Evidence for accuracy of pain assessment and painkillers utilization in neuropsychiatric symptoms of dementia in Calabria region,Italy

During the clinical course of dementia,beside cognitive impairment and memory loss,a very complex challenge is posed by the neuropsychiatric symptoms（NPSs）.Accurate evaluation and treatment of pain impacts positively the agitation of demented patients aged ≥ 65 years.To gather information on the utilization of pain killers in demented patients a preliminary survey has been conducted in collaboration with the Calabrian Pharmacovigilance Territorial Service of the health district of Catanzaro（Italy）.The study has taken into consideration the prescriptions of acetylcholinesterase inhibitors and memantine during the period ranging from July 2015 to June 2016 and the percentage of patients treated against pain with non steroidal antinflammatory drugs,opioids,and anticonvulsants have been monitored.The latter have been evaluated statistically for difference between the treatment before（pre） and after（post） the settlement of acetylcholinesterase inhibitors（ACh EI） or memantine therapy.The results do support accuracy in painkillers utilization in the course of dementia in the regional population of Calabria（Italy）.

Spectrum of neuropsychiatric symptoms in chronic post-stroke aphasia

BACKGROUND Neuropsychiatric symptoms(NPS)have been insufficiently examined in persons with aphasia(PWA)because most previous studies exclude participants with language and communication disorders.AIM To report a two-part study consisting of a literature review and an observational study on NPS in post-stroke aphasia.METHODS Study 1 reviewed articles obtained from PubMed,PsycINFO,Google Scholar and Cochrane databases after cross-referencing key words of post-stroke aphasia to NPS and disorders.Study 2 examined language deficits and activities of daily living in 20 PWA(median age:58,range:28-65 years;13 men)with the Western Aphasia Battery-Revised and the Barthel Index,respectively.Informants of these 20 PWA were proxy-evaluated with the Neuropsychiatric Inventory and domain-specific scales,including the Stroke Aphasia Depression Questionnaire-10 item version and the Starkstein Apathy Scale.In addition,an adapted version of the Hospital Anxiety and Depression Scale was directly administered to the PWA themselves.This observational study is based on the baseline assessment of an intervention clinical trial(EudraCT:2017-002858-36;ClinicalTrials.gov identifier:NCT04134416).RESULTS The literature review revealed a broad spectrum of NPS in PWA,including depression,anxiety,apathy,agitation/aggression,eating and sleep disorders,psychosis,and hypomania/mania.These findings alert to the need for improving assessment and treatment approaches of NPS taking into consideration their frequent occurrence in PWA.Study 2 showed that the 20 participants had mild-to-moderate aphasia severity and were functionally independent.A wide range of comorbid NPS was found in the post-stroke aphasic population(median number of NPS:5,range:1-8).The majority of PWA(75%)had depressive symptoms,followed by agitation/aggression(70%),irritability(70%),anxiety(65%)and appetite/eating symptoms(65%).Half of them also presented symptoms of apathy,whereas euphoria and psychotic symptoms were rare(5%).Domain-specific scales revealed that 45%of participants had apathy and 30%were diagnosed with depression and anxiety.CONCLUSION Concurrent NPS are frequent in the chronic period of post-stroke aphasia.Therefore,further research on reliable and valid assessment tools and treatment for this aphasic population is strongly warranted.

Legacy of neuropsychiatric symptoms associated with past COVID-19 infection:A cause of concern

Although primarily affecting the respiratory system,growing attention is being paid to the neuropsychiatric consequences of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infections.Acute and sub-acute neuropsychiatric manifestations of coronavirus disease 2019(COVID-19)disease and their mechanisms are better studied and understood currently than they had been when the pandemic began;however,many months or years will be necessary to fully comprehend how significant the consequences of such complications will be.In this editorial,we discuss the possible long-term sequelae of the COVID-19 pandemic,deriving our considerations on experiences drawn from past coronaviruses’outbreaks,such as the SARS and the middle east respiratory syndrome,and from the knowledge of the mechanisms of neurotropism and invasiveness of SARS-CoV-2.Acknowledging the global spread of COVID-19 and the vast number of people affected,to date amounting to many millions,the matter of this pandemic’s neuropsychiatric legacy appears concerning.Public health monitoring strategies and early interventions seem to be necessary to manage the possible emergence of a severe wave of neuropsychiatric distress among the survivors.

Effectiveness of music intervention on cognitive function and neuropsychiatric symptoms in the elderly with dementia:a meta-analysis

Dementia is increasing dramatically with an increasing elderly population.Pharmacological interventions are proven to have limited efficacy to treat many of the features of dementia.In such a situation,non-pharmacological means become important to help people with dementia,especially music therapy.The efficacy of music intervention on cognition has been barely explored in the literature,and the few studies that are available present inconsistent results.The aim of this systematic review is to have a meta-analysis on the effect of music therapy for improvements in cognitive functions as well as neuropsychiatric symptoms in the elderly with dementia.

