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1.  The paradox of sham therapy and placebo effect in osteopathy 
Medicine  2016;95(35):e4728.
Supplemental Digital Content is available in the text
Placebo, defined as “false treatment,” is a common gold-standard method to assess the validity of a therapy both in pharmacological trials and manual medicine research where placebo is also referred to as “sham therapy.” In the medical literature, guidelines have been proposed on how to conduct robust placebo-controlled trials, but mainly in a drug-based scenario. In contrast, there are not precise guidelines on how to conduct a placebo-controlled in manual medicine trials (particularly osteopathy). The aim of the present systematic review was to report how and what type of sham methods, dosage, operator characteristics, and patient types were used in osteopathic clinical trials and, eventually, assess sham clinical effectiveness.
A systematic Cochrane-based review was conducted by analyzing the osteopathic trials that used both manual and nonmanual placebo control. Searches were conducted on 8 databases from journal inception to December 2015 using a pragmatic literature search approach. Two independent reviewers conducted the study selection and data extraction for each study. The risk of bias was evaluated according to the Cochrane methods.
A total of 64 studies were eligible for analysis collecting a total of 5024 participants. More than half (43 studies) used a manual placebo; 9 studies used a nonmanual placebo; and 12 studies used both manual and nonmanual placebo. Data showed lack of reporting sham therapy information across studies. Risk of bias analysis demonstrated a high risk of bias for allocation, blinding of personnel and participants, selective, and other bias. To explore the clinical effects of sham therapies used, a quantitative analysis was planned. However, due to the high heterogeneity of sham approaches used no further analyses were performed.
High heterogeneity regarding placebo used between studies, lack of reporting information on placebo methods and within-study variability between sham and real treatment procedures suggest prudence in reading and interpreting study findings in manual osteopathic randomized controlled trials (RCTs). Efforts must be made to promote guidelines to design the most reliable placebo for manual RCTs as a means of increasing the internal validity and improve external validity of findings.
PMCID: PMC5008597  PMID: 27583913
complementary medicine; manual medicine; nocebo; osteopathy; pain; ultrasound
2.  Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study 
Previous case–control studies have suggested a possible increased risk of Amyotrophic Lateral Sclerosis (ALS) with physical activity (PA), but this association has never been studied in prospective cohort studies. We therefore assessed the association between PA and risk of death from ALS in the European Prospective Investigation into Cancer and Nutrition. A total of 472,100 individuals were included in the analysis, yielding 219 ALS deaths. At recruitment, information on PA was collected thorough standardised questionnaires. Total PA was expressed by the Cambridge Physical Activity Index (CPAI) and analysed in relation to ALS mortality, using Cox hazard models. Interactions with age, sex, and anthropometric measures were assessed. Total PA was weakly inversely associated with ALS mortality with a borderline statistically significant trend across categories (p = 0.042), with those physically active being 33 % less likely to die from ALS compared to those inactive: HR = 0.67 (95 % CI 0.42–1.06). Anthropometric measures, sex, and age did not modify the association with CPAI. The present study shows a slightly decreased—not increased like in case–control studies—risk of dying from ALS in those with high levels of total PA at enrolment. This association does not appear confounded by age, gender, anthropometry, smoking, and education. Ours was the first prospective cohort study on ALS and physical activity.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-016-0119-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4820490  PMID: 26968841
Amyotrophic Lateral Sclerosis; Physical activity; Cohort study; EPIC study; Vigorous physical activity; BMI
3.  The new challenge for Functional Neurology 
Functional Neurology  2016;30(4):215.
PMCID: PMC4758773  PMID: 26727699
6.  Effects of Bacille Calmette-Guérin after the first demyelinating event in the CNS 
Neurology  2014;82(1):41-48.
To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS).
In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months.
Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308–0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207–0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046–0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were −0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and −0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27–0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04–0.93; p = 0.04).
Early BCG may benefit CIS and affect its long-term course.
Classification of evidence:
BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).
