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The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Summary Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy. Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879. Findings Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI –2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [–1·6 to 3·6], –0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related. Interpretation A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy. Funding AbbVie Inc.

Background: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors. Objective: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer’s disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk. Methods: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia. Results: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0–21], with 79.2% exhibiting polypharmacy (n = 407). Sites differed in their prevalence of polypharmacy, χ2(3) = 56.0, p

Author(s): Casaletto, KB; Staffaroni, AM; Wolf, A; Appleby, B; Brushaber, D; Coppola, G; Dickerson, B; Domoto-Reilly, K; Elahi, FM; Fields, J; Fong, JC; Forsberg, L; Ghoshal, N; Graff-Radford, N; Grossman, M; Heuer, HW; Hsiung, G-Y; Huey, ED; Irwin, D; Kantarci, K; Kaufer, D; Kerwin, D; Knopman, D; Kornak, J; Kramer, JH; Litvan, I; Mackenzie, IR; Mendez, M; Miller, B; Rademakers, R; Ramos, EM; Rascovsky, K; Roberson, ED; Syrjanen, JA; Tartaglia, MC; Weintraub, S; Boeve, B; Boxer, AL; Rosen, H; Yaffe, K; ARTFL/LEFFTDS Study | Abstract: IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated g55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated gtwo-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Introduction Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. Methods Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. Results NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. Discussion The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of four intervention group for two years: usual care, Intensive Reduction of Vascular Risk factors (IRVR) with blood pressure and cholesterol reduction, exercise training (EX), and IRVR+EX. Neurocognitive function is measured at baseline, 6, 12, 18, and 24 months; brain MRIs are obtained at baseline and 24 months. We hypothesize that both IRVR and EX will improve global cognitive function, while IRVR+EX will provide a greater benefit than either IRVR or EX alone. We also hypothesize that IRVR and EX will slow brain atrophy, improve brain structural and functional connectivity, and improve brain perfusion. Finally, we will explore the mechanisms by which study interventions impact neurocognition and brain. If rrAD interventions are shown to be safe, practical, and successful, our study will have a significant impact on reducing the risks of AD in older adults. NCT Registration: NCT02913664

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.

Author(s): Heuer, Hilary W; Rojas, Julio C; Toller, Gianina; Rankin, Katherine; Brushaber, Danielle; Appleby, Brian; Bordelon, Yvette M; Dickerson, Brad C; Kimiko, Domoto‐Reilly; Faber, Kelley; Foroud, Tatiana M; Forsberg, Leah K; Ghoshal, Nupur; Grant, Ian; Graff‐Radford, Neill R; Grossman, Murray; Hsiung, Ging‐Yuek Robin; Huey, Edward D; Karydas, Anna M; Kaufer, Daniel; Kerwin, Diana R; Lagone, Emma; Litvan, Irene; Ljubenkov, Peter A; Mackenzie, Ian R; Mendez, Mario F; Miller, Bruce L; Onyike, Chiadi U; Ramos, Eliana Marisa; Rascovsky, Katya; Roberson, Erik D; Tartaglia, Carmela; Weintraub, Sandra; Boeve, Bradley F; Rosen, Howard J; Boxer, Adam L

BACKGROUND: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies. OBJECTIVE: To determine the associations of CRF measured by maximal oxygen uptake (VO(2)max) with WM fiber integrity and neurocognitive performance in older adults with MCI. METHODS: Eighty-one participants (age = 65 ± 7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO(2)max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach. RESULTS: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO(2)max. VO(2)max was associated positively with DTI metrics of fractional anisotropy in ~54% WM fiber tracts, and negatively with mean and radial diffusivities in ~46% and ~56 of the WM fiber tracts. The associations of VO(2)max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO(2)max were associated with executive function performance in MCI patients. CONCLUSIONS: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.

