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Neuro- memory

Primary Care Corner with Geoffrey Modest MD: Chronic pain and dementia

8 Jun, 17 | by

by Dr Geoffrey Modest

​​The MMWR recently published the finding that the age-adjusted rates of Alzheimer’s deaths have increased in 41 states and the District of Columbia from 1999 to 2014 (see ).


— Alzheimer’s disease is the 6th leading cause of death United States, accounting for 3.6% of all deaths in 2014

— 93,541 Alzheimer’s deaths occurred in the US in 2014, at an age-adjusted rate of 25.4 deaths per 100K population. This represents a 54.5% increase over 1999, when the rate was 16.5 deaths per 100K (44,536 deaths).

— Most deaths occur in nursing home or long-term care facility (though this was a decrease from 67.5% in 1999, to 54.1% in 2014). The number of deaths in a hospital declined from 14.7% in 1999 to 6.6% in 2014,; the percent who died at home increased from 13.9% in 1999 to 24.9% in 2014. In addition, 6.1% died in a hospice facility in 2014.

— the specific Alzheimer’s death rate per 100K population increased among those to age 75 to 84 from 129.5 to 185.6 per 100K population, as well as in those >85 years old, from 601.3 to 1006.8 per 100K population.

— Overall, the death rates were higher among all age groups, both sexes, all races/ethnicities, urban/rural, and in almost every state. But they were particularly high for women and non-Hispanic whites

— age-adjusted rates for the 50 states and DC range from 7.0 to 29.8 per 100K in 1999, and from 10.7 to 43.6 per 100K in 2014


— this MMWR report is based on death certificates, which are not necessarily accurate and may be influenced by the prevailing culture and the US system of reporting.  In particular, the death certificate-based data derive from what the patients’ clinicians decide is the major cause of death, which in my experience is often a best-guess after the fact. and this is likely influenced by several nonclinical factors, including the acceptability of Alzheimer’s disease itself as a cause of death (which may have increased in this time period, at least partly explaining the noted increase), or even the influence of the funeral home directors. In addition, there may be very real issues with deciding if Alzheimer’s is truly the responsible condition: the definitive diagnosis is in fact histopathologic, though there are clinical definitions of reasonable accuracy, but many clinicians may be hesitant to use this label (is it truly accurate??) and avoid coding it; also, at what degree of cognitive impairment does it reach the threshold to go on a death certificate? (and that threshold is likely very different from one clinician to another)

— And, this increased incidence of Alzheimer’s also raises the question of potentially modifiable factors in the development of Alzheimer’s, which may have changed over time. For example, obesity, diet, physical activity, perhaps medications, and levels of education have been found to be associated with Alzheimer’s. See blogs 

— one profound implication of an increasing incidence of Alzheimer’s disease is the tremendous effects on others, and especially the paid and unpaid caregiver burden. And this stresses the need for additional resources to educate and train caregivers in the care of Alzheimer’s patients, as well as providing respite care and case management



another article just came out suggesting an association between persistent chronic pain and memory decline/dementia, in a longitudinal cohort of elders (see doi:10.1001/jamainternmed.2017.1622).



–10,065 community-dwelling older adults in the Health and Retirement Study, who were at least 62 years old in 2000 and answered questionnaires on pain and cognition; they were followed through 2012 with sequential questionnaires

— 60% female, median age 73 at baseline.

— 10.9% had persistent moderate-to-severe pain at baseline (n= 1120), 76% female (versus 58% female in the nonpain group), 86% white/8% black/5% Hispanic, 58% ever-smokers, 45% nonmarried/non-partnered

— comorbidities (all with differences with p<0.001): hypertension (61% in pain group, 48% comparison)/diabetes (20% pain, 14% comparison) lung disease (14% pain, 8% comparison), heart disease (37% pain, 25% comparison), stroke (13% pain, 8% comparison), depression (50% pain, 20% comparison), alcohol use (less in pain group overall, 68% reporting none versus 53% in comparison), difficulty doing more than 1 ADL (46% pain, 12% comparison)

— primary outcomes included memory score (a compilation of several cognitive tests, by the patient or proxy) and dementia probability score (a different cognitive test which estimates the chance that an individual would reach the DSM3 or 4 diagnostic criteria for dementia

–the fully adjusted model controlled for: demographic measures (age, sex, race/ethnicity), education level, current or former tobacco use, medical comorbidities of self-reported hypertension/diabetes/cancer/chronic lung disease/heart disease/stroke, household financial status, marital status, current alcohol use, and depressive symptoms


— of the elderly who reported pain on the initial intake evaluation, 69% reported pain subsequently (persistent pain)

— after covariate adjustment, persistent pain was associated with a 9.2% (2.8% – 15.0%) more rapid memory decline as compared to those without persistent pain

— after 10 years, there was a 15.9% higher relative risk of inability to manage medications, and 11.8% higher relative risk of inability to manage finances independently

— adjusted dementia probability increased 7.7% faster (0.55%-14.2%) in those with persistent pain, an absolute 2.2% increase in dementia probability


— the prevalence of chronic pain increases with age, affecting 25 to 33% of older adults. Also the recovery from chronic pain is less likely in older people. Older people with chronic pain are also more likely to be consumed by their chronic pain, reporting pain as affecting their subjective health status

— pain in the elderly has been reported to be more likely to be associated with falls, functional impairment, and cognitive decline/dementia in prior studies. But these are largely cross-sectional, observational studies at a point in time, and not a longitudinal study as above.

–although there are some very important advantages of the current longitudinal study, there are some evident limitations in terms of the extent of the data collected:  lack of data on the source/site of the persistent pain, or even of  the degree of the medical or psychological comorbidities. Also, there were very significant differences in the baseline characteristics of those with and without persistent pain, both medical and psychosocial (especially for depression and impaired ADLs, but also for all of the major medical comorbidities), or even the medications or other therapies prescribed. So, even though they adjusted for many potential confounders, they really did not have the database to control well for them, and there are likely other unknown (and therefore uncontrolled) factors involved.

— there were also no data specifically on the types of pain medications given. There is concern that use of opioids, for example, might affect cognition, perhaps exacerbated by concomitant disability, depression, etc. However, another study of patients with chronic pain getting NSAIDs found about the same amount of cognitive effect as with opioids. I would however add that several of the adjuvant pain medications (gabapentin, pregabalin, tricyclics, etc) may have significant effects on cognition. and SSRIs or SNRIs themselves, if used to treat depression or pain, can also affect cognition (studies are mixed on this)

–there is a plausible mechanism for the association of persistent pain and cognitive decline. Stress, depression, and even sleep deprivation have been found to affect cortisol secretion, and perhaps through that, can lead to neurologic changes, including decreased neuronal density/function in the hippocampus, with decreased ability to form new memories.

