Cognitive reserve-mediated modulation of positron emission tomographic activations during memory tasks in Alzheimer disease

BACKGROUND: Cognitive reserve (CR) is the ability of an individual to cope with advancing brain pathological abnormalities so that he or she remains free of symptoms. Epidemiological data and evidence from positron emission tomography suggest that it may be mediated through education or IQ. OBJECTIVE: To investigate CR-mediated differential brain activation in Alzheimer disease (AD) subjects compared with healthy elderly persons. PARTICIPANTS: Using radioactive water positron emission tomography, we scanned 12 AD patients and 17 healthy elderly persons while performing a serial recognition memory task for nonverbalizable shapes under 2 conditions: low demand, in which one shape was presented in each study trial, and titrated demand, in which the study list length was adjusted so that each subject recognized shapes at approximately 75% accuracy. Positron emission tomographic scan acquisition included the encoding and recognition phases. A CR factor score that summarized years of education, National Adult Reading Test estimated IQ, and Wechsler Adult Intelligence Scale-Revised vocabulary subtest score (explaining 71% of the total variance) was used as an index of CR. Voxel-wise, multiple regression analyses were performed with the "activation" difference (titrated demand-low demand) as the dependent variables and the CR factor score as the independent one. Brain regions where regression slopes differed between the 2 groups were identified. RESULTS: The slopes were significantly more positive for the AD patients in the left precentral gyrus and in the left hippocampus and significantly more negative in the right fusiform, right middle occipital, left superior occipital, and left middle temporal gyri. CONCLUSION: Brain regions where systematic relationships (slopes) between subjects' education-IQ and brain activation differ as a function of disease status may mediate the differential ability to cope with (ie, delay or modify) clinical manifestations of AD.     

Early diagnosis of Alzheimer disease with positron emission tomography

The emergence of drugs that may slow progression of Alzheimer disease, if administered early during its course, has necessitated early diagnosis of the disease itself. Among the functional imaging methods that could assist in early diagnosis, positron emission tomography has an important role in providing quantitative measures of various aspects of brain function affected by the disease. Positron emission tomography studies in patients with Alzheimer disease have revealed a typical pattern of metabolic deficits in the temporal and parietal lobes. Additionally, converging evidence from numerous studies indicates that a similar pattern of deficits can be observed in nondemented subjects who are at risk of developing the disease, such as those with recognized genetic traits such as familial Alzheimer disease with mutations in chromosomes 21 and 14, Down syndrome, subjects with the epsilon4 allele of the apolipoprotein E gene, and individuals with mild cognitive impairment. These findings might have implications for the selection of patients for clinical trials, defining the outcome measures and evaluation of treatment efficacy and responder characteristics, but should be confirmed by prospective studies comprising larger samples and include clinicopathologic correlations.     

Clinical and positron emission tomographic studies in the 'extrapyramidal syndrome' of dementia of the Alzheimer type

Extrapyramidal signs, particularly rigidity and tremor, have been reported in a proportion of patients with dementia of the Alzheimer type. To test the hypothesis that these extrapyramidal signs are similar clinically and neurochemically to the extrapyramidal signs of Parkinson's disease, a group of 20 patients satisfying clinical criteria for probable Alzheimer's disease were studied and assessed clinically for the presence of rigidity, tremor, and bradykinesia. In those patients with extrapyramidal signs, qualitative differences were observed between the signs in these patients and in subjects with Parkinson's disease. Fifteen of 20 patients underwent fluoro-18-dopa scans, which showed no significant difference in fluoro-18-dopa uptake into the caudate and putamen between normal subjects and the rigid and nonrigid patients with Alzheimer's disease, in contrast to the marked reduction in fluoro-18-dopa uptake into the putamen that is observed in Parkinson's disease. This provides clinical and in vivo neurochemical support for the hypothesis that extranigral factors may be involved in the pathogenesis of rigidity in Alzheimer's disease.     

Brain acetylcholinesterase activity in Alzheimer disease measured by positron emission tomography

Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (-30%) and parietal cortices (-31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.     

Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study

BACKGROUND: Pathology reports have shown that cholinergic forebrain neuronal losses in parkinsonian dementia (PDem) are equal to or greater than those in Alzheimer disease (AD). We hypothesized that patients with PDem would have cholinergic deficits that were similar to or greater than those of patients with AD. OBJECTIVE: To determine in vivo cortical acetylcholinesterase (AChE) activity in healthy control subjects and in patients with mild AD, PDem, and Parkinson disease without dementia using AChE positron emission tomography. SETTING: University and Veterans' Administration medical center.Design and Patients Group comparison design of patients with AD (n = 12), PDem (n = 14), and Parkinson disease without dementia (n = 11), and controls (n = 10) who underwent AChE imaging between July 1, 2000, and January 31, 2003. Patients with AD and PDem had approximately equal dementia severity. MAIN OUTCOME MEASURES: Cerebral AChE activity. RESULTS: Compared with controls, mean cortical AChE activity was lowest in patients with PDem (-20.0%), followed by patients with Parkinson disease without dementia (-12.9%; P<.001). Mean cortical AChE activity was relatively preserved in patients with AD (-9.1%), except for regionally selective involvement of the lateral temporal cortex (-15%; P<.001). CONCLUSION: Reduced cortical AChE activity is more characteristic of patients with PDem than of patients with mild AD.     

A positron emission tomographic study in spontaneous migraine

BACKGROUND: Functional brain imaging in acute migraine has proved challenging because of the logistic problems associated with an episodic condition. Since the seminal observation of brainstem activation in migraine, there has been only a single case substantiating this finding. OBJECTIVE: To test the hypothesis that brainstem activation could be detected in migraine and to refine the anatomic localization with higher-resolution positron emission tomography than previously used. DESIGN: Using positron emission tomography with radioactive water (H(2)15O), we studied acute migraine attacks occurring spontaneously. Five patients underwent imaging in ictal and interictal states, and the differences were analyzed by means of statistical parametric mapping. SETTING: Tertiary referral center. PATIENTS: Six volunteers with episodic migraine were recruited from advertisements in migraine newsletters. One patient was excluded because of use of preventive medication. MAIN OUTCOME MEASURE: Brainstem activation during migraine state vs interictal state. RESULTS: Two patients had a typical migrainous aura before the onset of the headache. All of the attacks studied fulfilled standard diagnostic criteria for migraine. Comparing the migraine scans with interictal scans, there was significant activation in the dorsal pons, lateralized to the left (small volume correction, P = .003). Activation was also seen in the right anterior cingulate, posterior cingulate, cerebellum, thalamus, insula, prefrontal cortex, and temporal lobes. There was an area of deactivation in the migraine phase also located in the pons, lateralized to the right. CONCLUSIONS: Our findings provide clear evidence of dorsal pontine activation in migraine and reinforce the view that migraine is a subcortical disorder modulating afferent neural traffic.     

Cerebral imaging in healthy aging: contrast with Alzheimer disease

With age, the brain undergoes both structural and functional alterations. Overall, the literature consistently reports global brain atrophy in normal adults, generally more pronounced in frontal areas. As a result of different methodologies and inclusion criteria, other brain areas have been the matter of conflicting findings, notably the hippocampus. Regarding resting-state PET studies, they have consistently highlighted a metabolic deterioration of the frontal and anterior cingulated cortices. By contrast, relatively few investigations have sought to identify those areas that remain intact with aging, or undergo the least deterioration. We report a study designed to establish a comprehensive profile of both structural and functional changes in the aging brain, using up-to-date voxel-based methodology in 45 optimally healthy subjects aged 20-83 years. One of the main findings is that the lesser structural deterioration of the anterior hippocampal region, together with the lesser functional alteration of the posterior cingulate cortex, appear to mark the parting of the ways between normal aging and Alzheimer's disease, which is characterized by early and prominent deterioration of both structures. This paper also deals with studies set out to establish the relationship between changes in episodic memory retrieval in normal aging on the one hand and gray matter volume and 18FDG uptake on the other hand. Frontal areas dysfunction is involved in memory decline in older subjects, at least in some conditions, a finding which clearly contrasts with that found in Alzheimer's disease where the hippocampus plays a key role. Finally, compensatory mechanisms are reviewed through activation studies which often show supplementary activations in old subjects compared to young as well as in Alzheimer's disease patients compared to healthy elderly subjects. Paradoxically, those mechanisms seem to be underpinned, at least partially, by frontal areas in both populations, but researches are needed to better identify which subregions are involved.     

