Background and Purpose
This scientific statement provides an overview of the evidence on
vascular contributions to cognitive impairment and dementia. Vascular
contributions to cognitive impairment and dementia of later life are common.
Definitions of vascular cognitive impairment (VCI), neuropathology, basic
science and pathophysiological aspects, role of neuroimaging and vascular
and other associated risk factors, and potential opportunities for
prevention and treatment are reviewed. This statement serves as an overall
guide for practitioners to gain a better understanding of VCI and dementia,
prevention, and treatment.
Writing group members were nominated by the writing group co-chairs
on the basis of their previous work in relevant topic areas and were
approved by the American Heart Association Stroke Council Scientific
Statement Oversight Committee, the Council on Epidemiology and Prevention,
and the Manuscript Oversight Committee. The writing group used systematic
literature reviews (primarily covering publications from 1990 to May 1,
2010), previously published guidelines, personal files, and expert opinion
to summarize existing evidence, indicate gaps in current knowledge, and,
when appropriate, formulate recommendations using standard American Heart
Association criteria. All members of the writing group had the opportunity
to comment on the recommendations and approved the final version of this
document. After peer review by the American Heart Association, as well as
review by the Stroke Council leadership, Council on Epidemiology and
Prevention Council, and Scientific Statements Oversight Committee, the
statement was approved by the American Heart Association Science Advisory
and Coordinating Committee.
The construct of VCI has been introduced to capture the entire
spectrum of cognitive disorders associated with all forms of cerebral
vascular brain injury—not solely stroke—ranging from mild
cognitive impairment through fully developed dementia. Dysfunction of the
neurovascular unit and mechanisms regulating cerebral blood flow are likely
to be important components of the pathophysiological processes underlying
VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk
for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage
of the brain, and VCI. The neuropathology of cognitive impairment in later
life is often a mixture of Alzheimer disease and microvascular brain damage,
which may overlap and synergize to heighten the risk of cognitive
impairment. In this regard, magnetic resonance imaging and other
neuroimaging techniques play an important role in the definition and
detection of VCI and provide evidence that subcortical forms of VCI with
white matter hyperintensities and small deep infarcts are common. In many
cases, risk markers for VCI are the same as traditional risk factors for
stroke. These risks may include but are not limited to atrial fibrillation,
hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore,
these same vascular risk factors may be risk markers for Alzheimer disease.
Carotid intimal-medial thickness and arterial stiffness are emerging as
markers of arterial aging and may serve as risk markers for VCI. Currently,
no specific treatments for VCI have been approved by the US Food and Drug
Administration. However, detection and control of the traditional risk
factors for stroke and cardiovascular disease may be effective in the
prevention of VCI, even in older people.
Vascular contributions to cognitive impairment and dementia are
important. Understanding of VCI has evolved substantially in recent years,
based on preclinical, neuropathologic, neuroimaging, physiological, and
epidemiological studies. Transdisciplinary, translational, and transactional
approaches are recommended to further our understanding of this entity and
to better characterize its neuropsychological profile. There is a need for
prospective, quantitative, clinical-pathological-neuroimaging studies to
improve knowledge of the pathological basis of neuroimaging change and the
complex interplay between vascular and Alzheimer disease pathologies in the
evolution of clinical VCI and Alzheimer disease. Long-term vascular risk
marker interventional studies beginning as early as midlife may be required
to prevent or postpone the onset of VCI and Alzheimer disease. Studies of
intensive reduction of vascular risk factors in high-risk groups are another
important avenue of research.