–and there may be other associated changes in those with persistent pain which were not accounted for but could affect cognitive health: eg, physical exercise, diet (ability to shop, cook food, etc), limitations in social interactions/increased social isolation


so, though these studies are both significantly flawed, it is clear that dementia is really prevalent, that it is likely increasing overall and especially so as the population ages, that there are very significant medical and social costs (especially on the caregivers), that many lifestyle measures likely provide benefit (as per prior blogs, see below), and that chronic pain by itself may be associated with the increased incidence and progression of dementia.  In this latter case, I think it is important, especially in the elderly, to treat pain but preferably with nonsystemic medications, avoiding the multitude of toxic effects of NSAIDs (cardiac, renal, GI, etc, to which the elderly are likely more susceptible), opiates, and the typical adjuvants (gabapentin, tricyclics, etc). Perhaps it is best to treat with physical therapy and psychosocial therapies (cognitive behavioral therapy, mindfulness therapy, stress reduction therapies, etc) and/or with injections or topical medications. and, as I have mentioned many times, injections into joints, trigger points, muscle spasms, etc often really help the pain and improve the function, often for a very long time.



blog on article finding that prescribing opiates to the elderly is associated with subsequent opiate dependence

article on cognitive behavioral therapy for low back pain

study on tai chi and another on mindfulness for chronic pain

Primary Care Corner with Geoffrey Modest MD: Sugary beverages and Alzheimer’s

4 May, 17 | by

​​​The second study from the Framingham Study Offspring cohort database found that increased intake of sugary sweet beverages was associated with lower total brain volume by MRI and poorer performance on neuropsychological testing (see ). For first study, see here


–4276 participants had neuropsychological testing and 3846 had brain MRI imaging

–mean age 54, 46% male, 21% high school degree/31% some college/46% college grads, systolic BP 121 mmHg/17% on BP treatment, total chol 194/HDL 57, 8% diabetes, 2% atrial fibrillation, 10% current smoker, waist-to-hip ratio 0.9 (the WHO defines abdominal obesity as >0.90 for men and >0.85 for women)

–total consumption of sugary beverages:

–< 1x/d in 56%

–1-2 x/d in 29%

–> 2x/d in 15%

–31% consumed fruit juice ≥​​ 1x/d

–diet soft drinks were consumed more regularly than sugar-sweetened ones:  49% no diet soft drinks, 35% up to 6/wk, 16% ≥​​ 1/d

–total calorie intake 1942 cal/d, but increased from 1782 in those consuming <1 sugary beverage/d, to 2007 if 1-2/d, to 2413 if >2/d; similarly, saturated fat increased from 22 to 24 to 27 g/d


–as compared to consuming <1 sugary beverage/day, higher intake was associated with:

–lower brain volume (more so if >2/d than1-2/d)

–poorer performance on memory tests: both immediate and delayed recall

–lower hippocampal volume, borderline significant [the hippocampus is the part of the brain that consolidates short-term information into long-term memory]

–daily fruit juice intake was associated with:

–lower total brain volume, hippocampal volume, and poorer immediate and delayed recall

— however, none of these associations reached statistical significance in the most highly adjusted model, which included not just age, sex, caloric intake, education, blood pressure, smoking, cardiovascular disease, or cholesterol, but also included saturated fat, trans fat, dietary fiber, and physical activity.

— Diet soft drinks had only a small effect on total brain volume and on poor performance on the test of similarities but not other memory tests.

— Essentially no difference in subclinical markers of vascular brain injury (silent brain infarcts and white-matter hyperintensity volume)


–11 million metric tons of sugar were consumed by Americans in 2016 (per the US Dept of Agriculture)

–a recent blog  highlighted the remarkable statistic that “on average 26.3% of US adults consume at least one sugar-sweetened beverage daily, up to 41.4% in Mississippi, the highest of states, and that soda by itself was consumed by 24.5% of those 18-34 yo, and 47.4% in Mississippi). And a NHANES study (Welsh JA. JAMA 2010; 303(15): 1490) found that on average, 15.8% of calories came from added sugars, and that >25% of the patients got >25% of their total energy from added sugar.”

— Interestingly, there was not much of an association between sugar intake and vascular brain injury, despite studies showing that sugar consumption is associated with cardiovascular disease. Instead the current study found a more profound association with several markers of preclinical Alzheimer’s disease. This is also found in mice, where sucrose intake is associated with increased tau phosphorylation, amyloid-beta aggregation, hippocampal atrophy, and reduced brain-derived neurotrophic factor, BDNF. In the Framingham study cohort, these researchers have found that one standard deviation increase in BDNF was associated with a 33% lower risk of Alzheimer’s disease, suggesting that BDNF might be a factor in mediating the association between dietary sugar and Alzheimer’s. Other studies have found that impaired glucose tolerance and chronically elevated blood glucose are associated with poor memory, perhaps related to changes in the hippocampal volume and microstructure

— as a clinical perspective, daily fruit juice intake was equivalent to 1.5 years of brain aging in terms of  total brain volume and 3.5 years of brain aging for the delayed memory scores. And, relative to no intake, consuming more than 3 sugar-sweetened soft drinks per week was associated with lower brain volume equivalent to 2.6 years of brain aging, and lower immediate memory recall equivalent to 13.0 years!!!

— this trial also highlights the potentially bad effects of fruit juice, noting that the general public underestimates the sugar content of fruit juice by an average of 48%, even though 100% fruit juice, without added sugar, contains lots of fructose with negligible fiber content

— see here which reviews the sordid (ie not so sweet) history of the sugar industry in promoting sugar and shifting the blame away from sugar in increasing heart disease, dental caries, etc, since the 1950s, despite lots of scientific evidence to the contrary
–and, a couple of more references on lifestyle and cognitive function:

— lower adherence to a Mediterranean diet has been associated with increased brain volume loss, supplementing other studies finding higher incidence of clinical dementia related to lifestyle issues, especially diet and exercise (see review)

​– a just published systematic review/meta-analysis of exercise interventions for cognitive function in adults older than 50, found that physical exercise improved cognitive function regardless of the cognitive status of the participants. This was true for both aerobic and resistance exercise of at least moderate intensity with the duration of 45 to 60 minutes per session, done on as many days of the week as feasible (see doi.10.1136/bjsports-2016-096587.)

so, these 2 articles (including the earlier one) confirm and extend the bad health effects of excess sugar and artificial sweeteners to include adverse effects on cognition and stroke. These studies are observational ones from the Framingham Heart Study, and therefore do not definitively confirm causality, but they do add to the growing literature on their adverse effects on the brain. And, in terms of lifestyle interventions, over the years I have found that it is much easier to help people stop sodas and juices, substituting water, than other dietary interventions.​ The low-hanging fructose….

Primary Care Corner with Geoffrey Modest MD: Stroke and dementia, and artificial sweeteners

2 May, 17 | by

by Dr Geoffrey Modest

Two studies came out from the Framingham Heart Study database by the same authors in 2 different journals, one on the association between consuming artificially-sweetened beverages and the later development of stroke and dementia, and the other on sugary beverages and preclinical Alzheimer’s disease. I will divide these into 2 blogs.