The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

Author(s): Heuer, Hilary W; Wang, P; Rascovsky, K; Wolf, A; Appleby, B; Bove, J; Bordelon, Y; Brannelly, P; Brushaber, DE; Caso, C; Coppola, G; Dickerson, B; Dickinson, S; Domoto-Reilly, K; Faber, K; Ferrall, J; Fields, J; Fishman, A; Fong, J; Foroud, T; Forsberg, LK; Gearhart, D; Ghazanfari, B; Ghoshal, N; Goldman, J; Graff-Radford, J; Graff-Radford, N; Grant, I; Grossman, M; Haley, D; Hsiung, G-Y; Huey, E; Irwin, D; Jones, D; Kantarci, K; Karydas, A; Kaufer, D; Kerwin, D; Knopman, D; Kornak, J; Kramer, JH; Kraft, R; Kremers, WK; Kukull, W; Litvan, I; Ljubenkov, P; Mackenzie, IR; Maldonado, M; Manoochehri, M; McGinnis, S; McKinley, E; Mendez, MF; Miller, BL; Onyike, C; Pantelyat, A; Pearlman, R; Petrucelli, L; Potter, M; Rademakers, R; Ramos, EM; Rankin, KP; Roberson, ED; Rogalski, E; Sengdy, P; Shaw, L; Syrjanen, J; Tartaglia, MC; Tatton, N; Taylor, J; Toga, A; Trojanowski, J; Weintraub, S; Wong, B; Wszolek, Z; Boeve, BF; Rosen, HJ; Boxer, AL; ARTFL and LEFFTDS consortia | Abstract: IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Author(s): Ramos, Eliana Marisa; Dokuru, Deepika Reddy; Van Berlo, Victoria; Wojta, Kevin; Wang, Qing; Huang, Alden Y; Deverasetty, Sandeep; Qin, Yue; van Blitterswijk, Marka; Jackson, Jazmyne; Appleby, Brian; Bordelon, Yvette; Brannelly, Patrick; Brushaber, Danielle E; Dickerson, Bradford; Dickinson, Susan; Domoto-Reilly, Kimiko; Faber, Kelley; Fields, Julie; Fong, Jamie; Foroud, Tatiana; Forsberg, Leah K; Gavrilova, Ralitza; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathan; Graff-Radford, Neill; Grant, Ian; Grossman, Murray; Heuer, Hilary W; Hsiung, Ging-Yuek R; Huey, Edward; Irwin, David; Kantarci, Kejal; Karydas, Anna; Kaufer, Daniel; Kerwin, Diana; Knopman, David; Kornak, John; Kramer, Joel H; Kremers, Walter; Kukull, Walter; Litvan, Irene; Ljubenkov, Peter; Lungu, Codrin; Mackenzie, Ian; Mendez, Mario F; Miller, Bruce L; Onyike, Chiadi; Pantelyat, Alexander; Pearlman, Rodney; Petrucelli, Len; Potter, Madeline; Rankin, Katherine P; Rascovsky, Katya; Roberson, Erik D; Rogalski, Emily; Shaw, Leslie; Syrjanen, Jeremy; Tartaglia, Maria Carmela; Tatton, Nadine; Taylor, Joanne; Toga, Arthur; Trojanowski, John Q; Weintraub, Sandra; Wong, Bonnie; Wszolek, Zbigniew; Rademakers, Rosa; Boeve, Brad F; Rosen, Howard J; Boxer, Adam L; ARTFL/LEFFTDS consortium; Coppola, Giovanni | Abstract: IntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

Introduction The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. Methods We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. Results Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. Discussion Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

Introduction Behavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD). Methods We analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium. Results The CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®-SB) = 0. The CDR®-SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®-SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders. Discussion The BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

BACKGROUND The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI). OBJECTIVE To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ) plaque deposition in aMCI patients. METHODS This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and the Delis-Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition. RESULTS Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group. CONCLUSION The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group.

Introduction Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. Methods We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. Results Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). Discussion Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

ObjectiveTo investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD).MethodsWe investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation−, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation−). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation−, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy.ResultsRSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] −1.90 to −0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI −0.30 to −0.11).ConclusionsThe RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

