dementia

An evidence-based review of monoclonal antibody treatment of patients with Alzheimer's Disease. Very little benefit and significant risk. James W. Mold, MD, MPH

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Purpose: We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia.

Methods: We searched PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies. We included randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for Food and Drug Administration approval. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID).

Results: We identified 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies. There were small improvements over placebo in the Alzheimer's Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = -0.07; 95% CI, -0.10 to -0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =-0.18 points; 95% CI, -0.34 to -0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86).

Conclusions: Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms.

Keywords: ARIA; Alzheimer dementia; Alzheimer disease; aducanumab; aged; amyloid; antibodies, monoclonal; biological therapy; cerebral edema; cerebral hemorrhage; chronic disease; dementia; donanemab; drug approval; lecanemab; meta-analysis; risks and benefits; systematic review.

Author/s:

Mark H Ebell, Henry C Barry, Kanishka Baduni, Gabrielle Grasso

Frontotemporal dementia

Erin Blanchette — Wed, 13 Dec 2023 17:01:01 +0000

Date Added:

December 13, 2023

Journal/Publication:

Canadian Medical Association Journal

Publisher:

Canadian Medical Association

Publication Date:

December 10, 2023

Issue:

Volume:

195

Pages:

E1660

URL:

Frontotemporal dementia

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1503/cmaj.230407

Keywords

Frontotemporal Dementia

neurology

dementia

Alzheimer Disease

PMID (1):

38081627

MeSH

Frontotemporal Dementia

alzheimer disease

Pick Disease of the Brain

Cognition

brain

Temporal Lobe

Behavioral Symptoms/diagnosis

Magnetic Resonance Imaging

A concise review of fronto-temporal dementia. James W. Mold, MD, MPH

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Frontotemporal dementia should be considered in adults aged 50–75 years presenting with behavioural or language changes. After Alzheimer disease, it is the second most common cause of dementia among adults younger than 65 years.1 Frontal and temporal lobe degeneration results in behavioural or language impairment.

Author/s:

Raul Medina-Rioja, Gina Gonzalez-Calderon, Mario Masellis

Catheter ablation and lower risk of incident dementia and mortality in older adults with atrial fibrillation

Rowan Hutchins — Mon, 02 Oct 2023 05:00:00 +0000

Date Added:

October 2, 2023

Journal/Publication:

Journal of the American Geriatrics Society

Publisher:

American Geriatrics Society

Publication Date:

August 23, 2023

URL:

Catheter ablation and lower risk of incident dementia and mortality in older adults with atrial fibrillation

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1111/jgs.18538

Keywords

PMID (1):

37609682

MeSH

Urinary Catheters

Atrial Fibrillation* / diagnosis

RPR Commentary: It looks like catheter ablation is becoming the preferred treatment for many patients with atrial fibrillation for a variety of reasons including dementia prevention. James W. Mold, MD, MPH

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Background: Atrial fibrillation (AF) has consistently been associated with a higher risk of incident dementia. Observational evidence has suggested catheter ablation may be associated with a lower risk of dementia in patients with AF, but further research is needed. The objectives of this study were to use a global health research network to examine associations between catheter ablation, incident dementia and mortality in older adults with AF, and amongst subgroups by age, sex, co-morbidity status, and oral anticoagulant use.

Methods: The research network primarily included healthcare organizations in the United States. This network was searched on 28th September 2022 for patients aged ≥65 years with a diagnosis of AF received at least 5 years prior to the search date. Cox proportional hazard models were run on propensity-score matched cohorts.

Results: After propensity score matching, 20,746 participants (mean age 68 years; 59% male) were included in each cohort with and without catheter ablation. The cohorts were well balanced for age, sex, ethnicity, co-morbidities, and cardiovascular medications received. The risk of dementia was significantly lower in the catheter ablation cohort (Hazard Ratio 0.52, 95% confidence interval: 0.45-0.61). The catheter ablation cohort also had a lower risk of all-cause mortality (Hazard Ratio 0.58, 95% confidence interval: 0.55-0.61). These associations remained in subgroup analyses in individuals aged 65-79 years, ≥80 years, males, females, participants who received OACs during follow-up, participants with paroxysmal and non-paroxysmal AF, and participants with and without hypertension, diabetes mellitus, ischemic stroke, chronic kidney disease and heart failure, including heart failure with preserved ejection fraction and heart failure with reduced ejection fraction.