An evaluation of the Framingham Heart Study Offspring cohort, with data from 1971 and evaluated over 9  examination cycles, found that artificially-sweetened soft drink consumption was associated with a higher risk of stroke and dementia (see DOI: 10.1161/STROKEAHA.116.016027).



— 2888 participants >45yo were evaluated for incident stroke;  1484 who were >60yo were evaluated for incident dementia

— mean age 62 for the younger group and 45% men, 69 for the older group and 46% men

— beverage intake was quantified at cohort examinations 5 (1991-5), 6 (1995-8), and 7 (1998-2001). Total sugar-sweetened beverages included soft drinks, fruit juice, and fruit drinks.

— surveillance for incident events began at examination 7 and continued for 10 years

— there were 97 cases of incident stroke (82 ischemic), and 81 cases of incident dementia (63 consistent with Alzheimer’s)



— controlling for age, sex, education (for the dementia cohort), calorie intake, diet quality, physical activity, and smoking; when compared to a daily cumulative intake of 0 artificially-sweetened drinks per week:

— hazard ratio for ischemic stroke was 2.96 (1.26-6.97), p=0.01 (ie, about 3x higher). Relationship was strongest for ischemic stroke

— hazard ratio for Alzheimer’s disease 2.89 (1.18-7.07), p=0.02. There was also an association with all-cause dementia of similar magnitude, 2.47 (1.15-5.30), p=0.02. Both were statistically significant in the group having at least one drink per day.

— sugar-sweetened beverages were not associated with the stroke or dementia, only artificially-sweetened soft drinks

— the curves for event-free survival for both of these outcomes continued to decrease through year 10 (i.e. it was not plateauing), and there was a dose-response curve with the more artificially-sweetened soft drinks, the lower the event-free survival

— there was no interaction in the above analyses with waist-to-hip ratio, diabetes mellitus, or with the presence of apolipoprotein E4

— there was not much change in the associations when excluding diabetes from the analysis, given the potential interaction of those with diabetes drinking more artificially-sweetened beverages (diabetes was found to be only a partial mediator of the association).



— the Nurses’ Health Study and Health Professionals Follow-Up Study both reported a higher risk of incident stroke with greater consumption of sugar-and artificially-sweetened beverages. The above study is reported to be the 1st showing association between artificially-sweetened drinks and an increase in both all-cause dementia and Alzheimer’s.

— The above study predated the approval of Stevia

— there are studies which have shown that artificial sweeteners cause glucose intolerance in mice by altering the gut microbiome, and they are associated with glucose intolerance in humans. See here for a detailed review of these animal and human studies.

— Generalizability of these results: the Framingham study served as a model for epidemiologic studies given its long-term nature (began in 1948) and in the regular intensive follow-ups done over the years. However, it was limited by the lack of ethnic variation. It also was an observational study which limits drawing conclusions regarding causality.


So, bottom line (again): these no-calorie artificial sweeteners seem to be associated with significant problems, including glucose intolerance (despite the fact that we used to push diabetic patients to drink these over regular sodas). And there are suggestive data that they do not help even with weight loss (see here ). so, all in all, we should be promoting water as the best drink….

Primary Care Corner with Geoffrey Modest MD: 23andMe genetic analysis approved for direct advertising

20 Apr, 17 | by

 by Dr Geoffrey Modest

The FDA just approved direct-to-consumer marketing for genetic risk information (23andMe Personal Genome Service Genetic Health Risk) for 10 conditions, though noting that “the tests cannot determine a person’s overall risk of developing a disease or condition … there are many factors that contribute to the development of a health condition, including environmental and lifestyle factors.” This approved test involves saliva samples, assessing more than 500,000 genetic variants associated with increased risk of: Parkinson’s disease, late-onset Alzhemer’s, Celiac disease, Alpha-1 antitrypsin deficiency, Early-onset primary dystonia, Factor XI deficiency, Gaucher disease type 1, Glucose-6-phosphate dehydrogenase deficiency, Hereditary hemochromatosis, Hereditary thrombophilia. see

The FDA reviewed the data for 23andMe through a premarket review pathway for low-to-moderate risk devices, with expectations about assuring test accuracy, reliability and clinical relevance, and also to make sure the results be clearly understandable by consumers. But the FDA now intends to exempt further tests added on by 23andMe from further premarket review, and may well exempt other genetic testing companies after submitting their first premarket notification.  These exemptions “would allow other, similar tests to enter the market as quickly as possible and in the least burdensome way”. [and, I might add, this is before confirmation of Trump’s pro-industry FDA nominee Scott Gottlieb, who has “received millions of dollars from various investment and pharmaceutical firms” per Bloomberg Technology…..]

Statnews had a really impressive review of the 23andMe test, at the cost of $199, revealing many of its limitations (see​ ). For example, they note that those having the specific variant for Parkinson’s disease tested increases their risk 3-fold, from a baseline of 0.3% to 1%…. Or, that those with Apo ℇ4 alleles may not get Alzheimer’s, and those without it may (the frequency of the Apo ℇ4 allele varies by ethnicity, 15% in Caucasian, 25% African-Americans; the presence of one allele increases the risk of Alzheimer’s by 2-3 fold, and two alleles by 8-12 fold).  So, the presence of a genetic variant, either for the Parkinson’s gene or if only 1 allele of Apo ℇ4, still makes the development of the disease unlikely (and actually rare, in the Parkinson’s case). And still about 10% or so of those who are homozygous for Apo ℇ4 do not get dementia.


–the big issues here, to me, are:

–these tests may well have pretty low sensitivity and specificity, as well as low positive predictive value

–patients may have trouble understanding the wording: 3x higher incidence of Parkinson’s sounds like a lot, but the actual 1% incidence not so much. Can be very confusing

–and, there are real concerns about the psychological effects of finding out one has a somewhat higher likelihood of a bad disease for which there is no current treatment. Will there be more depression, anxiety, decreased social cohesion/more isolation, hopelessness/even suicide?

–focusing on the genes undercuts the very important role of environmental/lifestyle factors: it really reinforces the conceptual deterministic framework that one’s future is set by one’s genes, undercutting the oftentimes dominant message that our environment and lifestyle are really important

–and it reinforces the conception that technology is the answer to our ills…



Some recent article on dementia are tangentially related to the above.

–The WHO reported that dementia deaths have increased, unseating AIDS as one of the top killers in the world (see ), and taking over the number 7 slot of the top 10 causes of death. And, as per this article in Bloomberg News, about 100 experimental treatments for dementia have failed to make matters better. Part of the issue causing the “elevation” of dementia is the aging population and probably that it is more often diagnosed now. But, so far, drugs do not seem to be the answer

–in this light, and complementing the above point that genes often do not play a decisive role, there was a recent study finding that lower adherence to a Mediterranean diet was associated with more significant loss of brain volume (see Luciano M. Neurology 2017;88:1)..

