic treatments. Although such treatments restore motor symptoms, their impact on response inhibition is controversial. Most studies failed to show any effect of dopaminergic medicaments, although three studies found that these drugs selectively improved inhibitory control in early-stage patients. Importantly, all previous studies assessed only one domain of motor inhibition, i.e. reactive inhibition (the ability to react to a stop signal). The other domain, i.e. proactive inhibition (the ability to modulate reactive inhibition pre-emptively according to the current context), was utterly neglected. To re-examine this issue, we recruited cognitively unimpaired Parkinson's patients under dopaminergic treatment in the early (Hoehn and Yahr, 1-1.5, n = 20), intermediate (Hoehn and Yahr 2, n = 20), and moderate/advanced (Hoehn and Yahr, 2.5-3, n = 20) stages of the disease. Using a cross-sectional study design, we compared their performance on a simple reaction-time task and a stop-signal task randomly performed twice on dopaminergic medication (ON) and after medication withdrawal (OFF). Normative data were collected on 30 healthy controls. Results suggest that medication effects are stage-dependent. In Hoehn and Yahr 1-1.5 patients, drugs selectively impair reactive inhibition, leaving proactive inhibition unaffected. In the ON state, Hoehn and Yahr two patients experienced impaired proactive inhibition, whereas reactive inhibition is no longer affected, as it deteriorates even during the OFF state. By contrast, Hoehn and Yahr 2.5-3 patients exhibited less efficient reactive and proactive inhibition in the OFF state, and medication slightly improved proactive inhibition. This evidence aligns with the dopamine overdose hypothesis, indicating that drug administration may overdose intact dopamine circuitry in the earliest stages, impairing associated cognitive functions. In later stages, the progressive degeneration of dopaminergic neurons prevents the overdose and can exert some beneficial effects. Thus, our findings suggest that inhibitory control assessment might help tailor pharmacological therapy across the disease stage to enhance Parkinson's disease patients' quality of life by minimizing the hampering of inhibitory control and maximizing the reduction of motor symptoms

Differences Between Plasma and Cerebrospinal Fluid p-tau181 and p-tau231 in Early Alzheimer's Disease

Plasma phosphorylated tau species have been recently proposed as peripheral markers of Alzheimer's disease (AD) pathology. In this cross-sectional study including 91 subjects, plasma and cerebrospinal fluid (CSF) p-tau181 and p-tau231 levels were elevated in the early symptomatic stages of AD. Plasma p-tau231 and p-tau181 were strongly related to CSF phosphorylated tau, total tau and amyloid and exhibited a high accuracy-close to CSF p-tau231 and p-tau181-to identify AD already in the early stage of the disease. The findings might support the use as diagnostic and prognostic peripheral AD biomarkers in both research and clinical settings