Reduced Self-Awareness Following a Combined Polar and Paramedian Bilateral Thalamic Infarction. A Possible Relationship With SARS-CoV-2 Risk of Contagion?

Reduced self-awareness is a well-known phenomenon investigated in patients with vascular disease; however, its impact on neuropsychological functions remains to be clarified. Importantly, selective vascular lesions provide an opportunity to investigate the key neuropsychological features of reduced self-awareness in neurocognitive disorders. Because of its rarity, we present an unusual case of a woman affected by a combined polar and paramedian bilateral thalamic infarction. The patient underwent an extensive neuropsychological evaluation to assess cognitive, behavioral, and functional domains, with a focus on executive functions. She was assessed clinically in the acute phase and after 6 months from the stroke, both clinically and by magnetic resonance imaging. The patient developed a cognitive impairment, characterised by prevalent executive dysfunction associated with reduced self-awareness and mood changes, in terms of apathy and depression. Such condition persisted after 6 months. In May 2020, the patient underwent the serology test in chemiluminescence to detect IgG antibodies against SARS-CoV-2. The result of the quantitative test highlighted a high probability of previous contact with the virus. We suggest that reduced self-awareness related to executive dysfunction and behavioral changes may be due to combined polar and paramedian bilateral thalamic lesion. Metacognitive-executive dysfunction affecting the instrumental abilities of everyday life might make people less able to take appropriate precautions, facilitating the risk of SARS-CoV-2 contagion.

Neuropsychological correlates of instrumental activities of daily living in neurocognitive disorders: a possible role for executive dysfunction and mood changes.

ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily Living (i-ADL) over time and progression to Alzheimer's Disease (AD), we aimed to analyze the role of neuropsychological variables to outline which factors can contribute to functional impairment. Specific attention to executive functions (EFs) has been given.A total of 144 subjects complaining of different cognitive deficits - ranging from "MCI likely due to AD" to "mild AD patients" - underwent an overall neuropsychological assessment. The Behavioral Assessment of the Dysexecutive Syndrome was used to analyze EFs. We conducted multiple linear regression analyses to study whether the level of independent living skills - assessed with the Lawton-scale - could be associated with cognitive and behavioral measurements.We found a significant association between i-ADL and specific EFs measured by Rule Shift Cards (p = 0.04) and Modified Six Elements (p = 0.02). Moreover, considering i-ADL scores, we observed an involvement of mood changes and a reduced awareness of deficits in terms of Hamilton Depression Rating Scale (p = 0.02) and Awareness of Deficit Questionnaire - Dementia scale (p < 0.0001), respectively.Our results suggest the importance of considering the association between a reduction in i-ADL and executive dysfunction in patients who have AD etiopathology, for which the ability to inhibit a response, self-monitoring, set-shifting and mood deflection play a key role. Besides, no straightforward associations between i-ADL scores and global cognition, memory, language comprehension, attention, and perspective taking abilities were found.

Neuropsychological Correlates of Pre-Frailty in Neurocognitive Disorders: A Possible Role for Metacognitive Dysfunction and Mood Changes.

BACKGROUND: Recent studies have suggested that cognitive functions in patients with neurocognitive disorders have a significant role in the pathogenic mechanisms of frailty. Although pre-frailty is considered an intermediate, preclinical state, epidemiological research has begun to dislodge cognition and frailty into their specific subcomponents to understand the relationship among them. We aim to analyse the possible association between pre-frailty and neuropsychological variables to outline which factors can contribute to minor and major neurocognitive disorders. METHODS: 60 subjects complaining of different cognitive deficits underwent a deep-in-wide frailty and neuropsychological assessment. We conducted three multiple linear regression analyses adjusted for a combination of demographic measures and involving several neuropsychological-behavioural parameters selected by the literature on physical frailty. RESULTS: We found a significant association between frailty-as measured by the multidimensional prognostic index (MPI)-and action monitoring and monetary gain (cognitive domain), depression and disinhibition (behavioural domain). Moreover, an association between MPI and impaired awareness for instrumental activities disabilities exists. CONCLUSION: We propose a novel framework for understanding frailty associated with metacognitive-executive dysfunction.

A20 in Multiple Sclerosis and Parkinson's Disease: Clue to a Common Dysregulation of Anti-Inflammatory Pathways?