–Background: increased adherence to Mediterranean diet (lots of fruits, veges, legumes, cereals, olive oil as primary fat, moderate consumption of fish, low to moderate intake of dairy and wine, and low intake of red meat and poultry) is associated with less inflammation, better cognitive function, and lower risk of Parkinson’s and Alzheimer’s, as well as cardiovascular and cancer mortality. And cross-sectional studies have found higher consumption of components of the Mediterranean diet are associated with larger MRI-based brain volumes and cortical thickness. Higher fish and lower meat intake seemed to be the most important players.

–The current study was a prospective one of 562 Scottish men and women, assessing diet and brain structural changes from age 73 to 76

–50% female, 30% Apo ℇ4 positive, 4% diabetic/38% hypertensive/22% cardiovascular disease/BMI 28

–baseline cognitive ability: Mini-Mental Status Exam 29 (30=max, so no significant baseline dementia), and they assessed reading ability and general cognitive ability which relates to IQ (no comment on the scales they used or their validity). Diet was assessed only at baseline, age 70.

–change in brain structure from age 73 to 76:

–total brain volume: decreased 19 ml (from 990), gray matter volume decreased 9 ml (from 465), mean cortical thickness decreased 0.05 mm (from 3.11 mm)


–the group with highest adherence to Mediterranean diet had more carriers of Apo ℇ4 alleles (reason for this unclear in this healthy population who did not have underlying dementia), yet had greater total brain volume and gray matter volume at age 76

–in the fully adjusted model (controlling for those factors found in prior studies related to Mediterranean diet and brain MRI measures: age, sex, education, BMI, diabetes, general cognitive ability, MMSE), there was significant association between Mediterranean diet components and total brain volume change between age 73 to 76 (p=0.04), and presence of Apo 4 genotype did not change this. Fish and meat consumption were not found to be the drivers of this association. [perhaps it is a different combination, or even the all of the components together: parsing out specific components may be a tad reductionist and undercut potential interactions between the individual components. Better to eat well overall]


–so, there was a significant association between the diet and brain volume changes over this 3-year period

–and, the effect size of the Mediterranean diet on brain volume was substantial: half the size of that due to normal aging

​–of course, this was not a randomized controlled trial, so there could well be confounders (do those choosing to adhere to a more Mediterranean-type diet do other, unmeasured healthful things that may really be the ones that decrease cognitive decline, such as exercise??)

but, all in all, this study supports the concept of environmental/lifestyle factors being really important in the development of Alzheimer’s/cognitive decline, that this appeared to be  independent of the known genetic risk factor of Apo ℇ4​​, and adds to the argument against a genetic-determinant view of the development of this important condition (as is conceptually promoted by 23andMe etc)


Primary Care Corner with Geoffrey Modest MD: Intervention to Delay Functional Decline in Dementia

15 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A recent review was done which looked at 23 systematic reviews (i.e., a systematic review of systematic reviews) of interventions to delay functional decline in patients with dementia, finding a few nonpharmacologic (exercise, dyadic interventions) and a few pharmacologic ones (especially donepezil and memantine) seemed to be effective (see doi:10.1136/bmjopen-2015-010767).


  • Background re: dementia
    • 6 million people are affected by dementia worldwide, including 5-7% of those >60yo
    • One of the leading causes of morbidity and mortality
    • Huge personal and social costs: reduced quality of life, increased care burdens on family, increased costs to society to provide supportive and medical care
  • Interventions:
    • Most patients in the reviews had mild-to-moderate dementia, 65% with any type of dementia and rest with Alzheimer’s
    • Nonpharmacologic (11 reviews).
      • Exercise (6 studies, 289 people, standardized mean difference (SMD) of those doing exercise was 0.68: the largest magnitude of effect of any intervention, though studies considered low quality because of risk of bias.
      • Dyadic interventions (interventions targeted to patient and caregiver to maximize the patient’s quality of life and meaningful activities): 8 studies, 988 patients, SMD 0.37. Somewhat mixed findings in the studies, and many with risk of bias, so considered low quality evidence
      • Those not reaching statistical significance included: cognitive training, cognitive stimulation therapy, light therapy, aromatherapy, nutritional supplements, validation therapy, psychological treatment, or music therapy
    • Pharmacologic (reviews)
      • Acetylcholinesterase inhibitors and memantine (12 studies, 4661 patients, including a variety of meds and doses: e.g. donepezil 5 or 10mg, galantamine 24mg, and rivastigmine 12mg): a pretty small but significant effect, with SMD in the 0.15-0.20 range). Moderate quality of evidence.
      • Selegiline also had small effect on Activites of Daily Living (ADL) function after 8-17 weeks (7 studies, 810 patients, SMD 0.27)
      • Other therapies (meds for sleep, latrepirdine, melatonin, statins, lecithin, nimodipine, acupuncture, vitamin B supplements) were ineffective. Gingko biloba and Huperzine A did have effect (which was really remarkable for Huperzine A, with SMD of 1.48), but these treatments had such low quality that they could not be recommended, and the latter one was based on 2 studies with a total of 70 people). The studies on Ginko Biloba were more extensive (7 studies with 2530 people, SMD 0.36), the quality was very low and the studies had mixed results.


  • These types of reviews clearly are pretty large-scale data mining of studies of variable quality looking at different people (ages, types and severity of dementia), different interventions within the subgroups (different exercises, etc.), different outcomes measured (memory changes, or perhaps the more clinically/socially-relevant changes in ADL), sponsors (drug company vs not), sites (community-dwelling vs in institution), and qualities of the studies (as measured by the AMSTAR tool, assessing protocol data extraction, comprehensiveness, data synthesis, biases, documentation of conflicts of interest,…). But that’s all we got. Though I should mention again that unfortunately there are fewer studies and fewer patients in the non-pharmacologic arena, likely because of less available funding (most studies being funded by drug companies), with about ten-fold more patients in the pharmacologic studies reviewed.
  • Perhaps not so surprisingly, the two standouts here are exercise and dyadic therapies. In my limited experience, I have found that social day programs (these are adult day centers that I have many patients attend, with patients having social interactions, social activities, exercise, and some help with training family members in the care of patients) are really effective. I do need to lapse into one very recent anecdotal experience: a 78yo man who recently retired and after a short period of time, was forgetting how to find his house when either walking or driving (he soon stopped driving). I did start him on antidepressants, but the social day program was pretty immediately effective in both improving his mood dramatically and also improving his memory back to his baseline. Though I can’t draw unequivocal conclusions, I do find that overall one of the most important clinical interventions I do for my somewhat isolated older patients is to get them into these types of programs, encourage them to do more exercise, and help/support /get services for their caregivers.
  • So, bottom line to me: the most effective therapies for mild-to-moderate dementia (and perhaps those with the least potential for adverse effects) seem to be exercise and helping the patient/caregivers provide the most useful interventions to improve the ADLs, provide meaningful activities for the patient, etc.

