alzheimer's disease

This cohort study of patients with dementia appears to show that statins seem to reduce the rate of progression of cognitive decline. That is certainly reassuring for those of us who have been concerned about whether we are depriving our brain cells of the cholesterol they require. James W. Mold, MD, MPH

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Background
Disturbances in brain cholesterol homeostasis may be involved in the pathogenesis of Alzheimer’s disease (AD). Lipid-lowering medications could interfere with neurodegenerative processes in AD through cholesterol metabolism or other mechanisms.

Objective
To explore the association between the use of lipid-lowering medications and cognitive decline over time in a cohort of patients with AD or mixed dementia with indication for lipid-lowering treatment.

Methods
A longitudinal cohort study using the Swedish Registry for Cognitive/Dementia Disorders, linked with other Swedish national registries. Cognitive trajectories evaluated with mini-mental state examination (MMSE) were compared between statin users and non-users, individual statin users, groups of statins and non-statin lipid-lowering medications using mixed-effect regression models with inverse probability of drop out weighting. A dose-response analysis included statin users compared to non-users.

Results
Our cohort consisted of 15,586 patients with mean age of 79.5 years at diagnosis and a majority of women (59.2 %). A dose-response effect was demonstrated: taking one defined daily dose of statins on average was associated with 0.63 more MMSE points after 3 years compared to no use of statins (95% CI: 0.33;0.94). Simvastatin users showed 1.01 more MMSE points (95% CI: 0.06;1.97) after 3 years compared to atorvastatin users. Younger (< 79.5 years at index date) simvastatin users had 0.80 more MMSE points compared to younger atorvastatin users (95% CI: 0.05;1.55) after 3 years. Simvastatin users had 1.03 more MMSE points (95% CI: 0.26;1.80) compared to rosuvastatin users after 3 years. No differences regarding statin lipophilicity were observed. The results of sensitivity analysis restricted to incident users were not consistent.

Conclusions
Some patients with AD or mixed dementia with indication for lipid-lowering medication may benefit cognitively from statin treatment; however, further research is needed to clarify the findings of sensitivity analyses

Author/s:

Bojana Petek, Henrike Häbel, Hong Xu, Marta Villa-Lopez, Irena Kalar, Minh Tuan Hoang, Silvia Maioli, Joana B Pereira, Shayan Mostafaei, Bengt Winblad, Milica Gregoric Kramberger, Maria Eriksdotter, Sara Garcia-Ptacek

Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia

Brian Desmarais — Fri, 01 May 2020 15:44:37 +0000

Date Added:

May 1, 2020

Journal/Publication:

Comparative Effectiveness Review

Publisher:

Agency for Healthcare Research and Quality

Publication Date:

April 20, 2020

URL:

Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

https://doi.org/10.23970/AHRQEPCCER223

Keywords

cognitive screening tests

alzheimer's disease

treatment

MeSH

Cholinesterase Inhibitors

A review of the evidence regarding cognitive screening tests used to “diagnose” (identify patients with cognitive impairment that could be Alzheimer’s Disease) and the (lack of) effectiveness of currently available medications use to treat it. James W. Mold, MD, MPH

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Objective. To summarize evidence on: (1) the accuracy of brief cognitive tests for identifying clinical Alzheimer’s-type dementia (CATD) in individuals with suspected cognitive impairment; (2) the accuracy of biomarkers for identifying Alzheimer’s disease (AD) in individuals with dementia; and (3) the benefits and harms of prescription drugs and supplements for cognition, function, and behavioral and psychological symptoms of dementia (BPSD) in patients with CATD.

Data sources. Electronic bibliographic databases to March 2019, ClinicalTrials.gov, systematic review bibliographies.