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
In patients with chronic-phase traumatic brain injury (TBI), structural MRI is readily attainable and provides rich anatomical information, yet the relationship between whole-brain structural MRI measures and neurocognitive outcome is relatively unexplored and can be complicated by the presence of combined focal and diffuse injury. In this study, sixty-three patients spanning the full range of TBI severity received high-resolution structural MRI concurrent with neuropsychological testing. Multivariate statistical analysis assessed covariance patterns between volumes of grey matter, white matter, and sulcal/subdural and ventricular CSF across 38 brain regions and neuropsychological test performance. Patients with diffuse and diffuse + focal injury were analyzed both separately and together. Tests of speeded attention, working memory, and verbal learning and memory robustly covaried with a distributed pattern of volume loss over temporal, ventromedial prefrontal, right parietal regions, and cingulate regions. This pattern was modulated by the presence of large focal lesions, but held even when analyses were restricted to those with diffuse injury. Effects were most consistently observed within grey matter. Relative to regional brain volumetric data, clinically defined injury severity (depth of coma at time of injury) showed only weak relation to neuropsychological outcome. The results showed that neuropsychological test performance in patients with TBI is related to a distributed pattern of volume loss in regions mediating mnemonic and attentional processing. This relationship holds for patients with and without focal lesions, indicating that diffuse injury alone is sufficient to cause significant neuropsychological disability in relation to regional volume loss. Quantified structural brain imaging data provides a highly sensitive index of brain integrity that is related to cognitive functioning in chronic phase TBI.
Structural MRI; Neuropsychological assessment; Executive Function; Attention; Memory; Traumatic Brain Injury
Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).
With increasing knowledge of clinical in vivo biomarkers and the pathological intricacies of Alzheimer's disease (AD), nosology is evolving. Harmonized consensus criteria that emphasize prototypic illness continue to develop to achieve diagnostic clarity for treatment decisions and clinical trials. However, it is clear that AD is clinically heterogeneous in presentation and progression, demonstrating variable topographic distributions of atrophy and hypometabolism/hypoperfusion. AD furthermore often keeps company with other conditions that may further nuance clinical expression, such as synucleinopathy exacerbating executive and visuospatial dysfunction and vascular pathologies (particularly small vessel disease that is increasingly ubiquitous with human aging) accentuating frontal-dysexecutive symptomatology. That some of these atypical clinical patterns recur may imply the existence of distinct AD variants. For example, focal temporal lobe dysfunction is associated with a pure amnestic syndrome, very slow decline, with atrophy and neurofibrillary tangles limited largely to the medial temporal region including the entorhinal cortex. Left parietal atrophy and/or hypometabolism/hypoperfusion are associated with language symptoms, younger age of onset, and faster rate of decline - a potential 'language variant' of AD. Conversely, the same pattern but predominantly affecting the right parietal lobe is associated with a similar syndrome but with visuospatial symptoms replacing impaired language function. Finally, the extremely rare frontal variant is associated with executive dysfunction out of keeping with degree of memory decline and may have prominent behavioural symptoms. Genotypic differences may underlie some of these subtypes; for example, absence of apolipoprotein E e4 is often associated with atypicality in younger onset AD. Understanding the mechanisms behind this variability merits further investigation, informed by recent advances in imaging techniques, biomarker assays, and quantitative pathological methods, in conjunction with standardized clinical, functional, neuropsychological and neurobehavioral evaluations. Such an understanding is needed to facilitate 'personalized AD medicine', and eventually allow for clinical trials targeting specific AD subtypes. Although the focus legitimately remains on prototypic illness, continuing efforts to develop disease-modifying therapies should not exclude the rarer AD subtypes and common comorbid presentations, as is currently often the case. Only by treating them as well can we address the full burden of this devastating dementia syndrome.
Determine whether white matter signal fluctuation on T2* weighted BOLD contrast images are associated with aging and cerebral small vessel disease (SVD).
Resting state BOLD data were collected with a 250 ms repetition time (TR) to achieve unaliased, ungated cardiac sampled BOLD (cs-BOLD) images on 11 young adult controls, 10 healthy older adult controls and 7 adults with extensive white matter hyperintensities (WMH) from SVD. Tissue classes (WM and GM) were segmented on T1 images. WMH were identified on FLAIR images in the SVD group. Raw physiological noise (σphysio) and cardiac pulsatility (i.e. fluctuations at the cardiac frequency) were calculated voxel wise and group differences were tested by ANOVA. It was also possible to calculate σphysio in 2s TR cardiac aliased whole-brain BOLD (wb-BOLD) data (N = 84) obtained from the International Consortium for Brain Mapping.