Primary Care Corner with Geoffrey Modest MD: PPI Use and Dementia

25 Feb, 16 | by EBM

By Dr. Geoffrey Modest

A ​pharmacoepidemiological analysis, based on claims data, found an association between taking proton pump inhibitors (PPIs) and the risk of dementia in the elderly (see doi:10.1001/jamaneurol.2015.4791).


  • An observational database from 2004-2011 from the largest Germany health insurer insuring 1/3 of the population and 50% of the elderly, was used to assess inpatient and outpatient use of PPIs
  • 73679 participants, >=75yo and free of dementia at baseline. 2950 were on regular PPIs (mean age 83.8, 78% female), compared to 70,729 patients (mean age 83.0, 73.6% female)
  • 29510 patients received a diagnosis of dementia over the course of the study period (40% of the cohort)
  • Regular PPI use was defined as a prescription for a PPI each quarter of an 18-month interval during the study period


  • Those on PPIs had a 44% increased risk of incident dementia [HR 1.44 (1.36-1.52), p<0.001]
    • For males, HR 1.52 (1.33-1.74)
    • For females, HR 1.42 (1.33-1.51)
  • Other associations with dementia included: depression (HR 1.28), stroke (HR 1.37), and to a lesser extent, female sex (HR 1.15), diabetes (HR 1.05), polypharmacy (HR 1.16); all statistically significant
  • ​But, controlling for all these potentially confounding factors actually led to a higher association of dementia with PPI use [HR 1.66 (1.57-1.76)]
  • And, controlling for use of anticholinergics, itself a risk factor for dementia with its own HR of 1.80, did not change the association with PPIs (HR was still 1.44)
  • Looking at those patients who only occasionally used PPIs, there was a lower but significant HR of 1.16 (1.13-1.19).
  • Difference by type of PPI used: omeprazole had HR 1.51, pantoprazole HR 1.58, but somewhat higher with esomeprazole with HR 2.12
  • ​There was a slight decreasing effect with age: those 75-79 had HR 1.69, those 80-84 had HR 1.49 and those >84 had HR 1.32 (all significant)

A prior study by the same group, AgeCoDe (the German Study on Aging, Cognition and Dementia in Primary Care Patients), included 3327 community-dwelling persons >= 75 yo with 18-month neuropsychological assessments similarly found incident dementia to be associated with PPI usage, and with a similar HR of 1.38 (1.04-1.83), and with somewhat more dementia in the group on esomeprazole. All PPI associations controlled for age, sex, educational level, apoE4, depression, diabetes, stroke, ischemic heart disease, and polypharmacy.

So, this was a large computer-based study finding an association between PPI use and dementia; therefore it is not confirm a causal relationship. But a few points:

  • There is biological plausibility:
    • Mouse models find that PPIs increase the levels of b-amyloid in their brains, by affecting the enzymes b- and g-secretase; PPIs also could decrease the degradation of b-amyloid by lysosomes, which are pH-dependent, in microglia (and some PPIs cross the blood-brain barrier). Also, PPIs bind to tau.
    • PPIs are associated with vitamin B12 deficiency through malabsorption, and vitamin B12 deficiency is associated with cognitive decline
  • This study adds to the potential adverse effects of PPIs (see blogs below for some other problems with PPIs)
  • Of course, this study only finds an association. As above, they tried to account for many of the covariates for dementia (stroke, polypharmacy, depression, etc.), and they also found that there was not much difference in use of the health care system (all suggesting, but not proving, that the PPI-users and non-users were pretty similar in dementia risk). But the data are not so granular: i.e., even if the level of polypharmacy is the same in both groups, did those on PPIs might have more specific drugs that could affect cognition? And what about cigarette use, alcohol, or obesity which may be over-represented in the PPI-user group and may themselves be associated with dementia?
  • So, I think there are a couple of lessons here:
    • It is always important to remember that very few drugs really are targeted specifically to a single action. One might think (as perhaps most of us did) that a drug targeting acid release from the stomach’s parietal cells would not have potential widespread effects (other than collateral damage on nutrient absorption, etc.). The finding of clear effects on b-amyloid in mice brains and the potential effects of PPIs on human brains yet again brings us to the usual conclusion: use medications in their lowest dose and only if necessary, with an emphasis on helping patients try to make lifestyle changes as the primary approach to many medical problems.
    • As mentioned in prior blogs, it is really easy to just keep refilling PPI prescriptions since they work and it is sometimes a struggle to change paths with patients, and we often are quite busy just keeping up with the other more active medical problems. I.e., the approach of step-down therapy (moving from PPI to H2-blocker or just calcium) is in reality not done much in clinical practice. Which I think supports more of a step-up approach (staring with calcium then escalating to H2 blocker prior to PPI).

For a few of the recent blogs on PPIs, see which looks at microbiome changes with gastric acid suppression which looks at the possible association of PPIs with MIs found an association of PPIs with chronic kidney disease

Primary Care Corner with Geoffrey Modest MD: Lifestyle Interventions and Cognition

14 Dec, 15 | by EBM

By Dr. Geoffrey Modest

There have been several recent articles on interventions to prevent cognitive decline, including