Nonlinear progression of Parkinson disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity

BACKGROUND: The investigation of disease progression provides important information on the dynamics of cell death in Parkinson disease (PD). OBJECTIVE: To determine the progression of dopaminergic impairment in PD with the use of positron emission tomography (PET). DESIGN: Longitudinal prospective cohort study with a follow-up period of 64.5 +/- 22.6 months (mean +/- SD). SETTING: University hospital. PATIENTS: A consecutive sample of patients with PD (N = 31; age at symptom onset, 53.6 +/- 11.3 years) with a wide range of symptom duration and severity at the time of study entry. INTERVENTIONS: Investigation by serial fluorodopa F 18 ([(18)F]fluorodopa) PET as a marker for striatal dopaminergic function. MAIN OUTCOME MEASURES: Changes in caudate and putaminal [(18)F]fluorodopa influx constant (K(i)) values. RESULTS: In patients with PD, the decline rate of putaminal [(18)F]fluorodopa K(i) correlated inversely with disease duration before study inclusion (r = -0.46, P = .01) and positively with baseline K(i) values (r = 0.44, P = .01), indicating a negative exponential loss of dopamine neurons. Annual disease progression rates ranged from 4.4% in the caudate nucleus to 6.3% in the putamen. A mean preclinical period of 5.6 +/- 3.2 years was calculated with symptom onset at a putaminal K(i) threshold of 69% from controls. Assuming nonlinear progression kinetics, the required sample size to prove neuroprotection with the use of [(18)F]fluorodopa PET was found to increase strongly with the preceding symptom duration of study subjects. CONCLUSION: These data suggest that the neurodegenerative process in PD follows a negative exponential course and slows down with increasing symptom duration, contradicting the long-latency hypothesis of PD.     

Monosymptomatic resting tremor and Parkinson's disease: a multitracer positron emission tomographic study.

We sought to elucidate the relationship between monosymptomatic resting tremor (mRT) and Parkinson's disease (PD). We studied eight mRT patients (mean Hoehn and Yahr [H&Y], 1.1 +/- 0.4), eight patients with PD (mean H&Y, 1.5 +/- 0.8), who showed all three classic parkinsonian symptoms, and seven age-matched healthy subjects. Subjects underwent cerebral magnetic resonance imaging (MRI) and multitracer positron emission tomography (PET) with 6-[(18)F]fluoro-L-dopa (F-dopa), [(18)F]fluorodeoxyglucose (FDG), and [(11)C]raclopride (RACLO). PD and mRT patients did not show significant differences in F-dopa-, RACLO-, or FDG-PET scans. In F-dopa- and RACLO-PET, significant differences between the pooled patient data and control subjects were found for the following regions: anterior and posterior putamen ipsilateral and contralateral to the more affected body side, and ipsilateral and contralateral putaminal gradients of the K(i) values. Furthermore, we found a difference for the normalized glucose values of the whole cerebellum between the control group (0.94 +/- 0.06) and PD patients (1.01 +/- 0.04; P < 0.05) but not for the mRT group (0.97 +/- 0.03). Our findings indicate that monosymptomatic resting tremor represents a phenotype of Parkinson's disease, with a nearly identical striatal dopaminergic deficit and postsynaptic D2-receptor upregulation in both patient groups. We suggest that the cerebellar metabolic hyperactivity in PD is closer related to akinesia and rigidity rather than to tremor.     

Functional imaging of cognition in Alzheimer's disease using positron emission tomography

Positron emission tomography in Alzheimer's disease (AD) demonstrates a metabolic decrease, predominantly in associative posterior cortices (comprising the posterior cingulate cortex), and also involving medial temporal structures and frontal regions at a lesser degree. The level of activity in this wide network is roughly correlated with dementia severity, but several confounds (such as age, education or subcortical ischemic lesions) may influence the brain-behaviour relationship. Univariate analyses allow one to segregate brain regions that are particularly closely related to specific neuropsychological performances. For example, a relationship was established between the activity in lateral associative cortices and semantic performance in AD. The role of semantic capacities (subserved by temporal or parietal regions) in episodic memory tasks was also emphasized. The residual activity in medial temporal structures was related to episodic memory abilities, as measured by free recall performance, cued recall ability and recognition accuracy. More generally, AD patients' performance on episodic memory tasks was correlated with the metabolism in several structures of Papez's circuit (including the medial temporal and posterior cingulate regions). Multivariate analyses should provide complementary information on impaired metabolic covariance in functional networks of brain regions and the consequences for AD patients' cognitive performance. More longitudinal studies are being conducted that should tell us more about the prognostic value of initial metabolic impairment and the neural correlates of progressive deterioration of cognitive performance in AD.     

