Biomedical subjects

Leon J Thal

Publications and source records attributed to Leon J Thal.

At least 19 recordsLinked to original sources

PubMed2007

Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia.

BACKGROUND: Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician. OBJECTIVE: To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia. DESIGN: A 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study initially designed to evaluate the efficacy of donepezil hydrochloride or vitamin E vs placebo to delay progression of MCI to dementia. SETTING: Memory assessment centers. PATIENTS: A total of 190 individuals with MCI. MAIN OUTCOME MEASURES: Ratings of MTA performed using magnetic resonance images obtained at baseline. Log-rank tests and Cox proportional hazards ratios examining the significance of MTA estimates in predicting progression of MCI to dementia. RESULTS: A mean MTA score greater than 2.0 was associated with a greater than 2-fold increased likelihood of progression to dementia during the observation period (hazards ratio, 2.30; 95% confidence interval, 1.09-4.92; P = .03) after controlling for age, education, sex, and baseline Mini-Mental State Examination score. CONCLUSIONS: Adjusted estimates of MTA were associated with significantly increased risk of developing dementia within 3 years, suggesting that obtaining a magnetic resonance image during the evaluation of MCI may offer additional independent information about the risk of progression to dementia. Given the relatively high prevalence of MCI in the general population, use of this method as part of routine clinical evaluation may help identify individuals who might benefit from increased surveillance and future treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000173.

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PubMed2007

Disparate letter and semantic category fluency deficits in autopsy-confirmed frontotemporal dementia and Alzheimer's disease.

Patients with autopsy-confirmed frontotemporal dementia (FTD; n = 16) and Alzheimer's disease (AD; n = 32) were compared on first-letter and semantic category fluency tasks. Despite being matched on age, education, and dementia severity, FTD patients performed worse overall and showed similar impairment in letter and semantic category fluency, whereas AD patients showed greater impairment in semantic category than letter fluency. A measure of the disparity between letter and semantic category fluency (the semantic index) was effective in differentiating FTD from AD patients, and this disparity increased with increasing severity of dementia. These unique patterns of letter and semantic category fluency deficits may be indicative of differences in the relative contribution of frontal-lobe-mediated retrieval deficits and temporal-lobe-mediated semantic deficits in FTD and AD.

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PubMed2006

DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.

Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control sample set (WU) and replicated in each of two initial validation case-control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.

Alleles↗

PubMed2006

Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response.

Previous studies of episodic memory report a greater extent of blood-oxygenation-level-dependent (BOLD) response in non-demented older adults with the apolipoprotein E epsilon-4 (APOE epsilon4) allele than in those without the allele. We conducted a functional MRI study to investigate whether APOE genotype is related to brain response to verbal paired-associate encoding and consolidation, particularly in the right hemisphere, among non-demented older adults. Structurally segmented volumes and BOLD response were measured in 13 non-epsilon4 and 12 epsilon4 subjects. The epsilon4 group displayed greater activation than the non-epsilon4 group in multiple right hemisphere regions for previously encoded word pairs relative to fixation. Activation within manually outlined hippocampal regions of interest also displayed genotype-specific dissociations consistent with whole brain analyses. Furthermore, this differential BOLD response occurred in the presence of equivalent behavioral and neuropsychological performances as well as comparable hippocampal and overall structural segmentation volumes between groups. Results implicate a widely distributed and interconnected network of right hemisphere brain regions that may be involved in compensating for APOE epsilon4-related deficiencies associated with verbal episodic memory encoding and consolidation.

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PubMed2006

What best differentiates Lewy body from Alzheimer's disease in early-stage dementia?