PMCID: PMC3873620  PMID: 24306002
7.  Age-Related Psychophysiological Vulnerability to Phenylalanine in Phenylketonuria 
Background: Phenylketonuria (PKU) is caused by the inherited defect of the phenylalanine hydroxylase enzyme, which converts phenylalanine (Phe) into tyrosine (Tyr). Neonatal screening programs and early treatment have radically changed the natural history of PKU. Nevertheless, an increased risk of neurocognitive and psychiatric problems in adulthood remains a challenging aspect of the disease. In order to assess the vulnerability of complex skills to Phe, we explored: (a) the effect of a rapid increase in blood Phe levels on event-related potentials (ERP) in PKU subjects during their second decade of life; (b) the association (if existing) between psychophysiological and neurocognitive features.
Methods: Seventeen early-treated PKU subjects, aged 10–20, underwent ERP [mismatch negativity, auditory P300, contingent negative variation (CNV), and Intensity Dependence of Auditory Evoked Potentials] recording before and 2 h after an oral loading of Phe. Neurocognitive functioning, historical and concurrent biochemical values of blood Phe, Tyr, and Phe/Tyr ratio, were all included in the statistical analysis.
Results: Event-related potential components were normally detected in all the subjects. In subjects younger than 13 CNV amplitude, W2-CNV area, P3b latency, and reaction times in motor responses were negatively influenced by Phe-loading. Independently from the psychophysiological vulnerability, some neurocognitive skills were more impaired in younger patients. No correlation was found between biochemical alterations and neurocognitive and psychophysiological findings.
Conclusion: The vulnerability of the emerging neurocognitive functions to Phe suggests a strict metabolic control in adolescents affected by PKU and a neurodevelopmental approach in the study of neurocognitive outcome in PKU.
PMCID: PMC4066367  PMID: 25003100
PKU; event-related potentials; event-related potentials in PKU; neurocognitive outcome in PKU
9.  Use of health and social care services in a cohort of Italian dementia patients 
Functional Neurology  2014;28(4):265-273.
The aim of this study, conducted in the Region of Lazio, Italy, in 2008–2010, was to describe the use, over a one-year period, of health and social care services in a cohort of 712 patients with a diagnosis of dementia. These patients had never previously used such services.
We evaluated the association between the patients’ sociodemographic and clinical characteristics and their use of services. Sociodemographic and clinical data were collected at baseline using validated instruments, while the use of services was investigated at the end of the one-year follow-up through a structured (questionnaire-based) interview with the caregiver.
We found that 11.9% of patients used health or social care services. The most frequent diagnoses were: Alzheimer’s disease (72.1%), mixed dementia (20.5%), and vascular dementia (9.7%). A higher probability of use of services was observed in patients with: more than five years of schooling (OR=1.79; 95%CI:1.08–2.96); one or more comorbidity (OR=4.87; 95%CI:2.05–11.57); severe (OR=4.78; 95%CI:1.75–13.06) or moderate dementia (OR=2.08; 95%CI:0.98–4.40). The low health and social care service use among dementia patients in this study could be explained by a lack of availability of services. Public health authorities should plan adequate networks of services, considering both patients and caregivers’ needs.
PMCID: PMC3951254  PMID: 24598394
cohort study; dementia; health and social care services; healthcare system; memory clinics
10.  Clinical guidelines in pediatric headache: evaluation of quality using the AGREE II instrument 
The Appraisal of Guidelines for Research and Evaluation (AGREE II) tool is a validated questionnaire used to assess the methodological quality of clinical guidelines (CGs). We used the AGREE II tool to assess the development process, the methodological quality, and the quality of reporting of available pediatric CGs for the management of headache in children. We also studied the variability in responses related to the characteristics of eleven Italian neuropediatric centers, showing similarities and differences in the main recommendations reported in CGs.
A systematic literature search was conducted from January 2002 to June 2013 on Mediline, the Cochrane database, the National Guideline Clearinghouse website and the NHS evidence search tool, using the following terms: headache, cephalalgia, guidelines and children (MESH or text words). Six CGs providing information on the diagnosis and management of headache and specific recommendations for children were selected. Eleven neuropediatric centers assessed the overall quality and the appropriateness of all available CGs using of the AGREE II instrument.
