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Locus Coeruleus (LC) degeneration occurs early in Alzheimer's disease (AD) and this could affect several brain regions innervated by LC noradrenergic axon terminals, as these bear neuroprotective effects and modulate neurovascular coupling/neuronal activity. We used LC-sensitive Magnetic Resonance imaging (MRI) sequences enabling LC integrity quantification, and [18F]Fluorodeoxyglucose (FDG) PET, to investigate the association of LC-MRI changes with brain glucose metabolism in cognitively impaired patients (30 amnesticMCI and 13 demented ones). Fifteen cognitively intact age-matched controls (HCs) were submitted only to LC-MRI for comparison with patients. Voxel-wise regression analyses of [18F]FDG images were conducted using the LC-MRI parameters signal intensity (LC

Human neuropathological studies indicate that the pontine nucleus Locus Coeruleus (LC) undergoes significant and early degeneration in Alzheimer's disease. This line of evidence alongside experimental data suggests that the LC functional/structural decay may represent a critical factor for Alzheimer's disease pathophysiological and clinical progression. In the present prospective study, we used Magnetic Resonance Imaging (MRI) with LC-sensitive sequence (LC-MRI) to investigate in vivo the LC involvement in Alzheimer's disease progression, and whether specific LC-MRI features at baseline are associated with prognosis and cognitive performance in amnestic Mild Cognitive Impairment.LC-MRI parameters were measured at baseline by a template-based method on 3.0-T magnetic resonance images in 34 patients with Alzheimer's disease dementia, 73 patients with amnestic Mild Cognitive Impairment, and 53 cognitively intact individuals. A thorough neurological and neuropsychological assessment was performed at baseline and 2.5-year follow-up.In subjects with Mild Cognitive Impairment who converted to dementia (n = 32), the LC intensity and number of LC-related voxels were significantly lower than in cognitively intact individuals, resembling those observed in demented patients. Such a reduction was not detected in Mild Cognitive Impairment individuals, who remained stable at follow-up. In Mild Cognitive Impairment subjects converting to dementia, LC-MRI parameter reduction was maximal in the rostral part of the left nucleus. Structural equation modeling analysis showed that LC-MRI parameters positively correlate with cognitive performance.Our findings highlight a potential role of LC-MRI for predicting clinical progression in Mild Cognitive Impairment and support the key role of LC degeneration in the Alzheimer clinical continuum.

Converging translational and clinical research strongly indicates that altered immune and inflammatory homeostasis (neuroinflammation) plays a critical pathophysiological role in Alzheimer's disease (AD), across the clinical continuum. A dualistic role of neuroinflammation may account for a complex biological phenomenon, representing a potential pharmacological target. Emerging blood-based pathophysiological biomarkers, such as cytokines (Cyt) and interleukins (ILs), have been studied as indicators of neuroinflammation in AD. However, inconsistent results have been reported probably due to a lack of standardization of assays with methodological and analytical differences. We used machine-learning and a cross-validation-based statical workflow to explore and analyze the potential impact of key biological factors, such as age, sex, and apolipoprotein-E (APOE) genotype (the major genetic risk factor for late-onset AD) on Cyt. A set of Cyt was selected based on previous literature, and we investigated any potential association in a pooled cohort of cognitively healthy, mild cognitive impairment (MCI), and AD-like dementia patients. We also performed explorative analyses to extrapolate preliminary clinical insights. We found a robust sex effect on IL12 and an APOE-related difference in IL10, with the latter being also related to the presence of advanced cognitive decline. IL1β was the variable most significantly associated with MCI-to-dementia conversion over a 2.5 year-clinical follow-up. Although preliminary, our data support further clinical research to understand whether plasma Cyt may represent reliable and noninvasive tools serving the investigation of neuroimmune and inflammatory dynamics in AD and to foster biomarker-guided pathway-based therapeutic approaches, within the precision medicine development framework.

