A single center study: Aß42/p-Tau181 CSF ratio to discriminate AD from FTD in clinical setting.

Abnormal levels of beta amyloid (Aß42) 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 Aß42 and tau) in order to better discriminate between AD and FTD; we identified Aß42/p-Tau181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice.

Bipolar Disorder and Cognitive Dysfunction: A Complex Link.

The aim of this article was to describe the current evidence regarding phenomenon of cognitive functioning and dementia in bipolar disorder (BD). Cochrane Library and PubMed searches were conducted for relevant articles, chapters, and books published before 2016. Search terms used included "bipolar disorder," "cognitive dysfunction," and "dementia." At the end of the selection process, 159 studies were included in our qualitative synthesis. As result, cognitive impairments in BD have been previously considered as infrequent and limited to the affective episodes. Nowadays, there is evidence of stable and lasting cognitive dysfunctions in all phases of BD, including remission phase, particularly in the following domains: attention, memory, and executive functions. The cause of cognitive impairment in BD raises the question if it subtends a neurodevelopmental or a neurodegenerative process. Impaired cognitive functioning associated with BD may contribute significantly to functional disability, in addition to the distorted affective component usually emphasized.

Armed and Aging: Dementia and Firearms Do Not Mix !

The possibility that persons with dementia possess firearms is cause for concern, but only a limited number of research studies have been conducted on such a topic, usually in the form of case reports. Reducing the occurrence of the firearm-related violence requires effectively identifying dangerous individuals and keeping firearms out of their hands. The health care professionals, i.e. the social workers and the physicians, need to work together and to produce a suitable evaluation of patients with dementia to prevent firearm-related injuries and serious and irreparable damage to persons.

Evaluating the levels of interleukin-1 family cytokines in sporadic amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease leading to the death of affected individuals within years. The involvement of inflammation in the pathogenesis of neurodegenerative diseases, including ALS, is increasingly recognized but still not well understood. The aim of this study is to evaluate the levels of inflammation-related IL-1 family cytokines (IL-1ß, IL-18, IL-33, IL-37) and their endogenous inhibitors (IL-1Ra, sIL-1R2, IL-18BP, sIL-1R4) in patients with sporadic ALS (sALS), METHODS: Sera were collected from 144 patients (125 patients were characterized by disease form, duration, and disability, using the revised ALS functional rating scale (ALSFRS-R) and from 40 matched controls. Cerebrospinal fluid (CSF) was collected from 54 patients with sALS and 65 patients with other non-infectious non-oncogenic diseases as controls. Cytokines and inhibitors were measured by commercial ELISA. RESULTS: Among the IL-1 family cytokines tested total IL-18, its endogenous inhibitor IL-18BP, and the active form of the cytokine (free IL-18) were significantly higher in the sALS sera than in controls. No correlation between these soluble mediators and different clinical forms of sALS or the clinical setting of the disease was found. IL-18BP was the only mediator detectable in the CSF of patients. CONCLUSIONS: Among the IL-1 family cytokines, only IL-18 correlates with this disease and may therefore have a pathological role in sALS. The increase of total IL-18 suggests the activation of IL-18-cleaving inflammasome. Whether IL-18 upregulation in circulation of sALS patients is a consequence of inflammation or one of the causes of the pathology still needs to be addressed.

Nerve and muscle involvement in mitochondrial disorders: an electrophysiological study.

Involvement of the peripheral nervous system in mitochondrial disorders (MD) has been previously reported. However, the exact prevalence of peripheral neuropathy and/or myopathy in MD is still unclear. In order to evaluate the prevalence of neuropathy and myopathy in MD, we performed sensory and motor nerve conduction studies (NCS) and concentric needle electromyography (EMG) in 44 unselected MD patients. NCS were abnormal in 36.4% of cases, and were consistent with a sensori-motor axonal multineuropathy (multifocal neuropathy), mainly affecting the lower limbs. EMG evidence of myopathy was present in 54.5% of patients, again mainly affecting the lower limbs. Nerve and muscle involvement was frequently subclinical. Peripheral nerve and muscle involvement is common in MD patients. Our study supports the variability of the clinical expression of MD. Further studies are needed to better understand the molecular basis underlying the phenotypic variability among MD patients.

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.

Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration.

Categorising a problem: alcohol and dementia.