To determine which clinical feature(s) [among visual hallucinations (VH), extrapyramidal signs (EPS) and visuospatial impairment] in the earliest stages of disease best predicted a diagnosis of dementia with Lewy bodies (DLB) at autopsy, first-visit data of 23 pathologically proven DLB and 94 Alzheimer's disease cases were compared. There were no group differences with regard to age, gender, education or global severity of dementia at presentation (mean Mini-Mental State Examination: 24.0 versus 25.0, mean Dementia Rating Scale: 123.6 versus 125.7). DLB patients at initial presentation displayed an increased frequency of VH (P = 0.001), but not EPS (P = 0.3), compared to Alzheimer's disease patients. However, only a minority of DLB cases had either VH (22%), EPS (26%) or both (13%). In contrast, although not a core feature, visuospatial/constructional impairment was observed in most of the DLB cases (74%). Among clinical variables, presence/recent history of VH was the most specific to DLB (99%), and visuospatial impairment was the most sensitive (74%). As a result, VH at presentation were the best positive predictor of DLB at autopsy (positive predictive value: 83% versus 32% or less for all other variables), while lack of visuospatial impairment was the best negative predictor (negative predictive value: 90%). We conclude that the best model for differentiating DLB from Alzheimer's disease in the earliest stages of disease includes VH and visuospatial/constructional dysfunction, but not spontaneous EPS, as predictors. This suggests that clinical history plus a brief assessment of visuospatial function may be of the greatest value in correctly identifying DLB early during the course of disease.

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PubMed2005

The septohippocampal cholinergic system and spatial working memory in the Morris water maze.

The objective of the present study was to determine whether a systematic optimization of Morris water maze (mwm) testing parameters could reveal a significant role of the septohippocampal cholinergic system in spatial working memory. Young adult rats were lesioned using 192 IgG-saporin infused bilaterally into the medial septum. Lesions were near complete as measured by choline acetyltransferase (ChAT) activity and immunohistochemistry. Behavioral testing was performed in three phases. In the first, lesioned and unlesioned rats were trained in the mwm focusing on working memory, which was tested using novel platform locations daily. In the second phase, the optimal locations were retested with increasing intertrial intervals (ITI). In the third phase, intracerebroventricular infusions of nerve growth factor (NGF) were employed to enhance cholinergic activity of the unlesioned rats and potentially further separate group performance. Neither the standard or increased ITI resulted in a consistent significant difference in spatial working memory between groups. In addition, NGF treatment also failed to induce a significant difference in behavioral performance. In conclusion, impairments in working memory as assessed by the mwm could not be revealed despite a greater than 90% loss of hippocampal ChAT and the use of optimal testing parameters and NGF treatment.

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PubMed2005

Regulatable acetylcholine-producing fibroblasts enhance cognitive performance.

Regulatable gene therapy systems provide a method to alter neurotransmitter levels in vivo. We developed a rodent fibroblast cell line expressing the choline acetyltransferase (ChAT) cDNA that is silenced by doxycycline (DOX) administration. The ability of the cell line to improve cognition was tested by grafting after cholinergic lesions. Ibotenic acid was injected bilaterally into the nucleus basalis of rats, which were distributed into three groups. One group received no treatment, while the second group received cortical transplants (Graft). The third group received identical grafts but was treated with DOX to turn off ChAT expression (Graft/DOX). An unlesioned group served as control. Water maze acquisition was significantly better in the Graft group compared to the Graft/DOX group, an effect also seen in the retention and spatial probe trials. However, cognitive enhancement was restricted to spatial tasks, as inhibitory avoidance or open-field activity measures were unchanged. Molecular and biochemical analyses confirmed that DOX regulated transgene transcription and ACh levels. This study demonstrates that regulatable gene therapy has therapeutic value for single-gene disorders and also provides a mechanism to deliver small molecules in a spatiotemporal pattern to delineate the role of these compounds in discrete behavioral tasks.

Acetylcholine↗

PubMed2005

Vitamin E and donepezil for the treatment of mild cognitive impairment.

BACKGROUND: Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease. METHODS: In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function. RESULTS: A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers. CONCLUSIONS: Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo.

Alzheimer Disease↗

PubMed2005

Identification of Alzheimer disease risk by functional magnetic resonance imaging.

