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1.  Mild cognitive impairment in clinical care 
Neurology  2010;75(5):425-431.
To assess how neurologists view mild cognitive impairment (MCI) as a clinical diagnosis and how they treat patients with mild cognitive symptoms.
Members of the American Academy of Neurology with an aging, dementia, or behavioral neurology practice focus were surveyed by self-administered questionnaire.
Survey respondents were 420 providers (response rate 48%), and 88% reported at least monthly encounters with patients experiencing mild cognitive symptoms. Most respondents recognize MCI as a clinical diagnosis (90%) and use its diagnostic code for billing purposes (70%). When seeing these patients, most respondents routinely provide counseling on physical (78%) and mental exercise (75%) and communicate about dementia risk (63%); fewer provide information on support services (27%) or a written summary of findings (15%). Most (70%) prescribe cholinesterase inhibitors at least sometimes for this population, with memantine (39%) and other agents (e.g., vitamin E) prescribed less frequently. Respondents endorsed several benefits of a diagnosis of MCI: 1) involving the patient in planning for the future (87%); 2) motivating risk reduction activities (85%); 3) helping with financial planning (72%); and 4) prescribing medications (65%). Some respondents noted drawbacks, including 1) too difficult to diagnose (23%); 2) better described as early Alzheimer disease (21%); and 3) diagnosis can cause unnecessary worry (20%).
Patients with mild cognitive symptoms are commonly seen by neurologists, who view MCI as a useful diagnostic category. Information and treatments provided to patients with MCI vary significantly, suggesting a need for practice guidelines and further research on clinical decision-making with this population.
= age-associated memory impairment;
= American Academy of Neurology;
= Alzheimer disease;
= cognitive impairment, no dementia;
= Diagnostic and Statistical Manual of Mental Disorders, 5th edition;
= mild cognitive impairment;
= not otherwise specified.
PMCID: PMC2918467  PMID: 20679636
2.  The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer’s disease 
The use of psychotropic medications in Alzheimer’s disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study.
A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory – Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates.
At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total.
Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.
PMCID: PMC3448859  PMID: 22374884
Alzheimer’s disease; antidepressants; antipsychotics; SSRI; cognition; psychosocial function; neuropsychiatric symptoms; epidemiology; pharmacoepidemiology
3.  Head circumference, atrophy, and cognition 
Neurology  2010;75(2):137-142.
Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference.
A total of 270 patients with AD participating in the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study underwent cognitive testing, APOE genotyping, and MRI of the brain in a cross-sectional study. Linear regression analysis was used to examine the association between cerebral atrophy, as a proxy for AD pathology, and level of cognitive function, adjusting for age, duration of AD symptoms, gender, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity. An interaction term between atrophy and head circumference was introduced to explore if head circumference modified the association between cerebral atrophy and cognition.
There was a significant inverse association between atrophy and cognitive function, and a significant interaction between atrophy and head circumference. With greater levels of atrophy, cognition was higher for individuals with greater head circumference.
This study suggests that larger head circumference is associated with less cognitive impairment in the face of cerebral atrophy. This finding supports the notion that head circumference (and presumably brain size) offers protection against AD symptoms through enhanced brain reserve.
= Alzheimer disease;
= brain reserve;
= cognitive reserve;
= Multi-Institutional Research in Alzheimer's Genetic Epidemiology;
= Mini-Mental State Examination.
PMCID: PMC2905931  PMID: 20625166
4.  MRI-measured atrophy and its relationship to cognitive functioning in vascular dementia and Alzheimer's disease patients 
Recent pathological studies report vascular pathology in clinically diagnosed Alzheimer's disease (AD) and AD pathology in clinically diagnosed vascular dementia (VaD). We compared magnetic resonance imaging (MRI) measures of vascular brain injury (white matter hyperintensities (WMH) and infarcts) to neurodegenerative measures (medial-temporal atrophy (MTA) and cerebral atrophy (CA)) in clinically diagnosed subjects with either AD or VaD. We then examined relationships among these measures within and between the two groups and their relationships to mental status.
Semi-quantitative MRI measures were derived from blind ratings of MRI scans obtained from participants in a research clinical trial of VaD (N=694) and a genetic epidemiological study of AD (N=655).
CA was similar in the two groups, but differences in the mean of MTA and WMH were pronounced. Infarcts were significantly associated with CA in VaD, but were not in AD; MTA and WMH were associated with CA in both. WMH was associated with MTA in both groups, however MRI infarcts were associated with MTA in VaD but not with MTA among AD patients. MTA was strongly associated with MMSE scores in both groups while evidence of a modest association between WMH and MMSE was seen among VaD patients.
MRI data from two dementia cohorts with differing dementia etiologies find that the clinical consequences of dementia are most strongly associated with cerebral and medial-temporal atrophy suggesting that tissue loss is the major substrate of the dementia syndrome.
PMCID: PMC3166967  PMID: 21723205
Alzheimer's disease; MRI; Dementia; vascular; Hippocampus; Atrophy
5.  Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients 
British Journal of Cancer  2011;104(12):1906-1912.
In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs.
Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival.
In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4–7.4, P<10−6) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9–21.7, P<10−17), but was not associated with patient survival. Concordant results were obtained in Newfoundland.
Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.
PMCID: PMC3111198  PMID: 21587258
colorectal cancer; methylation; Wnt; microsatellite instability
6.  The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease 
Gut  2010;59(10):1369-1377.
Background and aims
Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied.
Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours.
4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX).
Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.
PMCID: PMC3047452  PMID: 20682701
7.  Effects of Cardiovascular Medications on Rate of Functional Decline in Alzheimer Disease 
Evidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD.
In the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors.
CDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline.
In this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.
PMCID: PMC2676234  PMID: 18978249
Alzheimer disease; risk factors in epidemiology; medications; prognosis
8.  Slowly progressive apraxia in Alzheimer's disease. 
Slowly progressive apraxia due to Alzheimer's disease was encountered in a 66 year old, right handed man whose initial impairments included coordinated movements of the left hand and some features of the alien hand syndrome. Over four years, the patient developed progressively worsening deficits of memory and language. A biopsy of his right temporal lobe showed numerous plaques and neurofibrillary tangles. Pronounced right parietal lobe hypoperfusion on serial SPECT suggests involvement of this region in contralateral praxis.
PMCID: PMC486038  PMID: 7673964

Results 1-10 (10)