Alcoholism is a chronic relapsing disorder that can include extended periods of abstinence followed by relapse to heavy drinking. Decades of evidence have clearly shown that long-term, chronic ethanol exposure produces brain damage in humans. The article aims to review the relationship between alcohol use and dementia. Medline and Google Scholar searches were conducted for relevant articles, chapters and books published until 2019. Search terms used included alcohol consumption, alcohol-related dementia, alcohol use disorders, chronic alcoholism, dementia. Publications found through this indexed search were reviewed for further relevant references. Alcohol acts on the central nervous system via both direct and indirect effects, frequently a combination of the two. There is consensus that alcohol contributes to the acquisition of cognitive deficits in late life. However, there are doubts regarding the aetiopathogenesis, nosological status and prevalence of alcohol-related dementia and still, there is much debate over how much alcohol consumption will lead to alcohol-related dementia.

Association study between XRCC1 gene polymorphisms and sporadic amyotrophic lateral sclerosis.

The aim of the present study was to investigate the possible contribution of three common functional polymorphisms in the DNA repair protein X-ray repair cross-complementing group 1 (XRCC1), namely Arg194Trp (rs1799782), Arg280His (rs25489) and Arg399Gln (rs25487), to sporadic amyotrophic lateral sclerosis (SALS). We genotyped 206 Italian SALS patients and 203 matched controls for XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms by means of PCR/RFLP technique, searching for association between any of the studied polymorphisms and disease risk, age and site of onset. We observed a statistically significant difference in XRCC1 Gln399 allele frequencies between SALS cases and controls (0.39/0.28; p=0.001). The present study suggests that the XRCC1 Arg399Gln polymorphism might contribute to SALS risk.

A complication of coronavirus disease 2019: delirium.

COVID-19 is predominantly a respiratory disease. However, some cases exhibit other features including Central Nervous System symptoms. In the older adult, COVID-19 may present with atypical symptoms, including delirium and its complications. The objective of this study is to describe the relationship between the new type of coronavirus infection and delirium. Systematic research (Cochrane Library and PubMed) was carried out (only upper time limit: April 2020). Publications found through this indexed search were reviewed and manually screened to identify relevant studies. Search terms used included "COVID-19, Delirium, Dementia, Intensive Care Unit". We manually added articles identified through other sources (i.e., key journals). Older people are at the greatest risk from COVID-19. If infected, they may present delirium. Moreover, it is not exclusive to older people. Delirium is not inevitable; rather, it is preventable. Delirium prevention programs are even more crucial in the era of COVID-19 and cannot be allowed to wither despite the challenges of integrating delirium prevention with COVID-19 care. An acute change in condition, behaviour, or mental status should prompt a delirium screen. As regards the treatment, it is advisable to use non-pharmacological interventions first where possible. Medication may be needed for patients with agitation where there is intractable distress or high risk to self/others.

Uncommon and/or bizarre features of dementia: part IV.

It is well established that the clinical picture of dementias is not clinically homogeneous. For example, non-amnestic presentations of Alzheimer's disease have been referred to as a typical variant. Careful examination of clinical characteristics contributes to understanding the neurobiology of Alzheimer's disease and other dementias and may in turn enhance knowledge of the potential risk factors involved. This study aimed at describing uncommon or bizarre symptoms/syndromes observed in patients suffering from dementia. Medline and Google scholar searches were conducted for relevant articles, chapters, and books published before 2019. Search terms used included dementia, déjà vu, zoophilia, pathological lying, and somatic symptom disorder. Publications found through this indexed search were reviewed for further relevant references. Uncommon/bizarre features of dementia were described as case reports and there were no systematic investigations.

Aging With Down Syndrome: The Dual Diagnosis: Alzheimer's Disease and Down Syndrome.

BACKGROUND: People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with aging, including dementia. OBJECTIVES: To explore the phenomenon of dementia in DS. METHODS: Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published until 2017. Search terms included Alzheimer's disease, cognitive impairment, dementia, DS, and trisomy 21. Publications found through this indexed search were reviewed for further references. RESULTS AND CONCLUSIONS: Virtually, all subject aged 35 to 40 show key neuropathologic changes characteristic of Alzheimer's disease, but only a part of them show clinical signs of dementia, usually around the age of 50 years. Early signs of dementia in people with DS may be different from those experienced by the general population. Failure to recognize this can delay diagnosis and subsequent interventions.

Danger in the Air: Air Pollution and Cognitive Dysfunction.

BACKGROUND: Clean air is considered to be a basic requirement for human health and well-being. OBJECTIVE: To examine the relationship between cognitive performance and ambient pollution exposure. METHODS: Studies were identified through a systematic search of online scientific databases, in addition to a manual search of the reference lists from the identified papers. RESULTS: Air pollution is a multifaceted toxic chemical mixture capable of assaulting the central nervous system. Despite being a relatively new area of investigation, overall, there is mounting evidence implicating adverse effects of air pollution on cognitive function in both adults and children. CONCLUSIONS: Consistent evidence showed that exposure to air pollution, specifically exposure to particulate matter, caused poor age-related cognitive performance. Living in areas with high levels of air pollution has been linked to markers of neuroinflammation and neuropathology that are associated with neurodegenerative conditions such as Alzheimer's disease-like brain pathologies.