BACKGROUND: Functional magnetic resonance imaging plays a promising role in the preclinical characterization of Alzheimer disease (AD) for use in early diagnosis and in preventive drug trials. OBJECTIVE: To determine whether functional magnetic resonance imaging can reliably distinguish risk groups for AD among cognitively normal middle-aged adults. DESIGN: Cross-sectional case-control study. SETTING: University of California, San Diego, Alzheimer Disease Research Center participants and San Diego community volunteers. PARTICIPANTS: Twenty cognitively normal individuals (10 high risk and 10 low risk), aged 58 to 65 years, were divided into 2 groups based on the presence or absence of the apolipoprotein E epsilon4 allele and a positive family history of AD. MAIN OUTCOME MEASURES: Word pairs were presented in a blocked design alternating between conditions of novel pairs, repeated pairs, and fixation. Whole-brain differences in blood oxygenation level-dependent brain responses between conditions were compared across risk groups. RESULTS: Compared with the low-risk group, the high-risk group showed many areas of differential blood oxygenation level-dependent response in regions commonly associated with AD pathology (eg, the left medial temporal lobe). Furthermore, different patterns of association between left medial temporal lobe activity and memory performance were demonstrated. CONCLUSIONS: Results support a theory of up-regulation in neuronal memory systems in people at risk for AD many years before the typical age at disease onset. They further demonstrate that functional magnetic resonance imaging is a viable technique to identify persons at risk for AD.

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PubMed2005

Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment.

BACKGROUND: Subjects with mild cognitive impairment (MCI) have been shown to have reduced hippocampal volumes relative to normal elderly control subjects. The presence of the apolipoprotein E epsilon4 (APOE*E4) allele has been associated with greater hippocampal atrophy in women than in men with Alzheimer disease. This relationship has not been demonstrated in MCI. OBJECTIVE: To examine the relationship between APOE genotype and hippocampal volume in men and women with MCI. DESIGN: This study evaluated MCI in 193 subjects (86 women and 107 men) participating in a multicenter clinical trial, all of whom underwent magnetic resonance imaging at their baseline visit. We evaluated the association among the number of APOE*E4 alleles, memory performance, and hippocampal volume in men and women with tests of means and multiple linear regressions. RESULTS: Compared with MCI subjects with no APOE*E4 alleles, women with 1 or 2 APOE*E4 alleles were found to have significantly reduced hippocampal volume, whereas men only showed a significant reduction in hippocampal volume when carrying 2 APOE*E4 alleles. Worsening of performance on a delayed word recall task (Alzheimer's Disease Assessment Scale cognitive subscale) showed an identical pattern in association with APOE*E4 allele dose and sex. Furthermore, when controlling for memory performance on delayed word recall, the APOE*E4 effect on hippocampal volumes was attenuated in men, but remained significant in women. CONCLUSION: The APOE*E4 genotype status appears to have a greater deleterious effect on gross hippocampal pathology and memory performance in women than in men.

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PubMed2005

Altered p59Fyn kinase expression accompanies disease progression in Alzheimer's disease: implications for its functional role.

Alzheimer's disease (AD) is characterized by progressive decline in memory and other cognitive domains, accompanied by early loss of presynaptic terminals, amyloid-bearing neuritic plaques and neurofibrillary tangles containing hyperphosphorylated tau. The mechanisms leading to neurodegeneration are not completely understood, however, recent evidence suggests that alterations in p59Fyn kinase, an Src family tyrosine kinase, might contribute to AD pathogenesis. In this context, the main objective of the present study was to investigate the relationship between Fyn protein levels and the neurological and neuropathological alterations in AD. We found, by quantitative immunoblotting, that in AD, Fyn levels were increased in the insoluble fraction and decreased in the soluble fraction. Soluble Fyn levels were directly correlated with the cognitive scores and levels of synaptophysin immunoreactivity, and inversely correlated with neurofibrillary tangle counts in the frontal cortex. Consistent with these findings, the immunocytochemical analysis showed that in AD cases, Fyn levels were decreased in the synapses and increased in the neuronal cell bodies where it was colocalized with neurofibrillary tangles. Taken together, these findings suggest that alterations in Fyn localization might be associated with neurofibrillary pathology and synapse loss in AD.