CS-BOLD metrics showed an aging and SVD effects (p<0.0005). Covariates such as thermal noise, WM volume and partial volume did not influence the significant aging effect seen on the cardiac pulsatility metric (p<0.017) but did influence the σphysio (p = 0.184). As a verification of the cs-BOLD findings, the wb-BOLD also showed a linear aging effect of σphysio in WM. In the SVD adults, cardiac pulsatility and σphysio were lower in WMH regions compared to normal appearing white matter (NAWM) regions (p<0.0013 and p<0.002, respectively). Cardiac pulsatility was better able to distinguish WMH regions from NAWM than σphysio as measured by effect size (Cohen’s d 2.2 and 0.88, respectively).
NAWM was found to have graded increases in cardiac pulsations due to age and SVD, independently. Within SVD participants, WMH lesions had reduced physiological noise compared to NAWM. Cardiac pulsatility in resting BOLD data may provide a complementary dynamic measure of WM integrity to add to static FLAIR anatomical images.
An efficient approach to certain types of biomedical research requires a scale that precludes involvement of all critical contributors in all aspects of experimental design, execution, and as well as writing of most, if not all, derived works. Guarantors of both the integrity of the data and of its subsequent analyses are required. When separate groups are responsible for each of these activities, each should be readily identifiable both in the primary publication and in all subsequent citations. We describe the publication policy of the Alzheimer Disease Neuroimaging Initiative (ADNI), its origins and its acceptance by the editorial and scientific communities.
There is a paucity of information regarding visuospatial (VS) and visuomotor (VM) task performance in patients with chronic right fronto-parietal lobe stroke, as the majority of knowledge to date in this realm has been gleaned from acute stroke patients. The goal of this paper is to determine how VS and VM performance in chronic stroke patients compare to the performance of healthy participants.
Nine patients with stroke involving the right fronto-parietal region were evaluated against match controls on neuropsychological tests and a computerized visuomotor assessment task.
Initial evaluation indicated that performance between participant groups were relatively similar on all measures. However, an in-depth analysis of variability revealed observable differences between participant groups. In addition, large effect sizes were also observed supporting the theory that using only conventional examination (e.g., p-values) measures may result in miss-identifying crucial stroke-related differences.
Through conventional evaluation methods it would appear that the chronic stroke participants had made significant functional gains relatively to a control group many years post-stroke. It was shown that the type of evaluation used is essential to identifying group differences. Thus, supplementary methods of evaluation are required to unmask the true functional ability of individuals many years post-stroke.
Stroke; Visuospatial; Visuomotor; Variability; Functional
The antisaccade task, a hands- and language-free metric, may provide a functional index of the dorsolateral prefrontal cortex (DLPFC), a region damaged in the later stages of Alzheimer's disease (AD). Our objective was to determine if patients with mild AD made more errors relative to age-matched controls. Thirty patients with mild AD (Mini Mental Status Exam [MMSE] ≥ 17) and 31 age-matched controls completed a laptop version of the prosaccades and antisaccades tasks. Patients with AD made more antisaccade errors, and corrected fewer errors, than age-matched controls. Error rates, corrected or uncorrected, were not correlated with AD MMSE or Dementia Rating Scale scores. Our findings indicate that antisaccade impairments exist in mild AD, suggesting clinically detectable DLPFC pathology may be present earlier than suggested by previous studies.
Alzheimer's disease; dementia; executive control; saccades
Frontotemporal lobar degeneration (FTLD) often presents with asymmetric atrophy. We assessed whether premorbid occupations in FTLD patients were associated with these hemispheric asymmetries. In a multi-center chart review of 588 patients, occupation information was related to location of tissue loss or dysfunction. Patients with atrophy lateralized to the right had professions more dependent on verbal abilities than patients with left-lateralized or symmetrical atrophy. In a subgroup of 96 well-characterized patients with quantified neuroimaging data, the lateralization effect was localized to the temporal lobes and included verbal and mathematical ability. Patients whose professions placed high demands on language and mathematics had relatively preserved left temporal relative to right temporal volumes. Thus, occupation selection occurring in early adulthood is related to lateralized brain asymmetry in patients who develop FTLD decades later in the relatively deficient hemisphere. The finding suggests that verbal and mathematical occupations may have been pursued due to developmental right-lateralized functional impairment that precedes the neurodegenerative process. Alternatively, long-term engagement of activities associated with these occupations contributed to left-lateralized reserve, right-lateralized dysfunction, or both.
