Brain Imaging Abnormalities in Mixed Alzheimer's and Subcortical Vascular Dementia.

BACKGROUND: A large proportion of Alzheimer's disease (AD) patients have coexisting subcortical vascular dementia (SVaD), a condition referred to as mixed dementia (MixD). Brain imaging features of MixD presumably include those of cerebrovascular disease and AD pathology, but are difficult to characterize due to their heterogeneity. OBJECTIVE: To perform an exploratory analysis of conventional and non-conventional structural magnetic resonance imaging (MRI) abnormalities in MixD and to compare them to those observed in AD and SVaD. METHODS: We conducted a cross-sectional, region-of-interest-based analysis of 1) hyperintense white-matter signal abnormalities (WMSA) on T2-FLAIR and hypointense WMSA on T1-weighted MRI; 2) diffusion tensor imaging; 3) quantitative susceptibility mapping; and 4) effective transverse relaxation rate (R2*) in N = 17 participants (AD:5, SVaD:5, MixD:7). General linear model was used to explore group differences in these brain imaging measures. RESULTS: Model findings suggested imaging characteristics specific to our MixD group, including 1) higher burden of WMSAs on T1-weighted MRI (versus both AD and SVaD); 2) frontal lobar preponderance of WMSAs on both T2-FLAIR and T1-weighted MRI; 3) higher fractional anisotropy values within normal-appear white-matter tissues (versus SVaD, but not AD); and 4) lower R2* values within the T2-FLAIR WMSA areas (versus both AD and SVaD). CONCLUSION: These findings suggest a preliminary picture of the location and type of brain imaging characteristics associated with MixD. Future imaging studies may employ region-specific hypotheses to distinguish MixD more rigorously from AD or SVaD.

Older Adults' Likelihood of Participating in Home-Based Cognitive Assessment.

INTRODUCTION: Timely detection of cognitive impairment among older adults has shown to lead to better health and financial outcomes but is hampered by psychological, financial, and physical barriers to participation in cognitive assessment. Home-based cognitive assessment (HBCA) could help overcome some of these barriers. This study aimed to examine older adults' likelihood of participation in HBCA and identify factors predicting this likelihood. MATERIALS AND METHODS: A cross-sectional online survey distributed through Amazon Mechanical Turk, was used to collect data from adults aged 50 years or older residing in the USA The survey was designed to gauge attitudes toward technology and cognitive assessment and to measure psychological variables including subjective cognitive decline (SCD), depression, and anxiety. Information on income and geographic location (rural vs. suburban and urban) was also collected. Univariate and hierarchical regression analyses were conducted to examine the contributions of these variables to a composite measure of likelihood of participation in HBCA. RESULTS: Complete data were obtained on n = 483 (age 50-79). Approximately, two-thirds of respondents described themselves as likely or very likely to participate in HBCA. In univariate analyses, younger age, higher income, higher technology assessment acceptance scores, and higher SCD burden were associated with higher likelihood of participation. Hierarchical regression revealed significant stepwise increments in explained variance: demographic variables 4.1%, technology acceptance 25.2%, assessment acceptance 15.4%, and SCD burden 1.6%. The contribution of SCD was moderated by sex and found for women but not for men. DISCUSSION/CONCLUSION: A large proportion of adults aged 50 and above described themselves likely to participate in HBCA. Middle-aged, technology-savvy, higher income adults expressed the most positive attitudes toward this type of service. Of interest is that HBCA may be particularly acceptable among older women with SCD, a group known to be at risk of cognitive decline. Our findings support the expansion of cognitive assessment services to the home setting.

Distance Assessment for Detecting Cognitive Impairment in Older Adults: A Systematic Review of Psychometric Evidence.