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PubMed2005

The Alzheimer's disease neuroimaging initiative.

With increasing life expectancy in developed countries, the incidence of Alzheimer's disease (AD) and its socioeconomic impact are growing. Increasing knowledge of the mechanisms of AD facilitates the development of treatment strategies aimed at slowing down or preventing neuronal death. AD treatment trials using clinical outcome measures require long observation times and large patient samples. There is increasing evidence that neuroimaging and cerebrospinal fluid and blood biomarkers may provide information that may reduce sample sizes and observation periods. The Alzheimer's Disease Neuroimaging Initiative will help identify clinical, neuroimaging, and biomarker outcome measures that provide the highest power for measurement of longitudinal changes and for prediction of transitions.

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PubMed2005

A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment.

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and might be mediated via the COX-2 enzyme. Previous studies with the selective COX-2 inhibitors, rofecoxib and celecoxib, have shown that they do not alter the progression of AD. We conducted a double-blind study to investigate whether rofecoxib could delay a diagnosis of AD in patients with mild cognitive impairment (MCI), a group with an expected annual AD diagnosis rate of 10-15%. MCI patients > or =65 years were randomized to rofecoxib 25 mg (N=725) or placebo (N=732) daily for up to 4 years. The primary end point was the percentage of patients with a clinical diagnosis of AD. The estimated annual AD diagnosis rate was lower than the anticipated 10-15%: 6.4% in the rofecoxib group vs 4.5% in the placebo group (rofecoxib : placebo hazard ratio=1.46 (95% CI: 1.09, 1.94), p=0.011). Analyses of secondary end points, including measures of cognition (eg the cognitive subscale of the AD Assessment Scale (ADAS-Cog)) and global function (eg the Clinical Dementia Rating (CDR)), did not demonstrate differences between treatment groups. There was also no consistent evidence that rofecoxib differed from placebo in post hoc analyses comparing ADAS-Cog and CDR-sum of boxes scores in overlapping subgroups of patients who had Mini Mental State Exam scores of 24-26 in the present MCI study and in a previous AD treatment study with a similar design. The results from this MCI study did not support the hypothesis that rofecoxib would delay a diagnosis of AD. In conjunction with the lack of effects observed in previous AD studies, the findings suggest that inhibition of COX-2 is not a useful therapeutic approach in AD.

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PubMed2005

Independence of changes in behavior from cognition and function in community-dwelling persons with Alzheimer's disease: a factor analytic approach.

The authors' main objective was to investigate the relationship between changes in psychopathological, cognitive and activity of daily living (ADL) instrument scores over 12 months in community-dwelling persons with Alzheimer's disease (AD). A secondary objective was to evaluate the validity of dividing the Clinical Dementia Rating (CDR), a global dementia staging instrument into cognitive and functional subscores. Changes in measures of psychopathology, cognition and function between the baseline and 12-month visits were entered into these post hoc analyses of data from a one-year clinical trial to evaluate behavioral, cognitive and functional assessment instruments for use in clinical trials with AD patients. Exploratory factor analysis was used to determine whether there was independence between changes in any of these three domains of interest for this disease population; participants were a cohort of 187 well-characterized, community-dwelling persons with AD. One-year change in the behavioral symptoms of this cohort of persons with AD was statistically independent from changes in scores on cognitive and functional measures. Some evidence of independence of 12 month changes in cognitive and functional measures was found. Cognitive and functional subscores for the CDR were supported. These findings suggest that changes in behavior and cognition in dementia may have distinct pathophysiologies.

Activities of Daily Living↗

PubMed2004

Long-term production of choline acetyltransferase in the CNS after transplantation of fibroblasts modified with a regulatable vector.