Frontotemporal dementia; laterality; reserve
Memantine has shown effects on cortical metabolism in Alzheimer’s disease (AD), and the mechanism of action may not be specific to AD alone. We hypothesized that participants with frontotemporal dementia taking memantine would show an increased cortical metabolic activity in frontal regions, temporal regions, or in salience network hubs.
Sixteen participants with behavioral or language variant frontotemporal dementia syndromes (FTD) were recruited from tertiary FTD clinics and treated with memantine hydrochloride 10 mg twice daily in this fixed-dose, open-label pilot study. The primary endpoint was enhancement of cortical metabolic activity after 7–8 weeks of treatment. Secondary endpoints were measures of mood and behavior disturbance, frontal executive function, and motor disturbance.
Voxel-wise parametric image analysis of positron emission tomography (PET) data from seven behavioral variant FTD patients, eight semantic dementia patients, and one progressive nonfluent aphasia patient, of mean age 64.3 years, mean duration of illness 4.25 years, and baseline mean sum of boxes Clinical Dementia Rating score 6.59, revealed an increase in [18F]-fluorodeoxyglucose (FDG) normalized metabolic activity in bilateral insulae and the left orbitofrontal cortex (P < 0.01). The increase on FDG-PET did not correlate with changes on behavioral inventories. Post hoc analysis indicated that semantic dementia participants drove this finding.
This open-label clinical PET study suggests that memantine induces an increase in metabolism in the salience network in FTD. A placebo-controlled follow-up study is warranted.
Alzheimer’s disease; frontotemporal dementia; metabolism; PET scan; semantic dementia
Background and Purpose
We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria.
This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale–Cognitive Subscale and Clinician’s Interview–Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method.
Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale–Cognitive Subscale (least-squares mean difference, −1.156; 95% CI, −1.98 to −0.33; P<0.01) but not on the Clinician’s Interview–Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group.
Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.
vascular dementia; donepezil; hippocampal atrophy; efficacy; safety
Activation of indoleamine 2,3-dioxygenase (IDO) and higher concentrations of several kynurenine metabolites have been observed post-stroke, where they have been associated with increased mortality. While lower tryptophan or a higher ratio of kynurenine/tryptophan (K/T) in peripheral blood have been associated with dementia and the severity of cognitive symptoms in Alzheimer's disease, the association between K/T ratios and post-stroke cognitive impairment (PSCI) has not been investigated.
Patients were recruited from the acute stroke unit of a general hospital within 1 month post-stroke. Assessments included the Standardized Mini-Mental State Examination (sMMSE) for cognition, the National Institutes of Health Stroke Scale (NIHSS) for stroke severity, and the Center for Epidemiological Studies-Depression Scale (CES-D) for depressive symptoms. Tryptophan and kynurenine concentrations were determined by high-performance liquid chromatography.
A total of 41 patients with ischemic stroke ([mean ± SD] age 72.3 ± 12.2 years, 53.7% male, sMMSE 25.6 ± 4.1, NIHSS 7.27 ± 5.55) were recruited. Higher K/T ratios were associated with lower post-stroke global cognition (i.e. sMMSE scores; β = -.327, P = .037). A backward stepwise elimination linear regression (F1,40=6.15, P=.005, adjusted R2=.205) showed that the highest K/T ratio tertile (β = -.412, P = .006) predicted lower sMMSE scores, controlling for age (β = -.253, p = .081), with NIHSS (β = -.027, P = 0.859), and lesion volume (β = -.066, P = 0.659) removed from the model. In receiver operating characteristic analysis, a K/T ratio of 78.3 μmol/mmol (top tertile) predicted significant cognitive impairment (sMMSE score ≤ 24) with 67% sensitivity and 86% specificity (area under the curve = 0.730, p = .022).
These data suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of kynurenine metabolites may be amenable to pharmacotherapeutic intervention, the K/T ratio may be a clinically important biomarker.
To determine whether basal ganglia atrophy known to be associated with apathy in non-dementia populations was associated with presence of apathy in patients with frontotemporal dementia (FTD).
