Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Case report: Neuronal intranuclear inclusion disease presenting with acute encephalopathy.

Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

Comparison of the telephone-Montreal Cognitive Assessment (T-MoCA) and Telephone Interview for Cognitive Status (TICS) as screening tests for early Alzheimer's disease.

INTRODUCTION: Remote screening for cognitive impairment associated with Alzheimer's disease (AD) has grown in importance with the expected rise in prevalence of AD in an aging population and with new potential treatment options. METHODS: The Telephone Interview for Cognitive Status (TICS) and new telephone adaptation of the Montreal Cognitive Assessment (T-MoCA) were administered to participants independently classified through in-person clinical evaluation as cognitively normal (CN; n = 167), mild cognitive impairment (MCI; n = 25), or dementia (n = 23). Cerebrospinal fluid AD biomarkers were measured (n = 79). RESULTS: TICS and T-MoCA were highly correlated (r = 0.787; P < 0.001): groups differed on both (CN

Preliminary Evidence that Memantine Enhances Prepulse Effects on Startle Magnitude and Latency in Patients with Alzheimer's Disease.

BACKGROUND: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects. OBJECTIVE: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients. METHODS: 18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency. RESULTS: Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p < 0.04; d = 0.40); this comparison reached a large effect size for the 60 ms interval (d = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency ("latency facilitation") and this effect was amplified after MEM (p = 0.03; d = 0.41; for 60 ms intervals, d = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures. CONCLUSION: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient's neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a "biomarker" measured at the outset on treatment can predict sensitivity to MEM's therapeutic effects.

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders.

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

Anticholinergic Drug Burden and Neurocognitive Performance in the Study of Latinos-Investigation of Neurocognitive Aging.

BACKGROUND: Studies of cumulative anticholinergic drug burden on cognitive function and impairment are emerging, yet few for Hispanics/Latinos. OBJECTIVE: To examine associations between anticholinergic use and neurocognitive performance outcomes among diverse Hispanics/Latinos. METHODS: This prospective cohort study included diverse Hispanic/Latino participants, enrolled in the Study of Latinos-Investigation of Neurocognitive, from New York, Chicago, Miami, and San Diego (n = 6,249). Survey linear regression examined associations between anticholinergic use (measured during baseline [Visit 1] and average 7-year follow up [Visit 2]) with global cognition, episodic learning, memory, phonemic fluency, processing speed, executive functioning, and average 7-year change. RESULTS: Anticholinergic use was associated with lower cognitive global cognition (ß= -0.21; 95% CI [-0.36; -0.05]), learning (ß= -0.27; 95% CI [-0.47; -0.07]), memory (ß= -0.22; 95% CI [-0.41; -0.03]), and executive functioning (ß= -0.22; 95% CI [-0.40; -0.03]) scores, particularly among those who took anticholinergics at both visits. Anticholinergic use was associated with faster decline in global cognition, learning, and verbal fluency (ß: -0.28 [95% CI: -0.55, -0.01]; ß: -0.28 [95% CI: -0.55, -0.01]; ß: -0.25, [95% CI -0.47, -0.04], respectively). Sex modified associations between anticholinergic use with global cognition, learning, and executive functioning (F3 = 3.59, F3 = 2.84, F3 = 3.88, respectively). CONCLUSION: Anticholinergic use was associated with lower neurocognitive performance, especially among those who used anticholinergics at both visits, among a study population of diverse Hispanics/Latinos. Findings will support evidence-based decisions regarding anticholinergic prescriptions and efforts to minimize cognitive impact.

Association of Neurofibrillary Tangle Distribution With Age at Onset-Related Clinical Heterogeneity in Alzheimer Disease: An Autopsy Study.

BACKGROUND AND OBJECTIVE: Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology. METHODS: The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51-60 (n = 40), 61-70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline. RESULTS: Patients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22-0.88), psychiatric symptoms (ß = -0.66, 95% CI -1.15 to -0.17), and functional impairment (ß = -1.25, 95% CI -2.34 to -0.16). TDP-43 (OR 2.00, 95% CI 1.23-3.35) and microvascular copathology (OR 2.02, 95% CI 1.24-3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (ß = -0.51, 95% CI -0.72 to -0.31) and midfrontal/hippocampal NFT ratio (ß = -0.18, 95% CI -0.26 to -0.10) were lower in those with later age at onset. Executive function (ß = 0.48, 95% CI 0.09-0.90) and visuospatial cognitive deficits (ß = 0.97, 95% CI 0.46-1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (ß = 0.21, 95% CI 0.08-0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities. DISCUSSION: Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.

