Screening for Aphasia in NeuroDegeneration for the Diagnosis of Patients with Primary Progressive Aphasia: Clinical Validity and Psychometric Properties.

BACKGROUND: We evaluated the psychometric proprieties of the Screening for Aphasia in NeuroDegeneration (SAND) battery in Italian primary progressive aphasia (PPA) and movement disorder (MD) patients. METHODS: The sample included 30 consecutive PPA and 45 MD patients who completed the SAND battery together with a clinical interview and a neurological/neuropsychological examination and 130 healthy controls (HC). RESULTS: The SAND battery showed good internal consistency and good convergent and divergent validity. receiver operating characteristic analysis revealed an area under the curve of 0.978 for PPA versus HC and of 0.786 for PPA versus MD. A cutoff ≥3 gave a sensitivity of 0.933% and a specificity of 0.946% for discriminating PPA versus HC, whereas a cutoff ≥5 gave a sensitivity of 0.767% and a specificity of 0.667% for discriminating PPA versus MD. CONCLUSION: These results indicate that the SAND battery is an adequate, reliable, and valid diagnostic tool for PPA.

The contribution of surgical brain mapping to the understanding of the anatomo-functional basis of syntax: A critical review.

A wide range of studies on language assessment during awake brain surgery is nowadays available. Yet, a consensus on a standardized protocol for intraoperative language mapping is still lacking. More specifically, very limited information is offered about intraoperative assessment of a crucial component of language such as syntax. This review aims at critically analyzing the intraoperative studies investigating the cerebral basis of syntactic processing. A comprehensive query was performed on the literature, returning a total of 18 studies. These papers were analyzed according to two complementary criteria, based on the distinction between morphosyntax and syntax. The first criterion focused on the tasks and stimuli employed intraoperatively. Studies were divided into three different groups: group 1 included those studies that overtly aimed at investigating morphosyntactic processes; group 2 included studies that did not explicitly focus on syntax, yet employed stimuli requiring morphosyntactic processing; and group 3 included studies reporting some generic form of syntactic deficit, although not further investigated. The second criterion focused on the syntactic structures of the sentences assessed intraoperatively, analyzing the canonicity of sentence structure (i.e., canonical versus non-canonical word order). The global picture emerging from our analysis indicates that what was investigated in the intraoperative literature is morphosyntactic processing, rather than pure syntax. The study of the neurobiology of syntax during awake surgery seems thus to be still at an early stage, in need of systematic, linguistically grounded investigations.

SAND: a Screening for Aphasia in NeuroDegeneration. Development and normative data.

Language assessment has a critical role in the clinical diagnosis of neurodegenerative diseases, in particular, in the case of Primary Progressive Aphasia (PPA). The current diagnostic criteria (Gorno-Tempini et al., 2011) identify three main variants on the basis of clinical features and patterns of brain atrophy. Widely accepted tools to diagnose, clinically classify, and follow up the heterogeneous language profiles of PPA are still lacking. In this study, we develop a screening battery, composed of nine tests (picture naming, word and sentence comprehension, word and sentence repetition, reading, semantic association, writing and picture description), following the recommendations of current diagnostic guidelines and taking into account recent research on the topic. All tasks were developed with consideration of the psycholinguistic factors that can affect performance, with the aim of achieving sensitivity to the language deficit to which each task was relevant, and to allow identification of the selective characteristic impairments of each PPA variant. Normative data on 134 Italian subjects pooled across homogeneous subgroups for age, sex, and education are reported. Although further work is still needed, this battery represents a first step towards a concise multilingual standard language examination, a fast and simple tool to help clinicians and researchers in the diagnosis of PPA.

Biomarkers for the diagnosis of Alzheimer's disease in clinical practice: an Italian intersocietal roadmap.