The prodromal stages of Alzheimer’s disease (AD) are the primary focus of research aimed at slowing disease progression. This study explores the influence of affective temperament on the motivation of people with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) to participate in clinical trials. One hundred four subjects with MCI and SCD were screened for participation in pharmacological and non-pharmacological trials. Affective temperament was assessed based on the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego (TEMPS) scale. Demographic variables and temperament subscales scores were compared between MCI and SCD patients and among patients participating in the pharmacological trial, the non-pharmacological trial and refusing participation. Twenty-one subjects consented to participate in the pharmacological trial, seventy consented to the non-pharmacological trial and thirteen refused to participate in any trial. Patients with SCD had greater education and more depressive temperamental traits than those with MCI. While older age, higher education and anxious temperament were negatively associated with participation in the pharmacological trial, irritable temperamental positively predicted pharmacological trial participation. In conclusion, temperamental features may affect the willingness of patients with MCI and SCD to take part in clinical trials and, especially, the choice to participate in pharmacological studies.

Background: Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are differentiated by the time of onset of cognitive and motor symptoms (‘1-year rule’). We explored the neuropsychological continuum of DLB and PDD subjects with different timing of dementia onset. Objective: Our aim was to compare the neuropsychological profile of DLB and PDD patients with different timing of dementia onset. Methods: Neuropsychological findings at the diagnosis of dementia of 66 PDD and 42 DLB patients were retrospectively compared. Patients with PDD were divided into three tertile subgroups according to the time interval between the onset of parkinsonism and dementia (N = 24, 2–4 years; N = 17, 5–7 years; N = 25 ≥8 years, respectively). Results: DLB patients performed worse on the Stroop and semantic fluency tests than PDD, even in comparison to PD with early dementia onset. No significant differences among PDD subgroups were reported. Conclusion: Executive and semantic language tests could differentiate DLB and PD patients with earlier development of dementia relative to parkinsonism.

Progressive supranuclear palsy (PSP) is an atypical Parkinsonism characterized by motor and neuropsycological disorders. Language could be impaired in PSP patients, also in Richardson variant (PSP-RS). The analysis of connected speech is used in neurodegenerative disorder to investigate different levels of language organization, including phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic processing. In our study, we aimed to investigate the language profile, especially connected speech, in early-stage PSP-RS and Parkinson’s disease (PD) patients without predominant speech or language disorders. Language was assessed using the Screening for Aphasia in NeuroDegeneration (SAND); connected speech analysis was conducted from the picture description subtest. We enrolled 48 patients, 22 PD and 26 PSP (18 PSP-RS and 8 non-RS). PSP-RS patients presented an impairment in language domain, particularly regarding connected speech. PSP-RS patients presented worse performances than PD in different scores. The output of PSP-RS patients was characterized by a reduction in number of sentences and subordinates with respect to PD; PSP presented also more repaired sequences and phonological and lexico-semantic errors than PD. Number of sentences and number of subordinates of the picture description task were identified as predictors of PSP diagnosis. In summary, the SAND scale is able to identify language impairment in PSP patients. The analysis of connected speech could highlight some important aspects of language impairment in PSP-RS patients, and it could be helpful in the differential diagnosis with PD.

BackgroundBehavioral and psychological symptoms of dementia (BPSD) have a high prevalence, and their presence is associated with a severe impact in terms of social costs. However, dedicated clinical tools or biomarkers to detect these symptoms are lacking. Thus, BPSD management in clinical settings is challenging. The aim of this study was to investigate the perception and the treatment strategies for BPSD in Italian centers working in the dementia field.MethodsA multicenter, national survey was developed by BPSD Study Group of the Italian Neurological Society for Dementia (SINDEM). The survey consisted of a semi-structured questionnaire that was e-mailed to SINDEM members, dementia centers part of the national network of memory clinics (Centers for Cognitive Deterioration and Dementia [CDCD]), and clinicians working in dementia care settings. The questions were focused on (1) perceived global frequency and relevance of BPSD; (2) tools used to assess BPSD; (3) pharmacological treatment for psychosis, apathy, agitation, aggression, depression, anxiety, sleep, and nutrition disturbances; (4) non-pharmacological treatments; (5) drugs side effects.ResultsOne-hundred and thirty-six clinicians participated in this study. Seventy-nine participants worked in a CDCD and 57 in other settings. The perceived frequency of BPSD was 74%. BPSD are detected by means of a clinical assessment for 96.3% or a caregiver interview for 97%. For psychosis treatment the first choice was atypical antipsychotics (83.3%), followed by typical antipsychotic (8.9%) and antidepressants (4.8%). For agitation, atypical antipsychotics were the first-choice treatment in 64% of cases and antidepressants in 16.1%. For aggression, the most used drugs were atypical antipsychotics (82.9%). For anxiety, 55.2% use antidepressants, 17.9% use atypical antipsychotics, and 16.9% use benzodiazepines. Interestingly, most of the centers apply non-pharmacological treatments for BPSD. Some differences emerged comparing the responses from CDCD and other care settings.ConclusionThe survey results revealed many differences in BPSD perception, treatment options, and observed side effect according to the clinical setting. This variability can be explained by the absence of clear guidelines, by differences in patients' characteristics, and by clinical practice based on subjective experience. These results suggest that producing guidelines for the pharmacological treatment of BPSD is a major need.

