Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial

Boxer, Adam L.; Knopman, David S.; Kaufer, Daniel I.; Grossman, Murray; Onyike, Chiadi U.; Graf-Radford, Neill; Mendez, Mario F.; Kerwin, Diana; Lerner, Alan J.; Wu, Chuang Kuo; Koestler, Mary; Shapira, Jill; Sullivan, Kathryn; Klepac, Kristen; Lipowski, Kristine; Ullah, Jerin; Fields, Scott; Kramer, Joel H.; Merrilees, Jennifer; Neuhaus, John; Mesulam, Marsel; Miller, Bruce L.

doi:10.1016/s1474-4422(12)70320-4

Cited by 196 publications

(112 citation statements)

References 26 publications

(39 reference statements)

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“…There is a discrepancy regarding clinical practice and the recommendations based upon clinical evidence (32). The aggregate analysis of neuropsychological, cognitive and functional performance across a cohort of patients with bvFTD in the present study indicated that treatment with memantine worsened a patient's cognitive function and ability to perform activities in daily living, and this is consistent with a previously reported randomized controlled clinical trial (16). Notably, each enrolled subject in the present study had significant neuropsychiatric disturbances, as assessed by NPI-Q and NPI-D scores.…”

Section: Mild (N=20)supporting

confidence: 79%

“…Furthermore, memantine was demonstrated to elevate cortical metabolic activities in the frontal and temporal regions, and in the salience network hubs in FTLD (14,15), thereby improving the quality of life of patients with FTLD and their families (12). These studies highlight the potential clinical applications of memantine in FTLD; however, a randomized controlled trial for memantine demonstrated little efficacy in the treatment of FTLD, and the results suggested that it may even hasten cognitive decline (16,17). This suggests that the drug should not be prescribed to patients with FTLD.…”

Section: Efficacy Of Memantine On Neuropsychiatric Symptoms Associatementioning

confidence: 95%

“…The mean survival from time of clinical diagnosis of FTLD is estimated to range between 3 and 4 years, which means that patients with FTLD admitted to hospital will progress to a moderate or severe stage in no more than 3 and 4 years (20,21). The majority of studies have focused on the effects of memantine on mild-to-moderate (MMSE score, >15) FTLD and have neglected its possible benefits for the treatment of patients in moderate-to-severe stages of FTLD (16).…”

Section: Efficacy Of Memantine On Neuropsychiatric Symptoms Associatementioning

confidence: 99%

“…Patients were divided into the following groups according to their MMSE score: Mild bvFTD (MMSE score, 21-26); and moderate-to-severe bvFTD (MMSE score, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Section: Study Design and Diagnostic Proceduresmentioning

confidence: 99%

“…Moderate-to-severe (n=20) a recent randomized controlled trial discouraged the prescription of memantine to FTLD patients (16,17). Despite this, the evidence-based clinical practices guidelines, clinical experience indicates that a high percentage of patients with FTLD are treated with AChEI, memantine or both.…”

Section: Mild (N=20)mentioning

confidence: 99%

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Efficacy of memantine on neuropsychiatric symptoms associated with the severity of behavioral variant frontotemporal dementia: A six-month, open-label, self-controlled clinical trial

Pan

Quan

Zhou

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Previous studies have focused on the curative effects of memantine in patients with mild-to-moderate frontotemporal lobar degeneration (FTLD); however, its benefits in patients with moderate-to-severe FTLD have not been investigated. The present study explores the behavioral, cognitive and functional effects of memantine on behavioral variant frontotemporal dementia (bvFTD) in patients with mild and moderate-to-severe stage bvFTD. A total of 42 patients with bvFTD completed a 6-month treatment plan of 20 mg memantine daily in an open-label, self-controlled clinical trial. Patients were divided into two groups according to their Mini-Mental State Examination (MMSE) score: Mild (score, 21-26); and moderate-to-severe (score, 4-20). Primary endpoints included Neuropsychiatric Inventory Questionnaire (NPI-Q) and Clinic Dementia Rating (CDR) scores, and secondary endpoints comprised Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D), MMSE, Montreal Cognitive Assessment (MoCA), Activity of Daily Life (ADL) and Hamilton Depression Rating Scale (HAMD) scores. Memantine treatment had no effect on overall NPI-Q scores, with the exception of the agitation subdomain in all patients with bvFTD. However, patients with moderate-to-severe bvFTD exhibited a better performance than patients with mild bvFTD, demonstrated by improved NPI-Q total scores and subscales of agitation, depression, apathy and disinhibition. In the moderate-to-severe group, CDR and HAMD scores remained stable, but MMSE, MoCA and ADL scores were reduced after 6 months of treatment. Memantine was well-tolerated in patients. In conclusion, patients with moderate-to-severe bvFTD responded significantly better to memantine in comparison to patients with mild bvFTD with regard to their neuropsychiatric scores, while memantine did not present any cognitive or functional benefits in patients with mild bvFTD. A randomized, double-blind, placebo-controlled clinical trial with a larger number of patients is required to verify these promising results for patients with moderate-to-severe bvFTD.