Conclusion: The observed lower risk of dementia and mortality with catheter ablation could be an important consideration when determining appropriate patient-centered rhythm control strategies for patients with AF. Further studies including data on the success of ablation are required.

Author/s:

Harrison, Stephanie L., Buckley, Benjamin J.R.

Parkinson disease primer, part 2: management of motor and nonmotor symptoms

Aubrey Delammermore — Thu, 23 Feb 2023 06:00:00 +0000

Date Added:

February 23, 2023

Journal/Publication:

Canadian Family Physician

Publication Date:

February 1, 2023

Issue:

Volume:

Pages:

91-96

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.46747/cfp.690291

Keywords

PMID (1):

36813521

MeSH

Levodopa

depression

Hypotension, Orthostatic

Physical Therapy Modalities

Sleep Wake Disorders

The second of a series of articles on management of Parkinson's Disease. James W. Mold, MD, MPH

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Objective To provide family physicians with an approach to the management of
motor and nonmotor symptoms of Parkinson disease (PD).
Sources of information Published guidelines on the management of PD were
reviewed. Database searches were conducted to retrieve relevant research
articles published between 2011 and 2021. Evidence levels ranged from I to III.
Main message Family physicians can play an important role in identifying and
treating motor and nonmotor symptoms of PD. Family physicians should initiate
levodopa treatment for motor symptoms if they affect function and if specialist
wait times are long, and they should be aware of basic titration approaches
and possible side effects of dopaminergic therapies. Abrupt withdrawal of
dopaminergic agents should be avoided. Nonmotor symptoms are common and
underrecognized and are a major factor in disability, quality of life, and risk of
hospitalization and poor outcomes for patients. Family physicians can manage
common autonomic symptoms such as orthostatic hypotension and constipation.
Family physicians can treat common neuropsychiatric symptoms such as
depression and sleep disorders, and they can help recognize and treat psychosis
and PD dementia. Referrals to physiotherapy, occupational therapy, speech
language therapy, and exercise groups are recommended to help preserve function.
Conclusion Patients with PD present with complex combinations of motor
and nonmotor symptoms. Family physicians should have basic knowledge of
dopaminergic treatments and their side effects. Family physicians can play
important roles in management of motor symptoms and particularly nonmotor
symptoms and can have a positive impact on patients’ quality of life. An
interdisciplinary approach involving specialty clinics and allied health experts
is an important part of management.

Author/s:

Frank, C., Chiu, R., Lee, J.

Olfactory Loss and Beyond: A Practical Review of Chemosensory Dysfunction

Saige Blanchard — Thu, 14 Apr 2022 05:00:00 +0000

Date Added:

April 14, 2022

Journal/Publication:

Journal of the American Board of Family Medicine

Publisher:

Journal of the American Board of Family Medicine

Publication Date:

April 4, 2022

Issue:

Volume:

Pages:

406-419

URL:

Olfactory Loss and Beyond: A Practical Review of Chemosensory Dysfunction

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.3122/jabfm.2022.02.210373

Keywords

PMID (1):

35379730

MeSH

A summary of the prevalence, causes, detection, and treatment of olfactory and other chemosensory dysfunctions. James W. Mold, MD, MPH

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Background: Our ability to smell and taste is dictated by 3 chemosensory systems with distinct physiologic mechanisms - olfaction, gustation, and chemesthesis. Although often overlooked, dysfunction of these special senses may have broad implications on multiple facets of patients' lives -including safety, nutritional status, quality of life, mental health, and even cognitive function. As "loss of smell or taste" emerged as a common symptom of coronavirus disease 2019 (COVID-19), the importance of intact chemosensory function has been thrust into the spotlight. Despite the growing recognition of chemosensory dysfunction, this already highly prevalent condition will increasingly impact a larger and more diverse population, highlighting the need for improved awareness and care of these patients.