Methylation levels of the mitochondrial displacement loop (D-loop) region have been reported to be altered in the brain and blood of Alzheimer’s disease (AD) patients. Moreover, a dynamic D-loop methylation pattern was observed in the brain of transgenic AD mice along with disease progression. However, investigations on the blood cells of AD patients in the prodromal phases of the disease have not been performed so far. The aim of this study was to analyze D-loop methylation levels by means of the MS-HRM technique in the peripheral blood cells of 14 mild cognitive impairment (MCI) patients, 18 early stage AD patients, 70 advanced stage AD patients, and 105 healthy control subjects. We found higher D-loop methylation levels in MCI patients than in control subjects and AD patients. Moreover, higher D-loop methylation levels were observed in control subjects than in AD patients in advanced stages of the disease, but not in those at early stages. The present pilot study shows that peripheral D-loop methylation levels differ in patients at different stages of AD pathology, suggesting that further studies deserve to be performed in order to validate the usefulness of D-loop methylation analysis as a peripheral biomarker for the early detection of AD.

Leukoaraiosis is one of the main contributors to mild cognitive impairment due to vascular damage (vascular MCI, VMCI), whose pathophysiology has not been fully elucidated yet. We aimed to shed light on such issue using functional MRI (fMRI). Sixteen patients with VMCI were enrolled and compared with twenty-five patients with MCI but without significant vascular damage (non-vascular MCI, NVMCI) and with fifteen healthy controls (HC). They all underwent fMRI with incidental verbal learning paradigm, using a 3T scanner. Differently from cases with NVMCI (versus HC), VMCI patients presented a higher BOLD activation in the right parieto-occipital cortex and a lower activation in the left superior and middle frontal gyri, anterior cingulum and in left fronto-opercular area when compared to HC. Cortical activation evaluated by fMRI may reflect specific patterns of damage and attempt of compensation in patients with MCI and different severity of leukoaraiosis.

Background: Red blood cells (RBCs) contain the majority of α-synuclein (α-syn) in blood, representing an interesting model for studying the peripheral pathological alterations proved in neurodegeneration. Objective: The current study aimed to investigate the diagnostic value of total α-syn, amyloid-β (Aβ1–42), tau, and their heteroaggregates in RBCs of Lewy body dementia (LBD) and Alzheimer’s disease (AD) patients compared to healthy controls (HC). Methods: By the use of enzyme-linked immunosorbent assays, RBCs concentrations of total α-syn, Aβ1–42, tau, and their heteroaggregates (α-syn/Aβ1–42 and α-syn/tau) were measured in 27 individuals with LBD (Parkinson’s disease dementia, n = 17; dementia with Lewy bodies, n = 10), 51 individuals with AD (AD dementia, n = 37; prodromal AD, n = 14), and HC (n = 60). Results: The total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in the LBD group and the AD group compared with HC, whereas α-syn/Aβ1–42 concentrations were significantly lower in the AD dementia group only. RBC α-syn/tau heterodimers had a higher diagnostic accuracy for differentiating patients with LBD versus HC (AUROC = 0.80). Conclusion: RBC α-syn heteromers may be useful for differentiating between neurodegenerative dementias (LBD and AD) and HC. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBD from HC. However, they are not consistently different between LBD and AD. Our findings also suggest that α-syn, Aβ1–42, and tau interact in vivo to promote the aggregation and accumulation of each other.

