Diagnostic Biomarkers of Amyloid and Tau Pathology in Alzheimer's Disease: An Overview of Tests for Clinical Practice in the United States and Europe.

Amyloid and tau biomarkers for Alzheimer's disease are widely recognized diagnostic tools for the identification of Alzheimer's disease pathology antemortem and are recommended by the most recent clinical and research guidelines. Approved biomarkers include positron emission tomography (PET)- and fluid-based markers derived from cerebrospinal fluid and, more recently, plasma. These biomarkers are still infrequently used in clinical practice, potentially due to challenges in access to and understanding of individual assay information and methodology. We provide an overview of the diagnostic biomarkers for amyloid and tau pathology that are currently available in the US and/or EU for clinical use. Available performance data from both labels/instructions for use and the scientific literature (with focus on autopsy or PET as standard of truth) are summarized to help healthcare providers navigate the biomarker landscape. All available PET amyloid and tau biomarkers demonstrate high accuracy in identifying amyloid and tau Alzheimer's disease pathology, respectively, at autopsy. Among cerebrospinal fluid biomarkers, all showed accurate prediction of Alzheimer's disease pathology, either based on autopsy or PET findings; greater accuracy was evident for concentration ratios (Aß42/40 or P-tau181/Aß42) versus individual biomarker concentrations. Among plasma biomarkers, Aß42/40 and P-tau181 demonstrated high agreement with PET findings. Overall, we conclude that commercially available PET, cerebrospinal fluid and plasma assays accurately identify Alzheimer's disease amyloid and tau pathology. The recent development of fully automated tests for fluid-based biomarkers improves test reliability. The continued development of plasma biomarkers holds promise for the future management of patients with Alzheimer's disease.

Costs and Resource Use Associated with Alzheimer's Disease in Italy: Results from an Observational Study.

BACKGROUND: The GERAS II study aimed to assess societal costs and resource use associated with Alzheimer's disease (AD) for patients and their primary caregivers in Italy and Spain, stratified for different severity stages of AD at baseline. This report presents baseline results for Italy. DESIGN: GERAS II was a prospective, multicentre, observational study of routine care in AD. SETTING: Community-dwelling patients attending specialist secondary care centres (memory clinics/Alzheimer's Evaluation Units) and their primary informal caregivers were recruited into the study. PARTICIPANTS: Patients were aged ≥55 years, presented within the normal course of care, had a diagnosis of probable AD and a Mini-Mental State Examination (MMSE) score of ≤26. Patients and caregivers were stratified according to patient AD dementia severity at baseline: mild, MMSE score 21-26; moderate, MMSE score 15-20; or moderately severe/severe, MMSE score <15. MEASUREMENTS: Data collected for patients and caregivers included demographics/clinical characteristics; current medication; patient cognitive, functional and behavioural assessments; patient and caregiver health-related quality of life (HRQoL); and patient and caregiver resource use. The costs associated with the resources used were calculated. Costs were broken down into patient healthcare costs, patient social care costs and caregiver informal care costs. RESULTS: Of 198 patients enrolled from Italy, 29 (15%) had mild AD dementia, 80 (40%) had moderate AD dementia, and 89 (45%) had moderately severe/severe AD dementia. Patient and caregiver characteristics showed some differences between AD dementia severity groups; for example, a numerically higher proportion of patients with mild and moderately severe/severe AD dementia were taking memantine compared with those with moderate AD dementia. Patient functioning and behavioural and psychological symptoms worsened with increasing AD dementia severity (p<0.05 between groups for all measures). No significant difference between the disease severity groups was observed in patient HRQoL, and there was no clear pattern in resource use. However, all measures of caregiver time spent helping the patient differed significantly between groups (p<0.05) and were highest in patients with moderately severe/severe AD dementia. Mean (standard deviation) total monthly societal costs per patient (2013 values) were €1850 (1901), €1552 (1322) and €2728 (2184) for patients with mild, moderate and moderately severe/severe AD dementia, respectively (p<0.001 between groups). Caregiver informal care costs were the greatest contributor to total societal costs and amounted to €1370, €1223 and €2223 per patient per month for mild, moderate and moderately severe/severe AD dementia groups, respectively (p<0.001 between groups). CONCLUSION: Total Italian societal costs generally increased with increasing AD dementia severity. However, costs were slightly lower for moderate than for mild AD dementia, possibly reflecting the observed unusual trend of greater caregiver time and higher memantine use in patients with mild versus moderate AD dementia.

Analysis of burden in caregivers of people with Alzheimer's disease using self-report and supervision hours.