  1. An op-ed piece in the NY Times (see​ ) . A few of their points, expanded a bit with the references:
  • A 6-week on-line study with 11,430 participants trained several times a week on cognitive tasks: there were 3 groups–one with 6 training tasks emphasizing reasoning, planning and problem-solving; another group was exposed to a broader range of cognitive tasks including tests of short-term memory, attention, visuospatial processing and mathematics, as is found in commercially available brain training devices; and a control group who did not do specific cognitive tasks but answered obscure questions using online resources (i.e., like Google). They found that each of these tasks improved through this training, but “no evidence was found for transfer effects to untrained tasks, even when those tasks were cognitively closely related” – i.e., there is no evidence that regular use of computerized specific cognitive tasks improves general cognitive function (see Nature. 2010 June 10; 465: 775)
  • Exercise does seem to help:
    • Mice who have regular exercise have more neurons in their hippocampus (that is the site where new memories are formed and converted to long-term memories, and one of the first sites affected by Alzheimer Disease (AD)
    • A small study of 86 women with subjective memory complaints were assigned to 3 groups: resistance training, aerobic training, or balance/tone (the control group). Those in the aerobic training group remembered more items; both aerobic and resistance training led to better spatial memory performance; and there was a significant correlation between spatial memory performance and overall physical capacity (see doi: 10.1155/2013/861893)
    • A study of 155 community-dwelling women 65-75 yo were randomized to resistance training vs balance/tone (control group) and found that resistance training reduced the progression of brain MRI white matter lesions (which are associated with cognitive impairment, and are markers of cerebral small-vessel disease — see J Am Geriatr Soc 2015; 63(10): 2052)
  • They note that BNDF levels (brain-derived neurotrophic factor, which is released in response to neuronal activity) are associated with brain size and function, and is increased with exercise (more below).
  1. A JAMA perspective on mitigating cognitive decline (see doi:10.1001/jama.2015.15390​)
  • In assessing >1200 brains in 2 different aging studies, there was not a great correlation between anatomic findings and cognitive health:
    • The Rush Memory and Aging Project  [Curr Alzheimer Res. 2012; 9(6): 646] of 1556 elders without dementia enrolled from retirement communities beginning in 1997, tracked cognitive function, relying on clinical diagnoses and an array of 21 cognition tests, found that:
      • Physical activity was associated with cognition
      • Incident Alzheimer dementia (AD) was associated with a decline in motor function
      • Social engagement (social activity and support) was associated with global cognition and a slower rate of cognitive and motor decline and disability
      • But at autopsy, the correlation between anatomic changes and cognition were not great: 90% of those meeting clinical criteria of AD did meet pathologic criteria for AD, but 1/2 of those with mild cognitive impairment and 1/3 of those without cognitive impairment also met pathologic criteria for AD.
    • The Religious Orders Study [Curr Alzheimer Res. 2012; 9(6): 628], a study from 1994-2011 of 1162 Catholic nuns, priests, and brothers from 40 groups across the US initially without dementia, similarly used a battery of 21 cognitive tests, also found the same relatively poor correlation as the Rush study between anatomic pathology and AD.
    • ​And, overall overt brain pathology accounted for only 1/2 of the cognitive decline documented
  • Animal studies support the role of BDNF in improving neuronal survival and function (especially in the hippocampus and cortex), and improve synaptic plasticity and long-term memory. Human epidemiologic studies find a correlation between low BDNF levels and AD (though unclear which came first). In this light the community-based Framingham Study was reviewed to see if higher BDNF levels in cognitively healthy adults seemed to protect against future development of AD, found that in 10 years of followup, 140 people developed dementia (117 with AD), and each SD increase in BDNF levels was associated with a 33% decreased risk of dementia overall and AD in particular. Comparing the top to bottom quintile of BDNF levels, there was a 51% decrease in risk of dementia (HR49, p=0.01) and AD (HR.46, p=0.02),  specifically in subgroups of women, people >80 yo and those with college degrees (see  JAMA Neurol. 2014; 71(1): 55)
  • Depression is associated with lower BNDF levels and more hippocampal shrinkage, and antidepressants block the depression-induced drop in BDNF.
  • And what increases BDNF levels??? Increased physical activity, reduced caloric intake, social support (and lack thereof is associated with lower BDNF levels). A review found that aerobic exercise increases BDNF as well as improves hippocampal atrophy, improves memory function, and reduces depression [see Neuroscientist 2012: 18(1): 82].  By the way, there are also data showing exercise is associated with decreases in b-amyloid in a transgenic Alzheimer mouse model.
  • Increased BDNF also reduces risk of stroke (I could not find this reference to review the primary data).
  • Also there are data finding that blood VEGF levels (vascular endothelial growth factor) may be protective of brain function. For example, a study found that VEGF levels in the CSF were higher in those with higher cognitive abilities, in comparing those with normal cognition to mild cognitive impairment to those with AD. And, exercise boosts VEGF.. ​
  1. A more recent article undercut the exercise/dementia link: the LIFE trial (Lifestyle Interventions and Independence for Elders) looked at the effects of a 24-month physical activity program for 1635 community-living people in the US, aged 70-89, who were at risk for mobility disability but able to walk 400 meters (seeJAMA. 2015;314(8):781-790). They assessed cognitive function as a secondary outcome (though this study was not specifically powered for this outcome) using several instruments, especially the Digit Symbol Coding subtest of Wechsler Adult Intelligance Scale and the revised Hopkiins Verbal Learning Test (12-item word list recall), comparing those in the structured moderate-intensity physical activity program of walking, resistance training, and flexibility exercises, to those in a health education program. They found no overall benefit to exercise, except in those >80 yo and in those with poorer baseline physical performance, noting an improvement in executive function in these groups (p=0.01). However, they did not measure BDNF levels, which may be particularly important in a group of patients who were physically challenged at baseline and perhaps unable to exercise very much. Also, only 57 patients overall developed dementia though 132 developed mild cognitive impairment (this LIFE was a well-educated cohort, and therefore more likely to show less cognitive decline by the cognitive tests).

So, things are usually more complicated than they seem. We are all (myself certainly included) prone to look for simple solutions that make sense physiologically. It makes sense that AD and dementia in general are neurologic degenerative disorders associated with specific anatomic pathology, but the actual correlation is not so clear. It also makes sense that keeping the brain active, through suduko or other cognitive puzzles would help preserve brain function, but it seems that overall brain function does not improve (though performance of the specific task, suduko in this case, does get better….).  However, the above studies suggest that there do seem to be a large array of potential benefits from exercise, including decreased depression, improved memory, and decreased progression of cognitive decline. And the data also support the benefit of a Mediterranean diet. Bottom line: I think it is not so useful to try to break down the specific components of diet or exercise which is beneficial (a tad reductionist), that cognitive decline is undoubtedly multifactorial (again arguing against a reductionist approach), but that nutrition and exercise are very likely necessary for brain health and likely more so than the too-often-advertized easy fixes of on-line memory games, etc. And this realization is a bit of a game-changer, in that perhaps our primary therapeutic focus in elderly people concerned about cognitive decline really should be on a healthy diet and exercise, which not only are good for the body but also for the mind.

For some other blogs on cognitive function, see: showing that chocolae improves cognitive function reviewed the Mediterranean diet and cogntive decline, showing decreased AD and also larger brain volumes, which tracked with the degree of adherence to a Mediterranean diet. ​


Primary Care Corner with Geoffrey Modest MD: Atrial Fibrillation – Should We Look Harder For It?