Association of the hOGG1 Ser326Cys polymorphism with sporadic amyotrophic lateral sclerosis.

Amyotropic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease causing the loss of motoneurons of the brain and the spinal cord. The etiology of ALS is still uncertain, but males are at increased risk for the disease than females. Several studies have suggested that motoneurons in ALS might be subjected to the double insult of increased DNA oxidative damage and deficiencies in DNA repair systems. Particularly, increased levels of 8-oxoguanine and impairments of the DNA base excision repair system have been observed in neurons of ALS patients. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. To evaluate the role of the hOGG1 Ser326Cys polymorphism in sporadic ALS (sALS), we screened 136 patients and 129 matched controls. In the total population, we observed association between both the Cys326 allele (p=0.02) and the combined Ser326Cys+Cys326Cys genotype (OR=1.65, 95% CI=1.06-2.88) and increased risk of disease. After stratification by gender, the Cys326 allele (p=0.01), both the Ser326Cys genotype (OR=2.14, 95% CI=1.09-4.19) and the combined Ser326Cys+Cys326Cys genotype (OR=2.15, 95% CI=1.16-4.01) were associated with sALS risk only in males. No significant association between the Ser326Cys polymorphism and disease phenotype, including age and site of onset and disease progression, was observed. Present results suggest a possible involvement of the hOGG1 Ser326Cys polymorphism in sALS pathogenesis.

Old and dangerous: Prison and dementia.

Older prisoners are the fastest growing group of prisoners in many countries. The purpose of this study is to explore the phenomenon of detention of persons suffering from dementia. Medline searches were conducted for relevant articles, chapters and books published until August 2016. Search terms included dementia, elderly, prison and criminal. Publications found through this indexed search were reviewed for further relevant references. As results, there is a lack of data about elderly with dementia in prisons. Given the rise in the average age, it is reasonable to hypothesize that the number of older prisoners is growing. Moreover, some elderly are imprisoned with a concomitant cognitive impairment or psychiatric disorder while others will develop such diseases once incarcerated. At the present time, legal and social systems seem unprepared to handle the phenomenon of dementia in prison. As proposal, health assessments for older first time offenders should become a practice inside the correctional facilities and include an evaluation for specific health issues, such as psychiatric comorbidity and cognitive impairment.

Eating Behaviors and Dietary Changes in Patients With Dementia.

BACKGROUND: Eating problems and dietary changes have been reported in patients with dementia. OBJECTIVES: The aim of this article is to explore the generalized problems with nutrition, diet, feeding, and eating reported among patients with dementia. METHODS: Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published before 2016. Search terms used included behavioral and psychological symptoms of dementia, dementia, dietary changes, eating behavior. Publications found through this indexed search were reviewed for further relevant references. RESULTS: Abnormal eating behaviors, eating problems, and dietary changes are present in most people with dementia, especially in the later stages of the condition. CONCLUSION: Individuals with dementia frequently develop serious feeding difficulties and changes in eating and dietary habits. The changes may be secondary to cognitive impairment or apraxia, or the result of insufficient caregiving, or the consequence of metabolic or neurochemical abnormalities occurring as part of the dementing process.

Violent and criminal manifestations in dementia patients.

Although the older adults have been studied as victims of violence, geriatric patients can display violent behavior. The purpose of the present review was to explore the phenomenon of criminal violations and violent acts in people with dementia. The authors used PubMed to search the MEDLINE database and other sources for original research and review articles on criminal and violent manifestation in demented patients combining the terms "criminal manifestation," "violence, aggressive behavior," "homicide," "suicide" and "homicide-suicide" together with "dementia". Possible biomarkers of violence are considered. The present review highlights the risk factors for violence in patients suffering from dementia, and reviews the literature about criminal violations and homicidal/suicidal behavior in this patient group. Geriatr Gerontol Int 2016; 16: 541-549.

Lack of association between nuclear factor erythroid-derived 2-like 2 promoter gene polymorphisms and oxidative stress biomarkers in amyotrophic lateral sclerosis patients.