OBJECTIVES: This study aimed to describe the baseline characteristics of informal carers of community-living Alzheimer's disease (AD) patients by AD severity group and to identify factors associated with two measures of caregiver burden. DESIGN AND SETTING: GERAS is a prospective observational study in France, Germany, and the UK, designed to assess costs and resource use associated with AD, for patients and their caregivers, stratified by disease severity. PARTICIPANTS: 1497 community-dwelling AD patients and their primary caregivers. MEASUREMENTS: Subjective caregiver burden assessed using the Zarit Burden Interview [ZBI] and time spent supervising patients (an objective measure of burden recorded using the Resource Utilization in Dementia instrument) during the month before the baseline visit were recorded. Separate multiple linear regression analyses using ZBI total score and caregiver supervision time as dependent variables were performed to identify patient and caregiver factors independently associated with caregiver burden. RESULTS: Increasing AD severity was associated with both subjective caregiver burden (ZBI total score) and overall caregiver time, which includes supervision time (both p<0.001, ANOVA). Better patient functioning (on instrumental activities of daily living) was independently associated with both a lower ZBI total score and less supervision time, whereas higher levels of caregiver distress due to patient behavior were associated with greater caregiver burden. Other factors independently associated with an increased ZBI total score included younger caregiver age, caregiver self-reported depression, caring for a male patient, and longer time since AD diagnosis. Caregivers living with the patient, being a male caregiver, patient living in a rural location, higher patient behavioral problem subdomain scores for apathy and psychosis, more patient emergency room visits, not receiving food delivery and receiving financial support for caregiving were all associated with greater caregiver supervision time. CONCLUSION: Our results show that subjective caregiver burden and caregiver time are influenced by different factors, reinforcing the need to consider both aspects of caregiving when trying to minimize the burden of AD. However, interventions that minimize caregiver distress and improve patient functioning may impact on both subjective and objective burden.

Childhood neglect and parental care perception in cocaine addicts: relation with psychiatric symptoms and biological correlates.

UNLABELLED: Childhood neglect and poor child-parent relationships have been reported to increase substance use disorders susceptibility. Stressful environmental factors, including emotional neglect, could affect individual personality traits and mental health, possibly inducing stable changes in hypothalamic-pituitary-adrenal (HPA) axis and brain mono-amine function, in turn involved in addictive behavior vulnerability. Therefore, we decided to investigate homovanillic (HVA) and prolactin (PRL) plasma levels, as expression of possible changes in dopamine function, ACTH and cortisol plasma levels, as measures of HPA axis function, and concomitant psychiatric symptoms profile in abstinent cocaine addicts, in relationship to their childhood history of neglect and poor parental care perception. METHODS: Fifty abstinent cocaine dependent patients, and 44 normal controls, matched for age and sex, were submitted to a detailed psychiatric assessment (DSM IV criteria). All patients and controls completed the Symptoms Check List-90 (SCL-90) and the Buss Durkee Hostility Inventory (BDHI), to evaluate psychiatric symptoms frequency and aggressiveness levels. The Childhood Experience of Care and Abuse-Questionnaire (CECA-Q) and Parental Bonding Instrument (PBI) have been used to retrospectively investigate parent-child relationships. Blood samples were collected to determine HVA, PRL, ACTH and cortisol basal plasma levels. RESULTS: Cocaine addicted individuals in general showed significantly lower HVA, and higher PRL, ACTH and cortisol basal levels respect to controls. In particular, neuroendocrine changes characterized cocaine addicts with childhood history of neglect and low perception of parental care. Obsessive-compulsive, depression and aggressiveness symptoms have been found related to poor parenting, inversely associated to HVA levels and directly associated to PRL, ACTH and cortisol levels. CONCLUSIONS: These findings suggest the possibility that childhood experience of neglect and poor parent-child attachment may partially contribute to a complex neurobiological derangement including HPA axis and dopamine system dysfunctions, playing a crucial role in addictive and affective disorders susceptibility.

A psychoeducational program for weight loss in patients who have experienced weight gain during antipsychotic treatment with olanzapine.

