Background: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the poten... more Background: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. Methods: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector ad-eno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. Results: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. Conclusions: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.
Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's dise... more Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease. To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF. Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume. Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior ...
Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzhe... more Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia. In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months...
The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal stu... more The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal study that recruited 644 cognitively healthy older subjects (aged between 75 and 93 years, 58% women) at baseline and evaluated their cognitive change over 4 years. The study was structured like a clinical trial to anticipate a prevention trial and to determine the performance of novel trial instruments in a longitudinal non-interventional trial framework. Behavioral symptoms were assessed at baseline. The existence of participant-reported behavioral symptoms at baseline predicted conversion to Clinical Dementia Rating scale score ≥0.5 over the 4-year period. The results imply that early anxiety and depression may be harbingers of future cognitive decline, and that patients exhibiting such symptoms, even in the absence of co-occurring cognitive symptoms, should be closely followed over time.
Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target indiv... more Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P < .001), partner (5.08, SE=0.59, P < .001), and self plus partner (7.04, SE=0.83, P < .001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P < .012) and self plus partner (1.56, SE=0.63, P < .014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.
measures. ApoE2 protected brain structure in normals; ApoE4 carriers atrophied faster within all ... more measures. ApoE2 protected brain structure in normals; ApoE4 carriers atrophied faster within all 3 diagnostic groups. Baseline atrophy predicted MCIto-AD conversion and 1-year decline in sum-of-boxes CDR. Atrophic rates correlated highly with CSF Tau/Abeta ratio, less so with Abeta-142, Tau, pTau/Abeta, pTau in that order; in AD, atrophic rates correlated with pTau and Tau more than Abeta. Automated hippocampal mapping: We automatically extracted 3D hippocampal surface models in 97 AD, 245 MCI, and 148 controls using an AdaBoost-based automated segmentation method that agrees with human raters as well as human raters agree with each other. Mean atrophic rates (5.59%/yr, AD; 3.12%/yr, MCI; 0.66%/yr, CTL) were correlated with baseline and interval changes in MMSE, CDR, and conversion to AD. More educated controls atrophied slower; ApoE4þ controls atrophied w2%/yr. faster to than ApoE4-controls, despite having similar baseline MMSE. ApoE4 accelerated left more than right HP atrophy in MCI. The rank order for pathological correlates for HP atrophy rates was (highest-to-lowest): Tau/Abeta, Abeta, Tau, pTau. Conclusions: TBM power was excellent (AD: n80 ¼ 50, MCI: n80 ¼ 75) compared with other imaging biomarkers. Power increased when summarizing changes in a statistically-defined region-of-interest, versus an anatomical ROI (e.g., temporal lobes). HP mapping revealed regionally detailed correlations with current and interval clinical decline and CSF pathology. These high-throughput markers will expedite clinical trials.
Background: Previous studies have shown APOE e4 allele frequencies for MCI to be intermediate bet... more Background: Previous studies have shown APOE e4 allele frequencies for MCI to be intermediate between normal controls and dementia cases. Frequencies also have been found to be somewhat lower in China than in the West. Methods: We conducted a pilot study of 32 normal controls, 30 amnestic Mild Cognitive Impairment (MCI) and 34 dementia cases in Shanghai, China between May and November 2008. Cases were frequency matched to controls by age and sex. All participants had extensive risk factor evaluation in addition to a neurologic and neuropsychological evaluation and MRI. APOE testing was done by the standard Hixson-Vernier method. Results: Mean ages were 73.4 (sd¼5.5), 74.9 (sd¼3.9) and 74.3 (sd¼5.6) for controls, MCI and dementia cases, respectively. There were no e2e2 genotypes. APOE-e4 allele frequencies were 0.05 for controls, 0.18 for MCIs, and 0.15 for dementia cases. One or two APOE-e4 alleles were found in 6.3% of controls, 23.3% of MCIs and 26.5% of dementia cases. The odds ratios comparing dementia cases to controls and MCIs to controls were similar in strength (education-adjusted OR for dementia vs. con-trols¼5.64, 95% CI¼1.09-28.27; education-adjusted OR for MCI vs. controls ¼4.72, 95% CI¼0.88-25.22). APOE-e4 status was not associated with white matter hyperintensities (p¼0.38), but was marginally negatively associated with brain volume (r¼-0.20, p¼0.07) and ventricle size (r¼0.19, p¼0.07). Conclusions: APOE-e4 frequency was marginally higher in MCI than in dementia cases. In comparison with Caucasian samples, our Chinese elders had a lower frequency of the e4 allele and a higher frequency of the e3 allele. Despite this, APOE-e4 remained a strong risk factor for dementia and MCI. APOE-e4 status also was not associated with white matter hyperintensities but appeared to be associated with atrophy on MRI.
Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that migh... more Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that might help to clinically distinguish it from Alzheimer's disease (AD). The main goal of this study was to assess performance on the copy intersecting-pentagon item of the Mini-Mental State Examination with the new Qualitative Scoring method for the Pentagon copy Test (QSPT). In order to determine which aspects of the drawings might differentiate DLB from AD, pentagon drawings of autopsy-verified DLB (n = 16) and AD (n = 15) patients were assessed using the QSPT. The qualitative scoring encompasses the assessment of different parameters of the drawing, such as number of angles, distance/intersection, closure/opening, rotation, and closing-in. The QSPT scores were compared between groups using linear analyses and artificial neural network analyses at four different time points. Linear analyses showed that during the first evaluation, number of angles was the only parameter that showed a si...
We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winb... more We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subt...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 8, 2014
We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular a... more We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular and Alzheimer's disease (AD) pathologies. Eighty-four AD patients underwent an assessment of vascular risk (blood pressure, cholesterol, smoking, cardiovascular disease, diabetes, atrial fibrillation, transient ischemic attack [TIA], or stroke) and later underwent brain autopsy. Given our aim to examine mild cerebrovascular changes (CVCs), individuals were excluded if autopsy revealed large stroke. The most common forms of CVC were circle of Willis atherosclerosis followed by arteriosclerosis, lacunes, and microinfarcts. Excluding the history of TIA/clinical stroke, individual vascular risk factors were not associated with CVC. However, the presence of multiple vascular risk factors was associated with CVC. Furthermore, the presence of CVC was associated with lower Braak and Braak stage. These findings highlight the importance of aggregate risk in the vascular contribution to dementia...
We assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within ... more We assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort and examined associated biomarkers and clinical outcomes. Cluster analysis was performed on neuropsychological data from 825 MCI ADNI participants. Four subtypes emerged: (1) dysnomic (n = 153), (2) dysexecutive (n = 102), (3) amnestic (n = 288), and (4) cluster-derived normal (n = 282) who performed within normal limits on cognitive testing. The cluster-derived normal group had significantly fewer APOE ε4 carriers and fewer who progressed to dementia compared with the other subtypes; they also evidenced cerebrospinal fluid Alzheimer's disease biomarker profiles that did not differ from the normative reference group. Identification of empirically derived MCI subtypes demonstrates heterogeneity in MCI cognitive profiles that is not captured by conventional criteria. The large cluster-derived normal group suggests that conventional diagnostic criteria are susceptible to false-positive errors, with the result that prior MCI studies may be diluting important biomarker relationships.
Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (M... more Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (MCI), despite their uncertain relationship to objective memory performance in MCI. We aimed to examine self-reported cognitive complaints in subgroups of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort to determine whether they are a valuable inclusion in the diagnosis of MCI or, alternatively, if they contribute to misdiagnosis. Subgroups of MCI were derived using cluster analysis of baseline neuropsychological test data from 448 ADNI MCI participants. Cognitive complaints were assessed via the Everyday Cognition (ECog) questionnaire, and discrepancy scores were calculated between self-and informant-report. Cluster analysis revealed Amnestic and Mixed cognitive phenotypes as well as a third Cluster-Derived Normal subgroup (41.3%), whose neuropsychological and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker profiles did not differ from a "robust" normal control group. This cognitively intact phenotype of MCI participants overestimated their cognitive problems relative to their informant, whereas Amnestic MCI participants with objective memory impairment underestimated their cognitive problems. Underestimation of cognitive problems was associated with positive CSF AD biomarkers and progression to dementia. Overall, there was no relationship between self-reported cognitive complaints and objective cognitive functioning, but significant correlations were observed with depressive symptoms. The inclusion of self-reported complaints in MCI diagnostic criteria may cloud rather than clarify diagnosis and result in high rates of misclassification of MCI. Discrepancies between self-and informant-report demonstrate that overestimation of cognitive problems is characteristic of normal aging while underestimation may reflect greater risk for cognitive decline.