Objectives: We examined whether multiple domains of baseline cognitive performance were associated with prospective physical activity (PA) adherence in the Lifestyle Interventions and Independence for Elders Pilot study (LIFE-P). Design, Setting, Participants: The LIFE-P study was a single-blind, multicenter, randomized controlled trial of a PA intervention compared to a successful aging educational intervention in sedentary, mobility-limited older adults. Intervention: A 12-month structured, moderate-intensity, multi-modal PA program that included walking, resistance training, and flexibility exercises. For the first 2 months (adoption), 3 center-based exercise sessions (40–60 min) / week were conducted. During the next 4 months (transition), center-based sessions were conducted 2 times / week. The subsequent maintenance phase consisted of optional once-to-twice-per-week center-based sessions and home-based PA. Measurements: Tests of executive and global cognitive functioning, working memory and psychomotor speed were administered at baseline. Median test scores were used to dichotomize participants into low or high cognitive performance groups. Results: 52 mobility-limited older adults (age: 76.9 ±5 yrs) were randomized to the PA arm of LIFE-P. Compared to participants with high cognitive performance, participants with low performance had similar PA adherence rates (all P ≥ 0.34). Furthermore, weak and non-significant univariate relationships were elicited between all measures of cognition and overall PA adherence levels (r values ranged: -0.20 to 0.12, P ≥ 0.12). Conclusion: These data suggest that cognitive performance does not limit long-term PA adherence in mobility-limited older adults. Additional studies in larger cohorts are warranted to verify these findings.

Ambulatory blood pressure (ABP) reflects the end-organ vascular stress in daily life; however, its influence on brain neuronal fiber integrity and cerebral blood flow (CBF) remains unclear. The objective of this study was to determine the associations among ABP, white matter (WM) neuronal fiber integrity, and CBF in older adults. We tested 144 participants via ABP monitoring and diffusion tensor imaging. The total level and pulsatile indices of CBF were measured by phase-contrast MRI and transcranial Doppler, respectively. Neuropsychological assessment was conducted in 72 participants. Among ambulatory and office BP measures, elevated 24-h pulse pressure (PP) was associated with the greatest number of WM skeleton voxels with decreased fractional anisotropy (FA) and increased mean diffusivity (MD). Furthermore, these associations remained significant after adjusting for age, antihypertensive use, aortic stiffness, WM lesion volume, and office PP. Radial diffusivity (RD) was elevated in the regions with decreased FA, while axial diffusivity was unaltered. The reduction in diastolic index explained a significant proportion of the individual variability in FA, MD, and RD. Executive function performance was correlated with WM fiber integrity. These findings suggest that elevated ambulatory PP may deteriorate brain neuronal fiber integrity via reduction in diastolic index.

Background Computer-administered assessment of cognitive function is being increasingly incorporated in clinical trials; however, its performance in these settings has not been systematically evaluated. Design The Seniors Health and Activity Research Program pilot trial (N = 73) developed a computer-based tool for assessing memory performance and executive functioning. The Lifestyle Interventions and Independence for Elders investigators incorporated this battery in a full-scale multicenter clinical trial (N = 1635). We describe relationships that test scores have with those from interviewer-administered cognitive function tests and risk factors for cognitive deficits and describe performance measures (completeness, intraclass correlations [ICC]). Results Computer-based assessments of cognitive function had consistent relationships across the pilot and full-scale trial cohorts with interviewer-administered assessments of cognitive function, age, and a measure of physical function. In the Lifestyle Interventions and Independence for Elders cohort, their external validity was further demonstrated by associations with other risk factors for cognitive dysfunction: education, hypertension, diabetes, and physical function. Acceptable levels of data completeness (>83%) were achieved on all computer-based measures; however, rates of missing data were higher among older participants (odds ratio = 1.06 for each additional year; p

Accurate prediction of Alzheimer’s disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.

There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin., Whether Alzheimer's disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

OBJECTIVES: To assess the relationship between body mass index (BMI) and waist–hip ratio (WHR) and the clinical end points of cognitive impairment and probable dementia in a cohort of older women enrolled in the Women's Health Initiative Memory Study (WHIMS). DESIGN: Prospective, randomized clinical trial of hormone therapies with annual cognitive assessments and anthropometrics. SETTING: Fourteen U.S. clinical sites of the WHIMS. PARTICIPANTS: Seven thousand one hundred sixty-three postmenopausal women aged 65 to 80 without dementia. MEASUREMENTS: Annual cognitive assessments, average follow-up of 4.4 years, including classification of incident cognitive impairment and probable dementia. Height, weight, waist, and hip measurements were assessed at baseline, and a waist–hip ratio (WHR) of 0.8 or greater was used as a marker of central adiposity. RESULTS: There were statistically significant interactions between BMI and WHR and incident cognitive impairment and probable dementia with and without adjustment for a panel of cognitive risk factors. Women with a WHR of 0.80 or greater with a BMI of 20.0 to 24.9 kg/m2 had a greater risk of cognitive impairment and probable dementia than more-obese women or women with a WHR less than 0.80, although women with a WHR less than 0.80 and a BMI of 20.0 to 24.9 kg/m2 had poorer scores on cognitive assessments. CONCLUSION: WHR affects the relationship between BMI and risk of cognitive impairment and probable dementia in older women. Underweight women (BMI