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Section: Mild (N=20)supporting

confidence: 79%

Section: Efficacy Of Memantine On Neuropsychiatric Symptoms Associatementioning

confidence: 95%

Section: Efficacy Of Memantine On Neuropsychiatric Symptoms Associatementioning

confidence: 99%

Section: Study Design and Diagnostic Proceduresmentioning

confidence: 99%

Section: Mild (N=20)mentioning

confidence: 99%

See 3 more Smart Citations

Efficacy of memantine on neuropsychiatric symptoms associated with the severity of behavioral variant frontotemporal dementia: A six-month, open-label, self-controlled clinical trial

Pan

Quan

Zhou

et al. 2016

Experimental and Therapeutic Medicine

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Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia

Rabinovici

Gatsonis

Apgar

et al. 2019

JAMA

404

360

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IMPORTANCE Amyloid positron emission tomography (PET) detects amyloid plaques in the brain, a core neuropathological feature of Alzheimer disease. OBJECTIVE To determine if amyloid PET is associated with subsequent changes in the management of patients with mild cognitive impairment (MCI) or dementia of uncertain etiology. DESIGN, SETTING, AND PARTICIPANTS The Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study was a single-group, multisite longitudinal study that assessed the association between amyloid PET and subsequent changes in clinical management for Medicare beneficiaries with MCI or dementia. Participants were required to meet published appropriate use criteria stating that etiology of cognitive impairment was unknown, Alzheimer disease was a diagnostic consideration, and knowledge of PET results was expected to change diagnosis and management. A total of 946 dementia specialists at 595 US sites enrolled 16 008 patients between February 2016 and September 2017. Patients were followed up through January 2018. Dementia specialists documented their diagnosis and management plan before PET and again 90 (±30) days after PET. EXPOSURES Participants underwent amyloid PET at 343 imaging centers. MAIN OUTCOMES AND MEASURES The primary end point was change in management between the pre-and post-PET visits, as assessed by a composite outcome that included Alzheimer disease drug therapy, other drug therapy, and counseling about safety and future planning. The study was powered to detect a 30% or greater change in the MCI and dementia groups. One of 2 secondary end points is reported: the proportion of changes in diagnosis (from Alzheimer disease to non-Alzheimer disease and vice versa) between pre-and post-PET visits. RESULTS Among 16 008 registered participants, 11 409 (71.3%) completed study procedures and were included in the analysis (median age, 75 years [interquartile range, 71-80]; 50.9% women; 60.5% with MCI). Amyloid PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% [95% CI, 59.1%-61.4%]) and 2859 of 4504 patients with dementia (63.5% [95% CI, 62.1%-64.9%]), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non-Alzheimer disease in 2860 of 11 409 patients (25.1% [95% CI, 24.3%-25.9%]) and from non-Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% [95% CI, 10.0%-11.1%]). CONCLUSIONS AND RELEVANCE Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes.

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Salience Network Resting-State Activity

Day¹,

Farb²,

Tang‐Wai³

et al. 2013

JAMA Neurol

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dvances in functional neuroimaging have provided a window into the brain's intrinsic connectivity, leading to the discovery of the salience network (SLN), composed of the anterior cingulate, insula, striatum, and amygdala. The SLN is activated in healthy patients during tasks requiring attentional selection, task switching, and self-regulation of behavior 1 and is an important neural substrate in frontotemporal dementia (FTD), 2 with dysfunction confirmed on histopathology 3 and resting-state functional magnetic resonance (fMR) imaging. 1,2 Within the SLN, the insula has emerged as a nodal point of particular importance for frontolimbic function and dysfunction. 2 Supporting this assertion, insular atrophy is recognized as one of the earliest structural biomarkers in behavioral variant FTD (bvFTD) and semantic dementia, 3,4 with insular loss correlated with worsening be-havioral inventory scores 5 and progressive accumulation of FTDassociated pathologic inclusions within insular von Economo neurons and Fork cells. 6,7 Abnormal activity within intrinsic brain networks may be clinically relevant, indicative of neurodegenerative disease. 1,2 Resting-state fMR imaging may provide a noninvasive biomarker for the diagnosis and longitudinal monitoring of patients with FTD. However, it remains to be determined whether this emerging technique can be used to identify patterns of network disruption in patients before the development of changes on clinical examination or structural neuroimaging. We explored the ability of baseline resting-state connectivity measures to predict behavioral changes in participants with bvFTD and semantic dementia during 8 weeks. IMPORTANCE Noninvasive measures of activity within intrinsic brain networks may be clinically relevant, providing a marker of neurodegenerative disease and predicting clinical behaviors. OBJECTIVE To correlate baseline resting-state measures within the salience network and changes in behavior among patients with frontotemporal dementia. DESIGN Baseline resting-state functional magnetic resonance imaging data and longitudinal clinical measures were obtained from prospectively accrued patients during 8 weeks. SETTING Tertiary academic care center specializing in the assessment and management of patients with neurodegenerative disease. PARTICIPANTS Fifteen patients with clinically diagnosed frontotemporal dementia (5 behavioral variant and 10 semantic dementia). MAIN OUTCOMES AND MEASURES Baseline resting-state functional magnetic resonance imaging data measured within regions of interest were regressed on serial behavioral measures from prospectively accrued patients with frontotemporal dementia to determine the ability of baseline resting-state activity to account for changes in behavior. RESULTS Low-frequency fluctuations in the left insula significantly predicted changes in Frontal Behavioral Inventory scores (standard β = 0.51, P = .049), accounting for 28% of the change variance. The trend was driven by changes in measures of apathy independent of dementia severity. ...

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Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial

Cited by 196 publications

References 26 publications

Efficacy of memantine on neuropsychiatric symptoms associated with the severity of behavioral variant frontotemporal dementia: A six-month, open-label, self-controlled clinical trial

Efficacy of memantine on neuropsychiatric symptoms associated with the severity of behavioral variant frontotemporal dementia: A six-month, open-label, self-controlled clinical trial

Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia

Salience Network Resting-State Activity

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