Methods: Comtemporary review of chemosensory function and assessments.

Conclusions: Although patient-reported chemosensory function measures highlight the ease of screening of chemosensory dysfunction, self-reported measures underestimate both the prevalence and degree of chemosensory dysfunction and do not adequately distinguish between olfaction, gustation, and chemesthesis. Meanwhile, psychophysical assessment tools provide opportunities for more accurate, thorough assessment of the chemosenses when appropriate. Primary care providers are uniquely situated to identify patients burdened by chemosensory dysfunction and raise patient and provider awareness about the importance of chemosensory dysfunction. Identification of chemosensory dysfunction, particularly olfactory dysfunction, may raise suspicion for many underlying medical conditions, including early detection of neurodegenerative conditions. Furthermore, identification and awareness of patients with chemosensory dysfunction may help primary care providers to identify those who may benefit from additional therapeutic and safety interventions, or consultations with specialists for more detailed evaluations and management.

Author/s:

Claus, L. E., Leland, E. M., Tai, K. Y., Schlosser, R. J., Kamath, V., Lane, A. P., Rowan, N. R.

APOE ɛ4 Allele Testing and Risk of Alzheimer Disease

Carly Hughes — Sat, 16 Jan 2021 19:31:55 +0000

Date Added:

January 16, 2021

Journal/Publication:

Journal of the American Medical Association

Publisher:

Journal of the American Medical Association

Publication Date:

January 14, 2021

URL:

APOE ɛ4 Allele Testing and Risk of Alzheimer Disease

Type:

Clinical Decision Aids

Format:

Article

DOI (1):

doi:10.1001/jama.2020.15085

Keywords

MeSH

A brief review of the interpretation of APOE tests for diagnosing and predicting dementia of the Alzheimer’s type. James W. Mold, MD, MPH

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A 64-year-old man presented with concern about an abnormal genetic test result for apolipoprotein E (APOE) obtained through his primary care physician. He reported forgetfulness and word-finding difficulties for 3 years but performed all activities of daily living independently and was generally healthy. His father and maternal great aunt developed dementia in their 70s. Physical (including neurologic) examination, basic laboratory studies, and brain magnetic resonance imaging results were normal. The Short Test of Mental Status (STMS) score was 33 (maximal attainable score of 38 indicates best performance). Neuropsychological assessment showed average to above-average performance in all cognitive domains, accounting for age and education. Results of his genetic testing for APOE were reported as follows: “This individual possesses an apolipoprotein E genotype (3 and 4) that indicates, with high specificity, that Alzheimer’s disease is the cause of or a contributor to the observed dementia.

Author/s:

Choudhury, Parichita, Boeve, Bradley F., Ramanan, Vijay K

Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study

Brian Desmarais — Thu, 27 Jun 2019 13:04:17 +0000

Date Added:

June 27, 2019

Journal/Publication:

Journal of the American Medical Association Internal Medicine

Publication Date:

June 24, 2019

URL:

Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1001/jamainternmed.2019.0677.

Keywords

MeSH

Muscarinic Antagonists

antipsychotic agents

Middle Aged

Anticonvulsants

Confounding Factors (Epidemiology)

Urinary Bladder

cholinergic antagonists

antidepressive agents

I am only posting this article because your patients may ask about it. The research design isn’t very strong, and the association strengths aren’t terribly impressive. The dementia diagnoses weren’t confirmed, and I can’t tell whether patients were still taking the meds, which we know can cause acute cognitive impairment.. James W. Mold, MD, MPH

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IMPORTANCE:

Anticholinergic medicines have short-term cognitive adverse effects, but it is uncertain whether long-term use of these drugs is associated with an increased risk of dementia.

OBJECTIVE:

To assess associations between anticholinergic drug treatments and risk of dementia in persons 55 years or older.