Brain muscarinic receptors in progressive supranuclear palsy and Parkinson's disease: a positron emission tomographic study

OBJECTIVES—To assessmuscarinic acetylcholine receptors (mAChRs) in the brains of patientswith progressive supranuclear palsy and Parkinson's disease, and tocorrelate the cholinergic system with cognitive function in progressivesupranuclear palsy and Parkinson's disease.
METHODS— Positronemission tomography (PET) and [¹¹C]N-methyl-4-piperidylbenzilate ([¹¹C]NMPB) was used to measure mAChRs in thebrain of seven patients with progressive supranuclear palsy, 12 patients with Parkinson's disease, and eight healthy controls. All ofthe patients with progressive supranuclear palsy were demented. TheParkinson's disease group consisted of 11 non-demented patients andone demented patient. The mini mental state examination (MMSE) was usedto assess the severity of cognitive dysfunction in all of the subjects. The modified Wisconsin card sorting test (WCST) was used to evaluate frontal cognitive function in the non-demented patients withParkinson's disease and controls.
RESULTS—The meanK₃ value, an index of mAChR binding, was significantlyhigher for the frontal cortex in the patients with Parkinson's diseasethan in the controls (p<0.01). By contrast, the patients withprogressive supranuclear palsy had no significant changes in theK₃ values of any cerebral cortical regions. The mean score of the MMSE in the progressive supranuclear palsy group wassignificantly lower than that in the control group. Although there wasno difference between the Parkinson's disease and control groups inthe MMSE, the non-demented patients with Parkinson's disease showedsignificant frontal lobe dysfunction in the WCST.
CONCLUSIONS—Theincreased mAChR binding in the frontal cortex of the patients withParkinson's disease may reflect denervation hypersensitivity caused byloss of the ascending cholinergic input to that region from the basalforebrain and may be related to frontal lobe dysfunction inParkinson's disease. The cerebral cortical cholinergic system may nothave a major role in cognitive dysfunction in progressive supranuclear palsy.

     

Cholinergic neuronal and axonal abnormalities are present early in aging and in Alzheimer disease

A large body of evidence indicates that basal forebrain cholinergic neurons are selectively vulnerable to degeneration early in Alzheimer disease (AD). Recent studies, however, demonstrate reductions in cortical activity of the cholinergic enzyme choline acetyltransferase only in late stages of AD. To address this apparent contradiction, we compared abnormalities in magnocellular basal forebrain cholinergic neurons and their axons in nondemented young (<65 years; n = 6), nondemented old (>65 years; n = 7), pathologically mild (n = 5), and pathologically severe (n = 5) AD cases. Cholinergic axon abnormalities (i.e. thickened fibers and ballooned terminals) were evident in nondemented middle-aged cases, increased in nondemented old cases, and reduced in density in severe AD. This suggests that loss of cortical cholinergic axons in AD occurs preferentially in fibers with these abnormalities. Paired helical filament 1-immunoreactive pretangles and tangles were observed as early as the third decade prior to their appearance in entorhinal/perirhinal cortex; they were increased in mild and severe AD. These results indicate that basal forebrain cholinergic neuron abnormalities are present very early in aging and in the course of AD. Therefore, despite the morphologic alterations, choline acetyltransferase activity, but not necessarily normal neuron functions, may be preserved.     

Motor learning in man: a positron emission tomographic study

We measured regional cerebral blood flow (rCBF) with positron emission tomography to study changes in anatomical structures during the course of learning a complicated finger sequence of voluntary movements. Motor learning was accompanied by rCBF increases in the cerebellum, decreases in all limbic and paralimbic structures, and striatal decreases which changed to striatal increases as the motor skill was learned. Simultaneously, activations of initially contributing non-motor parts of the cerebral cortex vanished. Both cerebellar circuits and striatal circuits appear important for the storage of motor skills in the brain.