Biomarkers of brain amyloidosis and neurodegeneration/synaptic dysfunction are featured in recent diagnostic criteria for Alzheimer's disease. Several gaps in our knowledge, however, need to be filled before they can be adopted clinically. The aim of this article is to describe a roadmap, developed by a multidisciplinary task force, to rationally implement biomarkers for Italian Memory Clinics. This roadmap is based on a framework comprising 5 sequential phases: identification of leads for potentially useful biomarkers; development of clinical assays for clinical disease; evaluation of detection of early stages; definition of operating characteristics in relevant populations; and estimation of reducing disease-associated mortality, morbidity, and disability. The roadmap was devised by identifying current evidence of validity, still missing evidence, and action needed to collect this missing evidence. With appropriate adaptation to local, country-specific circumstances, the roadmap can be translated to other countries.

Clinical validity of delayed recall tests as a gateway biomarker for Alzheimer's disease in the context of a structured 5-phase development framework.

Although Alzheimer's disease criteria promote the use of biomarkers, their maturity in clinical routine still needs to be assessed. In the light of the oncology framework, we conducted a literature review on measures used to assess delayed recall impairment due to medial temporal lobe dysfunction (i.e., free and cued word list recall tests). Ample evidence is available for phases 1 (rationale for use), 2 (discriminative ability), and 3 (early detection ability) for many of the tests in routine use. Evidence about phase 4 (performance in real world) and phase 5 (quantify impact and costs) is yet to come. Administration procedures have been standardized and cutoff scores are well validated in large Alzheimer's disease and mild cognitive impaired series. Some aspects (e.g., different task formats), however, hamper the comparability of results among different populations and the reproducibility between laboratories. No definite guideline for their use can thus be proposed at the moment. Accordingly, the maturity of such markers is not yet sufficient and requires future investigation to promote the proper use of memory measures in clinical settings.

Neuropsychological and FDG-PET profiles in VGKC autoimmune limbic encephalitis.

BACKGROUND: Limbic encephalitis (LE) is characterized by an acute or subacute onset with memory impairments, confusional state, behavioral disorders, variably associated with seizures and dystonic movements. It is due to inflammatory processes that selectively affect the medial temporal lobe structures. Voltage-gate potassium channel (VGKC) autoantibodies are frequently observed. In this study, we assessed at the individual level FDG-PET brain metabolic dysfunctions and neuropsychological profiles in three autoimmune LE cases seropositive for neuronal VGKC-complex autoantibodies. MATERIALS AND METHODS: LGI1 and CASPR2 potassium channel complex autoantibody subtyping was performed. Cognitive abilities were evaluated with an in-depth neuropsychological battery focused on episodic memory and affective recognition/processing skills. FDG-PET data were analyzed at single-subject level according to a standardized and validated voxel-based Statistical Parametric Mapping (SPM) method. RESULTS: Patients showed severe episodic memory and fear recognition deficits at the neuropsychological assessment. No disorder of mentalizing processing was present. Variable patterns of increases and decreases of brain glucose metabolism emerged in the limbic structures, highlighting the pathology-driven selective vulnerability of this system. Additional involvement of cortical and subcortical regions, particularly in the sensorimotor system and basal ganglia, was found. CONCLUSIONS: Episodic memory and fear recognition deficits characterize the cognitive profile of LE. Commonalities and differences may occur in the brain metabolic patterns. Single-subject voxel-based analysis of FDG-PET imaging could be useful in the early detection of the metabolic correlates of cognitive and non-cognitive deficits characterizing LE condition.

Brain connectivity in neurodegenerative diseases--from phenotype to proteinopathy.