DESIGN, SETTING, AND PARTICIPANTS:

This nested case-control study took place in general practices in England that contributed to the QResearch primary care database. The study evaluated whether exposure to anticholinergic drugs was associated with dementia risk in 58 769 patients with a diagnosis of dementia and 225 574 controls 55 years or older matched by age, sex, general practice, and calendar time. Information on prescriptions for 56 drugs with strong anticholinergic properties was used to calculate measures of cumulative anticholinergic drug exposure. Data were analyzed from May 2016 to June 2018.

EXPOSURES:

The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls (index date).

MAIN OUTCOMES AND MEASURES:

Odds ratios (ORs) for dementia associated with cumulative exposure to anticholinergic drugs, adjusted for confounding variables.

RESULTS:

Of the entire study population (284 343 case patients and matched controls), 179 365 (63.1%) were women, and the mean (SD) age of the entire population was 82.2 (6.8) years. The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date. There were significant increases in dementiarisk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. Results were similar when exposures were restricted to exposure windows of 3 to 13 years (AOR, 1.46; 95% CI, 1.41-1.52) and 5 to 20 years (AOR, 1.44; 95% CI, 1.32-1.57) before the index date for more than 1095 TSDDs. Associations were stronger in cases diagnosed before the age of 80 years. The population-attributable fraction associated with total anticholinergic drug exposure during the 1 to 11 years before diagnosis was 10.3%.

CONCLUSIONS AND RELEVANCE:

Exposure to several types of strong anticholinergic drugs is associated with an increased risk ofdementia. These findings highlight the importance of reducing exposure to anticholinergic drugs in middle-aged and older people.

Author/s:

Coupland, C.A.C., Hill, T., Dening, T., Morriss, R., Moore M., Hippisley-Cox J.

Some benefits from donepezil in Alzheimer’s disease

Brian Desmarais — Thu, 20 Jun 2019 12:57:52 +0000

Date Added:

June 20, 2019

Journal/Publication:

British Journal of General Practice

Publication Date:

March 1, 2013

Issue:

Volume:

608

Pages:

150

URL:

Some benefits from donepezil in Alzheimer’s disease

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.3399/bjgp13X664333

Keywords

MeSH

Cholinesterase Inhibitors

Synaptic Transmission

brain

RPR Commentary: This is a summary of the data available to date on the effectiveness of donepezil for treatment of patients with Alzheimer’s Disease. I told patients and their families that if a small improvement in functional abilities would make a huge difference in quality of life (e.g. could remain at home 6 months longer), it is probably worth trying donepezil. Otherwise the expense and side effects are not worth the very small benefit. 5 to 10mg seems to be enough. James W. Mold, MD, MPH

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CLINICAL QUESTION

How effective is exercise-based cardiac rehabilitation on mortality, morbidity, and health-related quality of life (QOL) in patients with coronary heart disease (CHD)?

BOTTOM LINE

Compared to usual care, in medium to longer-term follow-up (≥12 months) exercise-based cardiac rehabilitation was found to be effective in reducing overall and cardiovascular mortality in patients with CHD, and appeared to reduce the risk of hospital admissions in the shorter term (<12 months follow-up). There was no reduction seen in the risk of total myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty.

Author/s:

McAvoy, B.R.

Legal Advocacy To Improve Care For Older Adults With Complex Needs

Brian Desmarais — Mon, 20 May 2019 05:00:00 +0000

Date Added:

May 20, 2019

Journal/Publication:

Health Affairs

Publication Date:

May 17, 2019

URL:

Legal Advocacy To Improve Care For Older Adults With Complex Needs

Type:

Public Health Announcements

Format:

Web Page

Keywords

MeSH

A review of the important underappreciated role of legal advocates in supporting health care-related needs of older adults. James W. Mold, MD, MPH

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Legal advocacy is a recognized strategy to address social factors that influence the health of populations with complex care needs. Such advocacy can improve housing stability, increase access to public benefits that support a host of social needs, assure that medical and financial proxy decision makers are in place, and reduce psychosocial distress.

Author/s:

Hooper, Sarah, Parekh, Ami, Fabiny, Anne, Teitelbaum, Joel