Alzheimer's disease.

Alzheimer's disease (AD) dementia refers to a particular onset and course of cognitive and functional decline associated with age together with a particular neuropathology. It was first described by Alois Alzheimer in 1906 about a patient whom he first encountered in 1901. Modern clinical diagnostic criteria have been developed, and criteria have also been proposed to recognize preclinical (or presymptomatic) stages of the disease with the use of biomarkers. The primary neuropathology was described by Alzheimer, and in the mid-1980s subsequently evolved into a more specific neuropathologic definition that recognizes the comorbid neuropathologies that frequently contribute to clinical dementia. Alzheimer's disease is now the most common form of neurodegenerative dementia in the United States with a disproportionate disease burden in minority populations. Deficits in the ability to encode and store new memories characterizes the initial stages of the disease. Subsequent progressive changes in cognition and behavior accompany the later stages. Changes in amyloid precursor protein (APP) cleavage and production of the APP fragment beta-amyloid (Aß) along with hyperphosphorylated tau protein aggregation coalesce to cause reduction in synaptic strength, synaptic loss, and neurodegeneration. Metabolic, vascular, and inflammatory changes, as well as comorbid pathologies are key components of the disease process. Symptomatic treatment offers a modest, clinically measurable effect in cognition, but disease-modifying therapies are desperately needed.

Amygdala sign, a FDG-PET signature of dementia with Lewy Bodies.

BACKGROUND: Biomarkers are being used increasingly to support the diagnosis of dementia with Lewy bodies (DLB). Novel biomarkers that increase diagnostic specificity of DLB are needed. We assessed previously known FDG-PET occipital cortex hypometabolism, and cingulate island sign biomarkers of DLB against a novel amygdala signature. METHODS: Retrospective analysis of 49 patients evaluated at one tertiary memory clinic. All had a FDG-PET brain scan performed as part of their diagnostic work up evaluating three common neurodegenerative etiologies: Alzheimer dementia (AD), Frontotemporal dementia (FTD) and DLB. A consensus diagnosis of dementia was made based on accepted clinical criteria for AD, FTD and DLB. FDG-PET regional metabolism was delineated by automatic segmentation as well as manual tracing of amygdala and posterior cingulate volumes of interest. Mean normalized values calculated for regional FDG-PET signatures of DLB: occipital cortex hypometabolism and preservation of posterior cingulate and amygdala metabolism relative to whole brain metabolism were evaluated. RESULTS: Significant overlap between DLB and AD patients (occipital, parietal, temporal and frontal hypometabolism) and between DLB and FTD (frontal hypometabolism and the posterior cingulate sign) were identified. Right amygdala (p = 0.028) and right posterior cingulate (p = 0.035) mean normalized regional metabolism levels were preserved in DLB compared to AD. Among subjects at less advanced stages of dementia (MoCA>10), relative preservation of regional metabolism was notable across both left (p = 0.006) and right (p = 0.020) amygdala. CONCLUSION: Relative preservation of amygdala metabolism could complement previously described FDG-PET findings in earlier stages of DLB.

A Systematic Review of Positron Emission Tomography of Tau, Amyloid Beta, and Neuroinflammation in Chronic Traumatic Encephalopathy: The Evidence To Date.

Chronic traumatic encephalopathy (CTE) is associated with pathological changes, yet detecting these changes during life has proven elusive. Positron emission tomography (PET) offers the potential for identifying such pathology. Few studies have been completed to date and their approaches and results have been diverse. It was the objective of this review to systematically examine relevant research using ligands for PET that bind to identified pathology in CTE. We focused on identification of patterns of binding and addressing gaps in knowledge of PET imaging for CTE. A comprehensive literature search was conducted. Data used were published on or before May 22, 2017. As the extant literature is limited, any peer-reviewed article assessing military, contact sports athletes, or professional fighters was considered for inclusion. The main outcomes were regional binding to brain regions identified through control comparisons or through clinical metrics (e.g., standardized uptake volume ratios). A total of 1207 papers were identified for review, of which six met inclusion criteria. Meta-analyses were planned but were deemed inappropriate given the small number of studies identified. Methodological concerns in these initial papers included small sample sizes, lack of a control comparison, use of nonstandard statistical procedures to quantify data, and interpretation of potentially off-target binding areas. Across studies, the hippocampi, amygdalae, and midbrain had reasonably consistent increased uptake. Evidence for increased uptake in cortical regions was less consistent. The evidence suggests that the field of PET imaging in those at risk for CTE remains nascent. As the field evolves to include more stringent studies, ligands for PET may prove an important tool in identifying CTE in vivo.