A cross-sectional case study was conducted at two tertiary dementia care clinics in Toronto, Ontario. Striatal and thalamic grey matter volumes and apathy measures were collected from 21 subects with FTD; 6 of whom did not show apathy on the Neuropsychatric Inventory (NPI).
No significant differences in grey matter volumes were found between apathetic and non-apathetic groups for the striatum or for the thalamus.
Our findings imply that the etiology of apathy seen in FTD patients differs from that of patients with apathy after acquired injuries to the basal ganglia. Further study is needed to determine whether posterior thalamic atrophy correlates with apathy in FTD, or functional imaging techniques might successfully find a relationship between basal ganglia dysfunction and apathy.
frontotemporal dementia; basal ganglia; apathy; atrophy
Apathy is a very common and significant problem in patients with dementia, regardless of etiology. Observations on frontosubcortical circuit (FSC) syndromes indicate that apathy may have affective, behavioral or cognitive manifestations. We explored whether the apathy manifested in frontotemporal dementia (FTD) with its predominantly anterior brain neuropathology differs from the apathy in Alzheimer's disease (DAT) with its predominantly hippocampal and temporoparietal-based neuropathology. We also sought to determine whether other behavioral disturbances reported in FSC syndromes correlate with apathy.
Survey. Analyses included individual items within Neuropsychiatric Inventory (NPI) subscale items. Items of the Apathy/Indifference subscale were designated by consensus as: A) affective = lacking in emotions, B) behavioral = inactive, chores abandoned or C) cognitive = no interest in others' activities. Proportions of correlated non-apathy NPI items were calculated and displayed using Chernoff faces to facilitate comparison of apathy domains and dementia diagnoses.
Setting and Patients:
Several neurology specialty clinics contributed to our dataset of 92 participants with FTD and 457 with DAT.
Apathy was more prevalent in FTD than DAT, but when present, the specific apathy symptoms in both dementias were rarely restricted to one of the three domains of apathy. Dysphoria concurrent with apathy was unique to the DAT group and negatively correlated in FTD. Participants with affective apathy more frequently co-presented with an orbitofrontosubcortical syndrome in FTD (impulsivity and compulsions). Affective apathy also co-presented with uncooperative agitation, anger, and physical agitation in both dementias.
Apathy is common in FTD and in DAT, although it is more common in FTD. When present, it usually involves changes in affect, behavior, and cognition. It is associated with behaviors that have previously been shown to impact on patient safety, independence and quality of life.
Alzheimer's Disease; Apathy; Frontotemporal Dementia; Frontotemporal Degeneration
Investigators frequently quantify and evaluate the location and size of stroke lesions to help uncover cerebral anatomical correlates of deficits observed after first-ever stroke. However, it is common to discover silent infarcts such as lacunes in patients identified clinically as 'first-ever' stroke, and it is unclear if including these incidental findings may impact lesion-based investigations of brain-behaviour relationships. There is also debate concerning how to best define the boundaries of necrotic stroke lesions that blend in an ill-defined way into surrounding tissue, as it is unclear whether including this altered peri-necrotic tissue region may influence studies of brain-behaviour relationships. Therefore, for patients with clinically overt stroke, we examined whether including altered peri-necrotic tissue and incidental silent strokes influenced either lesion volume correlations with a measure of sensorimotor impairment or the anatomical localization of this impairment established using subtraction lesion analysis.
Chronic stroke lesions of 41 patients were manually traced from digital T1-MRI to sequentially include the: necrotic lesion core, altered peri-necrotic tissue, silent lesions in the same hemisphere as the index lesion, and silent lesions in the opposite hemisphere. Lesion volumes for each region were examined for correlation with motor impairment scores, and subtraction analysis was used to highlight anatomical lesion loci associated with this deficit.
For subtraction lesion analysis, including peri-necrotic tissue resulted in a larger region of more frequent damage being seen in the basal ganglia. For correlational analysis, only the volume of the lesion core was significantly associated with motor impairment scores (r = -0.35, p = 0.025). In a sub-analysis of patients with small subcortical index lesions, adding silent lesions in the opposite hemisphere to the volume of the index stroke strengthened the volume-impairment association.
Including peri-necrotic tissue strengthened lesion localization analysis, but the influence of peri-necrotic tissue and incidental lesions on lesion volume correlations with motor impairment was negligible barring a small index lesion. Overall, the potential influence of incidental lesions and peri-necrotic tissue on brain-behaviour relationships may depend on the characteristics of the index stroke and on whether one is examining the relationship between lesion volume and impairment or lesion location and impairment.
This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimer's disease (AD) and Lewy body disease (LBD) as it pertains to the use of cholinesterase inhibitors (ChEI). AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs.
Alzheimer's disease; cholinesterase inhibitors; endophenotype; Lewy body disease; neuroimaging; pharmacogenetics
People with vascular risk factors are at increased risk for cognitive impairment as well as vascular disease. The objective of this study was to evaluate whether vascular risk factor clinical practice guidelines consider cognition as an outcome or in connection with treatment compliance.
Articles from PubMed, EMBASE, and the Cochrane Library were assessed by at least two reviewers and were included if: (1) Either hypertension, high cholesterol, diabetes, or atrial fibrillation was targeted; (2) The guideline was directed at physicians; (3) Adult patients (aged 19 years or older) were targeted; and (4) The guideline was published in English. Of 91 guidelines, most were excluded because they were duplicates, older versions, or focused on single outcomes.
Of the 20 clinical practice guidelines that met inclusion criteria, five mentioned cognition. Of these five, four described potential treatment benefits but only two mentioned that cognition may affect compliance. No guidelines adequately described how to screen for cognitive impairment.
Despite evidence that links cognitive impairment to vascular risk factors, only a minority of clinical practice guidelines for the treatment of vascular risk factors consider cognition as either an adverse outcome or as a factor to consider in treatment.
clinical practice guidelines; evidence-based medicine; vascular risk; cognition; target organ damage
It has been unclear to what extent memory is affected in frontotemporal lobar degeneration (FTLD). Since patients usually have atrophy in regions implicated in memory function, the frontal and/or temporal lobes, one would expect some memory impairment, and that the degree of atrophy in these regions would be inversely related to memory function. The purposes of this study were 1) to assess episodic memory function in FTLD, and more specifically patients' ability to episodically re-experience an event, and determine its source; 2) to examine whether memory performance is related to quantified regional brain atrophy. FTLD patients (n=18) and healthy comparison subjects (n=14) were assessed with cued recall, recognition, “remember/know” (self-reported re-experiencing) and source recall, at 30 min and 24 hr after encoding. Regional gray matter volumes were assessed with high resolution structural MRI concurrently to testing. Patients performed worse than comparison subjects on all memory measures. Gray matter volume in the left medial temporal lobe was positively correlated with recognition, re-experiencing, and source recall. Gray matter volume in the left posterior temporal lobe correlated significantly with recognition, at 30 min and 24 hr, and with source recall at 30 min. Estimated familiarity at 30 min was positively correlated with gray matter volume in the left inferior parietal lobe. In summary, episodic memory deficits in FTLD may be more common than previously thought, particularly in patients with left medial and posterior temporal atrophy.
episodic memory; recollection; familiarity; frontotemporal dementia; MRI; temporal lobe; parietal lobe; atrophy
Ventral frontal cortex is commonly involved in traumatic brain injury (TBI). The Smell Identification Test (SIT), Object Alternation (OA), and the Iowa Gambling Task (IGT) are associated with this brain region in experimental and neuropsychological research. We examined the relationship of performance on these tests to residual structural brain integrity quantified from MRI in 58 TBI patients, including 18 patients with focal cortical contusions and 40 patients with diffuse injury only. Image analysis yielded regional volumetric measures of gray matter, white matter and cerebrospinal fluid. Multivariate analyses identified distributed patterns of regional volume loss associated with test performance across all three behavioral measures. The tasks were sensitive to effects of TBI. In multivariate analyses, performance in all three tasks was related to gray matter loss including ventral frontal cortex, but the SIT was most sensitive to ventral frontal cortex damage, even in patients without focal lesions. The SIT was further related to temporal lobe and posterior cingulate/retrosplenial volumes. OA and the IGT were associated with superior medial frontal volumes. Complex tasks, such as OA and the IGT, do not consistently localize to a single cortical region. The SIT is associated with the integrity of ventral frontal regions, but it is also affected by distributed damage, although the contribution of undetected olfactory tract or bulb damage could not be ruled out. This study illustrates the scope and limitations of functional localization in human ventral frontal cortex.
Head injury; diffuse axonal injury; focal lesions; neuropsychology; orbitofrontal cortex; partial least squares analysis
Depressive symptoms of varying severity are prevalent in up to 63% of Alzheimer disease (AD) patients and often result in greater cognitive decline and increased caregiver burden. The current study aimed to determine the neural correlates of depressive symptoms in a sample of AD patients.
Using the Cornell Scale for Depression in Dementia, we assessed 56 patients who met criteria for probable AD. Data obtained from Technetium-99m ethyl cysteinate dimer single photon emission computed tomography (SPECT) were analyzed with the use of a magnetic resonance imaging–derived region of interest (ROI) anatomic template before and after atrophy correction and statistical parametric mapping (SPM). The following 4 frontal ROIs were investigated bilaterally: middle frontal gyrus (Brodmann's area [BA] 46), orbitofrontal cortex (BA 11), superior prefrontal (BA 8/9) and anterior cingulate (BA 24/25/32/33).
Depressive symptoms were present in 27 of the AD patients (48%). Patients with depressive symptoms showed less perfusion in the right superior and bilateral middle frontal gyri (p < 0.005), left superior frontal (p < 0.05) and anterior cingulate gyri (p < 0.005) before atrophy correction. SPM analyses revealed significantly lower perfusion in bilateral dorsolateral and superior prefrontal cortex of patients with depressive symptoms (right, p < 0.005; left, p < 0.05). SPECT ROI analyses with atrophy correction revealed trends similar to data without atrophy correction but did not reach statistical significance.
In this study, depressive symptoms in AD patients were associated with relative hypoperfusion in the prefrontal cortex when they were compared with AD patients without depressive symptoms. These findings are consistent with previous reports in studies of primary depression suggesting that these regions are involved in affect and emotional regulation.
Alzheimer disease; depression; tomography, emission-computed, single-photon; magnetic resonance imaging
We examined autobiographical memory performance in two patients with semantic dementia using a novel measure, the Autobiographical Interview [Levine, Svoboda, Hay, Winocur, & Moscovitch (2002). Aging and autobiographical memory: Dissociating episodic from semantic retrieval. Psychology and Aging, 17, 677–689], that is capable of dissociating episodic and personal semantic recall under varying levels of retrieval support. Earlier reports indicated that patients with semantic dementia demonstrate autobiographical episodic memory loss following a “reverse gradient” by which recent memories are preserved relative to remote memories. We found limited evidence for this pattern at conditions of low retrieval support. When structured probing was provided, patients’ autobiographical memory performance was similar to that of controls. Retesting of one patient after 1 year indicated that retrieval support was insufficient to bolster performance following progressive prefrontal volume loss, as documented with quantified structural neuroimaging. These findings are discussed in relation to theories of limbic-neocortical interaction in autobiographical memory.
Episodic; Semantic; Temporal neocortex; Frontal lobes
Quantitative neuroimaging is increasingly used to study the effects of traumatic brain injury (TBI) on brain structure and function. This paper reviews quantitative structural and functional neuroimaging studies of patients with TBI, with an emphasis on the effects of diffuse axonal injury (DAI), the primary neuropathology in TBI. Quantitative structural neuroimaging has evolved from simple planometric measurements through targeted region-of-interest analyses to whole-brain analysis of quantified tissue compartments. Recent studies converge to indicate widespread volume loss of both gray and white matter in patients with moderate-to-severe TBI. These changes can be documented even when patients with focal lesions are excluded. Broadly speaking, performance on standard neuropsychological tests of speeded information processing are related to these changes, but demonstration of specific brain-behavior relationships requires more refined experimental behavioral measures. The functional consequences of these structural changes can be imaged with activation functional neuroimaging. Although this line of research is at an early stage, results indicate that TBI causes a more widely dispersed activation in frontal and posterior cortices. Further progress in analysis of the consequences of TBI on neural structure and function will require control of variability in neuropathology and behavior.
diffuse axonal injury; magnetic resonance imaging, neuroplasticity; neuropsychology