Six CGs meeting the inclusion and exclusion criteria were identified and assessed by 11 reviewers. Our study showed that the NICE CGs was “strongly recommended” while the French and Danish CGs were mainly “not recommended”. The comparison between the overall quality score of the French CGs and the NICE CGs was statistically significant (6.54 ± 0.69 vs 4.18 ± 1.08; p =0.001). The correlation analysis between quality domain score and guideline publication date showed a statistically significant association only for the “editorial independence” domain (r = 0.842 p = 0.035). The intra-class coefficients showed that the 11 reviewers had the highest agreement for the Lewis CGs (r = 0.857), and the lowest one for the NICE CGs (r = 0.656). Statistical analyses showed that professionals from outpatient services dedicated pediatric headache assigned a higher overall quality score to the NICE CGs as compared to professionals from non-outpatient services (6.86 ± 0.38 vs 6.0 ± 0.82; p = 0.038).
CGs resulted definitely of low-moderate quality and non “homogeneous”. Further major efforts are needed to update the existing CGs according to the principles of evidence based medicine.
PMCID: PMC4167157  PMID: 25178699
Guidelines; Pediatric headache; Agree II instrument; Quality of guidelines; Children
11.  Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis 
Neurology  2013;80(9):829-838.
The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design.
The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality.
Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the follow-up period (mean follow-up = 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p = 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio = 0.93, 95% confidence interval 0.86–0.99 per kg/m2); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio = 0.48, 95% confidence interval 0.25–0.93) with a borderline significant p value for trend across quartiles (p = 0.056).
Increased prediagnostic body fat is associated with a decreased risk of ALS mortality.
PMCID: PMC3598455  PMID: 23390184
12.  Rizatriptan in migraineurs with unilateral cranial autonomic symptoms: a double-blind trial 
The Journal of Headache and Pain  2012;13(5):407-414.
The objective and background is to confirm in a double-blind, placebo-controlled study the high triptan response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms. In this randomized, double-blind, placebo-controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo (ratio 1:1) and treated for a single moderate or severe migraine attack. The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h. Secondary endpoints included pain relief, no associated symptoms and sustained pain freedom or relief. Significantly more patients reported pain freedom at 2 h after taking rizatriptan (54 %) than after placebo (8 %) (therapeutic gain 46 % [28 %; 64 %]; P < 0.001). Similarly, significantly more patients reported total migraine freedom at 2 h after rizatriptan (51 %) than after placebo (8 %) (therapeutic gain 43 % [26 %; 61 %]; P < 0.001). Rizatriptan was also more effective than placebo on most secondary endpoints. We confirm in a placebo-controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans, probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular 5-HT1B/1D receptors. Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients.
PMCID: PMC3381061  PMID: 22460943
Migraine; Cranial autonomic symptoms; Trigemino-autonomic reflex; Treatment; Rizatriptan
13.  Chronic Obstructive Pulmonary Disease Is Associated with Altered Neuropsychological Performance in Young Adults 
Subjects with ischemic lesions have an increased risk of dementia. In addition, Alzheimer's disease (AD) and vascular cognitive impairment share many risk factors. These observations suggest that different diseases that cause altered blood perfusion of the brain or hypoxia promote AD neurodegeneration. In this case-control, cross-sectional study, we sought to test the hypothesis that hypoxia facilitates cognitive decline.
We looked for altered neuropsychological performance in subjects with chronic obstructive pulmonary disease (COPD) without apparent cardio- or cerebrovascular diseases or risk factors for atherosclerosis. A selected, homogeneous group of workers from two ceramic factories in a small town of central Italy was enrolled in this study.
The COPD patients had a slightly, but significantly worse performance than controls in a number of neuropsychological tests.
The findings are consistent with the working hypothesis that chronic hypoxia facilitates cognitive decline.
PMCID: PMC3243636  PMID: 22187547
Alzheimer's disease; Chronic hypoxia; Chronic obstructive pulmonary disease; Hypoperfusion; Neuropsychological tests
14.  How Are the Interests of Incapacitated Research Participants Protected through Legislation? An Italian Study on Legal Agency for Dementia Patients 
PLoS ONE  2010;5(6):e11150.