Background Red blood cells (RBC) account for more than 99% of α-syn concentrations in blood representing an interesting in vivo model for studying peripheral pathological alterations proved in neurodegeneration. The aim of the current study was to investigate the diagnostic value of total α-syn, Aβ 1-42 , tau and their heteroaggregates in RBCs of Lewy Body Dementias (LBDs) and Alzheimer’s disease (AD) patients compared to and healthy controls (HCs). Methods With a “home-made” sandwich enzyme-linked immunosorbent assay (ELISA) system, RBCs levels of total α-syn, Aβ 1-42 , tau and their heteroaggregates (α-syn/Aβ 1-42 and α-syn/tau) were measured in 27 subjects with LBDs (PDD, n = 17; DLB, n = 10), 51 subjects with AD (AD dementia, n = 37, prodromal AD, n = 14), and HC (n = 60). Results Compared with HC, total α-syn and tau concentrations as well as α-syn/tau heterodimers were significantly lower in LBDs group (p = 0.009, p = 0.009, and p < 0.001, respectively) and in AD group (p = 0.011, p = 0.003, and p < 0.001, respectively), whereas the heteroaggregates α-syn/Aβ 1-42 were significantly lower in AD dementia group (p < 0.001) only. RBC α-syn/tau heterodimers had the higher diagnostic accuracy for differentiating patients with LBD vs controls (AUROC = 0.80). Conclusion RBC α-syn heteroaggregates may be useful for differentiating between neurodegenerative dementias (LBD and AD) and healthy control. In particular, RBC α-syn/tau heterodimers have demonstrated good diagnostic accuracy for differentiating LBDs from HC. However, they are not consistently different between LBD and AD. Our findings also go beyond the clinical setting, suggesting that α-syn, Aβ 1-42 , and tau interact in vivo to promote the aggregation and accumulation of each other presumably accelerating cognitive dysfunction.

Background: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. Objective: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. Methods: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. Results: Wake after sleep onset (WASO) was higher (p

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer’s disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice.

BACKGROUND Dementia in Parkinson's disease (PDD) is common presumably due to combined neuropathological substrates. Amyloid-β (Aβ) plaques are well described in PDD but their contribution in synucleinopathies is still controversial. OBJECTIVE To investigate regional [18F]Florbetapir binding and its relative contribution to cognitive dysfunction in a cohort of PDD patients and to test whether PDD patients with comorbid amyloidopathy have different clinical and neuropsychological characteristics. METHODS 21 PDD patients, 20 with Alzheimer's disease (AD), and 9 control subjects underwent amyloid positron emission tomography (PET) imaging, neurological, and neuropsychological assessment. Radioligand binding was compared across the groups. PDD scans were interpreted qualitatively and semiquantitatively and categorized as positive or negative. Annual longitudinal Mini-Mental State Examination (MMSE) of PDD subjects was retrospectively collected in order to relate Aβ burden to the course of cognitive impairment. RESULTS [18F]Florbetapir PET imaging was positive in 11 PDD patients (52.38%) using the semi-quantitative method. There were no group differences between PDD subjects with increased cortical [18F]Florbetapir (+) and those without (-), according to demographic and clinical parameters. PDD+ performed worse on Digit Span Foward and on Rey Auditory Verbal Learning Test delayed recall than the PDD- with a significant negative correlation between global cortical retention and specific memory tests. Aβ load did not correlate with MMSE ratings although PDD+ demonstrated a faster clinical progression of dementia. CONCLUSIONS Significant Aβ deposition is common in PDD patients contributing to memory impairment and driving a faster rate of cognitive decline.