INTRODUCTION: Distance or remote cognitive assessments, administered via phone or computer platforms, have emerged as possible alternatives to traditional assessments performed during office visits. Distance refers to any nontraditional assessment feature, not only or necessarily location. We conducted a systematic review to examine the psychometric soundness of these approaches. METHOD: We searched PubMed, PsycINFO, AgeLine, and Academic Search Premier for articles published between January 2008 and June 2020. Studies were included if participants were over the age of 50, a structured assessment of cognitive function in older adults was evaluated, the assessment method was deemed distant, and validity and/or reliability data were reported. Assessment distance was defined as having any of the following features: use of an electronic test interface, nonroutine test location (e.g., home), test self-administered, and test unsupervised. Distance was categorized as low, intermediate, or high. RESULTS/DISCUSSION: Twenty-six studies met inclusion criteria. Sample sizes ranged from n = 8 to 8,627, and the mean age ranged from 57 to 83. Assessments included screens, brief or full batteries, and were performed via videoconferencing, phone, smartphone, or tablet/computer. Ten studies reported on low distance, 11 on intermediate distance, and 5 studies for high distance assessments. Invalid performance data were observed with older age and cognitive impairment. Convergent validity data were reported consistently and suggested a decline with increasing distance: r = 0.52-0.80 for low, 0.49-0.75 for intermediate, and 0.41-0.53 for high distance. Diagnostic validity estimates presented a similar pattern. Reliability data were reported too inconsistently to allow evaluation. CONCLUSION: The validity of cognitive assessments with older adults appears supported at lower but not higher distance. Less is known about the reliability of such assessments. Future research should delineate the person and procedure boundaries for valid and reliable test results.

Older Adults With Subjective Cognitive Decline Worry About the Emotional Impact of Cognitive Test Results.

INTRODUCTION: Older adults with subjective cognitive decline (SCD) would benefit from routine cognitive testing as they are twice as likely to develop dementia. Worries about concerning test results may diminish participation. The current study aimed to characterize the pattern of worries among older adults with and without SCD. METHODS: Adults 50 years or above completed the Attitudes Around Cognitive Testing questionnaire on Mechanical Turk.com or in a primary care setting. Mechanical Turk.com is an online crowdsourcing site where requesters (eg, researchers) post jobs (eg, surveys or tasks) and workers (eg, respondents) choose which jobs to do for pay. Respondents were asked about perceived cognitive decline and about different types of worries they anticipated having if they received concerning test results. RESULTS: We report data for 393 respondents (online: n=296, primary care: n=97), mean age of 63 years, age range of 50 to 91 years, and 60% endorsing SCD. Compared with No SCD, those with SCD anticipated a higher number of worries centered disproportionately on worries of becoming depressed, ashamed or embarrassed, feeling "stupid" and unable to do things, and being put in a nursing home. We observed this SCD pattern of worries in both samples. DISCUSSION: Individuals with SCD worry about the emotional consequences of cognitive testing. This at-risk group would benefit from interventions focused on these concerns to increase patient engagement with cognitive tests.

Quantitative assessment of field strength, total intracranial volume, sex, and age effects on the goodness of harmonization for volumetric analysis on the ADNI database.

When analyzing large multicenter databases, the effects of multiple confounding covariates increase the variability in the data and may reduce the ability to detect changes due to the actual effect of interest, for example, changes due to disease. Efficient ways to evaluate the effect of covariates toward the data harmonization are therefore important. In this article, we showcase techniques to assess the "goodness of harmonization" of covariates. We analyze 7,656 MR images in the multisite, multiscanner Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We present a comparison of three methods for estimating total intracranial volume to assess their robustness and correct the brain structure volumes using the residual method and the proportional (normalization by division) method. We then evaluated the distribution of brain structure volumes over the entire ADNI database before and after accounting for multiple covariates such as total intracranial volume, scanner field strength, sex, and age using two techniques: (a) Zscapes, a panoramic visualization technique to analyze the entire database and (b) empirical cumulative distributions functions. The results from this study highlight the importance of assessing the goodness of data harmonization as a necessary preprocessing step when pooling large data set with multiple covariates, prior to further statistical data analysis.

Predementia Brain Changes in Progranulin Mutation: A Systematic Review of Neuroimaging Evidence.