Patients with dementia may have limited capacity to give informed consent to participate in clinical research. One possible way to safeguard the patients' interests in research is the involvement of a proxy in the recruitment process. In Italy, the system of proxy is determined by the courts. In this study we evaluate the timing for appointment of a legal proxy in Italy and identify predictive variables of appointment.
Methodology/Principal Findings
Subjects were recruited among the outpatients seeking medical advice for cognitive complaints at the Centre for Research and Treatment of Cognitive Dysfunctions, University of Milan, “Luigi Sacco” Hospital.
The Centre was participating to the AdCare Study, a no-profit randomised clinical trial coordinated by the Italian National Institute of Health. The requirement that informed consent be given by a legal representative dramatically slowed down the recruitment process in AdCare, which was prematurely interrupted. The Centre for Research and Treatment of Cognitive Dysfunctions collected data on the timing required to appoint the legal representatives. Patients diagnosed with dementia and their caregivers were provided information on the Italian law on legal agency (law 6/2004). At each scheduled check-up the caregiver was asked whether she/he had applied to appoint a legal proxy for the patient and the time interval between the presentation of the law, the registration of the application at the law court chancellery and the sentence of appointment was registered. The study involved 169 demented patients. Seventy-eight patients (46.2%) applied to appoint a legal proxy. These subjects were usually younger, had been suffering from dementia for a longer time, had less than two children and made more use of memantine. The mean interval time between the presentation of the law and the patients' application to the law court chancellery was two months. The mean interval time between the patient's application to the law court chancellery and the sentence of appointment was four months.
In Italy the requirement that legal representatives be appointed by the courts slows down subjects' participation in research. Other procedures for legal agency of the incapacitated patients may be adopted, taking as examples other EU countries' systems.
PMCID: PMC2886844  PMID: 20585400
15.  Cholinesterase Inhibitors in Mild Cognitive Impairment: A Systematic Review of Randomised Trials 
PLoS Medicine  2007;4(11):e338.
Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia.
Methods and Findings
The terms “donepezil”, “rivastigmine”, “galantamine”, and “mild cognitive impairment” and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64–1.12), and 0.84 (0.57–1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain).
The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials.
A systematic review of trials of cholinesterase inhibitors for preventing transition of mild cognitive impairment (MCI) to dementia, conducted by Roberto Raschetti and colleagues, found no difference between treatment and control groups and concluded that uncertainty regarding the definition of MCI casts doubts on the validity of such trials.
Editors' Summary
Worldwide, more than 24 million people have dementia, a group of brain disorders characterized by an irreversible decline in memory, problem solving, communication, and other “cognitive” functions. The commonest form of dementia is Alzheimer disease (AD). The risk of developing AD increases with age—AD is rare in people younger than 65 but about half of people over 85 years old have it. The earliest symptom of AD is usually difficulty in remembering new information. As the disease progresses, patients may become confused and have problems expressing themselves. Their behavior and personality can also change. In advanced AD, patients need help with daily activities like dressing and eating, and eventually lose their ability to recognize relatives and to communicate. There is no cure for AD but a class of drugs called “cholinesterase inhibitors” can sometimes temporarily slow the worsening of symptoms. Three cholinesterase inhibitors—donepezil, rivastigmine, and galantamine—are currently approved for use in mild-to-moderate AD.
Why Was This Study Done?
Some experts have questioned the efficacy of cholinesterase inhibitors in AD, but other experts and patient support groups have called for these drugs to be given to patients with a condition called mild cognitive impairment (MCI) as well as to those with mild AD. People with MCI have memory problems that are more severe than those normally seen in people of their age but no other symptoms of dementia. They are thought to have an increased risk of developing AD, but it is not known whether everyone with MCI eventually develops AD, and there is no standardized way to diagnose MCI. Despite these uncertainties, several clinical trials have investigated whether cholinesterase inhibitors prevent progression from MCI to AD. In this study, the researchers have assessed whether the results of these trials provide any evidence that cholinesterase inhibitors can prevent MCI progressing to AD.