2 Dec, 15 | by EBM

By Dr. Geoffrey Modest

Over the years, I have had several patients who have presented with significant strokes related to previously-undetected atrial fibrillation (AF). I have also had a couple of patients with dementia and no evident prior stroke, who on workup have had multiple small infarcts, again possibly related to AF. In this light, there was an interesting editorial in JAMA (see JAMA 2015; 314: 1911) ​ raising the question of whether we should be screening regularly for AF. Although not part of their argument, I think that the potential and not clearly well-defined relationship between AF and cognitive decline may be part of the incentive to screen (see below). Their argument is basically (all references are in the text):

  • AF is really common (1 in 4 lifetime risk in those >40, with 0.5% age 40, increasing to up to 15% at age 80)
  • Treatment is pretty effective: oral anticoagulation (OA) reduces stroke risk by 2/3 and mortality by 1/3, with relatively small risk of major bleeding (hence the use of pretty universal guidelines to anticoagulate if the CHA2DS2-VASc score is 2 or greater)
  • The effectiveness of OA is much more impressive than many of the other recommended screening activities/interventions
  • AF is a common cause of stroke: a recent Swedish Stroke survey of 94K patients with ischemic stroke found AF in 31K of them, which is probably an underestimate (see Stroke 2014; 45: 2599)
  • So, can asymptomatic AF be picked up by screening??
    • A systematic review found that in 123K patients, a single screen using either pulse palpation or EKG found undiagnosed AF in 1% of people overall and 1.4% of those >65yo.
    • The European Society of Cardiology 2012 guidelines on AF recommended routine checking the pulse of patients >=65 years of age, followed by an electrocardiogram as needed, for the timely detection of AF.
    • There are cheap handheld or smartphone EKG-type devices which may be useful. Preliminary studies suggest an AF pickup of 1.5-3.0%, all of whom qualified for OA.
  • Prognosis of incidental AF
    • A UK study found people with incidentally detected asymptomatic AF had stroke rate of 4% in 1.5 years and all-cause mortality of 7% in those untreated. Those on warfarin had stroke and death rates of 1% and 4% respectively
  • Cost-effectiveness
    • ​Smartphone based screening in those 65-85yo: $4066 per quality-adjusted life-year gained, $20,695 per stroke prevented (i.e., better than most preventative interventions). This age group has high incidence of AF and essentially all people >65 would qualify for OA
  • The authors suggest that we in the US follow the European guidelines and check the pulse during office visits.

So, AF has potentially devastating consequences, with significant morbidity and mortality. A few points:

  • The relationship between AF and multi-infarct dementia (MID) is not clear, and AF is not listed as a risk factor for MID by the NIH. But there was a population-based study (Rotterdam Study) which followed 6514 patients aged >55 and found a strong association between dementia and impaired cognitive function in those who developed AF and were <67 yo (see A recent article on AF and cognition (see Stroke 2015;46:3316-3321) noted that:
    • The mechanism is unclear (?multiple small emboli, ?AF-associated cerebral hypoperfusion)– and, evidently, if the mechanism were the latter, it would be hard to attribute the cognitive decline to AF, since there would not necessarily be dectectable infarcts on brain imaging.
    • There have been meta-analyses (see Neurology 2011; 76:914, Ann Intern Med 2013; 158: 338) finding >2-fold increased risk of cognitive impairment in those with AF and subsequent stroke.
    • A few meta-analyses have found a 40% increased risk of dementia in those with AF and without stroke (see Heart Rhythm 2012; 9: 1761).
    • But, as we know, associations are not necessarily causal, and AF/dementia do have shared risk factors.
    • ​And, one of my concerns is that in many of these studies, our measurement of dementia (e.g. Mini-mental state exam) is a very blunt instrument and does not pick up subtle changes which may be very significant for the person at that time, and ultimately over years, progress to our definition of dementia.
  • Given the potential devastation of stroke/cognitive impairment, as well as the potential damage from other peripheral emboli, it seems to me that we should have a randomized controlled intervention study looking at treatment for AF and its overall effects. For that study, there would need to be some agreement on the following:
    • What is AF?  Is it a random pick-up on a routine exam (i.e., 1-minute evaluation for an irregular pulse and then followed by an EKG)? Is it a 24-hour Holter monitor, or a 30-day event monitor??? (clearly there are people with very intermittent, paroxysmal AF who have clinical emboli, and checking a pulse is going to find those with sustained AF predominantly)
    • ​What is cognitive decline? This study should include doing a more extensive evaluation for subtle cognitive decline (e.g., the Cardiovascular Health Study did look at a few instruments, including the Modified MMSE and Digit Symbol Substitution Test, as well as telephone interviews, finding those with incident AF had faster and earlier onset cognitive decline — see Neurology 2013; 81: 119).
  • But at this point, I will continue doing what I have been doing: pretty much always checking my own manual blood pressures on patients, after waiting several minutes in a reasonably relaxed atmosphere (as per prior blogs). In this setting I sometimes do pick up AF (and, by the way, the automated cuffs are pretty unreliable for blood pressure measurement in those with AF, further supporting checking manual blood pressures in those >50yo or so). But I will now add on checking the pulse for irregularities, and then follow the guidelines for treatment when I find AF. And, perhaps more aggressive assessments for AF than pulse-checking at the time of exams should be done (given the high prevalence of AF, especially in our aging population, a more intensive AF assessment such as Holter monitoring could be a very cost-effective strategy, especially given the dramatic quality-of-life issues associated with stroke/dementia). But this would need studies to determine.

Primary Care Corner with Geoffrey Modest MD: Mediterranean Diet and Brain Volume

1 Dec, 15 | by EBM

By Dr. Geoffrey Modest

I sent out a recent blog on a Spanish intervention trial of a Mediterranean Diet, which was associated with a decrease in breast cancer risk. This same study (the PREDIMED study) also found decrease likelihood of developing atrial fibrillation, coronary artery disease, diabetes and improved cognition (see prior blogs: ,, ). The PREDIMED substudy on cognitive decline looked at 522 participants at high vascular risk, randomized them to 2 Mediterranean diets (one high in extra-virgin olive oil and the other high in nuts) vs a low-fat control. They tracked participants with the Mini-Mental State Exam (MMSE) and Clock Drawing Test for 6.5 years and found that, controlling for apo E genotype, family history of cognitive impairment/dementia, depression and the array of cardiovascular risk factors, participants in either of the Mediterranean diets did better (though those on the high extra-virgin olive oil did a little better than the high nut one) –see J Neurol Neurosurg Psychiatry 2013;84:1318–1325.

There was a recent study which looked at Mediterranean diet and brain structure. Patients were in the Washington Heights-Inwood Columbia Aging Project (WHICAP), following 2,258 community-dwelling non-cognitively impaired individuals in New York and prospectively evaluating them for Alzheimer’s Disease every 1.5 years. They found 262 incident cases of Alzheimer’s over 4 years, and found an overall 9% decreased risk of Alzheimer’s with greater adherence to a Mediterranean diet, with a 40% decreased risk in comparing the highest to the lowest tertile of consuming a Mediterranean diet, in a multivariate analysis controlling for the usual suspects (seeAnn Neurol 2006;59:912–921​). These results have been confirmed in several observational studies, but not all.

In the current study, researchers looked at adherence to a Mediterranean diet and several MRI-determined variables of brain architecture (see doi.10.1212/WNL.0000000000002121). They scored adherence to the Mediterranean diet from 0-9.


  • 674 subjects of whom 370 had lower adherence to Med diet (score 0-4) and 304 with higher adherence (score 5-9)
  • Mean age 80.1, 10.7 years of education, 67% female, 25% apo e-4 positive, 28% white/35% black/36% Hispanic, BMI 27.8, 21% with diabetes, 74% hypertension, 10.5% stroke.