Comparing the Electronic and Standard Versions of the Montreal Cognitive Assessment in an Outpatient Memory Disorders Clinic: A Validation Study.

The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns.

Neuropsychological Testing in Pathologically Verified Alzheimer Disease and Frontotemporal Dementia: How Well Do the Uniform Data Set Measures Differentiate Between Diseases?

BACKGROUND/AIMS: Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. OBJECTIVES: To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? METHODS: Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. RESULTS: As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. CONCLUSIONS: Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in differentiating FTLD from AD at the initial visit. These results highlight the difficulty of obtaining an accurate early diagnosis of FTLD and argue for adding supplemental tests to those included in the UDS to assess cognition in FTD and AD patients.

Structural and Functional MRI Differences in Master Sommeliers: A Pilot Study on Expertise in the Brain.

Our experiences, even as adults, shape our brains. Regional differences have been found in experts, with the regions associated with their particular skill-set. Functional differences have also been noted in brain activation patterns in some experts. This study uses multimodal techniques to assess structural and functional patterns that differ between experts and non-experts. Sommeliers are experts in wine and thus in olfaction. We assessed differences in Master Sommeliers' brains, compared with controls, in structure and also in functional response to olfactory and visual judgment tasks. MRI data were analyzed using voxel-based morphometry as well as automated parcellation to assess structural properties, and group differences between tasks were calculated. Results indicate enhanced volume in the right insula and entorhinal cortex, with the cortical thickness of the entorhinal correlating with experience. There were regional activation differences in a large area involving the right olfactory and memory regions, with heightened activation specifically for sommeliers during an olfactory task. Our results indicate that sommeliers' brains show specialization in the expected regions of the olfactory and memory networks, and also in regions important in integration of internal sensory stimuli and external cues. Overall, these differences suggest that specialized expertise and training might result in enhancements in the brain well into adulthood. This is particularly important given the regions involved, which are the first to be impacted by many neurodegenerative diseases.

Relationship between the Activities of Daily Living Questionnaire and the Montreal Cognitive Assessment.

INTRODUCTION: The Activities of Daily Living Questionnaire (ADL-Q) is an informant report questionnaire assessing functional impairment in daily living skills. Previous research has demonstrated correlations between ADL-Q and cognitive screening measures among patients with dementia. This study examined the relationship between ADL-Q and the Montreal Cognitive Assessment (MoCA), a brief cognitive screening. METHODS: Records of 448 individuals from an outpatient neurology clinic were reviewed. Pearson correlations were calculated between ADL-Q scores and MoCA scores. Linear regression models were fit using demographic information to predict ADL-Q scores. MoCA scores were then added to the models to determine the increase in predictive value of the MoCA. RESULTS: Lower MoCA scores were associated with higher levels of functional impairment. For each model, adding the MoCA significantly improved model fit. DISCUSSION: Low scores on the MoCA, among patient's presenting for memory complaints, should raise concerns about functional decline and prompt for further assessment of functional ability.

Memory Test Performance on Analogous Verbal and Nonverbal Memory Tests in Patients with Frontotemporal Dementia and Alzheimer's Disease.

BACKGROUND: Patients with frontotemporal dementia (FTD) typically have initial deficits in language or changes in personality, while the defining characteristic of Alzheimer's disease (AD) is memory impairment. Neuropsychological findings in the two diseases tend to differ, but can be confounded by verbal impairment in FTD impacting performance on memory tests in these patients. METHODS: Twenty-seven patients with FTD and 102 patients with AD underwent a neuropsychological assessment before diagnosis. By utilizing analogous versions of a verbal and nonverbal memory test, we demonstrated differences in these two modalities between AD and FTD. DISCUSSION: Better differentiation between AD and FTD is found in a nonverbal memory test, possibly because it eliminates the confounding variable of language deficits found in patients with FTD. These results highlight the importance of nonverbal learning tests with multiple learning trials in diagnostic testing.

Randomized controlled trials in frontotemporal dementia: cognitive and behavioral outcomes.

Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia (FTD). Targets for intervention have been identified, therapies are being developed, and clinical trials are advancing. A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes. The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction, language impairments and behavioral disturbance. Behavioral variant FTD is characterized by an initial presentation of changes in personality, behavior and/or emotion, which are often difficult to objectively capture using traditional neuropsychological measures. The two principal language variants of FTD are Progressive Nonfluent Aphasia (PNFA) with predominant agrammatic/non-fluent impairments and Semantic Dementia (SD) with semantic impairments and visual agnosia. Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change, yet specific enough to isolate signal from noise, and acceptable to regulatory agencies. Given the anticipated potential for small effect sizes, measures must be able to identify small incremental changes over time. It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest. Selected outcome measures should be suitable for repeat administration, yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability. To facilitate widespread adoption as an endpoint, measures should be readily accessible. We provide several examples of potential global, composite, and individual cognitive measures, as well as behavioral measures promising for FTD trials. Development and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients.

Neuropsychiatric symptom profile differs based on pathology in patients with clinically diagnosed behavioral variant frontotemporal dementia.

BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is pathologically heterogeneous. With emerging therapeutics, determining underlying pathology during life is increasingly important. Neuropsychiatric symptoms are prevalent and diagnostic in bvFTD. METHODS: We assessed the neuropsychiatric profile of patients with clinically diagnosed bvFTD as a function of pathology at autopsy. Patients with a clinical diagnosis of bvFTD at the initial visit were selected from the National Alzheimer's Coordinating Center (NACC) database. Neuropsychiatric symptoms endorsed on the Neuropsychiatric Inventory Questionnaire (NPI-Q) were analyzed. RESULTS: Of 149 patients with clinically diagnosed bvFTD, pathology was primarily Alzheimer's disease (AD) in 20.5%. These patients differed from those with underlying frontotemporal lobar degeneration: patients with AD pathology (plaques and tangles) were more likely to have hallucinations, delusions, or agitation. Patients were further differentiated into tau-positive (30% of cases, including Pick's disease, FTD and parkinsonism with tau-positive or argyrophilic inclusions, and other tauopathies) or tau-negative cases (70% of cases, including bvFTD tau-negative ubiquitin-positive inclusions). These patients also differed in some of the neuropsychiatric symptoms seen. Tau-negative cases were more likely to demonstrate depression, delusions, and changes in appetite and eating. CONCLUSIONS: These preliminary findings contribute to our increasing ability to predict, using simple clinical tools, the neuropathological underpinnings of bvFTD during life.

Novel disease-modifying therapeutics for the treatment of Alzheimer's disease.

Alzheimer's disease is the most common cause of dementia and is becoming a global health concern. Despite a well-established understanding of the molecular mechanism involved in its pathogenesis, and millions of dollars of investment in drug discovery and clinical trials, no single molecule has yet been approved for its treatment since the advent of cholinesterase inhibitors and memantine. This review examines first the optimal use of currently approved agents and then explores in detail the current Phase II and III clinical trial landscape, while spending some time on the mechanistic details. Driven by the increasing knowledge gleaned from numerous Phase III failures and improvements in early detection and biomarkers, there is renewed enthusiasm that a cure is taking shape along the visible horizon.

Pharmacological treatment of Alzheimer disease.

OBJECTIVE: To review the different pharmacological approaches to the cognitive, functional, and behavioural manifestations of Alzheimer disease (AD). METHODS: We searched and critically analyzed the most recent relevant literature on pharmacological treatment of AD. RESULTS: The current pharmacological approach to AD treatment is based on vascular prevention and symptomatic therapy with cholinesterase inhibitors (ChEIs) and memantine, an N-methyl-d-aspartic acid antagonist. Clinical trials of 6- to 12-month duration have shown statistically significant benefits with ChEIs and memantine on cognitive, global, functional, and behavioural outcome measures. In general, these benefits are modest. However, they are dose-dependent and reproducible across studies. Most importantly, these benefits are symptomatic as they do not alter disease course. According to the third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, these agents are considered standard treatment options in AD. We will discuss practical issues related to current pharmacological management, such as setting realistic expectations, management of side effects, switching ChEIs, and the decision to discontinue treatment. The results of clinical trials studying potentially disease-modifying approaches in AD will also be reviewed. Unfortunately, although there remains much promise and enthusiasm, none of these agents has shown consistent benefits, and none are available for use in clinical practice. CONCLUSION: Pharmacological options are presently available for the symptomatic treatment of AD. These treatments provide mild but sustained benefits. Before disease-modifying approaches become available, optimizing the use of the available treatment options is crucial.