BACKGROUND: Mutations in the progranulin (GRN) gene are a major cause of familial frontotemporal dementia. They result in a loss of progranulin levels and in GRN-related brain degenerative changes that unfold over years if not decades. The aim of our review was to summarize the evidence on emerging functional and structural brain abnormalities in carriers of GRN mutations. SUMMARY: We performed a systematic search for studies that used at least one modality (structural MRI, fMRI, fluorodeoxyglucose positron emission tomography, diffusion tensor imaging) to compare mutation carriers to non-carrier controls. Our search produced 13 studies published between 2008 and 2017, the majority cross-sectional, with carrier sample sizes ranging from 5 to 65. Key Messages: The aggregate findings suggest that (1) measurable brain changes are detectable in at least some mutation carriers 20-25 years prior to disease onset; (2) functional/metabolic changes progress more consistently over time than structural changes; (3) the topographic pattern is anterior to posterior, not always asymmetric, and maps onto known functional networks.

The Impact of Covert Lacunar Infarcts and White Matter Hyperintensities on Cognitive and Motor Outcomes After Stroke.

BACKGROUND AND AIMS: In addition to overt stroke lesions, co-occurring covert lesions, including white matter hyperintensities (WMH) and covert lacunar infarcts (CLI), contribute to poststroke outcome. The purpose of this study was to examine the relationship between covert lesions, and motor and cognitive outcomes in individuals with chronic stroke. METHODS: Volumetric quantification of clinically overt strokes, covert lesions (periventricular and deep: pWMH, dWMH, pCLI, dCLI), ventricular and sulcal CSF (vCSF, sCSF), and normal appearing white (NAWM) and gray matter (NAGM) was performed using structural magnetic resonance imaging. We assessed motor impairment and function, and global cognition, memory, and other cognitive domains. When correlation analysis identified more than one MR parameter relating to stroke outcomes, we used regression modeling to identify which factor had the strongest impact. RESULTS: Neuropsychological and brain imaging data were collected from 30 participants at least 6 months following a clinically diagnosed stroke. Memory performance related to vCSF (r = -0.52, P = .004). The strongest predictor of nonmemory domains was pCLI (r2 = 0.28, P = .004). Motor impairment and function were most strongly predicted by the volume of stroke and NAWM (r2 = 0.36; P = .001), and dWMH (r2 = 0.39; P = .001) respectively. CONCLUSIONS: Covert lesion type and location have important consequences for post-stroke cognitive and motor outcome. Limiting the progression of covert lesions in aging populations may enhance the degree of recovery post-stroke.

Associations between cerebral amyloid and changes in cognitive function and falls risk in subcortical ischemic vascular cognitive impairment.

BACKGROUND: To determine the association between amyloid-beta (Aß) plaque deposition and changes in global cognition, executive functions, information processing speed, and falls risk over a 12-month period in older adults with a primary clinical diagnosis of subcortical ischemic vascular cognitive impairment (SIVCI). METHODS: This is a secondary analysis of data acquired from a subset of participants (N = 22) who were enrolled in a randomized controlled trial of aerobic exercise (NCT01027858). The subset of individuals completed an 11C Pittsburgh compound B (PIB) scan. Cognitive function and falls risk were assessed at baseline, 6-months, and 12-months. Global cognition, executive functions, and information processing speed were measured using: 1) ADAS-Cog; 2) Trail Making Test; 3) Digit Span Test; 4) Stroop Test, and 5) Digit Symbol Substitution Test. Falls risk was measured using the Physiological Profile Assessment. Hierarchical multiple linear regression analyses determined the unique contribution of Aß on changes in cognitive function and falls risk at 12-months after controlling for experimental group (i.e. aerobic exercise training or usual care control) and baseline performance. To correct for multiple comparisons, we applied the Benjamini-Hochberg procedure to obtain a false discovery rate corrected threshold using alpha = 0.05. RESULTS: Higher PIB retention was significantly associated with greater decrements in set shifting (Trail Making Test, adjusted R2 = 35.3%, p = 0.002), attention and conflict resolution (Stroop Test, adjusted R2 = 33.4%, p = 0.01), and information processing speed (Digit Symbol Substitution Test, adjusted R2 = 24.4%, p = 0.001) over a 12-month period. Additionally, higher PIB retention was significantly associated with increased falls risk (Physiological Profile Assessment, adjusted R2 = 49.1%, p = 0.04). PIB retention was not significantly associated with change in ADAS-Cog and Verbal Digit Span Test (p > 0.05). CONCLUSIONS: Symptoms associated with SIVCI may be amplified by secondary Aß pathology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01027858 , December 7, 2009.