Functional and structural connectivity measures, as assessed by means of functional and diffusion MRI, are emerging as potential intermediate biomarkers for Alzheimer disease (AD) and other disorders. This Review aims to summarize current evidence that connectivity biomarkers are associated with upstream and downstream disease processes (molecular pathology and clinical symptoms, respectively) in the major neurodegenerative diseases. The vast majority of studies have addressed functional and structural connectivity correlates of clinical phenotypes, confirming the predictable correlation with topography and disease severity in AD and frontotemporal dementia. In neurodegenerative diseases with motor symptoms, structural--but, to date, not functional--connectivity has been consistently found to be associated with clinical phenotype and disease severity. In the latest studies, the focus has moved towards the investigation of connectivity correlates of molecular pathology. Studies in cognitively healthy individuals with brain amyloidosis or genetic risk factors for AD have shown functional connectivity abnormalities in preclinical disease stages that are reminiscent of abnormalities observed in symptomatic AD. This shift in approach is promising, and may aid identification of early disease markers, establish a paradigm for other neurodegenerative disorders, shed light on the molecular neurobiology of connectivity disruption and, ultimately, clarify the pathophysiology of neurodegenerative diseases.

Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention.

Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative damage. Using two-dimensional electrophoresis, we investigated ceruloplasmin patterns in the CSF of human Parkinson's disease patients. Parkinson's disease ceruloplasmin profiles proved more acidic than those found in healthy controls and in other human neurological diseases (peripheral neuropathies, amyotrophic lateral sclerosis, and Alzheimer's disease); degrees of acidity correlated with patients' pathological grading. Applying an unsupervised pattern recognition procedure to the two-dimensional electrophoresis images, we identified representative pathological clusters. In vitro oxidation of CSF in two-dimensional electrophoresis generated a ceruloplasmin shift resembling that observed in Parkinson's disease and co-occurred with an increase in protein carbonylation. Likewise, increased protein carbonylation was observed in Parkinson's disease CSF, and the same modification was directly identified in these samples on ceruloplasmin. These results indicate that ceruloplasmin oxidation contributes to pattern modification in Parkinson's disease. From the functional point of view, ceruloplasmin oxidation caused a decrease in ferroxidase activity, which in turn promotes intracellular iron retention in neuronal cell lines as well as in primary neurons, which are more sensitive to iron accumulation. Accordingly, the presence of oxidized ceruloplasmin in Parkinson's disease CSF might be used as a marker for oxidative damage and might provide new insights into the underlying pathological mechanisms.

Brain activation changes before and after PAP treatment in obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is associated with cognitive and functional deficits, most of which are corrected after positive airway pressure (PAP) treatment. Previous studies investigating the neural underpinnings of OSAS failed to provide consistent results both on the cerebral substrates underlying cognitive deficits and on the effect of treatment on these anomalies. The aims of the study were a) to investigate whether never-treated OSA patients demonstrated differences in brain activation compared to healthy controls during a cognitive task; and b) to investigate whether any improvements in cognitive functioning found in OSA patients after treatment reflected a change in the underlying cerebral activity. DESIGN: OSA patients and healthy controls underwent functional magnetic resonance imaging (fMRI) scanning. They were compared on performance and brain activation during a 2-back working-memory task. Patients were also re-evaluated after 3 months treatment with PAP. Cognitive functions were evaluated using neurocognitive tests. Sleepiness (ESS), mood (Beck Depression Inventory) and, quality-of-life (SF-36) were also assessed. SETTING: The Sleep Disorders Center and CERMAC at the Vita-Salute San Raffaele University. PATIENTS OR PARTICIPANTS: 17 OSA patients and 15 age- and education-matched healthy controls. INTERVENTIONS: PAP treatment for 3 months. MEASUREMENTS AND RESULTS: Compared to controls, never-treated OSA patients showed increased activations in the left frontal cortex, medial precuneus, and hippocampus, and decreased activations in the caudal pons. OSA patients showed decreases in activation with treatment in the left inferior frontal gyrus and anterior cingulate cortex, and bilaterally in the hippocampus. Most neurocognitive domains, impaired at baseline, showed significant improvement after treatment. CONCLUSIONS: OSA patients showed an overrecruitment of brain regions compared to controls, in the presence of the same level of performance on a working-memory task. Decreases of activation in prefrontal and hippocampal structures were observed after treatment in comparison to baseline. These findings may reflect a neural compensation mechanism in never-treated patients, which is reduced by effective treatment.