A plethora of complex misfolded protein combinations have been found in Alzheimer disease (AD) brains besides the classical pathological hallmarks. Recently, α-synuclein (α-syn) and its heterocomplexes with amyloid-β (Aβ) and tau have been suggested to be involved in the pathophysiological processes of neurodegenerative diseases. These pathological features are not limited to the brain, but can be also found in peripheral fluids. In this respect, red blood cells (RBCs) have been suggested as a good model to investigate the biochemical alterations of neurodegeneration. Our aim is to find whether RBC concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) were different in AD patients compared with healthy controls (HC). The levels of homo- and heteroaggregates of α-syn, Aβ and tau, were analyzed in a cohort of AD patients at early stage either with dementia or prodromal symptoms (N = 39) and age-matched healthy controls (N = 39). All AD patients received a biomarker-based diagnosis (low cerebrospinal fluid levels of Aβ peptide combined with high cerebrospinal fluid concentrations of total tau and/or phospho-tau proteins; alternatively, a positivity to cerebral amyloid-PET scan). Our results showed lower concentrations of α-syn and its heterocomplexes (i.e., α-syn/Aβ and α-syn/tau) in RBCs of AD patients with respect to HC. RBC α-syn/Aβ as well as RBC α-syn/tau heterodimers discriminated AD participants from HC with fair accuracy, whereas RBC α-syn concentrations differentiated poorly the two groups. Although additional investigations are required, these data suggest α-syn heteroaggregates in RBCs as potential tool in the diagnostic work-up of early AD diagnosis.

The main condition at increased risk of dementia is considered to be mild cognitive impairment. Mild cognitive impairment has been defined as a transitional state between normal aging and dementia, of which it may represent a prodrome. The aim of our study was to evaluate whether sleep variables (both conventional and microstructural ones) in subjects with mild cognitive impairment correlate with conversion to dementia. Nineteen subjects with amnestic mild cognitive impairment (mean age 68.5 ± 7.0 years) and 11 cognitively intact healthy elderly individuals (mean age 69.2 ± 12.6 years) underwent ambulatory polysomnography for the evaluation of nocturnal sleep architecture and cyclic alternating pattern parameters. Amnestic mild cognitive impairment subjects were clinically and cognitively re-evaluated after 2 years, during routine follow-up, and further classified as amnestic mild cognitive impairment converters (that is, patients developing Alzheimer's disease, N = 11) and amnestic mild cognitive impairment non-converters. Compared with healthy elderly individuals, amnestic mild cognitive impairment showed disrupted sleep with decreased rapid eye movement sleep, cyclic alternating pattern rate and cyclic alternating pattern slow-wave-related phases (A1 index). Standard sleep architecture analysis did not show significant differences between the two subgroups of amnestic mild cognitive impairment, whereas cyclic alternating pattern analysis showed that cyclic alternating pattern rate, A1 index and A3 index are significantly reduced in converters compared with non-converters. Our data confirm that in amnestic mild cognitive impairment subjects there is a sleep impairment, particularly when considering more refined sleep parameters and that sleep variables at baseline are different among converters versus non-converters at the 2-year follow-up. Specific sleep alterations might represent potential further biomarkers for the diagnosis and prognosis of early-phase cognitive impairment.

Evidence of cortical beta-amyloid (Aβ) load, assessed by Aβ positron emission tomography (Aβ-PET), is an established in vivo biomarker of Alzheimer’s disease (AD)-related pathophysiology. Qualitative assessment of Aβ-PET provides binary information; meanwhile semiquantitative approaches require a parcellation of PET image either manually or by placement of atlas-based volumes of interest. We supposed that a whole-brain approach with voxel-by-voxel standardized uptake value ratio (SUVr) parametric images may better elucidate the spatial trajectories of Aβ burden along the continuum of AD. Methods: We recruited 32 subjects with a diagnosis of probable AD dementia (ADD, n = 20) and mild cognitive impairment due to AD (MCI-AD, n = 12) according to the NIA-AA 2011 criteria. We also enrolled a control group of 6 cognitively healthy individuals (HCs) with preserved cognitive functions and negative Aβ-PET scan. The PET images were spatially normalized using the AV45 PET template in the MNI brain space. Subsequently, parametric SUVr images were calculated using the whole cerebellum as a reference region. A voxel-wise analysis of covariance was used to compare (between groups) the Αβ distribution pattern considering age as a nuisance covariate. Results: Both ADD and MCI-AD subjects showed a widespread increase in radiotracer uptake when compared with HC participants (p < 0.001, uncorrected). After applying a multiple comparison correction (p < 0.05, corrected), a relative large cluster of increased [18F]-flor­betapir uptake was observed in the precuneus in the ADD and MCI-AD groups compared to HCs. Voxel-wise regression analysis showed a significant positive linear association between the voxel-wise SUVr values and the disease duration. Conclusions: The voxel-wise semiquantitative analysis shows that the precuneus is a region with higher vulnerability to Aβ depositions when compared to other cortical regions in both MCI-AD and ADD subjects. We think that the precuneus is a promising PET-based outcome measure for clinical trials of drugs targeting brain Aβ. We found a positive association between the overall Aβ-PET SUVr and the disease duration suggesting that the region-specific slow saturation of Aβ deposition continuously takes place as the disease progresses.