The prevalence of depressive symptoms in frontotemporal dementia: a meta-analysis.

BACKGROUND: Depression is common in Alzheimer's and vascular dementia and is associated with poorer outcomes; however, less is known about the impact of depression on frontotemporal dementia (FTD). Here, we conducted a meta-analysis of diagnostic methods and the prevalence of depressive symptoms in FTD. METHODS: PubMed, EMBASE and PsychINFO were queried for 'depression' and/or 'depressive mood' in behavioral- and language-variant FTD. The prevalence and diagnosis of depressive symptoms were extracted from relevant studies and the results pooled using a random-effects model. RESULTS: We included 29 studies in this meta-analysis, with sample sizes ranging from 3 to 73 (n = 870). The omnibus estimated event rate of depressed mood was 0.334 (33%; 95% CI: 0.268-0.407). Symptoms were most commonly assessed via standardized neuropsychiatric rating scales, with other methods including subjective caregiver reports and chart reviews. The study results were heterogeneous due to the variability in diagnostic methods. CONCLUSIONS: Depressive symptoms similar to those in other dementias are commonly detected in FTD. However, the diagnostic methods are heterogeneous, and symptoms of depression often overlap with manifestations of FTD. Having a standardized diagnostic approach to depression in FTD will greatly facilitate future research in this area.

C-TOC (Cognitive Testing on Computer): investigating the usability and validity of a novel self-administered cognitive assessment tool in aging and early dementia.

INTRODUCTION: Cognitive Testing on Computer (C-TOC) is a novel computer-based test battery developed to improve both usability and validity in the computerized assessment of cognitive function in older adults. METHODS: C-TOC's usability was evaluated concurrently with its iterative development to version 4 in subjects with and without cognitive impairment, and health professional advisors representing different ethnocultural groups. C-TOC version 4 was then validated against neuropsychological tests (NPTs), and by comparing performance scores of subjects with normal cognition, Cognitive Impairment Not Dementia (CIND) and Alzheimer disease. C-TOC's language tests were validated in subjects with aphasic disorders. RESULTS: The most important usability issue that emerged from consultations with 27 older adults and with 8 cultural advisors was the test-takers' understanding of the task, particularly executive function tasks. User interface features did not pose significant problems. C-TOC version 4 tests correlated with comparator NPT (r=0.4 to 0.7). C-TOC test scores were normal (n=16)>CIND (n=16)>Alzheimer disease (n=6). All normal/CIND NPT performance differences were detected on C-TOC. Low computer knowledge adversely affected test performance, particularly in CIND. C-TOC detected impairments in aphasic disorders (n=11). DISCUSSION: In general, C-TOC had good validity in detecting cognitive impairment. Ensuring test-takers' understanding of the tasks, and considering their computer knowledge appear important steps towards C-TOC's implementation.

Exploring the effects of coexisting amyloid in subcortical vascular cognitive impairment.