INTRODUCTION: The aim of this study was to evaluate the efficacy of a psychoeducational program (PEP) for weight control in patients who had experienced an increase of body weight during treatment with olanzapine. METHODS: Eligible patients were randomised to the PEP (Group 1) or to no intervention (Group 2) and continued on olanzapine. After 12 weeks, the PEP was also started in Group 2 and continued in Group 1, up to week 24. Body weight was measured every month. Other measures included quality of life, and change in plasma glucose and lipids levels. RESULTS: Patients in Group 1 (n=15) had a mean weight loss of 3.6 kg at week 12 and 4.5 kg at week 24 (p<0.01 at both times, p<0.01 between groups at week 12), while those in Group 2 (n=18) had no changes at week 12 and a significant weight loss at week 24 (-3.6 kg from week 12, p<0.01). Changes of BMI paralleled those of body weight. Quality of life (Q-LES-Q-SF categorisation) and functioning (GAF) significantly improved in the total population at endpoint (p<0.01). No significant changes were observed in fasting glucose and lipid profile, while insulin levels significantly decreased from baseline to endpoint in both groups (p<0.05). HOMA index and hepatic insulin sensitivity improved, too. DISCUSSION: Patients with increased BMI during treatment with olanzapine experienced significant weight and BMI loss following a structured psychoeducational program.

Homovanillic acid (HVA) plasma levels inversely correlate with attention deficit-hyperactivity and childhood neglect measures in addicted patients.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) seems to be a risk condition for substance use disorders, possibly in relationship to common neurobiological changes, underlying both addictive and externalising behaviour susceptibility. Although this vulnerability has been primarily attributed to gene variants, previous studies suggest that also adverse childhood experiences may influence neurotransmission, affecting in particular brain dopamine (DA) system and possibly concurring to the development of behavioural disorders. Therefore, we decided to investigate ADHD symptoms and plasma concentrations of the DA metabolite homovanillic acid (HVA) in abstinent addicted patients, in comparison with healthy control subjects, evaluating whether ADHD scores were related with HVA levels, as expression of DA turnover, and whether HVA values, in turn, were associated with childhood emotional neglect. METHODS: Eighty-two abstinent drug dependent patients, and 44 normal controls, matched for age and sex, completed the Wender Utah Rating Scale (WURS), measuring ADHD symptoms, and the Childhood Experience of Care and Abuse Questionnaire (CECA-Q). Blood samples were collected to determine HVA plasma levels. RESULTS: Addicted individuals showed significantly higher ADHD scores and lower HVA levels respect to control subjects. ADHD scores at WURS in addicted patients negatively correlated with plasma HVA values. In turn, plasma HVA levels were inversely associated with childhood neglect measures, reaching statistical significance with "mother-antipathy" and "mother neglect" scores. CONCLUSIONS: These findings suggest the possibility that childhood experience of neglect and poor mother-child attachment may have an effect on central dopamine function as an adult, in turn contributing to both ADHD and substance abuse neurobiological vulnerability.

From mild cognitive impairment to dementia: a prevalence study in a district of Tuscany, Italy.

OBJECTIVE: A door-to-door two-phase study was designed in order to estimate the prevalence of cognitive deficit amongst the residents of a district in Tuscany (central Italy). Identification of cases with mild cognitive impairment (MCI) was given high priority, because this condition has been suggested as a term for the boundary area between normal aging and dementia. METHODS: Of the 1600 subjects who completed the screening phase, 354 scored under the cut-off point of the Mini Mental State Examination and Clinical Dementia Rating and were investigated by means of a standardized diagnostic protocol. RESULTS: The prevalence of MCI and age-related cognitive decline was 4.9 and 9.3%, respectively; low levels of education significantly increased the risk of these conditions. The prevalence of dementia over age 65 was 6.2%, with a significant risk association with age. In our population, Alzheimer's disease was the most frequent type of dementia (prevalence rate 4.2%) and increased risk depending on age, sex and education has been found. CONCLUSIONS: Our findings are somewhat similar to previous studies. Further epidemiological and longitudinal studies are warranted to identify which diagnostic category is more predictive for dementia.

Environmental factors and Parkinson's disease: a case-control study in the Tuscany region of Italy.

To date the aetiology of Parkinson's disease (PD) is unknown although both genetic susceptibility and environmental factors appear to play an important role in the development of the disease. Recent data have also indicated that chronic exposure to a common pesticide can reproduce the neurochemical, behavioral and neuropathological features of PD. The epidemiological studies previously carried on the prevalence of PD in population exposed to environmental factors have produced controversial results, probably because of different trial design and different analysis methods. A case-control retrospective study was conducted in a well-defined geographic area in Tuscany-Italy with the aim to identify environmental factors possibly related to PD. No significant difference between PD patients and control subjects was observed in time spent in rural or industrial residence, in well water drinking and in the exposure to herbicides and pesticides. A significant difference between patients with PD and controls was reported for cigarette smoking, controls resulting more likely cigarette smokers in comparison with PD patients. The present findings support the view of a protective effect of cigarette smoking and do not show any significant association between environmental factors and the risk of development of PD.

