Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer's disease dementia.

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. All patients underwent PET scans with [18F]THK5317 (tau deposition) and [18F]FDG (glucose metabolism) at baseline and follow-up, neuropsychological assessment at baseline and follow-up and a scan with [11C]PIB (amyloid-ß deposition) at baseline only. At a group level, patients with AD (prodromal or dementia) showed unchanged [18F]THK5317 retention over time, in contrast to significant decreases in [18F]FDG uptake in temporoparietal areas. The pattern of changes in [18F]THK5317 retention was heterogeneous across all patients, with qualitative differences both between the two AD groups (prodromal and dementia) and among individual patients. High [18F]THK5317 retention was significantly associated over time with low episodic memory encoding scores, while low [18F]FDG uptake was significantly associated over time with both low global cognition and episodic memory encoding scores. Both patients with corticobasal syndrome had a negative [11C]PIB scan, high [18F]THK5317 retention with a different regional distribution from that in AD, and a homogeneous pattern of increased [18F]THK5317 retention in the basal ganglia over time. These findings highlight the heterogeneous propagation of tau pathology among patients with symptomatic AD, in contrast to the homogeneous changes seen in glucose metabolism, which better tracked clinical progression.

White matter changes in familial Alzheimer's disease.

BACKGROUND: Familial Alzheimer's disease (FAD) resulting from gene mutations in PSEN1, PSEN2 and APP is associated with changes in the brain. OBJECTIVE: The aim of this study was to investigate changes in grey matter (GM), white matter (WM) and the cerebrospinal fluid (CSF) in FAD. SUBJECTS: Ten mutation carriers (MCs) with three different mutations in PSEN1 and APP and 20 noncarriers (NCs) were included in the study. Three MCs were symptomatic and seven were presymptomatic (pre-MCs). METHODS: Whole-brain GM volume as well as fractional anisotropy (FA) and mean diffusivity (MD) using voxel-based morphometry and tract-based spatial statistics analyses, respectively, were compared between MCs and NCs. FA and MD maps were obtained from diffusion tensor imaging. RESULTS: A significant increase in MD was found in the left inferior longitudinal fasciculus, cingulum and bilateral superior longitudinal fasciculus in pre-MCs compared with NCs. After inclusion of the three symptomatic MCs in the analysis, the regions became wider. The mean MD of these regions showed significant negative correlation with the CSF level of Aß42, and positive correlations with P-tau181p and T-tau. No differences were observed in GM volume and FA between the groups. CONCLUSIONS: The results of this study suggest that FAD gene mutations affect WM diffusivity before changes in GM volume can be detected. The WM changes observed were related to changes in the CSF, with similar patterns previously observed in sporadic Alzheimer's disease.

Including a subject-paced trial may make the PASAT more acceptable for MS patients.

UNLABELLED: The Paced Auditory Serial Addition Test (PASAT) is regularly used in the evaluation of cognition in multiple sclerosis (MS). However, the test may impose frustration, distress, and anxiety in patients, which may result in refusal to participate by many patients. OBJECTIVES: In this study, a subject- and experimenter-paced PASAT was compared and analyzed, with regard to independent measures of cognitive functions, as well as disability, fatigue, depression, and anxiety. METHODS: A population-based sample of patients with MS (n = 34; mean age 47.2 ± 8.6) was examined with the PASAT, including a subject-paced condition, in addition to the standard experimenter-paced conditions using three levels of interstimuli intervals (ISI: 3.0, 2.5, and 2.0 s). A comprehensive set of neuropsychological tests, measures of disease severity, fatigue, anxiety, and depression were studied as potentially associated factors. RESULTS: Subject- and experimenter-paced PASAT performance correlated significantly and the subject-paced administration correlated even higher with measures of information processing speed, executive function, attention, and working memory than standard experimenter-paced administration of PASAT. DISCUSSION: The associations between PASAT performance and measures of fatigue, anxiety, and depression were not significant. CONCLUSION: The results indicate that the altered PASAT procedure measures the same cognitive functions in MS as the standard procedure. At the same time, the altered procedure may make the PASAT more user-friendly for patients with MS.