BACKGROUND: Mixed pathology, particularly Alzheimer's disease with cerebrovascular lesions, is reported as the second most common cause of dementia. Research on mixed dementia typically includes people with a primary AD diagnosis and hence, little is known about the effects of co-existing amyloid pathology in people with vascular cognitive impairment (VCI). The purpose of this study was to understand whether individual differences in amyloid pathology might explain variations in cognitive impairment among individuals with clinical subcortical VCI (SVCI). METHODS: Twenty-two participants with SVCI completed an (11)C Pittsburgh compound B (PIB) position emission tomography (PET) scan to quantify global amyloid deposition. Cognitive function was measured using: 1) MOCA; 2) ADAS-Cog; 3) EXIT-25; and 4) specific executive processes including a) Digits Forward and Backwards Test, b) Stroop-Colour Word Test, and c) Trail Making Test. To assess the effect of amyloid deposition on cognitive function we conducted Pearson bivariate correlations to determine which cognitive measures to include in our regression models. Cognitive variables that were significantly correlated with PIB retention values were entered in a hierarchical multiple linear regression analysis to determine the unique effect of amyloid on cognitive function. We controlled for age, education, and ApoE ε4 status. RESULTS: Bivariate correlation results showed that PIB binding was significantly correlated with ADAS-Cog (p < 0.01) and MOCA (p < 0.01); increased PIB binding was associated with worse cognitive function on both cognitive measures. PIB binding was not significantly correlated with the EXIT-25 or with specific executive processes (p > 0.05). Regression analyses controlling for age, education, and ApoE ε4 status indicated an independent association between PIB retention and the ADAS-Cog (adjusted R-square change of 15.0%, Sig F Change = 0.03). PIB retention was also independently associated with MOCA scores (adjusted R-Square Change of 27.0%, Sig F Change = 0.02). CONCLUSION: We found that increased global amyloid deposition was significantly associated with greater memory and executive dysfunctions as measured by the ADAS-Cog and MOCA. Our findings point to the important role of co-existing amyloid deposition for cognitive function in those with a primary SVCI diagnosis. As such, therapeutic approaches targeting SVCI must consider the potential role of amyloid for the optimal care of those with mixed dementia. TRIAL REGISTRATION: NCT01027858.

Early neuropsychological characteristics of progranulin mutation carriers.

Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature.

Cognitive impairment in lacunar strokes: the SPS3 trial.

OBJECTIVE: Lacunar strokes are a leading cause of cognitive impairment and vascular dementia. However, adequate characterization of cognitive impairment is lacking. The aim of this study was to estimate the prevalence and characterize the neuropsychological impairment in lacunar stroke patients. METHODS: All English-speaking participants in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (National Clinical Trial 00059306) underwent neuropsychological testing at baseline. Raw scores were converted to z scores using published norms. Those with impairment (z ≤ -1.5) in memory and/or nonmemory domains were classified as having mild cognitive impairment (MCI). RESULTS: Among the 1,636 participants, average z scores on all tests were < 0, with the largest deficits seen on tests of episodic memory (range of means, -0.65 to -0.92), verbal fluency (mean, -0.89), and motor dexterity (mean, -2.5). Forty-seven percent were classified as having MCI (36% amnestic, 37% amnestic multidomain, 28% nonamnestic). Of those with modified Rankin score 0-1 and Barthel score = 100, 41% had MCI. Younger age (odds ratio [OR] per 10-year increase, 0.87), male sex (OR, 1.3), less education (OR, 0.13-0.66 for higher education levels compared to 0-4 years education), poststroke disability (OR, 1.4), and impaired activities of daily living (OR, 1.8) were independently associated with MCI. INTERPRETATION: In this large, well-characterized cohort of lacunar stroke patients, MCI was present in nearly half, including many with minimal or no physical disabilities. Cognitive dysfunction in lacunar stroke patients may commonly be overlooked in clinical practice but may be as important as motor and sensory sequelae.

A Systematic Review of Subjective Cognitive Characteristics Predictive of Longitudinal Outcomes in Older Adults.

BACKGROUND AND OBJECTIVES: Subjective cognitive decline (SCD) is a common experience of self-perceived decline without objective cognitive impairment among older adults. SCD has been conceptualized as very early Alzheimer's disease (AD), but the specific SCD features predictive of clinical or cognitive decline remain unclear. This systematic review is the first to characterize specific SCD features and their relation to longitudinal outcomes. RESEARCH DESIGN AND METHODS: Multiple electronic databases were searched from inception until August 2021 for longitudinal studies of adults aged ≥50 (mean ≥60) and free of dementia, with baseline SCD measurement and clinical or cognitive follow-up. Studies were screened for inclusion criteria and assessed for risk of bias using weight-of-evidence ratings. RESULTS: Five hundred and seventy potentially relevant studies were identified, and 52 studies were evaluated for eligibility after initial screening. Thirty-three studies with medium to high weight-of-evidence ratings were included, and results were narratively synthesized. Measurement methods varied substantially across studies: the majority (n = 27) assessed SCD symptom types and intensity, and consistently reported that a higher symptom burden increased the risk for mild cognitive impairment (MCI) and dementia. The evidence was less compelling for cognitive outcomes. A handful of studies (n = 5) suggested a predictive role for SCD symptom consistency and informant corroboration. DISCUSSION AND IMPLICATIONS: SCD symptom intensity emerged from our review as the most reliable predictor of future clinical outcomes. Combinations of SCD-Plus symptoms also had predictive utility. No single symptom was uniquely prognostic. Our findings support the quantitative evaluation of SCD symptoms in the assessment of risk for progression to MCI or dementia.