Psychiatric comorbidity in a population of Parkinson's disease patients.

Behavioural disturbances are frequently observed in Parkinson's disease (PD), including mood and anxiety disorders. The existence of a comorbidity between such psychiatric disorders in PD patients has been suggested only in a few studies. To assess the prevalence of mood and anxiety disturbances, and the rate of comorbidity of such disorders in PD. Secondary aim was to correlate the prevalence of psychiatric disorders in PD with age, sex, laterality of motor symptomatology, clinical features, severity of disease, age of onset and PD duration, and anti-parkinsonian therapy. Ninety consecutive PD outpatients, and 90 age- and sex-matched controls were included. All PD patients enrolled were non-fluctuating (21 de novo, 69 treated with levodopa or dopamine agonists). PD patients and controls with Mini Mental State Examination score <23 were excluded. Psychiatric diagnosis was performed by semistructured interview according with DSM-IV criteria and the severity of depressive and anxious symptoms was rated with clinical rating scales. Major depression was found in 21.1% PD patients vs. 3.3% controls (P < 0.01, chi-square analysis), dystimia in 18.8% PD patients vs. 4.4% controls (P < 0.05), panic disorders in 30% PD patients vs. 5.5% controls (P < 0.01). No difference in the prevalence of other anxiety disorders was observed between the two groups. The comorbidity of mood and anxiety disorders was found in 19.3% PD patients vs. 8.6% controls (P < 0.01). No correlation was reported between the prevalence of behavioural disturbances and any of the demographic, clinical or pharmacological data taken into account. Our findings might suggest the existence of a wide spectrum of psychiatric disorders in PD ranging from pure depressive disorders, comorbid depressive and anxiety disorders, and pure anxiety disorders, presumably linked to the same neurobiological substrate.

IV amantadine improves chorea in Huntington's disease: an acute randomized, controlled study.

The acute antidyskinetic effects of IV amantadine in HD were evaluated. A 2-hour IV infusion of amantadine or placebo was administered to nine patients with HD on two different days in a double-blind, randomized crossover fashion. All patients subsequently received oral amantadine unblinded for a 1-year period. A reduction of dyskinesia scores was reported during both IV and oral amantadine treatment (p < 0.05). No significant changes were observed in neuropsychological tests or psychiatric rating scales.

Contribution of cerebellum and brainstem in the control of eye movement: evidence from a functional study in a clinical model.

The idiopathic cerebellar ataxias (IDCA) comprise a wide spectrum of neurodegenerative diseases with heterogeneous neuropathology, characterized by the negativity of search for any known genetic mutation. On the basis of both their clinical presentation and their magnetic resonance imaging pattern, patients with IDCA can be subdivided into patients with a purely cerebellar syndrome and atrophy of the cerebellum (IDCA-C) and patients with additional noncerebellar symptoms and atrophy of both cerebellum and brainstem (IDCA-P). The aim of the present study was to evaluate the disaggregated contribution of brainstem and cerebellum in the control of eye movements, by means of an extensive battery of quantitative tests covering most oculomotor subfunctions related to lesions of the cerebellum and the brainstem. The smooth-pursuit movement analysis showed a decrease in gain and magnitude in both subgroups of IDCA with respect to normal controls, without any significant differences in the prevalence pattern between the two subgroups; the mean values of these parameters, however, were significantly lower in IDCA-P than in IDCA-C subjects in both gain (P < 0.01) and magnitude (P < 0.001). No statistically significant difference was observed between the two subgroups in the analysis of saccadic movements or in the other parameters investigated. The distinction between IDCA-P and IDCA-C subgroups has clinical implications, as a poorer prognosis is related to brainstem involvement, which may occur late in the course of the disease. Thus, the possibility to detect the brainstem involvement, also in association with cerebellar impairment, by a relatively simple eye-movement analysis, potentially useful mainly in follow-up investigations, needs to be evaluated further.

Amantadine in Huntington's disease: open-label video-blinded study.

Huntington's disease (HD) is characterized by chorea, cognitive and behavioral changes. Amantadine, a non-competitive NMDA receptor antagonist, has shown an antidyskinetic effect on levodopa-induced dyskinesias, which are known to have strict pathogenetic analogies with choreic hyperkinesias. The antidyskinetic efficacy of amantadine and its effects on cognitive and behavioural symptoms were evaluated. Eight HD patients received oral amantadine (100 mg tid) unblinded for a 1-year period. A significant reduction of dyskinesias was reported ( p<0.01). No changes were observed in neuropsychologic and psychiatric assessments after 6 and 12 months of therapy. These data may have relevance to the treatment of HD with amantadine.