OBJECTIVES: To determine whether body mass index (BMI) is independently associated with cognitive function in postmenopausal women and the relationship between body fat distribution as estimated by waist-hip ratio (WHR). DESIGN: Cross-sectional data analysis. SETTING: Baseline data from the Women’s Health Initiative (WHI) hormone trials. PARTICIPANTS: Eight thousand seven hundred forty-five postmenopausal women aged 65 to 79 free of clinical evidence of dementia who completed the baseline evaluation in the WHI hormone trials. MEASUREMENTS: Participants completed a Modified Mini-Mental State Examination (3MSE), health and lifestyle questionnaires, and standardized measurements of height, weight, body circumference, and blood pressure. Statistical analysis was performed of associations between 3MSE score, BMI, and WHR after controlling for known confounders. RESULTS: With the exception of smoking and exercise, vascular disease risk factors, including hypertension, waist measurement, heart disease, and diabetes mellitus, were significantly associated with 3MSE score and were included as covariables in subsequent analyses. BMI was inversely related to 3MSE score; for every 1-unit increase in BMI, 3MSE score decreased 0.988 points (Po.001) after adjusting for age, education, and vascular disease risk factors. BMI had the most pronounced association with poorer cognitive functioning scores in women with smaller waist measurements. In women with the highest WHR, cognitive scores increased with BMI. CONCLUSION: Higher BMI was associated with poorer cognitive function in women with smaller WHR. Higher WHR, estimating central fat mass, was associated with higher cognitive function in this cross-sectional study. Further research is needed to clarify the mechanism for this association. J Am Geriatr Soc 58:1427–1432, 2010.

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions., Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

To determine whether cortical β-amyloid (Aβ) deposition is associated with circadian blood pressure (BP) profiles and dynamic cerebral blood flow (CBF) regulation in patients with amnestic mild cognitive impairment (aMCI).Forty participants with aMCI were included in this study. Cortical Aβ depositions were measured by (18)F-florbetapir PET and expressed as the standardized uptake value ratio (SUVR) relative to the cerebellum. Circadian BP profiles were measured by 24-hour ambulatory monitoring during awake and sleep periods. The dipping status of sleep BP (i.e., the percent changes from the awake BP) was calculated and dichotomized into the dipper (≥10%) and nondipper (10%) groups. Dynamic CBF regulation was assessed by a transfer function analysis between beat-to-beat changes in BP and CBF velocity measured from the middle cerebral artery during a repeated sit-stand maneuver.Age was positively correlated with a greater Aβ deposition in the posterior cingulate, precuneus, and mean cortex. Accounting for the age effect, attenuated reductions in sleep systolic BP were associated with higher levels of posterior cingulate SUVR. Consistently, the nondippers exhibited a higher SUVR in the posterior cingulate than the dippers. Transfer function gain between changes in BP and CBF velocity was diminished in the nondippers, and moreover those individuals with a lower gain exhibited a higher SUVR in the posterior cingulate.Attenuated reductions in sleep BP are associated with a greater Aβ burden in the posterior cingulate and altered dynamic CBF regulation in patients with aMCI.