Journal of Clinical and Experimental Neuropsychology, 1989
An abbreviated form of Moss et al.'s (1986) Recognition Span Test (RST) w... more An abbreviated form of Moss et al.'s (1986) Recognition Span Test (RST) was administered to patients with mild or moderate dementia of the Alzheimer type (DAT) and to intact control (NC) subjects. Memory spans for verbal (i.e., words), spatial and configurational (i.e., faces) information were assessed. Delayed recall (15 s and 2 min) of the words used on the verbal recognition span was also determined. The results showed that both DAT patient groups were impaired on the three recognition tasks and that the spatial and verbal forms differentiated the mildly from the moderately demented patients. The mean overall recognition span scores (spatial + verbal + facial) differentiated between DAT patients and intact controls, with 37 of the 39 patients falling beyond the 95% confidence limits derived from the control subjects' scores. On verbal recall, both the mildly and moderately demented patients were severely impaired and evidenced a very rapid rate of forgetting between the 15-s and 2-min recall attempts. These findings suggest that the RST is not only highly sensitive to memory disorders in the early stages of DAT but also effective in discriminating among various stages of this disorder.
As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we... more As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies. For the 2 studies that collected data on Aβ level...
Journal of Clinical and Experimental Neuropsychology, 1998
This study investigated focused attention in two subcortical degenerative disorders by examining ... more This study investigated focused attention in two subcortical degenerative disorders by examining the performance of patients with Huntington's disease (HD) and Parkinson's disease (PD) on a task utilizing global-local stimuli. Participants were presented with global-local figures ...
The cognitive impairment in patients with Alzheimer's disease is closely associated with synaptic... more The cognitive impairment in patients with Alzheimer's disease is closely associated with synaptic loss in the neocortex and limbic system. Although the neurotoxic effects of aggregated amyloid-β (Aβ) oligomers in Alzheimer's disease have been widely studied in experimental models, less is known about the characteristics of these aggregates across the spectrum of Alzheimer's disease. Here, postmortem frontal cortex samples from control and Alzheimer's disease patients were fractioned and analyzed for levels of oligomers and synaptic proteins. We found that levels of oligomers correlated with the severity of cognitive impairment (Blessed score and Mini-Mental), and with the loss of synaptic markers. Reduced levels of the synaptic vesicle protein vesicleassociated membrane protein-2 and the postsynaptic protein post-synaptic density-95 (PSD95) correlated with levels of oligomers in the various fractions analyzed. The strongest associations were found with Aβ dimers and pentamers. Co-immunoprecipitation and double-labeling experiments support the possibility that Aβ and PSD95 interact at the synaptic sites. Similarly, in transgenic mice expressing high levels of neuronal amyloid precursor protein (APP), Aβ coimmunoprecipitated with PSD95. This was accompanied by a reduction in the levels of the postsynaptic proteins Shank1 and 3 in Alzheimer's disease patients and in the brains of APP transgenic mice. In conclusion, this study suggests that the presence of a subpopulation of Aβ oligomers in the brains of patients with Alzheimer's disease might be related to alterations in selected synaptic proteins and cognitive impairment.
For over 50 years, cognitive psychologists and neuropsychologists have relied almost exclusively ... more For over 50 years, cognitive psychologists and neuropsychologists have relied almost exclusively on a method for computing semantic clustering on list-learning tasks (recall-based formula) that was derived from an outdated assumption about how learning occurs. A new procedure for computing semantic clustering (list-based formula) was developed for the CVLT-II to correct the shortcomings of the traditional method. In the present study we compared the clinical utility of the traditional recall-based method versus the new list-based method using results from the original CVLT administered to 87 patients with Alzheimer's disease and 86 matched normal control participants. Logistic regression and score distribution analyses indicated that the new list-based method enhances the detection of differences in semantic-clustering ability between the groups.
Background: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the poten... more Background: Nerve growth factor (NGF) is an endogenous neurotrophic-factor protein with the potential to restore function and to protect degenerating cholinergic neurons in Alzheimer's disease (AD), but safe and effective delivery has proved unsuccessful. Methods: Gene transfer, combined with stereotactic surgery, offers a potential means to solve the long-standing delivery obstacles. An open-label clinical trial evaluated the safety and tolerability, and initial efficacy of three ascending doses of the genetically engineered gene-therapy vector ad-eno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110). Ten subjects with AD received bilateral AAV2-NGF stereotactically into the nucleus basalis of Meynert. Results: AAV2-NGF was safe and well-tolerated for 2 years. Positron emission tomographic imaging and neuropsychological testing showed no evidence of accelerated decline. Brain autopsy tissue confirmed long-term, targeted, gene-mediated NGF expression and bioactivity. Conclusions: This trial provides important evidence that bilateral stereotactic administration of AAV2-NGF to the nucleus basalis of Meynert is feasible, well-tolerated, and able to produce long-term, biologically active NGF expression, supporting the initiation of an ongoing multicenter, double-blind, sham-surgery-controlled trial.
Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's dise... more Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease. To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF. Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume. Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior ...
Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzhe... more Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia. In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months...
The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal stu... more The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal study that recruited 644 cognitively healthy older subjects (aged between 75 and 93 years, 58% women) at baseline and evaluated their cognitive change over 4 years. The study was structured like a clinical trial to anticipate a prevention trial and to determine the performance of novel trial instruments in a longitudinal non-interventional trial framework. Behavioral symptoms were assessed at baseline. The existence of participant-reported behavioral symptoms at baseline predicted conversion to Clinical Dementia Rating scale score ≥0.5 over the 4-year period. The results imply that early anxiety and depression may be harbingers of future cognitive decline, and that patients exhibiting such symptoms, even in the absence of co-occurring cognitive symptoms, should be closely followed over time.
Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target indiv... more Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P < .001), partner (5.08, SE=0.59, P < .001), and self plus partner (7.04, SE=0.83, P < .001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P < .012) and self plus partner (1.56, SE=0.63, P < .014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.
measures. ApoE2 protected brain structure in normals; ApoE4 carriers atrophied faster within all ... more measures. ApoE2 protected brain structure in normals; ApoE4 carriers atrophied faster within all 3 diagnostic groups. Baseline atrophy predicted MCIto-AD conversion and 1-year decline in sum-of-boxes CDR. Atrophic rates correlated highly with CSF Tau/Abeta ratio, less so with Abeta-142, Tau, pTau/Abeta, pTau in that order; in AD, atrophic rates correlated with pTau and Tau more than Abeta. Automated hippocampal mapping: We automatically extracted 3D hippocampal surface models in 97 AD, 245 MCI, and 148 controls using an AdaBoost-based automated segmentation method that agrees with human raters as well as human raters agree with each other. Mean atrophic rates (5.59%/yr, AD; 3.12%/yr, MCI; 0.66%/yr, CTL) were correlated with baseline and interval changes in MMSE, CDR, and conversion to AD. More educated controls atrophied slower; ApoE4þ controls atrophied w2%/yr. faster to than ApoE4-controls, despite having similar baseline MMSE. ApoE4 accelerated left more than right HP atrophy in MCI. The rank order for pathological correlates for HP atrophy rates was (highest-to-lowest): Tau/Abeta, Abeta, Tau, pTau. Conclusions: TBM power was excellent (AD: n80 ¼ 50, MCI: n80 ¼ 75) compared with other imaging biomarkers. Power increased when summarizing changes in a statistically-defined region-of-interest, versus an anatomical ROI (e.g., temporal lobes). HP mapping revealed regionally detailed correlations with current and interval clinical decline and CSF pathology. These high-throughput markers will expedite clinical trials.
Background: Previous studies have shown APOE e4 allele frequencies for MCI to be intermediate bet... more Background: Previous studies have shown APOE e4 allele frequencies for MCI to be intermediate between normal controls and dementia cases. Frequencies also have been found to be somewhat lower in China than in the West. Methods: We conducted a pilot study of 32 normal controls, 30 amnestic Mild Cognitive Impairment (MCI) and 34 dementia cases in Shanghai, China between May and November 2008. Cases were frequency matched to controls by age and sex. All participants had extensive risk factor evaluation in addition to a neurologic and neuropsychological evaluation and MRI. APOE testing was done by the standard Hixson-Vernier method. Results: Mean ages were 73.4 (sd¼5.5), 74.9 (sd¼3.9) and 74.3 (sd¼5.6) for controls, MCI and dementia cases, respectively. There were no e2e2 genotypes. APOE-e4 allele frequencies were 0.05 for controls, 0.18 for MCIs, and 0.15 for dementia cases. One or two APOE-e4 alleles were found in 6.3% of controls, 23.3% of MCIs and 26.5% of dementia cases. The odds ratios comparing dementia cases to controls and MCIs to controls were similar in strength (education-adjusted OR for dementia vs. con-trols¼5.64, 95% CI¼1.09-28.27; education-adjusted OR for MCI vs. controls ¼4.72, 95% CI¼0.88-25.22). APOE-e4 status was not associated with white matter hyperintensities (p¼0.38), but was marginally negatively associated with brain volume (r¼-0.20, p¼0.07) and ventricle size (r¼0.19, p¼0.07). Conclusions: APOE-e4 frequency was marginally higher in MCI than in dementia cases. In comparison with Caucasian samples, our Chinese elders had a lower frequency of the e4 allele and a higher frequency of the e3 allele. Despite this, APOE-e4 remained a strong risk factor for dementia and MCI. APOE-e4 status also was not associated with white matter hyperintensities but appeared to be associated with atrophy on MRI.
Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that migh... more Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that might help to clinically distinguish it from Alzheimer's disease (AD). The main goal of this study was to assess performance on the copy intersecting-pentagon item of the Mini-Mental State Examination with the new Qualitative Scoring method for the Pentagon copy Test (QSPT). In order to determine which aspects of the drawings might differentiate DLB from AD, pentagon drawings of autopsy-verified DLB (n = 16) and AD (n = 15) patients were assessed using the QSPT. The qualitative scoring encompasses the assessment of different parameters of the drawing, such as number of angles, distance/intersection, closure/opening, rotation, and closing-in. The QSPT scores were compared between groups using linear analyses and artificial neural network analyses at four different time points. Linear analyses showed that during the first evaluation, number of angles was the only parameter that showed a si...
We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winb... more We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subt...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 8, 2014
We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular a... more We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular and Alzheimer's disease (AD) pathologies. Eighty-four AD patients underwent an assessment of vascular risk (blood pressure, cholesterol, smoking, cardiovascular disease, diabetes, atrial fibrillation, transient ischemic attack [TIA], or stroke) and later underwent brain autopsy. Given our aim to examine mild cerebrovascular changes (CVCs), individuals were excluded if autopsy revealed large stroke. The most common forms of CVC were circle of Willis atherosclerosis followed by arteriosclerosis, lacunes, and microinfarcts. Excluding the history of TIA/clinical stroke, individual vascular risk factors were not associated with CVC. However, the presence of multiple vascular risk factors was associated with CVC. Furthermore, the presence of CVC was associated with lower Braak and Braak stage. These findings highlight the importance of aggregate risk in the vascular contribution to dementia...
We assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within ... more We assessed whether mild cognitive impairment (MCI) subtypes could be empirically derived within the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort and examined associated biomarkers and clinical outcomes. Cluster analysis was performed on neuropsychological data from 825 MCI ADNI participants. Four subtypes emerged: (1) dysnomic (n = 153), (2) dysexecutive (n = 102), (3) amnestic (n = 288), and (4) cluster-derived normal (n = 282) who performed within normal limits on cognitive testing. The cluster-derived normal group had significantly fewer APOE ε4 carriers and fewer who progressed to dementia compared with the other subtypes; they also evidenced cerebrospinal fluid Alzheimer's disease biomarker profiles that did not differ from the normative reference group. Identification of empirically derived MCI subtypes demonstrates heterogeneity in MCI cognitive profiles that is not captured by conventional criteria. The large cluster-derived normal group suggests that conventional diagnostic criteria are susceptible to false-positive errors, with the result that prior MCI studies may be diluting important biomarker relationships.
Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (M... more Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (MCI), despite their uncertain relationship to objective memory performance in MCI. We aimed to examine self-reported cognitive complaints in subgroups of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort to determine whether they are a valuable inclusion in the diagnosis of MCI or, alternatively, if they contribute to misdiagnosis. Subgroups of MCI were derived using cluster analysis of baseline neuropsychological test data from 448 ADNI MCI participants. Cognitive complaints were assessed via the Everyday Cognition (ECog) questionnaire, and discrepancy scores were calculated between self-and informant-report. Cluster analysis revealed Amnestic and Mixed cognitive phenotypes as well as a third Cluster-Derived Normal subgroup (41.3%), whose neuropsychological and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker profiles did not differ from a "robust" normal control group. This cognitively intact phenotype of MCI participants overestimated their cognitive problems relative to their informant, whereas Amnestic MCI participants with objective memory impairment underestimated their cognitive problems. Underestimation of cognitive problems was associated with positive CSF AD biomarkers and progression to dementia. Overall, there was no relationship between self-reported cognitive complaints and objective cognitive functioning, but significant correlations were observed with depressive symptoms. The inclusion of self-reported complaints in MCI diagnostic criteria may cloud rather than clarify diagnosis and result in high rates of misclassification of MCI. Discrepancies between self-and informant-report demonstrate that overestimation of cognitive problems is characteristic of normal aging while underestimation may reflect greater risk for cognitive decline.