Chronic inflammation significantly contributes to the pathogenesis of several neurodegenerative disorders. In physiological conditions, a chronic inflammatory state is prevented through the termination of the acute inflammatory response once the triggering insult is eliminated. Several mechanisms regulate the resolution of inflammation. Among these, a potent inhibitor of the pro-inflammatory NF-kB signaling known as A20 has emerged as a key player. Recent studies have shown reduced blood levels of A20 in the patients of diverse chronic inflammatory diseases. Similar results have also been demonstrated in patients of multiple sclerosis (MS), a neurodegenerative disease characterized by persisting inflammation. In the present study, we investigate whether other similar neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) also demonstrate deregulated levels of A20 expression as compared to healthy controls (HC) and treatment-naive MS patients. Our results confirm previous data that the A20 expression is reduced in whole blood of MS patients as compared to HC. Additionally, we demonstrate that significantly diminished A20 expression is also evident in PD patients. The dysregulation of the A20 pathway could then contribute to the persistence of inflammation in these disorders. It would thus be interesting to investigate further whether such commonly deregulated pathways between different inflammatory diseases could represent novel targets for therapy.

A novel framework for understanding reduced awareness of dyskinesias in Parkinson's Disease.

BACKGROUND: Although dyskinesias-reduced-self-awareness (DRSA) in Parkinson's disease (PD) is related to deficit in metacognition, other factors, such as "Theory of Mind" (ToM), could operate. METHODS: Forty-one PD patients were assessed using the Global Awareness of Movement Disorders (GAM) and the Dyskinesias Subtracted-Index (DS-I). To study whether GAM and DS-I scores could be influenced by second-type ToM or Reading the Mind in the Eyes (RME) tasks, we conducted two multiple logistic regression analyses. RESULTS: The association between the GAM, the DS-I and RME task were highly significant. The association between DS-I and Trail Making Test B-A version was also verified. CONCLUSION: DRSA was related with affective component of ToM and executive functions, thus caused by a complex interplay between specific neuropsychological and motor factors.

Altered NR4A Subfamily Gene Expression Level in Peripheral Blood of Parkinson's and Alzheimer's Disease Patients.

Parkinson's disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer's disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.

Self-unawareness of levodopa induced dyskinesias in patients with Parkinson's disease.

The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinson's disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon. PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to assess the executive functions of the prefrontal-ventral-striatal circuitry. Data showed that a reduction of self-awareness using the Dyskinesia rating scale was associated with global monitoring (p=.04), monitoring resolution (p=.04) and control sensitivity (p=.04). Patients failed to perceive their performance, distinguish between correct and incorrect sorts, be confident in their choice and consequently decide to gamble during the task. We did not find any association with executive functions using the hypo-bradykinesia rating scale. Our findings indicate that when the comparator mechanism for monitoring attentive performance is compromised at a prefrontal striatal level, patients lose the ability to recognize their motor disturbances that do not achieve conscious awareness.

Impaired awareness of deficits in Alzheimer's disease: the role of everyday executive dysfunction.

The present study analyzed the awareness of deficits in 117 mild Alzheimer's disease participants. Since few studies have examined the cognitive and behavioral domains of reduced awareness in detail, we performed a domain-specific assessment using the Awareness of deficit Questionnaire - Dementia scale with the novel aim of describing the relationship with everyday executive dysfunction. Through the use of the subtests of the Behavioral Assessment of the Dysexecutive Syndrome, we hypothesized that executive cognitive functions may play an important role in the reduced awareness of deficits. We also considered other variables of interest to provide a novel comprehensive explanation of this phenomenon. Our first approach to the study was a factor analysis considering the role of these variables in the awareness of deficits; subsequently, regression analysis models were used to define which variables were associated with a reduction of awareness in cognitive and behavioral domains. In particular, the factors retained from the factor analysis, in terms of inhibition, self-monitoring, set-shifting, and mood orientation changes, appear to be important skills for awareness of instrumental activities of daily living (R(2) = .32). We also found hypo manic mood orientation and a tendency through apathy to be prominent indications of reduced behavioral awareness (R(2) = .13).

Unawareness of deficits in Alzheimer's disease: role of the cingulate cortex.

Unawareness of deficits is a symptom of Alzheimer's disease that can be observed even in the early stages of the disease. The frontal hypoperfusion associated with reduced awareness of deficits has led to suggestions of the existence of a hypofunctioning prefrontal pathway involving the right dorsolateral prefrontal cortex, inferior parietal lobe, anterior cingulate gyri and limbic structures. Since this network plays an important role in response inhibition competence and patients with Alzheimer's disease who are unaware of their deficits exhibit impaired performance in response inhibition tasks, we predicted a relationship between unawareness of deficits and cingulate hypofunctionality. We tested this hypothesis in a sample of 29 patients with Alzheimer's disease (15 aware and 14 unaware of their disturbances), rating unawareness according to the Awareness of Deficit Questionnaire-Dementia scale. The cognitive domain was investigated by means of a wide battery including tests on executive functioning, memory and language. Neuropsychiatric aspects were investigated using batteries on behavioural mood changes, such as apathy and disinhibition. Cingulate functionality was assessed with functional magnetic resonance imaging, while patients performed a go/no-go task. In accordance with our hypotheses, unaware patients showed reduced task-sensitive activity in the right anterior cingulate area (Brodmann area 24) and in the rostral prefrontal cortex (Brodmann area 10). Unaware patients also showed reduced activity in the right post-central gyrus (Brodmann area 2), in the associative cortical areas such as the right parietotemporal-occipital junction (Brodmann area 39) and the left temporal gyrus (Brodmann areas 21 and 38), in the striatum and in the cerebellum. These findings suggest that the unawareness of deficits in early Alzheimer's disease is associated with reduced functional recruitment of the cingulofrontal and parietotemporal regions. Furthermore, in line with previous findings, we also found apathy and disinhibition to be prominent features of the first behavioural changes in unaware patients.