The Medical College of Wisconsin (MCW) and the Wisconsin Geriatric Education Center (WGEC) are committed to developing educational materials for primary care physicians in training. In response to the opportunity created by the Accreditation Council for Graduate Medical Education (ACGME) competency mandate, an MCW-led interdisciplinary working group has developed competency-linked video-based assessment tools for use in primary care residency training programs. Modeled after the Objective Structured Clinical Examinations (OSCE), used as part of the medical licensing examination process, we created geriatric-focused Objective Structured Video Examinations (OSVEs) as a strategy to infuse geriatrics into residency training. Each OSVE tool contains a 1-3 minute video trigger that is associated with a series of multiple choice and/or constructed response questions (e.g., fill in the blank). These questions assess residents' understanding of video-demonstrated ACGME competencies including professionalism, systems-based practice, communication, and practice-based learning. An instructor's guide and scoring key are provided for each tool. Response to the OSVEs has been overwhelmingly enthusiastic including greater than 90% commitment by statewide faculty to use the tools in residency training.

Cerebral hypoperfusion elevates the risk of brain white matter (WM) lesions and cognitive impairment. Central artery stiffness impairs baroreflex, which controls systemic arterial perfusion, and may deteriorate neuronal fiber integrity of brain WM. The purpose of this study was to examine the associations among brain WM neuronal fiber integrity, baroreflex sensitivity (BRS), and central artery stiffness in older adults. Fifty-four adults (65 ± 6 years) with normal cognitive function or mild cognitive impairment (MCI) were tested. The neuronal fiber integrity of brain WM was assessed from diffusion metrics acquired by diffusion tensor imaging. BRS was measured in response to acute changes in blood pressure induced by bolus injections of vasoactive drugs. Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). The WM diffusion metrics including fractional anisotropy (FA) and radial (RD) and axial (AD) diffusivities, BRS, and cfPWV were not different between the control and MCI groups. Thus, the data from both groups were combined for subsequent analyses. Across WM, fiber tracts with decreased FA and increased RD were associated with lower BRS and higher cfPWV, with many of the areas presenting spatial overlap. In particular, the BRS assessed during hypotension was strongly correlated with FA and RD when compared with hypertension. Executive function performance was associated with FA and RD in the areas that correlated with cfPWV and BRS. These findings suggest that baroreflex-mediated control of systemic arterial perfusion, especially during hypotension, may play a crucial role in maintaining neuronal fiber integrity of brain WM in older adults.

Kaycee M Sink,1 Mark A Espeland,2 Julia Rushing,2 Cynthia M Castro,3 Timothy S Church,4 Ronald Cohen,5 Thomas M Gill,6 Leora Henkin,2 Janine M Jennings,7 Diana R Kerwin,8 Todd M Manini,5 Valerie Myers,9 Marco Pahor,5 Kieran F Reid,10 Nancy Woolard,1 Stephen R Rapp,11 Jeff D Williamson1 On behalf of LIFE Investigators 1Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA; 2Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA; 4Pennington Biomedical, Louisiana State University, Baton Rouge, LA, USA; 5Institute on Aging and Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; 6Yale School of Medicine, Department of Internal Medicine, New Haven, CT, USA; 7Department of Psychology, Wake Forest University, Winston-Salem, NC, USA; 8Texas Alzheimer’s and Memory Disorders, Texas Health Presbyterian Hospital Dallas, TX, USA; 9Klein Buendel, Inc., Golden, CO, USA; 10Nutrition, Exercise Physiology and Sarcopenia Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA; 11Department of Psychiatry and Behavioral Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA Abstract: Observational studies have shown beneficial relationships between exercise and cognitive function. Some clinical trials have also demonstrated improvements in cognitive function in response to moderate–high intensity aerobic exercise; however, these have been limited by relatively small sample sizes and short durations. The Lifestyle Interventions and Independence for Elders (LIFE) Study is the largest and longest randomized controlled clinical trial of physical activity with cognitive outcomes, in older sedentary adults at increased risk for incident mobility disability. One LIFE Study objective is to evaluate the effects of a structured physical activity program on changes in cognitive function and incident all-cause mild cognitive impairment or dementia. Here, we present the design and baseline cognitive data. At baseline, participants completed the modified Mini Mental Status Examination, Hopkins Verbal Learning Test, Digit Symbol Coding, Modified Rey–Osterrieth Complex Figure, and a computerized battery, selected to be sensitive to changes in speed of processing and executive functioning. During follow up, participants completed the same battery, along with the Category Fluency for Animals, Boston Naming, and Trail Making tests. The description of the mild cognitive impairment/dementia adjudication process is presented here. Participants with worse baseline Short Physical Performance Battery scores (prespecified at ≤7) had significantly lower median cognitive test scores compared with those having scores of 8or 9 with modified Mini Mental Status Examination score of 91versus (vs) 93, Hopkins Verbal Learning Test delayed recall score of 7.4vs 7.9, and Digit Symbol Coding score of 45vs 48, respectively (all P