Associations of AT(N) biomarkers with neuropsychiatric symptoms in prechnical Alzheimer’s disease and cognitively unimpaired individuals

The development of in vivo biomarkers of Alzheimer's disease(AD)has advanced the diagnosis of AD from a clinical syndrome to a biological construct.The preclinical stage of AD continuum is defined by the identification of AD biomarkers crossing the pathological threshold in cognitively unimpaired individuals.While neuropsychiatric symptoms(NPS)are non-cognitive symptoms that are increasingly recognized as early manifestations of AD,the associations of NPS with AD pathophysiology in preclinical AD remain unclear.Here,we review the associations between NPS and AD biomarkers amyloid-(3(Aβ),tau and neurodegeneration in preclinical AD and cognitivelyunimpaired individuals in 19 eligible English-language publications(8 cross-sectional studies,10 longitudinal,1 both cross-sectional and longitudinal).The cross-sectional studies have consistently shown that NPS,particularly depressive and anxiety symptoms,are associated with higher Aβ.The longitudinal studies have suggested that greater NPS are associated with higher Aβ and cognitive decline in cognitively unimpaired subjects over time.However,most of the studies have either cross-sectionally or longitudinally shown no association between NPS and tau pathology.For the association of NPS and neurodegeneration,two studies have shown that the cerebrospinal fluid total-tau is linked to longitudinal increase in NPS and that the NPS may predict longitudinal metabolic decline in preclinical AD,respectively.However,evidence for the association between atrophy and NPS in preclinical AD is less consistent.Therefore,future longitudinal studies with well-designed methodologies and NPS measurements are required not only to determine the relationship among AT(N)biomarkers,NPS and cognitive decline,but also to elucidate the contribution of comorbid pathology to preclinical AD.

A pilot study on the relationship between thyroid status and neuropsychiatric symptoms in patients with Alzheimer disease

Background Growing evidence links alternation of the thyroid function to the pathogenesis and progression of Alzheimer disease （AD）. However, only a few studies evaluate the association between thyroid hormone levels and neuropsychiatric manifestations in patients with AD. This study aimed to investigate the relationship of thyroid hormone levels and neuropsychiatric symptoms in euthyroid patients with AD. Methods Forty patients with AD （26 women and 14 men）, with no prior AD treatment within 4 weeks before study entry, were evaluated on their thyroid status （total triiodothyronine （TT3）,total thyroxine （TT4）, and thyroid-stimulating hormone （TSH）, cognition （Mini-Mental State Examination （MMSE） and Alzheimer＇s disease Assessment Scale-Cognitive Subscale （ADAS-cog）, neuropsychiatric symptoms （Neuropsychiatric Inventory （NPI） and depression （Hamilton Rating Scale for Depression （HAMD17）. The unique relationship between thyroid hormones and cognitive function and mood was examined with multivariate linear regression analyses. The thyroid status between the neuropsychiatric symptoms group and the non-neuropsychiatric symptoms group was examined with independent-samples t-test. Results In euthyroid AD patients with agitation and irritability has lower TSH serum level than those without these symptoms （t=-2.130, P 〈0.05; t=-2.657, P 〈0.05）; and core score of HAMD is significantly associated with the serum level of TSH （β=0.395, P 〈0.01）. There is no significant association between thyroid hormone levels and cognition （MMSE, ADAS-cog and its subscale score）.

Neuropsychiatric symptoms are early indicators of an upcoming metabolic decline in Alzheimer's disease

Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological progression in AD remains unclear.Dominantly inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.Hence,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies.In this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.Methods:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status.The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers.Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results:A total of 119 mutation carriers and 102 non-carriers were studied.The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation carriers.The neuropsychiatric subsyndromes of agitation,disinhibition,irritability and depression interacted with the EYO to drive the[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions:The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD,which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD.Further studies using different methodological approaches to identify NPS in predinical AD are needed to validate our findings.

Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

Impact of COVID-19 pandemic on the neuropsychiatric status of Wilson’s disease

We have read with interest the Letter to the Editor by Drs.Zhuang and Zhong,who presented the clinical data of 68 patients with Wilson’s disease(WD)who were admitted to the hospital before and during the coronavirus disease 2019(COVID-19)pandemic,and appreciated their findings on hepatic and some extrahepatic manifestations.Nevertheless,given the strong impact of the pandemic on patients with neurological and psychiatric disorders,we would have expected a worsening of the psychiatric and/or neurological impairments in these patients.In contrast,according to the authors,these manifestations remained,somewhat unexpectedly,unchanged.This finding is in contrast with most of the current literature that highlights not only an increased incidence of mental health disorders in the general population but also an exacerbation of neurological and psychiatric symptoms in patients with chronic diseases,especially in those with pre-existing neuropsychiatric disorders,such as WD.Although the study was mainly focused on the hepatic features of WD patients taking anti-copper treatment,a generic and cumulative definition of neurological and psychiatric manifestations,as in this study,does not allow for further considerations.Future studies during and after the pandemic are necessary to clarify the real impact,either direct or indirect,of the COVID-19 pandemic on the neurological and psychiatric symptoms of WD patients.