This study is aimed at relating social cognition in Huntington&rsquo, s Disease (HD) to plasma levels of the social hormone oxytocin (OT). Indeed, HD patients commonly display reduced social skills and OT is involved in bonding behavior and improved recognition of facial emotions. Twelve mild-symptomatic HD patients (stage II Shoulson &amp, Fahn) and 11 gender/age matched controls (healthy controls, HC), without concurrent psychiatric disorders, were investigated at baseline (T0) for OT plasma levels and social cognition through an extensive battery of neuropsychological tests. Social cognition was also re-examined after two years (T1) in 8 of the 12 patients. Results showed a trend for reduced T0-OT levels in HD vs. HC, mean &plusmn, stardard deviation: 6.5 &plusmn, 2.4 vs. 9.9 &plusmn, 7.2 pg/mL, without reaching statistical significance. At T0, patients showed significantly lower performances than controls at the &ldquo, Faux-Pas&rdquo, and &ldquo, Strange Stories&rdquo, tests (p &lt, 0.05, p &lt, 0.01), a reduced perception of visual emotions (p &lt, 0.01) and verbal stimuli (p &lt, 0.01) was also reported, involving anger, fear, and sadness (p &lt, 0.01). Additionally, in the HD population, OT concentrations positively correlated with T1-performances at NeutralFaux-Pas test (p &lt, 0.05), whereas the cognitive Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) scores positively correlated with psychosocial perception at the &ldquo, and Karolinska Directed Emotional Faces (KDEF) tests (p &lt, 0.05). This study, despite its limitations, supports correlations between OT and HD social cognition, suggesting a possible therapeutic use of this hormone. More subjects and additional body tissues/fluids, such as cerebrospinal fluid, should be investigated to confirm this hypothesis.

Background: Dementia has been recently viewed as a predominantly vascular disorder. Indeed, reduced brain NO availability causes increased ß-amyloid deposition by several mechanisms, including hypoperfusion. Purpose: To investigate the relationship between cerebral blood flow in the hippocampal and parahippocampal regions (CBF-hipp and CBF-parahipp), crucial areas for memory and processing of non-verbal/spatial information, and systemic endothelial function in individuals with mild cognitive impairment (MCI), a subclinical condition predisposing to dementia. Methods: CBF-hipp and CBF-parahipp were evaluated by magnetic resonance imaging (arterial spin labeling, GE HDxt 1.5 T Signa Neuro-optimized System) and systemic endothelial function by flow-mediated dilation (FMD) in the brachial artery. Results: Complete data about CBF and FMD at enrollment were available for 66 individuals with MCI and 32 without (non-MCI). The two groups were matched for age (75 ± 5 vs 74 ± 5 years, p = 0.22), sex (men 45 vs 50%, p = 0.18) and mean BP (96 ± 10 vs 97 ± 9 mmHg, p = 0.41). FMD was significantly lower in MCI than in non-MCI (2.93 ± 2.18 vs 3.74 ± 2.03%, p = 0.02); CBF-hipp (64.3 ± 9.43 vs 69.5 ± 7.03 ml/100 gr/min, p = 0.002) and CBF-parahipp (66.3 ± 8.02 vs 70.0 ± 8.12 ml/100 gr/min, p = 0.002) were significantly lower in MCI as well. Among MCI, FMD was significantly correlated with CBF-parahipp (r = 0.26, p = 0.03) and CBF-hipp (r = 0.32, p = 0.009). In multiple regression models, including age, sex, mean BP, BMI, brachial artery diameter as confounders, FMD remained an independent determinant of CBF-parahipp (beta = 0.93, r2 = 0.063, p = 0.04) and CBF-hipp (beta = 1.31, r2 = 0.089, p = 0.01). Nor CBF-parahipp (r = −0.13, p = 0.48) neither CBF-hipp (r = 0.05, p = 0.80) were correlated with FMD in non-MCI group. Conclusions: An independent association between hippocampal and parahippocampal CBF and systemic endothelial function is present in individuals with MCI.