A rat fibroblast cell line was modified to contain the Drosophila choline acetyltransferase (ChAT) cDNA under the control of a tetracycline-regulated system. Several clonal lines were assessed in vitro and in vivo to establish the optimal clone for gene therapy experiments. The influence of in vitro cell density on ChAT expression was compared to biological activity detected after grafting to the rat brain. While each clone had different ChAT activity patterns, all clones had low activity immediately post-grafting which increased over time, reaching a plateau between 1 and 2 months which was maintained for at least 1 year. The clones expressed a high basal ChAT activity level in vitro that was repressed in a dose- and time-dependent manner with doxycycline (DOX) treatment. In the absence of DOX, high levels of ChAT activity were maintained for at least 2 months in vitro. DOX induced a rapid and strong (200-fold) suppression of ChAT activity within 48 h. A dose-response curve indicated that the fibroblasts were very sensitive to low concentrations of DOX (ED50 12 pg/ml). Removal of DOX led to a derepression of ChAT activity within 2 days. These cells will be useful for ex vivo gene therapy of the cholinergic system.

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PubMed2004

Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency.

Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons. The rate-limiting factor in ACh production is the provision of choline to ChAT. Cholinergic neurons are relatively unique in their expression of the choline transporter 1 (CHT1), which exhibits high-affinity for choline and catalyzes its uptake from the extracellular space to the neuron. Multiple lines of evidence indicate that the activity of CHT1 is a key determinant of choline supply for ACh synthesis. We examined the interaction of ChAT and ChT activity using mice heterozygous for a null mutation in the Chat gene (Chat+/-). In these mice, brain ChAT activity was reduced by 40-50% relative to the wild type, but brain ACh levels as well as ACh content and depolarization-evoked ACh release in hippocampal slices were normal. However, the amount of choline taken up by CHT1 and ACh synthesized de novo from choline transported by CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1 protein in several regions of the CNS, were 50-100% higher in Chat+/- than in Chat+/+ mice. Thus, haploinsufficiency of ChAT leads to an increased expression of CHT1. Increased ChT activity may compensate for the reduced ChAT activity in Chat+/- mice, contributing to the maintenance of apparently normal cholinergic function as reflected by normal performance of these mice in several behavioral assays.

Acetylcholine↗

PubMed2004

Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials.

BACKGROUND: Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. OBJECTIVE: To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. DESIGN: Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. SETTING: Memory disorder centers in the United States and Canada. PATIENTS: A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. MAIN OUTCOME MEASURES: Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. RESULTS: Mean +/- SD Alzheimer's Disease Assessment Scale-Cognitive Subscale scores were 5.6 +/- 3.3 for controls, 11.3 +/- 4.4 for patients with MCI, 18.0 +/- 6.2 for the AD CDR 0.5 group, and 25.2 +/- 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E epsilon4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. CONCLUSIONS: Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

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PubMed2004

Executive dysfunction in Alzheimer disease.

BACKGROUND: Executive dysfunction (EDF) is common in Alzheimer disease (AD); however, its relationship to other symptoms is difficult to assess in patients with AD. OBJECTIVES: To determine the prevalence of EDF and study its relationship to cognitive, functional, and neuropsychiatric symptoms in patients with AD. DESIGN, SETTING, AND PATIENTS: A retrospective analysis of data from participants in the English Instruments Protocol of the Alzheimer's Disease Cooperative Study. Subjects were drawn from a sample of patients evaluated at tertiary referral centers. RESULTS: A total of 64% of AD patients were classified as having EDF. Patients with EDF performed worse on tests of cognition (P <.001), dementia severity (P <.001), and activities of daily living (P =.01) and had more frequent symptoms of psychosis (P =.03) with greater emergence during the 12-month interval (P =.03) compared with patients with normal executive function. Less than 30% of the variance in executive function performance was explained by cognitive measures. CONCLUSION: These findings support the assessment of executive function in persons with AD and the importance of frontal lobe dysfunction in AD.

Activities of Daily Living↗