Callosal atrophy in multiple sclerosis is related to cognitive speed.

BACKGROUND: Long-term changes regarding corpus callosum area (CCA) and information processing speed in cognitive and sensory-motor tasks have rarely been studied in multiple sclerosis (MS). OBJECTIVE AND METHODS: Information processing speed in cognitive (Symbol Digit Modalities Test, SDMT), sensory (visual and auditory reaction time) and motor (finger-tapping speed, FT; right and left hand) tasks as well as auditory inter-hemispheric transfer (verbal dichotic listening, VDL) was related to CCA, measured by MRI at baseline and at follow-up after nine years in 22 patients with MS. Possible confounding by demographic (age, gender and education), clinical (symptom onset, duration, severity of disease) and relative brain volume (RBV) as well as T2 lesion load was taken into account. RESULTS: The smaller the CCA at baseline, the slower was SDMT performance at baseline. In a similar way, CCA at follow-up was associated with poor SDMT result at follow-up. Furthermore, the higher the annual rate of change in CCA, the poorer was performance in VDL on the left ear and the more pronounced was the right ear advantage. A positive relationship between performance in VDL right ear and annual rate of change in RBV was also seen. Sensory-motor tests were not significantly associated with CCA. T2 lesion load at baseline was associated with FT performance at baseline. Demographic, clinical and radiological (RBV and T2 lesion load) characteristics did not confound the significant relation between CCA and SDMT. CONCLUSIONS: CCA unlike RBV and T2 lesion load was associated with SDMT, which indicated a marked cognitive rather than perceptual-motor component.

Regional differences in effects of APOE ε4 on cognitive impairment in non-demented subjects.

BACKGROUND: The APOE ε4 allele is a risk factor for Alzheimer's disease (AD). APOE ε4 is common in non-demented subjects with cognitive impairment. In both healthy people and people with AD, its prevalence has a north-south gradient across Europe. In the present study, we investigated whether the relation between the APOE ε4 allele and cognitive impairment varied across Northern, Middle and Southern Europe. We also investigated whether a north-south gradient existed in subjects with subjective cognitive impairment (SCI), amnestic mild cognitive impairment (MCI) and non-amnestic MCI. METHODS: Data from 16 centers across Europe were analyzed. RESULTS: A north-south gradient in APOE ε4 prevalence existed in the total sample (62.7% for APOE ε4 carriers in the northern region, 42.1% in the middle region, and 31.5% in the southern region) and in subjects with SCI and amnestic MCI separately. Only in Middle Europe was the APOE ε4 allele significantly associated with poor performance on tests of delayed recall and learning, as well as with the amnestic subtype of MCI. CONCLUSION: The APOE ε4 allele frequencies in subjects with SCI and amnestic MCI have a north-south gradient. The relation between the APOE ε4 allele and cognition is region dependent.

Selective decline in information processing in subgroups of multiple sclerosis: an 8-year longitudinal study.

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS) that causes white matter and cortical lesions over many years. The CNS is selectively affected by the disease with a great variety of symptoms between patients. In this study, we describe the impact on various aspects of cognition over an 8-year follow-up period in 31 consecutive MS patients subgrouped as relapsing remitting (RR) MS, secondary progressive (SP) MS, and primary progressive (PP) MS. Results showed a differential pattern of cognitive decline already at baseline in speed of information processing. During the follow-up, a pronounced decline occurred in speed of information processing, finger-motor speed, copying geometrical designs, episodic memory, and visuospatial short-term memory. A striking difference was observed between a marked decline in visual reaction time, whereas no significant change was seen in auditory reaction time. In contrast, there was no time-related decline in verbal abilities. However, an initial marked cognitive impairment predicted further cognitive decline over the 8-year follow-up. Information-processing tests were found to be an especially strong predictor of long-term cognitive decline. In addition, high EDSS score at follow-up was associated with decline in information processes. Results also showed that SP-MS patients deteriorated significantly more than the other two groups, particularly in visual compared to auditory information processing. To conclude, cognitive decline appeared particularly in SP-MS patients and in visual information processing.