To determine the prevalence of unrecognized lower extremity peripheral arterial disease (PAD) among men and women aged 55 years and older in a general internal medicine (GIM) practice and to identify characteristics and functional performance associated with unrecognized PAD.Cross-sectional.Academic medical center.We identified 143 patients with known PAD from the noninvasive vascular laboratory, and 239 men and women aged 55 and older with no prior PAD history from a GIM practice. Group 1 consisted of patients with PAD consecutively identified from the noninvasive vascular laboratory (n = 143). Group 2 included GIM practice patients found to have an ankle brachial index less than 0.90, consistent with PAD (n = 34). Group 3 consisted of GIM practice patients without PAD (n = 205).Leg functioning was assessed with the 6-minute walk, 4-meter walking velocity, and Walking Impairment Questionnaire (WIQ). Of GIM practice patients, 14% had unrecognized PAD. Only 44% of patients in Group 2 had exertional leg symptoms. Distances achieved in the 6-minute walk were 1,130, 1,362, and 1,539 feet for Groups 1, 2, and 3, respectively, adjusting for age, gender, and race (P.001). The degree of difficulty walking due to leg symptoms as reported on the WIQ was comparable between Groups 2 and 3 and significantly greater in Group 1 than Group 2. In multiple logistic regression analysis including Groups 2 and 3, current cigarette smoking was associated independently with unrecognized PAD (odds ratio [OR], 6.82; 95% confidence interval [95% CI], 1.55 to 29.93). Aspirin therapy was nearly independently associated with absence of PAD (OR, 0.37; 95% CI, 0.12 to 1.12).Unrecognized PAD is common among men and women aged 55 years and older in GIM practice and is associated with impaired lower extremity functioning. Ankle brachial index screening may be necessary to diagnose unrecognized PAD in a GIM practice.

Objective: To review evidence-based guidance on the primary care of Alzheimer’s disease and clinical research on models of primary care for Alzheimer’s disease to present a practical summary for the primary care physician regarding the assessment and management of the disease. Data Sources: References were obtained via search using keywords Alzheimer’s disease AND primary care OR collaborative care OR case finding OR caregivers OR guidelines. Articles were limited to English language from January 1, 1990, to January 1, 2013. Study Selection: Articles were reviewed and selected on the basis of study quality and pertinence to this topic, covering a broad range of data and opinion across geographical regions and systems of care. The most recent published guidelines from major organizations were included. Results: Practice guidelines contained numerous points of consensus, with most advocating a central role for the primary care physician in the detection, diagnosis, and treatment of Alzheimer’s disease. Review of the literature indicated that optimal medical and psychosocial care for people with Alzheimer’s disease and their caregivers may be best facilitated through collaborative models of care involving the primary care physician working within a wider interdisciplinary team. Conclusions: Evidence-based guidelines assign the primary care physician a critical role in the care of people with Alzheimer’s disease. Research on models of care suggests the need for an appropriate medical/nonmedical support network to fulfill this role. Given the diversity and breadth of services required and the necessity for close coordination, nationwide implementation of team-based, collaborative care programs may represent the best option for improving care standards for patients with Alzheimer’s disease.