Background:Oxidative stress (OS) is a physiological age-related brain process, dramatically overexpressed in neurodegenerative disorders like Alzheimer’s disease (AD). Nevertheless, the pathophysiological role of OS in AD pathology has not been clarified yet. OS as a biomarker for AD is a controversial issue. A comparison of previous data is difficult due to a remarkable methodological variability. Most of the previous studies have shown higher levels of OS markers and lower antioxidant power in patients with dementia when compared to mild cognitive impairment (MCI) and healthy controls.Methods:We followed a strict protocol in order to limit intrasite variability of OS assessment. In addition, we have taken into account possible confounding factors.Results:In agreement with previous reports, we found both lower plasmatic OS and higher plasmatic antioxidant defenses when comparing patients with AD having dementia that is stably treated to patients with MCI-AD.Discussion:A speculative hypothesis based on co...

ANT1 is one of the nuclear genes responsible of autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA multiple deletions. The course of ANT1- related adPEO is relatively benign, symptoms being generally restricted to skeletal muscle. Here we report the case of an Italian 74 years old woman with ANT1-related adPEO and dementia. Further studies are needed to assess the prevalence of central neurological manifestations in ANT1 mitochondrial disease.

Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65–89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects.

A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients. APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis. We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p0.0001) and MCI patients (p0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p0.05) superoxide dismutase activity with respect to non-E4 carriers. This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor.

Objective Juvenile Myoclonic Epilepsy (JME) is a common genetic generalized epilepsy syndrome. Several studies have detailed cognitive and imaging abnormalities pointing to frontal lobe dysfunction, as well as disadvantageous behavioral traits and poor social outcome, challenging the commonly held view of JME being a benign disorder. Social cognition is the ability to elaborate mental representations of social interactions and to use them correctly in social contexts, and includes Theory of Mind (ToM), which pertains to the attribution of cognitive and affective mental states to self and others and seems to rely on complex fronto-temporal interactions. ToM has been recently assessed in focal epilepsy syndromes, but little is available for generalized epilepsies. We performed a cross-sectional study to assess social cognition, with an emphasis on ToM, as well as standard cognitive functions in patients with JME. Method We recruited twenty JME patients and twenty matched controls. Tests used to assess social cognition and ToM included the Emotion Attribution Task, Strange Stories Task (SST), Faux Pas Task (FPT), Reading the Mind in the Eyes Task and Social Situation Task. Subjects were also assessed via an extensive neuropsychological battery. Results Patients exhibited worse performance in the SST and in several scores of the FPT. They also showed widespread cognitive impairment, involving executive functions, psychomotor speed, verbal and visuo-spatial memory. Conclusions In addition to cognitive impairment for fronto-temporal tasks, some features of social cognition are also altered in JME. The latter deficit may underlie the poor social outcome previously described for these patients, and might also relate to imaging findings of frontal lobe dysfunction.

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau

Mild Cognitive Impairment (MCI) is an intermediate condition between normal aging and dementia, associated with an increased risk of progression into the latter within months or years. Olfactory impairment, a well-known biomarker for neurodegeneration, might be present in the condition early, possibly representing a signal for future pathological onset. Our study aimed at evaluating olfactory function in MCI and healthy controls in relation to neurocognitive performance and endothelial function. A total of 85 individuals with MCI and 41 healthy controls, matched for age and gender, were recruited. Olfactory function was assessed by Sniffin' Sticks Extended Test (Burghart, Medizintechnik, GmbH, Wedel, Germany). A comprehensive neurocognitive assessment was performed. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery by ultrasound. MCI individuals showed an impaired olfactory function compared to controls. The overall olfactory score is able to predict MCI with a good sensitivity and specificity (70.3 and 77.4% respectively). In MCI, olfactory identification score is correlated with a number of neurocognitive abilities, including overall cognitive status, dementia rating, immediate and delayed memory, visuospatial ability and verbal fluency. FMD was reduced in MCI (2.90 ± 2.15 vs. 3.66 ± 1.96%, P = 0.016) and was positively associated with olfactory identification score (ρs =0.219, P = 0.025). The association remained significant after controlling for age, gender, and smoking. In conclusion, olfactory evaluation is able to discriminate between MCI and healthy individuals. Systemic vascular dysfunction might be involved, at least indirectly, in olfactory dysfunction in MCI.