Neuropsychiatric symptoms underlying caregiver stress and insight in Alzheimer's disease.

OBJECTIVE: Cluster analysis based on Alzheimer's disease (AD) neuropsychiatric profile demonstrated validity on caregiver burden, nursing-home placement and survival. The aims of our study were to explore the validity of this approach on caregiver burden, lack of insight and cognitive impairment and to examine the impact of neuropsychiatric profiles on these variables. METHOD: A data-driven approach (two-step cluster analysis) identified groups of patients based on similarities of their neuropsychiatric symptom profile, as assessed by the Neuropsychiatric Inventory (NPI). ANOVAs and chi(2) tests were used to compare groups with regard to continuous and categorical variables. Linear regressions tested the relationships between NPI and clinical variables. RESULTS: Psychotic/behavioral, depressive and minimally symptomatic clusters differed for caregiver burden and lack of insight. Patients in the minimally symptomatic cluster showed better insight than those in the depressive cluster. Caregivers of the psychotic/behavioral cluster experienced the highest burden. We found positive relationships between NPI and lack of insight in the depressive and minimally symptomatic clusters and between NPI and caregiver burden in all three clusters. Caregiver burden was influenced by the type of symptoms. CONCLUSIONS: The cluster analysis was valid for lack of insight and caregiver burden. Symptoms predominant on caregiver burden could become targets for therapy.

Metaphor comprehension in Alzheimer's disease: novelty matters.

The comprehension of non-literal language was investigated in 20 probable Alzheimer's disease (pAD) patients by comparing their performance to that of 20 matched control subjects. pAD patients were unimpaired in the comprehension of conventional metaphors and idioms. However, their performance was significantly lower in the case of non-conventional (novel) metaphor comprehension. This ability was not related to global cognitive deterioration or to deficits in the cognitive domains of attention, memory and language comprehension. On the other hand, the impairment in verbal reasoning appeared to be relevant for both novel and conventional metaphor comprehension. The relationship between novel metaphor comprehension and performance in the visual-spatial planning task of the Behavioral Assessment of the Dysexecutive Syndrome (BADS) suggests that executive impairment, possibly related to prefrontal dysfunction, may be responsible for the pAD patients' poor performance in novel metaphor comprehension. The present findings suggest a role of the prefrontal cortex in novel metaphor comprehension.

Spectral electroencephalogram analysis in hepatic encephalopathy and liver transplantation.

The aim of this study is to evaluate the role of spectral electroencephalogram (EEG) analysis ((S)EEG) in quantitating brain dysfunction in cirrhotic patients, showing conditions of minimal hepatic encephalopathy (HE), and determining the impact of orthotopic liver transplantation (OLT) on its correction. (S)EEG was compared with visual EEG ((V)EEG) in 44 cirrhotic patients waiting for OLT and 44 healthy controls. Eighteen patients had overt HE, and 26 patients had no apparent HE. Twenty-one transplant recipients were reexamined 6 months after OLT. Computerized (S)EEG was performed by mean dominant frequency (MDF) and the occipital alpha-theta ratio, expressed as its logarithmic transformation (LogR). All patients underwent psychometric assessment. MDF and LogR correlated significantly with Child-Pugh score (P <.05) and the presence of HE (P <.0001). (S)EEG and (V)EEG determined minimal HE in 8 (31%) and 6 (23%) of 26 patients without overt HE, respectively. (S)EEG did not correlate with age, sex, cause of liver disease, portal hypertension, or psychometric test results. MDF and LogR improved in many transplant recipients. LogR was significantly lower in OLT candidates who died before OLT compared with OLT survivors. In conclusion, (S)EEG provides reliable quantitative information to evaluate the degree of HE and appears more sensitive than (V)EEG to discriminate a subclinical stage of HE. The improvement in (S)EEG results observed in transplant recipients confirms the reversibility of bioelectric brain dysfunction with restoration of liver functions.