Review methods. Cognitive test accuracy studies must have used explicit CATD diagnostic criteria and a non-CATD control group. Biomarker accuracy studies must have used neuropathologic criteria to define AD cases and non-AD controls. All treatment trials must have enrolled participants with CATD; those evaluating BPSD enrolled individuals with CATD and BPSD. Minimum trial duration was 2 weeks for agitation, aggression, psychosis, and disinhibited sexual behavior, and 24 weeks for other outcomes. Two reviewers rated risk of bias (ROB) and strength of evidence. One reviewer extracted data; a second checked accuracy. We analyzed English-language studies with low or medium ROB.

Results. We analyzed 56 unique studies on the accuracy of brief cognitive tests for CATD, 24 on accuracy of biomarkers for AD (15 brain imaging, nine cerebrospinal fluid [CSF] testing), and 67 trials of CATD treatment (54 reporting cognition or function, 13 reporting BPSD). Multiple brief cognitive tests were highly sensitive and specific (>0.8) for distinguishing CATD from normal cognition, but less so for distinguishing mild CATD from normal cognition or CATD from mild cognitive impairment (MCI). Based on few studies, compared with clinical evaluation alone, amyloid positron emission tomography (PET), fluorodeoxyglucose (FDG)-PET, and combinations of CSF tests added to clinical evaluation may improve accuracy for distinguishing AD from non-AD dementia. Regardless of CATD severity, cholinesterase-inhibitors produced small improvements in cognition and function compared with placebo but may increase serious adverse events and withdrawals due to adverse events. For moderate to severe CATD, memantine plus a cholinesterase inhibitor slightly improved global change and inconsistently improved cognition, but not function, compared with a cholinesterase inhibitor alone. Evidence was mostly insufficient about the effects of prescription drugs and supplements on agitation, aggression, psychosis, or disinhibited sexual behavior.

Conclusion. Brief cognitive tests accurately distinguished CATD from normal cognition, but were less accurate distinguishing smaller clinical differences. Whether biomarkers improve diagnostic accuracy when added to clinical evaluation needs further verification, but potential benefits of testing are limited by lack of effective treatments for AD and non-AD dementias. Cholinesterase-inhibitors slightly outperformed placebo for cognition and function, but evidence of whether any drug treatments improved BPSD was largely insufficient.

Author/s:

Hemmy, L.S, Fink, H.A., Linskens, E.J., Silverman, P.G., MacDonald, R., McCarten, J.R., Talley, K.M.C., Desai, P.J., Forte, M.L., Miller, M.A., Brasure, M., Nelson, V.A., Taylor, B.C., Ng, W., Ouellette, J.M., Greer, N.L., Sheets, K.M., Wilt, T.J., Butler, M.

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.

Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

Tracy Ashby — Fri, 25 Jan 2019 06:00:00 +0000

Date Added:

January 25, 2019

Journal/Publication:

Science Advances

Publisher:

American Association for the Advancement of Science

Publication Date:

January 22, 2019

Issue:

Volume:

URL:

Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

Type:

Clinical Research Results

Format:

Article

DOI (1):

10.1126/sciadv.aau3333

Keywords

alzheimer's disease

porphyromonas gingivalis

small molecule inhibitors

MeSH

porphyromonas gingivalis

chronic periodontitis

argingipain, porphyromonas gingivalis

adhesins, bacterial cysteine endopeptidases

This relatively new theory regarding the etiology of Alzheimer’s Disease seemed worth posting. If nothing else, it is a reminder of how important oral health is to general health.

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Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalisinfection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aβ1–42production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer’s disease.

Author/s:

Dominy, Stephen S., Lynch, Casey, Ermini, Florian, Benedyk, Malgorzata, Marczyk, Agata, Konradi, Andrei, Nguyen, Mai, Haditsch, Ursula, Raha, Debasish, Griffin, Christina, Holsinger, Leslie J., Arastu-Kapur, Shirin, Kaba, Samer, Lee, Alexander, Ryder, Mark I., Potempa, Barbara, Mydel, Piotr, Hellvard, Annelie, Adamowicz, Karina, Hasturk, Hatice, Walker, Glenn D., Reynolds, Eric C., Faull, Richard L., Curtis, Maurice A., Dragunow, Mike, Potempa, Jan