Alzheimer's disease with sleep insufficiency:a cross-sectional study on correlations among clinical characteristics,orexin,its receptors,and the bloodbrain barrier

Previous studies have shown that reduced sleep duration,sleep fragmentation,and decreased sleep quality in patients with Alzheimer's disease are related to dysfunction in orexin signaling.At the same time,blood-brain barrier disruption is considered an early biomarker of Alzheimer's disease.However,currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimer's disease with sleep insufficiency.This cross-sectional study included 50 patients with Alzheimer's disease who received treatment in 2019 at Beijing Tiantan Hospital.Patients were divided into two groups:those with insufficient sleep(sleep duration≤6 hours,n=19,age 61.58±8.54 years,10 men)and those with normal sleep durations(sleep duration>6 hours,n=31,age 63.19±10.09 years,18 men).Demographic variables were collected to evaluate cognitive function,neuropsychiatric symptoms,and activities of daily living.The levels of orexin,its receptor proteins,and several blood-brain barrier factors were measured in cerebrospinal fluid.Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains.Furthermore,levels of orexin and its receptors were upregulated in the cerebrospinal fluid,and the blood–brain barrier was destroyed.Both these events precipitated each other and accelerated the progression of Alzheimer's disease.These findings describe the clinical characteristics and potential mechanism underlying Alzheimer's disease accompanied by sleep deprivation.Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimer's disease.

Diagnostic value of amygdala volume on structural magnetic resonance imaging in Alzheimer’s disease

BACKGROUND The main clinical manifestation of Alzheimer’s disease(AD)is memory loss,which can be accompanied by neuropsychiatric symptoms at different stages of the disease.Amygdala is closely related to emotion and memory.AIM To evaluate the diagnostic value of amygdala on structural magnetic resonance imaging(sMRI)for AD.METHODS In this study,22 patients with AD and 26 controls were enrolled.Their amygdala volumes were measured by sMRI and analyzed using an automatic analysis software.RESULTS The bilateral amygdala volumes of AD patients were significantly lower than those of the controls and were positively correlated with the hippocampal volumes.Receiver operating characteristic curve analyses showed that the sensitivity of the left and right amygdala volumes in diagnosing AD was 80.8%and 88.5%,respectively.Subgroup analyses showed that amygdala atrophy was more serious in AD patients with neuropsychiatric symptoms,which mainly included irritability(22.73%),sleep difficulties(22.73%),apathy(18.18%),and hallucination(13.64%).CONCLUSION Amygdala volumes measured by sMRI can be used to diagnose AD,and amygdala atrophy is more serious in patients with neuropsychiatric symptoms.

Relationship Between Clinical and Immunological Features with Magnetic Resonance Imaging Abnormalities in Female Patients with Neuropsychiatric Systemic Lupus Erythematosus

Background：Conventional magnetic resonance imaging （MRI） is the preferred neuroimaging method in the evaluation ofneuropsychiatric systemic lupus erythematosus （NPSLE）.The purpose of this study was to investigate the association between clinical and immunological features with MRI abnormalities in female patients with NPSLE,to screen for the value of conventional MRI in NPSLE.Methods：A total of 59 female NPSLE patients with conventional MRI examinations were enrolled in this retrospective study.All patients were classified into different groups according to MRI abnormalities.Both clinical and immunological features were compared between MRI abnormal and normal groups.One-way analysis of variance was used to compare the systemic lupus erythematosus disease activity index （SLEDAI） score for MRI abnormalities.Multivariate logistic regression analysis investigated the correlation between immunological features,neuropsychiatric manifestations,and MRI abnormalities.Results：Thirty-six NPSLE patients （61%） showed a variety of MRI abnormalities.There were statistically significant differences in SLEDAI scores （P 〈 0.001）,incidence of neurologic disorders （P =0.001）,levels of 24-h proteinuria （P =0.001） and immunoglobulin M （P =0.004）,and incidence of acute confusional state （P =0.002）,cerebrovascular disease （P =0.004）,and seizure disorder （P =0.028） between MRI abnormal and normal groups.In the MRI abnormal group,SLEDAI scores for cerebral atrophy （CA）,cortex involvement,and restricted diffusion （RD） were much higher than in the MRI normal group （P 〈 0.001,P =0.002,P =0.038,respectively）.Statistically significant positive correlations between seizure disorder and cortex involvement （odds ratio [OR] =14.90;95% confidence interval [CI],1.50-151.70;P =0.023） and cerebrovascular disease and infratentorial involvement （OR =10.00;95% CI,1.70-60.00;P =0.012） were found.Conclusions：MRI abnormalities in NPSLE,especially CA,cortex involvement,and RD might be markers of high systemic lupus erythematosus activity.Some MRI abnormalities might correspond to neuropsychiatric manifestations and might be helpful in understanding the pathophysiology of NPSLE.