Prevalence of mild cognitive impairment and its subtypes in the Mexican population.

BACKGROUND/AIM: To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes, taking into account education and health status. METHODS: This is the first report of our Study on Aging and Dementia in Mexico. This study included 2,944 elderly individuals 60 years old or more with in-home assessment for cognitive impairment. The prevalence of MCI was based on Petersen criteria. MCI was classified as amnestic of single domain (a-MCI-s) or multiple domain (a-MCI-md) or nonamnestic of single domain (na-MCI-s) or multiple domain (na-MCI-md). In addition to a battery of neuropsychological measures, a self-report depression measure and a medical history including history of stroke, heart disease and other health conditions were recorded. RESULTS: The global estimated prevalence of MCI in the Mexican population was 6.45%. Of these subjects, 2.41% met criteria for a-MCI-s, 2.56% for a-MCI-md, 1.18% for na-MCI-s and 0.30% for na-MCl-md. Women showed a higher prevalence of MCI than men (63.7 vs. 36.3%, respectively). The analysis showed that heart disease [odds ratio (OR) 1.5], stroke (OR 1.2) and depression (OR 2.1) were associated with an increased risk of MCI. CONCLUSIONS: The prevalence of MCI in Mexico is similar to that in other countries. The results suggest that stroke, heart disease and depression may have an important role in the etiology of MCI.

Reshaping the path of mild cognitive impairment by refining exercise prescription: a study protocol of a randomized controlled trial to understand the "what," "for whom," and "how" of exercise to promote cognitive function.

BACKGROUND: Targeted exercise training is a promising strategy for promoting cognitive function and preventing dementia in older age. Despite the utility of exercise as an intervention, variation still exists in exercise-induced cognitive gains and questions remain regarding the type of training (i.e., what), as well as moderators (i.e., for whom) and mechanisms (i.e., how) of benefit. Both aerobic training (AT) and resistance training (RT) enhance cognitive function in older adults without cognitive impairment; however, the vast majority of trials have focused exclusively on AT. Thus, more research is needed on RT, as well as on the combination of AT and RT, in older adults with mild cognitive impairment (MCI), a prodromal stage of dementia. Therefore, we aim to conduct a 6-month, 2 × 2 factorial randomized controlled trial in older adults with MCI to assess the individual effects of AT and RT, and the combined effect of AT and RT on cognitive function and to determine the possible underlying biological mechanisms. METHODS: Two hundred and sixteen community-dwelling adults, aged 65 to 85 years, with MCI from metropolitan Vancouver will be recruited to participate in this study. Randomization will be stratified by biological sex and participants will be randomly allocated to one of the four experimental groups: (1) 4×/week balance and tone (BAT; i.e., active control); (2) combined 2×/week AT + 2×/week RT; (3) 2×/week AT + 2×/week BAT; or (4) 2×/week RT + 2×/week BAT. The primary outcome is cognitive function as measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus. Secondary outcomes include cognitive function, health-related quality of life, physical function, actigraphy measures, questionnaires, and falls. Outcomes will be measured at baseline, 6 months (i.e., trial completion), and 18 months (i.e., 12-month follow-up). DISCUSSION: Establishing the efficacy of different types and combinations of exercise training to minimize cognitive decline will advance our ability to prescribe exercise as "medicine" to treat MCI and delay the onset and progression of dementia. This trial is extremely timely as cognitive impairment and dementia pose a growing threat to global public health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737878 . Registered on April 14, 2016.

FDG-PET in presymptomatic C9orf72 mutation carriers.