The current availability of Magnetic Resonance (MR) systems that operate at ultra high magnetic field (≥ 7 Tesla) allows the representation of anatomical structures at sub-millimeter resolution. Interestingly, small structures of the brain, such as the subfields of the hippocampus, the inner structures of the basal ganglia and of the brainstem become visible. Suitable software packages that allow analyzing and measuring such small structures are not currently readily available. We developed a semi-automated procedure to measure the thickness of the stratum radiatum and lacunosum-moleculare (SRLM) of the hippocampus. The change in the thickness of this subfield of the hippocampal formation is supposed to have a role in the pathological cognitive decline. Once we developed and validated the semiautomatic procedure on the 7T high-resolution T2*-weighted images of a healthy volunteer, we carried out a preliminary study on a population affected by Mild Cognitive Impairment to investigate the correlations of the SRLM thickness with the clinical scores of the patients, e.g. the Mini-Mental State Examination score and the Free and Cued Selective Reminding Test.

Background Myotonic dystrophy type 1 (Steinert’s disease or DM1), the most common form of autosomal dominant muscular dystrophy in adults, is a multisystem disorder, affecting skeletal muscle as well as eyes, heart, gastrointestinal tract, endocrine system, and central nervous system, finally responsible of increasing disabilities and secondary social consequences. To date, DM1-related brain involvement represents a challenging field of research. It is well known that DM1 patients frequently present neuropsychological disturbances and psychiatric comorbidities among which reduced awareness of disease burden and its progression, also defined as anosognosia, is common in clinical practice, this leading to secondary misattribution of symptoms, delay in timely diagnostic procedures and low compliance to treatment. Methods Here we present an observational cross sectional study in which disease-related cognitive dysfunctions and quality of life were assessed by a protocol finally designed to estimate the prevalence of disease awareness in a sample of 65 adult-onset DM1 patients. Results Our analysis showed that in DM1 patients several cognitive functions, including executive and mnesic domains with visuo-spatial involvement, were affected. The assessment of anosognosia revealed that a high percentage (51.6 %) of DM1 subjects was disease unaware. The reduced illness awareness occurs across different physical and life domains, and it appears more prominent in Activities and Independence domains investigated by the Individualized Neuromuscular Quality Of Life (INQoL) questionnaire. Moreover, the unawareness resulted significantly related (at p

Increasing evidence points to an epigenetic contribution in Alzheimer’s disease (AD) pathogenesis. In this regard, variants and polymorphisms of DNA methyltransferase genes (DNMTs) are being investigated for their contribution to cognitive decline and dementia, but results are still scarce or controversial. In the present study we genotyped 710 Caucasian subjects of Italian descent, including 320 late-onset AD (LOAD) patients, 70 individuals with amnestic Mild Cognitive Impairment (MCI), and 320 matched healthy controls, for the presence of a functional DNMT3A -448A>G (rs1550117) polymorphism, searching for association with disease risk. In addition, we searched for correlation between the studied polymorphism and circulating levels of folate, homocysteine (hcy) and vitamin B12, all involved in DNA methylation reactions and available from 189 LOAD patients and 186 matched controls. Both allele and genotype frequencies of rs1550117 were closely similar between MCI, LOAD and control subjects, and no association with dementia or pre-dementia conditions was observed. Plasma hcy levels were significantly higher (p = 0.04) and serum folate levels significantly lower (p = 0.01) in LOAD than in controls, but no difference in circulating folate, hcy or vitamin B12 levels was seen between carriers and non-carriers of the minor DNMT3A -448A allele. Collectively, present results confirmed previous associations of increased hcy and decreased folate with LOAD risk, but do not support an association between the DNMT3A -448A>G polymorphism and AD in our population.

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD.