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1.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).
To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.
Design and Setting
A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.
Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants.
Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing.
Main Outcome Measures
Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.
Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.
Conclusions and Relevance
In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
PMCID: PMC3771392  PMID: 23400560
2.  Antihypertensive therapy and cerebral hemodynamics in Executive Mild Cognitive Impairment: results of a Pilot randomized clinical trial 
Journal of the American Geriatrics Society  2013;61(2):10.1111/jgs.12100.
The comparative effects of antihypertensive therapy on cerebral hemodynamics in the contest of cognitive decline related to hypertension are unknown.
To compare antihypertensive medicationsthat modulate the renin angiotensin system in cerebral hemodynamic and cognitive effects in hypertensive individuals with executive dysfunction.
double-blind randomized clinical trial.
Subjects were ≥60 years with hypertension and executive dysfunction.
lisinopril, candesartan, or hydrochlorothiazide for 1 year
Cerebral blood flow velocity (Transcranial Doppler ultrasonography during rest, sitting, standing, hypercapnia, and hypocapnia), cognition and blood pressure were measured at baseline, 6 and 12 months. Linear mixed models were used to compare the3 groups.
Of the 53 enrolled, 47 had successful insonation (mean age=72 years; 70% white; 57% women). There was a tendency for increased blood flow velocity (BFV) in the candesartan groupcompared to a decline in the lisinopril or HCTZ groups (between group p-value =0.57). This was significant in those with relative low BFV at baseline (
This pilot study suggests that angiotensin receptor blockers may preferentially preserve cerebral hemodynamics and improved executive function in those with executive dysfunction. These findings warrant further investigation in a larger trial.
PMCID: PMC3608194  PMID: 23350899
angiotensin receptor blocker; cerebrovascular circulation; executive function hemodynamics; hypertension
PLoS ONE  2014;9(1):e87747.
The purpose of this preliminary study was to test the hypothesis that subsyndromal depression is associated with the volume of medial prefrontal regional gray matter and that of white matter lesions (WMLs) in the brains of cognitively normal older people. We also explored the relationships between subsyndromal depression and medial prefrontal regional gray matter volume, limbic regional gray matter volume, and lobar WMLs in the brains of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We performed a cross-sectional study comparing patients with subsyndromal depression and nondepressed controls with normal cognition (n = 59), MCI (n = 27), and AD (n = 27), adjusting for sex, age, years of education, and results of the Mini-Mental State Examination. Frontal WML volume was greater, and right medial orbitofrontal cortical volume was smaller in cognitively normal participants with subsyndromal depression than in those without subsyndromal depression. No volume differences were observed in medial prefrontal, limbic, or WML volumes according to the presence of subsyndromal depression in cognitively impaired patients. The absence of these changes in patients with MCI and AD suggests that brain changes associated with AD pathology may override the changes associated with subsyndromal depression.
PMCID: PMC3909227  PMID: 24498184
Background and Purpose
To investigate whether the Framingham Cardiovascular Risk Profile (FCRP) and carotid artery intima-media thickness (CIMT) are associated with cortical volume and thickness.
Consecutive subjects participating in a prospective cohort study of aging and mild cognitive impairment enriched for vascular risk factors for atherosclerosis underwent structural MRI scans at 3T and 4T MRI at three sites. Freesurfer (v5.1) was used to obtain regional measures of neocortical volumes (mm3) and thickness (mm). Multiple linear regression was used to determine the association of FCRP and CIMT with cortical volume and thickness
152 subjects (82 men) were aged 78 (±7) years old, 94 had a CDR of 0, 58 had a clinical dementia rating (CDR) of 0.5 and the mean mini-mental status examination (MMSE) was 28 ± 2. FCRP score was inversely associated with total gray matter (GM) volume, parietal and temporal GM volume (adjusted p<0.04). FCRP was inversely associated with parietal and total cerebral GM thickness (adjusted p<0.03). CIMT was inversely associated with thickness of parietal GM only (adjusted p=0.04). Including history of myocardial infarction or stroke and radiologic evidence of brain infarction, or apoE genotype did not alter relationships with FCRP or CIMT.
Increased cardiovascular risk was associated with reduced GM volume and thickness in regions also affected by Alzheimer’s disease (AD), independent of infarcts and apoE genotype. These results suggest a “double hit” toward developing dementia when someone with incipient AD also has high cardiovascular risk.
PMCID: PMC3732460  PMID: 22984010
Framingham cardiovascular risk profile; carotid intima media thickness; gray matter; cortical volume; cortical thickness; atrophy
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.
PMCID: PMC3778669  PMID: 21778438
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
Neurobiology of Aging  2011;33(9):1979-1987.
This study investigated the hypothesis that vascular risk factors are amyloidogenic. Participants were 43 persons, most with normal cognition or mild cognitive impairment. Vascular risk was quantified using the Framingham Coronary Risk Profile score (FCRP). Cerebral amyloid was measured by 11C-PIB PET and quantified with a Global PIB index, which is the average of distribution volume ratios in selected cortical regions of interest. In a bivariate model FCRP accounted for 16% of the variance in PIB index (p < .008) and the positive association remained significant controlling for age and sex. The effect of FCRP was independent of APOE genotype, which was also associated as expected with PIB. Carotid intima-media thickness was not associated with PIB index. Effects of individual FCRP component risk factors, cholesterol and glycemic status on PIB index were all non-significant, suggesting an aggregate effect of risk factors. Although this is a correlational observation it may represent a causal relationship as there are multiple, plausible, amyloidogenic mechanisms of vascular risk factors.
PMCID: PMC3371309  PMID: 22078485
vascular risk factors; coronary risk factors; cerebral amyloid; Mild Cognitive Impairment; Normal Aging; Alzheimer’s disease
Coppola, Giovanni | Chinnathambi, Subashchandrabose | Lee, Jason JiYong | Dombroski, Beth A. | Baker, Matt C. | Soto-Ortolaza, Alexandra I. | Lee, Suzee E. | Klein, Eric | Huang, Alden Y. | Sears, Renee | Lane, Jessica R. | Karydas, Anna M. | Kenet, Robert O. | Biernat, Jacek | Wang, Li-San | Cotman, Carl W. | DeCarli, Charles S. | Levey, Allan I. | Ringman, John M. | Mendez, Mario F. | Chui, Helena C. | Le Ber, Isabelle | Brice, Alexis | Lupton, Michelle K. | Preza, Elisavet | Lovestone, Simon | Powell, John | Graff-Radford, Neill | Petersen, Ronald C. | Boeve, Bradley F. | Lippa, Carol F. | Bigio, Eileen H. | Mackenzie, Ian | Finger, Elizabeth | Kertesz, Andrew | Caselli, Richard J. | Gearing, Marla | Juncos, Jorge L. | Ghetti, Bernardino | Spina, Salvatore | Bordelon, Yvette M. | Tourtellotte, Wallace W. | Frosch, Matthew P. | Vonsattel, Jean Paul G. | Zarow, Chris | Beach, Thomas G. | Albin, Roger L. | Lieberman, Andrew P. | Lee, Virginia M. | Trojanowski, John Q. | Van Deerlin, Vivianna M. | Bird, Thomas D. | Galasko, Douglas R. | Masliah, Eliezer | White, Charles L. | Troncoso, Juan C. | Hannequin, Didier | Boxer, Adam L. | Geschwind, Michael D. | Kumar, Satish | Mandelkow, Eva-Maria | Wszolek, Zbigniew K. | Uitti, Ryan J. | Dickson, Dennis W. | Haines, Jonathan L. | Mayeux, Richard | Pericak-Vance, Margaret A. | Farrer, Lindsay A. | Ross, Owen A. | Rademakers, Rosa | Schellenberg, Gerard D. | Miller, Bruce L. | Mandelkow, Eckhard | Geschwind, Daniel H.
Human Molecular Genetics  2012;21(15):3500-3512.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
PMCID: PMC3392107  PMID: 22556362
PLoS ONE  2013;8(6):e65175.
The goal of this study was to assess the relationship between Aβ deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 78±7 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0–0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume >0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Aβ deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Aβ deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Aβ deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE ε4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue.
PMCID: PMC3675157  PMID: 23762308
Neurobiology of Aging  2011;33(5):1006.e25-1006.e36.
The present study evaluated cerebrovascular disease (CVD), β-amyloid (Aβ), and cognition in clinically normal elderly adults. Fifty-four participants underwent MRI, PIB-PET imaging, and neuropsychological evaluation. High white matter hyperintensity burden and/or presence of infarct defined CVD status (CVD−: N = 27; CVD+: N = 27). PIB-PET ratios of Aβ deposition were extracted using Logan plotting (cerebellar reference). Presence of high levels of Aβ in prespecified regions determined PIB status (PIB−: N = 33; PIB+: N = 21). Executive functioning and episodic memory were measured using composite scales. CVD and Aβ, defined as dichotomous or continuous variables, were unrelated to one another. CVD+ participants showed lower executive functioning (P = 0.001) when compared to CVD− individuals. Neither PIB status nor amount of Aβ affected cognition (Ps ≥ .45), and there was no statistical interaction between CVD and PIB on either cognitive measure. Within this spectrum of normal aging CVD and Aβ aggregation appear to be independent processes with CVD primarily affecting cognition.
PMCID: PMC3274647  PMID: 22048124
PIB; cerebrovascular disease; episodic memory; executive functioning; cognition
Archives of neurology  2012;69(12):1632-1638.
Angiotensin II may be involved in amyloid metabolism in the brain. Angiotensin receptor blockers (ARB) may also prevent cognitive decline. We evaluated the impact of ARBs on the neuropathology in the National Alzheimer’s Coordinating Center (NACC) database which includes aggregated data and brain autopsies from 29 Alzheimer’s Disease Centers throughout the USA.
Data from Participants were self- or provider-referred and included those with and without cognitive disorders. Our sample included hypertensive participants and excluded cognitively and neuro-pathologically normal participants (n=890, mean (range) age at death 81 (39–107) years, 43% women, 94% white). Neuropathological data included neuritic plaque and neurofibrillary tangle densities assessed by NIA-Reagan criteria and vascular injury markers. Multiple logistic regression was used to compare the pathological findings in subjects on ARBs to other antihypertensive treatment and to those who did not receive antihypertensive medications.
Participants who were exposed to ARBs, with or without AD, showed less amyloid deposition markers compared to those treated with other antihypertensives (lower CERAD OR=0.47, 95% confidence interval =0.27 to 0.81; ADRDA OR=0.43, CI=0.21 to 0.91; BRAAK & BRAAK OR=0.52, CI= 0.31 to 0.85; neuritic plaques OR=0.59, CI=0.37 to 0.96). They also had less AD-related pathology compared to untreated hypertensives. Participants receiving ARBs were more likely to have had a stroke and hence had more frequent pathological evidence of large vessel infarct and hemorrhage.
Treatment with ARBs is associated with less AD-related pathology on autopsy evaluations. The effect of ARBs on cognitive decline in those with dementia or AD needs further investigation.
PMCID: PMC3608189  PMID: 22964777
White matter hyperintensities (WMH) and silent brain infarcts (SBI) have been associated with both vascular factors and cognitive decline. We examined among cognitively normal elderly, whether vascular factors predict cognitive decline and whether these associations are mediated by MRI measures of subclinical vascular brain injury.
Prospective multi-site longitudinal study of subcortical ischemic vascular diseases
Memory and aging centers in California
We studied 74 participants who were cognitively normal at entry and received at least 2 neuropsychological evaluations and 2 MRI exams over an average follow-up of 6.9 years.
Item response theory was used to create composite scores of global, verbal memory, and executive functioning. Volumetric MRI measures included WMH, SBI, hippocampus, and cortical gray matter (CGM). We used linear mixed effects models to examine the associations between vascular factors, MRI measures, and cognitive scores.
History of coronary artery disease (CAD) was associated with greater declines in global, verbal memory, and executive cognition. The CAD associations remained after controlling for changes in WMH, SBI, hippocampal and CGM volumes.
History of CAD may be a surrogate marker for clinically significant atherosclerosis which also affects the brain. Structural MRI measures of WMH and SBI do not fully capture the potential adverse effects of atherosclerosis on the brain. Future longitudinal studies of cognition should incorporate direct measures of atherosclerosis in cerebral arteries, as well as more sensitive neuroimaging measures.
PMCID: PMC3302932  PMID: 22283410
cognitively normal elderly; coronary artery disease; cognitive decline; MRI
This chapter focuses on the role that personal risk and resilience factors play as adults of all ages cope with the stressors encountered in everyday life. Theorists have suggested that researchers should focus on the effects of daily stress and coping rather than focusing exclusively on major life events and chronic stress and have proposed that understanding how adults cope with daily stress is a key aspect of understanding long-term well-being and adaptation in adulthood. After presenting a conceptual model outlining the major components of the daily stress process, the chapter reviews the existing empirical literature on personal risk and resilience factors in the context of daily stress. This research clearly suggests that there is no universal generalization that can be made regarding whether chronological age, in and of itself, confers greater vulnerability or resilience onto adults. Instead, we argue that researchers should ask when and under what conditions is age associated with greater vulnerability to daily stress and when and under what conditions is age associated with greater resilience to daily stress. Age differences in reactivity to daily stress are clearly embedded within a complex system of factors—structural, individual, and situational—that influence stress reactivity and stress recovery in several ways. This complexity should not be taken to mean that stress reactivity and recovery cannot be charted or understood. Researchers, however, will need to approach this complexity with a great deal of theoretical, methodological, and statistical rigor to move our understanding of the importance of age in shaping risk and resilience to daily stress forward. The final section of the chapter outlines several directions for future research in the area of aging and resilience. In particular, we argue that a focus on personal risk and resilience factors in the context of daily stress, in combination with the application of sophisticated statistical methods (e.g., dynamic systems modeling), will contribute to a more dynamic and person-centered understanding of processes of resilience.
PMCID: PMC3462024  PMID: 23049156
BMC Neurology  2012;12:83.
To test the hypothesis that white matter lesions (WML) are primarily associated with regional frontal cortical volumes, and to determine the mediating effects of these regional frontal cortices on the associations of WML with depressive symptoms and cognitive dysfunction.
Structural brains MRIs were performed on 161 participants: cognitively normal, cognitive impaired but not demented, and demented participants. Lobar WML volumes, regional frontal cortical volumes, depressive symptom severity, and cognitive abilities were measured. Multiple linear regression analyses were used to identify WML volume effects on frontal cortical volume. Structural equation modeling was used to determine the MRI-depression and the MRI-cognition path relationships.
WML predicted frontal cortical volume, particularly in medial orbirtofrontal cortex, irrespective of age, gender, education, and group status. WML directly predicted depressive score, and this relationship was not mediated by regional frontal cortices. In contrast, the association between WML and cognitive function was indirect and mediated by regional frontal cortices.
These findings suggest that the neurobiological mechanisms underpinning depressive symptoms and cognitive dysfunction in older adults may differ.
PMCID: PMC3482604  PMID: 22920586
Leukoaraiosis; Depression; Cognition; Frontal lobe; Mediation
The Montreal Cognitive Assessment Chinese-Language Los Angeles version (MoCA-ChLA) was developed and administered during an in-home interview to 1,192 participants (mean age 62.5 years, mean education 11.6 years) in a population-based Chinese American Eye Study (CHES) in Los Angeles. The MoCA-ChLA score (mean ± SD) was 23.8 ± 4.2 with little ceiling and no floor effects. The score increased with higher education, decreased with advancing age, and was not related to gender. Compared to the education 1–6 years group, the mean MoCA-ChLA score was 2.6 and 4.6 higher in the education 7–11 and 12–20 years groups, respectively. The Mandarin- (n = 612) and Cantonese- (n = 612) speaking subgroups performed comparably; Cronbach's alpha of the MoCA-ChLA score was 0.78 and 0.79 for these two groups, respectively. Item response theory analysis showed good discriminating power for executive function and memory. These properties support the MoCA-ChLA as a useful screening tool for aging and dementia studies for Mandarin or Cantonese speakers.
PMCID: PMC3399373  PMID: 22830073
Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.
PMCID: PMC3471388  PMID: 22182734
Brain and Behavior  2012;2(4):435-442.
Hippocampal sclerosis (HS) is a common and often asymmetric neuropathological finding among elderly persons who experience progressive memory loss, but its cause is unknown and it is rarely diagnosed during life. In order to improve both understanding and diagnosis of late-life HS, bilateral hippocampi and cerebral hemispheres were reviewed in 130 consecutive autopsy cases drawn from a longitudinal study of subjects with subcortical ischemic vascular dementia (IVD), Alzheimer disease (AD) and normal aging. HS was found in 31 of 130 cases (24.5%). Of these, 45% were bilateral, 32% left-sided, and 23% right-sided. The majority of HS cases involved the entire rostral-caudal extent of the hippocampus. However, in 7 cases HS was focal in nature and was only found at or anterior to the lateral geniculate nucleus. In 77% of cases, HS was accompanied by other types of pathology (‘mixed’ HS), but in 23% of cases it was the sole neuropathologic finding (‘pure’ HS). TDP-43-positive cytoplasmic inclusions were found in dentate granule cells in 93% of all HS cases, 55% of AD cases with no HS, but 0% of IVD cases with no HS. MRI hippocampal volumes were significantly lower in bilateral HS compared to AD (p < 0.001) and in unilateral HS cases compared to cases with intact hippocampi (p < 0.001). Since HS may occur unilaterally in approximately a quarter of cases, its prevalence may be underestimated if only one cerebral hemisphere is examined. The presence of TDP-43 inclusions in HS cases, regardless of accompanying pathologies (e.g., AD, IVD, FTLD), is consistent with an underlying neurodegenerative pathogenetic mechanism. Further studies are warranted to determine whether greater severity of hippocampal atrophy on MRI may assist the clinical differentiation of HS from AD.
PMCID: PMC3432966  PMID: 22950047
Hippocampal volume; MRI; neurology; neuroscience; TDP-43
Neurogenetics  2006;7(4):277-279.
Nine families with autosomal dominant Alzheimer’s disease (AD), all of whom had the Ala431Glu substitution in the PSEN1 gene and came from Jalisco State in Mexico, have been previously reported. As they shared highly polymorphic flanking dinucleotide marker alleles, this strongly suggests that this mutation arose from a common founder. In the current letter, we expand this observation by describing an additional 15 independent families with the Ala431Glu substitution in the PSEN1 gene and conclude that this mutation is not an uncommon cause of early-onset autosomal dominant AD in persons of Mexican origin.
PMCID: PMC3378247  PMID: 16897084
Presenilin-1; Mexican; Founder effect; A431E; Ala431Glu; Alzheimer’s disease
This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment/dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor regulating prevalence estimates of Alzheimer’s disease (AD) is the severity of cognitive impairment used for case ascertainment. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than studies aimed at identifying persons in the earliest stages of AD. There is limited autopsy data from the above-mentioned epidemiologic studies to address accuracy in the diagnosis of etiologic subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment (MCI) meet pathologic criteria for AD, and a large minority of persons without dementia or MCI also meets pathologic criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the highest published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiologic studies.
PMCID: PMC3039838  PMID: 21255742
Alzheimer’s disease; Dementia; Mild cognitive impairment; Cognitive impairment not dementia; Diagnostic criteria; Population-based; Prevalence, Incidence
Psychiatry research  2010;181(2):90.
Depressed mood is a frequent co-morbidity of dementia suggesting that they might share a common neuropathological substrate. Gray matter (GM) atrophy and white matter lesions (WML) have been described in both conditions. Our aims were to determine the relationship of GM and WML with cognition and depressed mood in the same population. Structural brain images were obtained from 42 controls, 20 Alzheimer’s disease (AD) patients and 32 subjects with cognitive impairment/dementia due to subcortical cerebrovascular disease (vascCIND/IVD) and segmented to obtain lobar GM, white matter and WML volumes. Lobar WML had a negative effect on GM in all lobes in controls, on frontal, parietal and occipital GM in AD and on frontal GM in vascCIND/IVD. Frontal, temporal and hippocampal GM were associated with cognitive functions and frontal WML load with depressed mood. Cognitive function is associated with GM atrophy and depressed mood is associated with frontal WML. This indicates that although both often occur together depressed mood and cognitive impairment are caused by different pathological correlates.
PMCID: PMC2814971  PMID: 20074914
white matter lesion; gray matter atrophy; depression; mood; cognition; MRI
The Clinical neuropsychologist  2008;23(3):446-461.
Impaired everyday function is a diagnostic criterion for dementia, and a determinant of healthcare utilization and caregiver burden. Although many previous studies have demonstrated a cross-sectional relationships between cognition (particularly executive functions and memory) and everyday function in older adults, very little is known about longitudinal relationships between these domains. This study examined the association between longitudinal change in episodic memory (MEM) and executive functioning (EXEC) and change in everyday function. Participants were a cognitively heterogeneous group of 100 elderly persons including those with normal cognition, as well as those with mild cognitive impairment and dementia. They were followed for an average of five years. Random effects modeling showed that change in both MEM and EXEC were independently associated with rate of change in informant-rated instrumental activities of daily living (IADLs), even after controlling for age, education, and gender. Findings indicate that declines in MEM and EXEC over time make unique and independent contributions to declines in older adults’ ability to function in daily life.
PMCID: PMC2881703  PMID: 18821181
Memory; Executive functioning; Everyday Function; dementia; Alzheimer’s disease
Impaired ability to conduct daily activities is a diagnostic criterion for dementia and a determinant of healthcare services utilization and caregiver burden. What predicts decline in instrumental activities of daily living (IADLs) is not well understood. This study examined measures of episodic memory, executive function, and MRI brain volumes in relation to baseline IADLs and as predictors of rate of IADL change. Participants were 124 elderly persons with cognitive function between normal and moderate dementia both with and without significant small vessel cerebrovascular disease. Random effects modeling showed that baseline memory and executive function (EXEC) were associated with baseline IADL scores, but only EXEC was independently associated with rate of change in IADLs. Whereas hippocampal and cortical gray matter volumes were significantly associated with baseline IADL scores, only hippocampal volume was associated with IADL change. In a model including cognitive and neuroimaging predictors, only EXEC independently predicted rate of decline in IADL scores. These findings indicate that greater executive dysfunction at initial assessment is associated with more rapid decline in IADLs. Perhaps executive function is particularly important with respect to maintaining IADLs. Alternatively, executive dysfunction may be a sentinel event indicating widespread cortical involvement and poor prognosis.
PMCID: PMC2877031  PMID: 17521485
Alzheimer’s disease; Vascular dementia; Memory; Everyday function; Neuroimaging; Frontal lobe
The American journal of psychiatry  2010;167(5):589-597.
The authors examined predictors of mortality in individuals age 50 or older with or without cognitive impairment in a 12-year prospective naturalistic study of subcortical ischemic vascular disease focusing on symptoms of depressed mood, apathy, anhedonia, or anergia.
A total of 498 participants were recruited from the community and from memory clinics into a multicenter longitudinal study of subcortical ischemic vascular disease. For baseline cognitive status, 36% of participants were assessed as cognitively intact, 31% as cognitively impaired, and 33% as demented. All participants underwent a research protocol MRI, and 41% were classified as having subcortical lacunes. Depressed mood, anhedonia, anergia, and apathy were assessed at baseline using a structured behavioral assessment. Cox regression models were used to investigate the associations between neuropsychiatric symptoms and mortality, controlling for age, gender, race, education level, cognitive status, presence of vascular lacunes, and vascular risk factors.
Of 498 participants, 175 (35%) died over the follow-up period, with a median survival time of 5.6 years. In the multivariate analyses, cognitive impairment, age, male gender, depressed mood, and the presence of lacunes predicted higher mortality. Participants with both lacunes and depressed mood had the shortest survival among all cognitive groups. The mortality hazard ratio for participants with depressed mood was 2.2 (95% CI=1.5–3.2) after adjustment for cognitive status, age, gender, education level, race, lacunes, and all vascular conditions.
These findings suggest the importance of detecting depressed mood in individuals with cerebrovascular disease and of developing more aggressive treatment and preventive interventions for this vulnerable population.
PMCID: PMC2864365  PMID: 20160005
The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer’s Disease Centers (ADC) program of the National Institute on Aging (NIA) consists of brief measures of attention, processing speed, executive function, episodic memory and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3,268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered “clinically cognitively normal” based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease (AD) in a relatively well-educated sample. Regression models investigating the impact of age, education, and gender on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: 1) determining the psychometric properties of the battery; 2) establishing normative data, including norms for different ethnic minority groups; and 3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with AD and other forms of dementia.
PMCID: PMC2743984  PMID: 19474567
Neuropsychology  2007;21(4):412-418.
Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly.
PMCID: PMC2780018  PMID: 17605574
normal aging; memory; executive function; hippocampal volumes; white matter signal hyperintensity

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