OBJECTIVE: Our aim is to investigate patterns of brain glucose metabolism using fluorodeoxyglucose positron emission tomography (FDG-PET) in presymptomatic carriers of the C9orf72 repeat expansion to better understand the early preclinical stages of frontotemporal dementia (FTD). METHODS: Structural MRI and FDG-PET were performed on clinically asymptomatic members of families with FTD caused by the C9orf72 repeat expansion (15 presymptomatic mutation carriers, C9orf72+; 20 non-carriers, C9orf72-). Regional glucose metabolism in cerebral and cerebellar gray matter was compared between groups. RESULTS: The mean age of the C9orf72+ and C9orf72- groups were 45.3 ± 10.6 and 56.0 ± 11.0 years respectively, and the mean age of FTD onset in their families was 56 ± 7 years. Compared to non-carrier controls, the C9orf72+ group exhibited regional hypometabolism, primarily involving the cingulate gyrus, frontal and temporal neocortices (left > right) and bilateral thalami. CONCLUSIONS: The C9orf72 repeat expansion is associated with changes in brain glucose metabolism that are demonstrable up to 10 years prior to symptom onset and before changes in gray matter volume become significant. These findings indicate that FDG-PET may be a particularly sensitive and useful method for investigating and monitoring the earliest stages of FTD in individuals with this underlying genetic basis.

Promotion of the mind through exercise (PROMoTE): a proof-of-concept randomized controlled trial of aerobic exercise training in older adults with vascular cognitive impairment.

BACKGROUND: Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitive impairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is mounting that exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercise have been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training may be of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitive impairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out a proof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence of efficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mild sub-cortical ischaemic vascular cognitive impairment. METHODS/DESIGN: A proof-of-concept single-blinded randomized trial comparing a six-month, thrice-weekly, aerobic-based exercise training group with usual care on cognitive and everyday function. Seventy older adults who meet the diagnostic criteria for sub-cortical ischaemic vascular cognitive impairment as outlined by Erkinjuntti and colleagues will be recruited from a memory clinic of a metropolitan hospital. The aerobic-based exercise training will last for 6 months. Participants will be followed for an additional six months after the cessation of exercise training. DISCUSSION: This research will be an important first step in quantifying the effect of an exercise intervention on cognitive and daily function among seniors with sub-cortical ischaemic vascular cognitive impairment, a recognized risk state for progression to dementia. Exercise has the potential to be an effective, inexpensive, and accessible intervention strategy with minimal adverse effects. Reducing the rate of cognitive decline among seniors with sub-cortical ischaemic vascular cognitive impairment could preserve independent functioning and health related quality of life in this population. This, in turn, could lead to reduced health care resource utilization costs and avoidance of early institutional care.

Differentiating the frontal variant of Alzheimer's disease.

OBJECTIVE: Individuals with a clinical diagnosis of Alzheimer's disease (AD) may have prominent features of executive dysfunction and language impairment as well as behavioral abnormalities early in the disease ('high frontality'). When this occurs differentiation from frontotemporal dementia (FTD) is difficult. It is hypothesized that AD patients with high frontality may have clinical and pathological features that distinguish them from less frontal AD patients. METHODS: In a well-characterized cohort of people with cognitive impairment, we used the Frontal Behavioral Inventory (FBI) in an attempt to identify AD patients with prominent frontal features (high-FBI AD) and distinguish them from the remainder of AD patients (low-FBI AD). RESULTS: The 18 high-FBI AD patients were compared with the 26 FTD patients who had an FBI performed and the 53 other low FBI AD patients. The individual FBI items did not differ significantly between the FTD and the high-FBI AD patients, and the high FBI AD patients were more like the FTD patients than the other AD patients with respect to presence of a family history of AD, proportion with homozygous apolipoprotein E(4) status, disability as measured by the Disability Assessment for Dementia (DAD) Scale and the Functional Rating Scale (FRS) and neuropsychiatric impairment as measured by the Neuropsychiatric Inventory (NPI). Memory symptom duration was similar in the high FBI AD group compared to the low FBI AD group. CONCLUSIONS: There is a subgroup of AD patients with high frontality that can be clinically distinguished from the remainder of AD patients but which requires pathological verification.