SSRIs do not worsen Parkinson's disease: evidence from an open-label, prospective study.

Selective serotonin reuptake inhibitors (SSRIs) have been reported to be useful in the treatment of depression in patients with Parkinson's disease (PD). However, a few reports have suggested that SSRIs may worsen parkinsonian motor symptomatology and extrapyramidal side effects have been reported in depressed patients treated with SSRIs. So far, no prospective trial comparing the effects of different SSRIs in depressed patients with PD has been performed. The aim of the present study was to assess the effects of four SSRIs (citalopram, fluoxetine, fluvoxamine, and sertraline) on motor performance and their efficacy on depression in a group of patients with PD. Sixty-two consecutive nondemented, nonfluctuating, depressed patients with PD were included in four treatment groups (15 patiens received citalopram, 16 fluoxetine, 16 fluvoxamine, and 15 sertraline). The evaluation of extrapyramidal and depressive symptomatology was performed with use of the Unified Parkinson's Disease Rating Scale (UPDRS), Beck Depression Inventory, and Hamilton Depression Rating Scale at baseline and after 1, 3, and 6 months. Fifty-two patients completed the study. UPDRS scores were not significantly modified by the add-on therapy with each of the SSRIs studied. A significant improvement in depressive symptoms from baseline to the end of the trial was obtained with all SSRIs (Beck and Hamilton scores improving; p < 0.05 according to an analysis of variance). Our findings suggest that SSRIs do not significantly worsen extrapyramidal symptomatology and may ameliorate depression in patients with PD.

Paroxetine in Parkinson's disease: effects on motor and depressive symptoms.

Selective serotonin reuptake inhibitors have been used in the treatment of depression in patients with PD. Conflicting data as to whether selective serotonin reuptake inhibitors worsen parkinsonian motor symptomatology have been reported. In this study, the additional 6 months therapy with paroxetine 20 mg/d in a group of depressed patients with PD did not modify parkinsonian motor function (Unified Parkinson's Disease Rating Scale scores); however, in one patient, fully reversible worsening of tremor was observed. Depression, as evaluated by Beck Depression Inventory and Hamilton Depression Rating Scale, improved from baseline to final visit (p < 0.05 by analysis of variance).

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease.

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.

Long-term follow-up after flunarizine or nimodipine discontinuation in migraine patients.

Various open and controlled studies have confirmed the antimigraine action of flunarizine, while the antimigraine properties of nimodipine are still open to controversy. Moreover, only a few studies include an additional follow-up after discontinuation of migraine prophylaxis with either drug. We carried out a single blind evaluation of the efficacy and tolerance of flunarizine (25 patients) in comparison with nimodipine (25 patients) and the long-term effect after discontinuation of a 6-month treatment. Both medications significantly reduced migraine frequently and severity. Flunarizine was more efficacious than nimodipine in reducing migraine frequency (p < 0.001), pain severity (p < 0.05), migraine index (p < 0.05) and corrected migraine index (p < 0.05). The positive effect lasted 8.4 +/- 4.0 months after discontinuation of flunarizine and 4.9 +/- 3.5 months after nimodipine (p < 0.05). Our results suggest that flunarizine is more effective than nimodipine in the prophylactic treatment of migraine. The positive effect after drug discontinuation lasts longer with flunarizine, compared to nimodipine.

Amitriptyline and dexamethasone combined treatment in drug-induced headache.

Frequent or regular intake of antimigraine drugs, including analgesics, constitutes a common cause of chronic daily headache. Discontinuation of symptomatic medication can produce an increase in head pain accompanied by withdrawal symptoms. We report the favourable outcome of treating a group of outpatients with the combination of amitriptyline, dexamethasone and sumatriptan. Dexamethasone (4 mg/day) was given intramuscularly for 2 weeks, amitriptyline orally at night (50 mg/day) for at least 6 months, and sumatriptan subcutaneously to treat acute headache attacks. Eighteen out of 20 patients abstained from drug abuse. Eleven of these 18 patients showed a marked reduction in headache frequency (at least 75% in relation to the basal value), and were considered "very good responders". The other seven patients experienced at least 50% reduction in headache frequency compared to baseline. This preliminary report suggests that drug-induced headache can be treated effectively in outpatients using dexamethasone, amitriptyline and sumatriptan in combination with significant benefit in everyday life conditions.