Summary Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26-week open-label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the neuropsychiatric inventory (NPI). We aimed to determine whether memantine is an effective treatment for FTD. Methods We did a randomised, parallel group, double-blind, placebo-controlled trial of 20 mg memantine taken orally daily for 26 weeks in patients with FTD. Participants met Neary criteria for behavioural variant FTD (bvFTD) or semantic dementia and had characteristic brain atrophy. Use of acetylcholinesterase inhibitors was prohibited. Individuals were randomly assigned to receive either memantine or matched placebo tablets (1:1) in blocks of two and four patients. All patients and study personnel were masked to treatment assignment. Primary endpoints were the change in total NPI score and clinical global impression of change (CGIC) score after 26 weeks and were analysed by intention to treat. This study is registered with Clinicaltrials.gov, number NCT00545974. Findings Of 100 patients screened, 81 were randomly assigned to receive memantine (39 patients) or placebo (42 patients). Five (6%) patients discontinued, and 76 completed the 26-week treatment. Enrolment numbers were lower than planned because of many patients' preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. Memantine treatment had no effect on either the NPI (mean difference 2·2, 95% CI −3·9 to 8·3, p=0·47) or CGIC (mean difference 0·0, −0·4 to 0·4, p=0·90) after 26 weeks of treatment. Memantine was generally well tolerated; however, patients in the memantine group had more frequent cognitive adverse events (six patients) than those in the placebo group (one). Interpretation Memantine treatment showed no benefit in patients with FTD. These data do not support memantine use in FTD. Funding Forest Research Institute.

This paper evaluates the relationship of blood pressure (BP) levels at Women's Health Initiative (WHI) baseline, treatment of hypertension, and white matter abnormalities among women in conjugated equine estrogen (CEE) and medroxyprogesterone acetate and CEE-alone arms. The WHI Memory Study-Magnetic Resonance Imaging (WHIMS-MRI) trial scanned 1424 participants. BP levels at baseline were significantly positively related to abnormal white matter lesion (WML) volumes. Participants treated for hypertension but who had BP > or = 140/90 mm Hg had the greatest amount of WML volumes. Women with untreated BP > or = 140/90 mm Hg had intermediate WML volumes. Abnormal WML volumes were related to hypertension in most areas of the brain and were greater in the frontal lobe than in the occipital, parietal, or temporal lobes. Level of BP at baseline was strongly related to amount of WML volumes. The results of the study reinforce the relationship of hypertension and BP control and white matter abnormalities in the brain. The evidence to date supports tight control of BP levels, especially beginning at younger and middle age as a possible and perhaps only way to prevent dementia.

Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive and functional disability and affects an estimated 5.1 million Americans.1 Although available treatments do not cure or reverse the course of AD, clinical studies have demonstrated that the cholinesterase inhibitors (ChEIs) and an N-methyl-D-aspartic acid (NMDA) antagonist can delay or slow the progression of cognitive and functional impairment, with greatest benefits achieved when medication is started early and utilized persistently.1,2 Research also shows that psychosocial interventions providing support, education, and counseling to patients and caregivers can improve the quality of life of those afflicted as well as their families.3 Moreover, early diagnosis of AD provides time for patients and families to prepare for the future and obtain necessary services.4,5 Despite the potential benefits of early diagnosis of AD, patients are often diagnosed later in the course of the disease and frequently by a consultant rather than the primary care physician (PCP).6 A recent Internet survey of 539 caregivers of AD patients conducted by Harris Interactive on behalf of the Alzheimer's Foundation of America found that the typical patient experiences symptoms for more than 2 years (26.1 months) and visits an average of 2.3 doctors before being diagnosed with AD.7 At the time of diagnosis, only 43% of patients were in the mild stage of the disease, whereas 23% were in the moderate stage, and the remaining patients (34%) had severe AD.7 The diagnosis and treatment of AD in the primary care setting may already be occurring with increasing frequency. According to GfK Market Measures' 2007 Alzheimer's Disease Caregiver Study, 68% of caregivers identified PCPs as key health care providers for both diagnosing and managing their loved one's AD.8 In fact, PCPs are often in the best position to both make the diagnosis and share it with the patient and the family because of the often long-term, ongoing relationship that the PCP has with the patient and family. Optimal involvement of primary care physicians in making and sharing the diagnosis of AD should result in patients being diagnosed at an earlier stage of the disease, allowing the patients themselves to make decisions about their own health care and express preferences regarding choices that they will be unable to make in the future.3,5 Clinical Points ♦ Making and sharing the diagnosis of Alzheimer's disease may best be accomplished by the patient's primary care physician. ♦ Skillful communication with patients, caregivers, and family members is of paramount importance in the diagnosis and treatment of Alzheimer's disease. ♦ Treatments “work” mostly by slowing progression of the disease. Effectively sharing the diagnosis of AD with patients and their families and communicating with them over the course of the illness concerning the myriad issues that arise presents a formidable challenge for many PCPs. Not surprisingly, significant gaps in communication between PCPs and patients with AD and their caregivers have been identified.9 Although guidelines have been issued by several organizations for sharing the diagnosis of AD and for providing education to patients and caregivers,2,10 there is a need for more practical and detailed guidance concerning how to accomplish this challenging task, particularly in a primary care setting. Accordingly, a national roundtable was convened on March 14, 2008, with the principal goal of arriving at a consensus on a set of recommendations to be offered to PCPs suggesting how best to communicate with patients and families regarding the diagnosis and ongoing management of AD. This roundtable included 4 leading academic physicians with diverse backgrounds (a geriatric psychiatrist, a neuropsychiatrist, a neurologist, and a geriatrician) from geographically diverse regions of the United States, who were invited on the basis of their national reputation in the field and experience working with minority populations with dementia; the executive director of a national AD advocacy organization; the executive director of a national advocacy organization for caregivers; and a medical correspondent with expertise in interviewing and small group leadership. This article, based on those proceedings and intended to be a practical resource for PCPs, will present these recommendations (Table 1), highlighting their potential to improve the quality of medical care for patients with AD, the quality of life for their caregivers, and satisfaction with the medical encounter for the PCP. Expert opinion is supported by the academic literature (search limited to PubMed, English language, 1996–2008, search terms: Alzheimer's disease, primary care, diagnosis, management, caregiver, family, patient-physician relationship). Only statements endorsed by all authors were included in this article. Table 1 Key Recommendations of the Expert Consensus Panel for Sharing the Diagnosis and Management of Alzheimer's Disease (AD)

