ContextMild cognitive impairment (MCI) may be a precursor to dementia, at least
in some cases. Dementia and MCI are associated with neuropsychiatric symptoms
in clinical samples. Only 2 population-based studies exist of the prevalence
of these symptoms in dementia, and none exist for MCI.ObjectiveTo estimate the prevalence of neuropsychiatric symptoms in dementia
and MCI in a population-based study.DesignCross-sectional study derived from the Cardiovascular Health Study,
a longitudinal cohort study.Setting and ParticipantsA total of 3608 participants were cognitively evaluated using data collected
longitudinally over 10 years and additional data collected in 1999-2000 in
4 US counties. Dementia and MCI were classified using clinical criteria and
adjudicated by committee review by expert neurologists and psychiatrists.
A total of 824 individuals completed the Neuropsychiatric Inventory (NPI);
362 were classified as having dementia, 320 as having MCI; and 142 did not
meet criteria for MCI or dementia.Main Outcome MeasurePrevalence of neuropsychiatric symptoms, based on ratings on the NPI
in the previous month and from the onset of cognitive symptoms.ResultsOf the 682 individuals with dementia or MCI, 43% of MCI participants
(n = 138) exhibited neuropsychiatric symptoms in the previous month (29% rated
as clinically significant) with depression (20%), apathy (15%), and irritability
(15%) being most common. Among the dementia participants, 75% (n = 270) had
exhibited a neuropsychiatric symptom in the past month (62% were clinically
significant); 55% (n = 199) reported 2 or more and 44% (n = 159) 3 or more
disturbances in the past month. In participants with dementia, the most frequent
disturbances were apathy (36%), depression (32%), and agitation/aggression
(30%). Eighty percent of dementia participants (n = 233) and 50% of MCI participants
(n = 139) exhibited at least 1 NPI symptom from the onset of cognitive symptoms.
There were no differences in prevalence of neuropsychiatric symptoms between
participants with Alzheimer-type dementia and those with other dementias,
with the exception of aberrant motor behavior, which was more frequent in
Alzheimer-type dementia (5.4% vs 1%; P = .02).ConclusionsNeuropsychiatric symptoms occur in the majority of persons with dementia
over the course of the disease. These are the first population-based estimates
for neuropsychiatric symptoms in MCI, indicating a high prevalence associated
with this condition as well. These symptoms have serious adverse consequences
and should be inquired about and treated as necessary. Study of neuropsychiatric
symptoms in the context of dementia may improve our understanding of brain-behavior
relationships.

https://jamanetwork.com/journals/jama/articlepdf/195320/JOC20689.pdf

Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study.

Article abstract—Objective: To update the 1994 practice parameter for the diagnosis of dementia in the elderly. Background: The AAN previously published a practice parameter on dementia in 1994. New research and clinical developments warrant an update of some aspects of diagnosis. Methods: Studies published in English from 1985 through 1999 were identified that addressed four questions: 1) Are the current criteria for the diagnosis of dementia reliable? 2) Are the current diagnostic criteria able to establish a diagnosis for the prevalent dementias in the elderly? 3) Do laboratory tests improve the accuracy of the clinical diagnosis of dementing illness? 4) What comorbidities should be evaluated in elderly patients undergoing an initial assessment for dementia? Recommendations: Based on evidence in the literature, the following recommendations are made. 1) The DSM-III-R definition of dementia is reliable and should be used (Guideline). 2) The National Institute of Neurologic, Communicative Disorders and Stroke‐AD and Related Disorders Association (NINCDS-ADRDA) or the Diagnostic and Statistical Manual, 3rd edition, revised (DSM-IIIR) diagnostic criteria for AD and clinical criteria for Creutzfeldt‐Jakob disease (CJD) have sufficient reliability and validity and should be used (Guideline). Diagnostic criteria for vascular dementia, dementia with Lewy bodies, and frontotemporal dementia may be of use in clinical practice (Option) but have imperfect reliability and validity. 3) Structural neuroimaging with either a noncontrast CT or MR scan in the initial evaluation of patients with dementia is appropriate. Because of insufficient data on validity, no other imaging procedure is recommended (Guideline). There are currently no genetic markers recommended for routine diagnostic purposes (Guideline). The CSF 14-3-3 protein is useful for confirming or rejecting the diagnosis of CJD (Guideline). 4) Screening for depression, B12 deficiency, and hypothyroidism should be performed (Guideline). Screening for syphilis in patients with dementia is not justified unless clinical suspicion for neurosyphilis is present (Guideline). Conclusions: Diagnostic criteria for dementia have improved since the 1994 practice parameter. Further research is needed to improve clinical definitions of dementia and its subtypes, as well as to determine the utility of various instruments of neuroimaging, biomarkers, and genetic testing in increasing diagnostic accuracy.

https://n.neurology.org/content/neurology/56/9/1143.full.pdf

Practice parameter: Diagnosis of dementia (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

Background
** This review is awaiting update with a new protocol. The methods used for the review were acceptable when the review was published but do not meet contemporary standards, and the review is also considerably out of date. Therefore, readers should note that the review may not represent a reliable basis for decision making. **

Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.

The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the clinical manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed.

Objectives
To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease based on evidence summarised in three existing Cochrane Reviews

Search methods
The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases.