What Did the Researchers Do and Find?
The researchers conducted a systematic review of the medical literature to find trials that had addressed this issue, which met criteria that they had defined clearly in advance of their search. They identified three published and five unpublished randomized controlled trials (studies in which patients randomly receive the test drug or an inactive placebo) that investigated the effect of cholinesterase inhibitors on the progression of MCI. The researchers obtained the results of six of these trials—four examined the effect of cholinesterase inhibitors on the conversion of MCI to clinically diagnosed AD or dementia (the primary end point); all six examined the effect of the drugs on several secondary end points (for example, individual aspects of cognitive function). None of the drugs produced a statistically significant difference (a difference that is unlikely to have happened by chance) in the probability of progression from MCI to AD. The only statistically significant secondary end point after adjustment for multiple comparisons (when many outcomes are considered, false positive results can occur unless specific mathematical techniques are used to prevent this problem) was a decrease in the rate of brain shrinkage associated with galantamine treatment. More patients treated with cholinesterase inhibitors dropped out of trials because of adverse effects than patients given placebo. Finally, in the one trial that reported all causes of deaths, one participant who received placebo and six who received galantamine died.
What Do These Findings Mean?
These findings suggest that the use of cholinesterase inhibitors is not associated with any delay in the onset of clinically diagnosed AD or dementia in people with MCI. They also show that the use of these drugs has no effect on most surrogate (substitute) indicators of AD but that the risks associated with their use are not negligible. However, because MCI has not yet been clearly defined as a clinical condition that precedes dementia, some (even many) of the patients enrolled into the trials that the researchers assessed may not actually have had MCI. Thus, further clinical trials are needed to clarify whether cholinesterase inhibitors can delay the progression of MCI to dementia, but these additional trials should not be done until the diagnosis of MCI has been standardized.
Additional Information.
Please access these Web sites via the online version of this summary at
An essay by Matthews and colleagues, in the October 2007 issue of PLoS Medicine, discusses how mild cognitive impairment is currently diagnosed
The US Alzheimer's Association provides information about all aspects of Alzheimer disease, including fact sheets on treatments for Alzheimer disease and on mild cognitive impairment
The UK Alzheimer's Society provides information for patients and caregivers on all aspects of dementia, including drug treatments and mild cognitive impairment
The UK charity DIPEx provides short video clips of personal experiences of care givers of people with dementia
PMCID: PMC2082649  PMID: 18044984
16.  High prevalence of extrapyramidal signs and symptoms in a group of Italian dental technicians 
BMC Neurology  2007;7:24.
Occupational and chronic exposure to solvents and metals is considered a possible risk factor for Parkinson's disease and essential tremor. While manufacturing dental prostheses, dental technicians are exposed to numerous chemicals that contain toxins known to affect the central nervous system, such as solvents (which contain n-hexane in particular) and metals (which contain mercury, iron, chromium, cobalt and nickel).
We performed an epidemiological and clinical study on all 27 dental technicians working in a school for dental technicians. We asked all the technicians to fill in a self-administered questionnaire on extrapyramidal symptoms, and the General Health Questionnaire (GHQ), a self-administered screening instrument, to detect any psychiatric disorders. Moreover, we invited all 27 dental technicians to undergo a neurological examination and provide a detailed occupational history in our clinic.
Of the 14 subjects who underwent the neurological examination, four had postural tremor and one had a diagnosis of Parkinson's disease.
We found a high prevalence of extrapyramidal signs and symptoms in this group of male dental technicians working in a state technical high school in Rome. We believe that this finding may be due to the presence of toxins in the dental technician's work.
PMCID: PMC1988798  PMID: 17686154
17.  Cholinesterase Inhibitors: Drugs Looking for a Disease? 
PLoS Medicine  2006;3(4):e140.
Maggini and colleagues examine the evidence on cholinesterase inhibitors for treating dementia. "What seemed a biologically plausible intervention," they say, "has not led to a proven, real improvement in patients' well-being."
PMCID: PMC1434488  PMID: 16597173

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