  • ​Those with higher total brain volume were younger, had higher education, more often male, less likely to have diabetes, and had lower BMI.
  • Those with higher Med diet adherence (5-9) vs lower (0-4) had:
    • Higher total brain volume by 13.11 ml (p=0.007)
    • Higher total gray matter volume by 5.00 ml (p=0.05)
    • Higher total white matter volume by 6.41 ml (p=0.05)
  • Specific components of the Mediterranean Diet:
    • Higher fish consumption and lower meat consumption were associated with higher total gray matter volume
    • Lower meat intake was associated with larger total brain volume
    • Higher fish intake was associated with a 0.019 mm larger mean cortical thickness (p=0.03)
    • Volumes of the cingulate cortex, parietal lobe, temporal lobe, and hippocampus, and cortical thickness of the superior-frontal region were associated with dietary factors, esp. higher fish and lower meat intakes
  • Overall, Med Diet adherence was associated with less brain atrophy, equivalent to the effects of 5 years of aging, with higher fish and lower meat intakes being the most significant association.

So, this is yet another study confirming the benefits of eating well. The constellation of findings, whether related to developing diabetes, heart afflictions, or cognitive decline, reinforce that diet is important for the whole body, and that in some ways our reductionist approach (looking just at coronary artery disease, for example) can lead to the wrong conclusions (just put people on statins and aspirin and don’t worry). So, I bring up this study mostly to reinforce overall the benefits of healthy lifestyle and that it probably is one of the most important messages we in primary care can impart on our patients. Of course, some of these suggestions are structurally difficult in our society (eating well requires access to affordable healthy foods, exercise requires access to safe neighborhoods in which to walk, etc.), but, at least in Boston, there are lots of grassroots initiatives to improve access to food and safe neighborhoods, from which my patients have benefited significantly. [And it would be great to generalize/develop access to good foods and safe neighborhoods more broadly…..]

Primary Care Corner with Geoffrey Modest MD: Atrial Fibrillation and Dementia

30 Oct, 15 | by EBM

By Dr. Geoffrey Modest

The studies on the relationship between atrial fibrillation (AF) and dementia are inconsistent. This long-term, prospective population-based observational Rotterdam Study provided insight into this relationship (see doi:10.1001/jamaneurol.2015.2161).


  • 6514 participants (mean age 68, 59% female, BMI 26, 10% diabetic, BP 139/74, chol/HDL ratio of 290/54, 42% former/23% current smokers, 8% with coronary artery disease, and 3% with heart failure)
  • 318 (5%) had prevalent AF at start of study; 994 (15%) developed incident dementia over 20 years of follow-up


  • Prevalent AF was associated with increased risk of dementia, with HR 1.33 (1.02-1.73), meaning a 33% increase vs those without prevalence AF
  • Of 6196 without prevalent AF (79K person-years of follow-up), 723 (12%) developed incident AF and 932 (15%) developed incident dementia
  • Incident AF was associated with an increased risk of dementia in those <67yo, with HR 1.81 (1.11-2.94), but was not significant in those >67yo
  • The risk of dementia was strongly related to the duration of exposure to AF:  those younger patients with the longest exposure had HR 3.30 (1.16-9.38, with p=0.003 for trend), though not in those >67yo
  • The above relationships were independent of clinical stroke, and didn’t vary by whether the dementia was classified as “Alzheimer” or “non-Alzheimer”

The above study found an impressive relationship between AF and dementia in those <67yo, with an apparent dose-response curve (the longer the AF exposure, the more dementia). There are some important caveats:

  • The definition of dementia was basically a clinical one, relying on the MIni-Mental State Exam and Geriatric Mental State Schedule, with further clinical differentiation of Alzheimer vs non-Alzheimer. These tests are insensitive to picking up early dementia, especially in high-functioning adults
  • There was no systematic neuroimaging, so unclear if there were either subclinical strokes, or even asymptomatic emboli (lacunar strokes are associated with cognitive decline)
  • The above study did not have any information about whether the patients with AF were anticoagulated (nor how good the level of anticoagulation was)
  • ​It is difficult to attribute causality in an observational study: was the issue that the AF caused cerebral hypoperfusion (AF is associated with decreased cardiac output) or small cerebral emboli leading to cognitive decline? Or that both AF and cognitive decline share similar causes (those who had AF were more likely to be smokers, have lower HDL levels, be on treatment for hypertension, be diabetics)?
  • ​AF is often undetected in asymptomatic individuals, since it is often intermittent. In a study as the above one, with clinic visits/EKGs done every 3-4 years, we may well miss asymptomatic intermittent AF. Perhaps we should have a more aggressive approach to AF diagnosis?? 24 or more hour monitoring every year??

So, the real issues in primary care are:

  • AF is really common and increasing as the population ages
  • The data on rhythm control (e.g., reverting to normal sinus rhythm) vs rate control (just controlling the ventricular rate) did not assess long-term cognitive issues (e.g. the AFFIRM and RACE trials, which somewhat favored rate control, basically assessed mortality, strokes/hemorrhages, serious arrhythmias, and used somewhat toxic antiarrhythmics and did not maintain full anticoagulation in those with rhythm control). It is certainly possible that restoration of normal sinus rhythm is in fact better in the prevention of cognitive decline.
  • But, it is hard to maintain normal sinus rhythm with these pretty toxic meds. Even with radiofrequency ablation, there are not-so-infrequent AF recurrences (meta-analysis of ablation found only about 50% were in NSR after 3 years with a single ablation, though increases to about 80% with multiple ablations, though ablations themselves are also associated with emboli –e.g., see JACC 2013; 62:531 or Circ 2010; 122:1667.) and who knows how sustained normal rhythm will actually be in longer-term studies? Or even if some who have “NSR” still have occasional episodes of AF which could be associated with small, inapparent emboli? Maybe we should aim for sinus rhythm but continue with anticoagulation??
  • And, it would be very interesting to know if either rhythm control (as best as we can measure it) or adequate anticoagulation diminishes cognitive decline (one possible study might be in those with low CHA2DS2-VASc scores, who are not generally given anticoagulation, to be randomized to anticoagulation vs not, to see if there is a long-term cognitive difference. There is a study lending some support to this — those in AF on anticoagulants and more often in therapeutic range had less dementia –see  Heart Rhythm 2014: 11:2206 — though this was not a randomized control study, so there may have been important differences in those achieving better control than the others.)
  • But, the finding above that the duration of AF being associated with more cognitive decline, is somewhat reassuring since it is likely that those with less evident AF seem to be at lower risk, supporting the concept that decreasing the numbers of episodes of AF may be helpful.
  • In some ways the real value of a quick-and-dirty study as the Rotterdam one above serves to raise a much bigger issue: we perhaps should not be so complacent with just achieving rate control, the current general approach, but should pursue studies to see if another very important endpoint (cognitive decline) might be better achieved by more aggressive attempts to reinstate sinus rhythm.​

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