The number and age of patients with Alzheimer's disease (AD) continues to increase dramatically with more patients requiring long-term skilled care. The care of patients with AD, particularly those with severe AD, is a challenge that long-term care administrators are facing with increasing frequency. The therapeutic approach to patients in the moderate to severe stages of AD is a combination of pharmacologic agents to maximize patient function and independence and is cost effective for the nursing home facility and the patient. Here we review the use of drug therapy in patients with severe AD, focusing on function and long-term care perspectives.

Objective To estimate oral clearance of nifedipine and to determine demographic and clinical covariates that affect nifedipine clearance in a clinical population. Methods Apparent oral clearance of nifedipine and protein binding were measured in 226 patients receiving sustained-release nifedipine formulations for hypertension and coronary artery disease (black men, n = 111; black women, n = 27; white men, n = 64; white women, n = 24). Mean age ± SD was 71 ± 11 years, and mean weight was 86 ± 17 kg. Nifedipine concentrations were analyzed by HPLC, protein binding was measured by equilibrium dialysis, clearance and covariate effects were estimated by a nonlinear mixed effects population model, and statistical analyses were performed by a nonlinear mixed-effects model (clearance) and ANOVA (protein binding). Results Clearance was significantly slower in black subjects (8.9 ± 0.7 mL/min/kg; mean ± SE) compared with white subjects (11.6 ± 0.8 mL/min/kg; P = .00004) and in men compared with women (9.3 ± 0.6 versus 12.1 ± 1.5 mL/min/kg; P = .0021). Reported alcohol use (alcohol, 8.6 ± 1.1 versus no alcohol, 10.8 ± 0.6 mL/min/kg; P = .0002) and smoking status (smoker, 8.8 ± 2.0 versus nonsmoker, 10.2 ± 0.6 mL/min/kg; P = .0362) also affected nifedipine clearance. Race and sex had no effect on protein binding of nifedipine (P = .29 and P = .44, respectively). No effects of age, stable coronary artery disease, or reported intake of β-blockers on nifedipine clearance were detected in this primarily elderly population with hypertension. Conclusions The data suggest that race, sex, and environmental factors are identifiable sources of interindividual variation in the oral clearance of nifedipine, a CYP3A substrate. Our experience also suggests that data from clinical populations may be biased with regard to age, sex, and formulation selection, and covariates may not be independently distributed, which can limit analyses. Clinical Pharmacology & Therapeutics (2000) 68, 130–142; doi: 10.1067/mcp.2000.108678