Oxidative stress involvement has been strongly hypothesized among the possible pathogenic mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The intracellular redox balance is finely modulated by numerous complex mechanisms critical for cellular functions, among which the nuclear factor erythroid-derived 2-like 2 (NFE2L2/Nrf2) pathways. We genotyped, in a cohort of ALS patients (n = 145) and healthy controls (n = 168), three SNPs in Nrf2 gene promoter: -653 A/G, -651 G/A, and -617 C/A and evaluated, in a subset (n = 73) of patients, advanced oxidation protein products (AOPP), iron-reducing ability of plasma (FRAP), and plasma thiols (-SH) as oxidative damage peripheral biomarkers. Nrf2 polymorphisms were not different among patients and controls. Increased levels of AOPP (P < 0.05) and decreased levels of FRAP (P < 0.001) have been observed in ALS patients compared with controls, but no difference in -SH values was found. Furthermore, no association was found between biochemical markers of redox balance and Nrf2 polymorphisms. These data confirm an altered redox balance in ALS and indicate that, while being abnormally modified compared to controls, the oxidative stress biomarkers assessed in this study are independent from the -653 A/G, -651 G/A, and -617 C/A Nrf2 SNPs in ALS patients.

Hereditary spastic paraparesis in adults. A clinical and genetic perspective from Tuscany.

OBJECTIVE: Hereditary spastic paraparesis or paraplegias (HSPs) are a group of neurogenetic conditions with prominent involvement of the pyramidal tracts. Aim of this study is the clinical and molecular characterization of a cohort of patients with HSP. Moreover, we aim to study the minimum prevalence of HSP in our area and to propose a schematic diagnostic approach to HSP patients based on the available data from the literature. METHODS: Retrospective/perspective study on the subjects with clinical signs and symptoms indicative of pure or complicated HSP, in whom other possible diagnosis were excluded by appropriate neuroradiological, neurophysiologic and laboratory studies, who have been evaluated by the Neurogenetic Service of our Clinic in last two years (2011-2012). RESULTS: 45 patients were identified. The minimum prevalence of HSP in our area was of about 2.17-3.43/100,000. The SF-36 (quality of life) and SPRS (disease progression) scores were inversely related; the time-saving, four-stage scale of motor disability could predict the SPRS scores with a high statistical significance, and we encourage its use in HSP. Our study confirms SPG4 as the major cause of HSP. All SPG4 patients had a pure HSP phenotype, and the dominant inheritance was evident in the great majority of these subjects. SPG7 was the second genetic cause. Other genotypes were rarer (SPG10, SPG11, SPG17). CONCLUSION: Exact molecular diagnosis will allow a more accurate patient counseling and, hopefully, will lead to specific, targeted, therapeutic options for these chronic, still incurable diseases.

Structural and functional evaluation of cortical motor areas in Amyotrophic Lateral Sclerosis.

The structural and functional data gathered with Magnetic Resonance Imaging (MRI) techniques about the brain cortical motor damage in Amyotrophic Lateral Sclerosis (ALS) are controversial. In fact some structural MRI studies showed foci of gray matter (GM) atrophy in the precentral gyrus, even in the early stage, while others did not. Most functional MRI (fMRI) studies in ALS reported hyperactivation of extra-primary motor cortices, while contradictory results were obtained on the activation of the primary motor cortex. We aimed to investigate the cortical motor circuitries in ALS patients by a combined structural and functional approach. Twenty patients with definite ALS and 16 healthy subjects underwent a structural examination with acquisition of a 3D T1-weighted sequence and fMRI examination during a maximal force handgrip task executed with the right-hand, the left-hand and with both hands simultaneously. The T1-weighted images were analyzed with Voxel-Based Morphometry (VBM) that showed several clusters of reduced cortical GM in ALS patients compared to controls including the pre and postcentral gyri, the superior, middle and inferior frontal gyri, the supplementary motor area, the superior and inferior parietal cortices and the temporal lobe, bilaterally but more extensive on the right side. In ALS patients a significant hypoactivation of the primary sensory motor cortex and frontal dorsal premotor areas as compared to controls was observed. The hypoactivated areas matched with foci of cortical atrophy demonstrated by VBM. The fMRI analysis also showed an enhanced activation in the ventral premotor frontal areas and in the parietal cortex pertaining to the fronto-parietal motor circuit which paralleled with disease progression rate and matched with cortical regions of atrophy. The hyperactivation of the fronto-parietal circuit was asymmetric and prevalent in the left hemisphere. VBM and fMRI identified structural and functional markers of an extended cortical damage within the motor circuit of ALS patients. The functional changes in non-primary motor cortices pertaining to fronto-parietal circuit suggest an over-recruitment of a pre-existing physiological sensory-motor network. However, the concomitant fronto-parietal cortical atrophy arises the possibility that such a hyper-activation reflects cortical hyper-excitability due to loss of inhibitory inter-neurons.