Journal of Clinical and Experimental Neuropsychology, 1989
An abbreviated form of Moss et al.'s (1986) Recognition Span Test (RST) w... more An abbreviated form of Moss et al.'s (1986) Recognition Span Test (RST) was administered to patients with mild or moderate dementia of the Alzheimer type (DAT) and to intact control (NC) subjects. Memory spans for verbal (i.e., words), spatial and configurational (i.e., faces) information were assessed. Delayed recall (15 s and 2 min) of the words used on the verbal recognition span was also determined. The results showed that both DAT patient groups were impaired on the three recognition tasks and that the spatial and verbal forms differentiated the mildly from the moderately demented patients. The mean overall recognition span scores (spatial + verbal + facial) differentiated between DAT patients and intact controls, with 37 of the 39 patients falling beyond the 95% confidence limits derived from the control subjects' scores. On verbal recall, both the mildly and moderately demented patients were severely impaired and evidenced a very rapid rate of forgetting between the 15-s and 2-min recall attempts. These findings suggest that the RST is not only highly sensitive to memory disorders in the early stages of DAT but also effective in discriminating among various stages of this disorder.
As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we... more As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes. To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study). With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies. For the 2 studies that collected data on Aβ level...
Journal of Clinical and Experimental Neuropsychology, 1998
This study investigated focused attention in two subcortical degenerative disorders by examining ... more This study investigated focused attention in two subcortical degenerative disorders by examining the performance of patients with Huntington's disease (HD) and Parkinson's disease (PD) on a task utilizing global-local stimuli. Participants were presented with global-local figures ...
The cognitive impairment in patients with Alzheimer's disease is closely associated with synaptic... more The cognitive impairment in patients with Alzheimer's disease is closely associated with synaptic loss in the neocortex and limbic system. Although the neurotoxic effects of aggregated amyloid-β (Aβ) oligomers in Alzheimer's disease have been widely studied in experimental models, less is known about the characteristics of these aggregates across the spectrum of Alzheimer's disease. Here, postmortem frontal cortex samples from control and Alzheimer's disease patients were fractioned and analyzed for levels of oligomers and synaptic proteins. We found that levels of oligomers correlated with the severity of cognitive impairment (Blessed score and Mini-Mental), and with the loss of synaptic markers. Reduced levels of the synaptic vesicle protein vesicleassociated membrane protein-2 and the postsynaptic protein post-synaptic density-95 (PSD95) correlated with levels of oligomers in the various fractions analyzed. The strongest associations were found with Aβ dimers and pentamers. Co-immunoprecipitation and double-labeling experiments support the possibility that Aβ and PSD95 interact at the synaptic sites. Similarly, in transgenic mice expressing high levels of neuronal amyloid precursor protein (APP), Aβ coimmunoprecipitated with PSD95. This was accompanied by a reduction in the levels of the postsynaptic proteins Shank1 and 3 in Alzheimer's disease patients and in the brains of APP transgenic mice. In conclusion, this study suggests that the presence of a subpopulation of Aβ oligomers in the brains of patients with Alzheimer's disease might be related to alterations in selected synaptic proteins and cognitive impairment.
For over 50 years, cognitive psychologists and neuropsychologists have relied almost exclusively ... more For over 50 years, cognitive psychologists and neuropsychologists have relied almost exclusively on a method for computing semantic clustering on list-learning tasks (recall-based formula) that was derived from an outdated assumption about how learning occurs. A new procedure for computing semantic clustering (list-based formula) was developed for the CVLT-II to correct the shortcomings of the traditional method. In the present study we compared the clinical utility of the traditional recall-based method versus the new list-based method using results from the original CVLT administered to 87 patients with Alzheimer's disease and 86 matched normal control participants. Logistic regression and score distribution analyses indicated that the new list-based method enhances the detection of differences in semantic-clustering ability between the groups.
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Papers by David Salmon