Selection criteria
All unconfounded, blinded, randomized trials of at least six months in which treatment with a ChEI at the usual recommended dose was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease.

Data collection and analysis
Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment, estimated.

Main results
The results of 10 randomized, double blind, placebo controlled trials demonstrate that treatment for 6 months, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.37 points (95%CI -2.73 to -2.02, p<0.00001), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large.

The effects are similar for patients with severe dementia, although there is very little evidence, from only two trials.

More patients leave ChEI treatment groups, (29%), than leave the placebo groups (18%).

There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo.

There is only one randomized, double blind study in which two ChEIs are compared, donepezil compared with rivastigmine.
There is no evidence of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine.

Authors' conclusions
The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. The evidence from one large trial shows fewer adverse events associated with donepezil compared with rivastigmine.

Cholinesterase inhibitors for Alzheimer's disease

ContextNeuropsychiatric symptoms of dementia are common and associated with
poor outcomes for patients and caregivers. Although nonpharmacological interventions
should be the first line of treatment, a wide variety of pharmacological agents
are used in the management of neuropsychiatric symptoms; therefore, concise,
current, evidence-based recommendations are needed.ObjectiveTo evaluate the efficacy of pharmacological agents used in the treatment
of neuropsychiatric symptoms of dementia.Evidence AcquisitionA systematic review of English-language articles published from 1966
to July 2004 using MEDLINE, the Cochrane Database of Systematic Reviews, and
a manual search of bibliographies was conducted. Inclusion criteria were double-blind,
placebo-controlled, randomized controlled trials (RCTs) or meta-analyses of
any drug therapy for patients with dementia that included neuropsychiatric
outcomes. Trials reporting only depression outcomes were excluded. Data on
the inclusion criteria, patients, methods, results, and quality of each study
were independently abstracted. Twenty-nine articles met inclusion criteria.Evidence SynthesisFor typical antipsychotics, 2 meta-analyses and 2 RCTs were included.
Generally, no difference among specific agents was found, efficacy was small
at best, and adverse effects were common. Six RCTs with atypical antipsychotics
were included; results showed modest, statistically significant efficacy of
olanzapine and risperidone, with minimal adverse effects at lower doses. Atypical
antipsychotics are associated with an increased risk of stroke. There have
been no RCTs designed to directly compare the efficacy of typical and atypical
antipsychotics. Five trials of antidepressants were included; results showed
no efficacy for treating neuropsychiatric symptoms other than depression,
with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTs
investigating valproate showed no efficacy. Two small RCTs of carbamazepine
had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors
generally showed small, although statistically significant, efficacy. Two
RCTs of memantine also had conflicting results for treatment of neuropsychiatric
symptoms.ConclusionsPharmacological therapies are not particularly effective for management
of neuropsychiatric symptoms of dementia. Of the agents reviewed, the atypical
antipsychotics risperidone and olanzapine currently have the best evidence
for efficacy. However, the effects are modest and further complicated by an
increased risk of stroke. Additional trials of cholinesterase inhibitors enrolling
patients with high levels of neuropsychiatric symptoms may be warranted.

/pdf/pharmacological-treatment-of-neuropsychiatric-symptoms-of-5fneydzs9c.pdf

Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence.

Background: Galantamine is a reversible, competitive cholinesterase inhibitor that also allosterically modulates nicotinic acetylcholine receptors. These mechanisms of action provided the rationale for a therapeutic trial of galantamine in AD. Methods: A 6-month, multicenter, double-blind trial was undertaken in 636 patients with mild to moderate AD. Patients were randomly assigned to placebo or galantamine and escalated to maintenance doses of 24 or 32 mg/d. Eligible patients then entered a 6-month, open-label study of the 24 mg/d dose. Primary efficacy measures were the 11-item AD Assessment Scale cognitive subscale (ADAS-cog/11) and the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). The Disability Assessment for Dementia (DAD) scale was a secondary efficacy variable. Results: Galantamine significantly improved cognitive function relative to placebo; the treatment effects were 3.9 points (lower dose) and 3.8 points (higher dose) on the ADAS-cog/11 scale at month 6 ( p p APOE genotype. At 12 months, mean ADAS-cog/11 and DAD scores had not significantly changed from baseline for patients who received galantamine 24 mg/d throughout the 12 months. The most common adverse events, which were predominantly gastrointestinal, decreased in frequency during long-term treatment. There was no evidence of hepatotoxicity. Conclusions: Galantamine is effective and safe in AD. At 6 months, galantamine significantly improved cognition and global function. Moreover, cognitive and daily function were maintained for 12 months with the 24 mg/d dose.

Galantamine in AD A 6-month randomized, placebo-controlled trial with a 6-month extension

Objective: To investigate the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. Methods: A 5-month multicenter, placebo-controlled, double-blind trial. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24 mg/day. Outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog), the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory. Standard safety evaluations and adverse event monitoring were carried out. Results: After 5 months, the galantamine–placebo differences on ADAS-cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group ( p Conclusions: Galantamine 16 and 24 mg/day significantly benefits the cognitive, functional, and behavioral symptoms of AD as compared with placebo. Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events.

P. R. Solomon

Papers

A 5-month, randomized, placebo-controlled trial of galantamine in AD