Visual rating of age-related white matter changes on magnetic resonance imaging: scale comparison, interrater agreement, and correlations with quantitative measurements.

BACKGROUND AND PURPOSE: To provide further insight into the MRI assessment of age-related white matter changes (ARWMCs) with visual rating scales, 3 raters with different levels of experience tested the interrater agreement and comparability of 3 widely used rating scales in a cross-sectional and follow-up setting. Furthermore, the correlation between visual ratings and quantitative volumetric measurement was assessed. METHODS: Three raters from different sites using 3 established rating scales (Manolio, Fazekas and Schmidt, Scheltens) evaluated 74 baseline and follow-up scans from 5 European centers. One investigator also rated baseline scans in a set of 255 participants of the Austrian Stroke Prevention Study (ASPS) and measured the volume of ARWMCs. RESULTS: The interrater agreement for the baseline investigation was fair to good for all scales (kappa values, 0.59 to 0.78). On the follow-up scans, all 3 raters depicted significant ARWMC progression; however, the direct interrater agreement for this task was poor (kappa, 0.19 to 0.39). Comparison of the interrater reliability between the 3 scales revealed a statistical significant difference between the scale of Manolio and that of Fazekas and Schmidt for the baseline investigation (z value, -2.9676; P=0.003), demonstrating better interrater agreement for the Fazekas and Schmidt scale. The rating results obtained with all 3 scales were highly correlated with each other (Spearman rank correlation, 0.712 to 0.806; P< or =0.01), and there was significant agreement between all 3 visual rating scales and the quantitative volumetric measurement of ARWMC (Kendall W, 0.37, 0.48, and 0.57; P<0.001). CONCLUSIONS: Our data demonstrate that the 3 rating scales studied reflect the actual volume of ARWMCs well. The 2 scales that provide more detailed information on ARWMCs seemed preferential compared with the 1 that yields more global information. The visual assessment of ARWMC progression remains problematic and may require modifications or extensions of existing rating scales.

Neuropsychological features of early Alzheimer's disease: preclinical and clinical stages.

In the preclinical stage of Alzheimer's disease (AD), studies of asymptomatic mutation carriers have identified impairments in episodic memory. Other cognitive functions show no or slight impairment suggesting that preclinical AD is a unifunctional cognitive syndrome; the brain is affected selectively and predominantly in the medial temporal structures. In the early clinical stage, deficits occur in episodic memory, verbal abilities, visuospatial functions, attention, and executive functions. AD becomes a multifunctional cognitive syndrome and the brain's association cortices are affected. Nevertheless, sensory-motor performance and procedural memory seem to be intact and only slight impairment may be seen in primary memory. In advanced AD, cognitive dysfunction including deficits is global in primary memory, although sensory-motor performance may be well preserved. The brain's association cortices are severely affected. The sequence of cognitive decline; from unifunctional to global deficits, conforms to the three-stage development of neurofibrillary tangles described by Braak and Braak.

Neuropsychological assessment of dementia: state of the art.

A comprehensive neuropsychological examination includes an assessment of both cognitive functions and personality characteristics. In order to evaluate dementia, the patient's present as well as the premorbid functioning has to be assessed, which is performed by means of tests, behavioral observations, rating scales, and inquiries. These methods are used for diagnostic purposes, for differential diagnostics, follow-up studies, and for evaluation of treatment effects. Recent research has shown that neuropsychological methods have a high sensitivity and specificity in detection of dementia, utilizing measures of episodic memory. For staging of dementia, episodic memory as well as other cognitive functions are necessary. The effectiveness of dementia differentiation by means of neuropsychological methods varies from quite good regarding frontal lobe degeneration to less good regarding cerebrovascular dementias, probably due to the variation in site, extent, number, and temporal characteristics of the lesion. Future development is required regarding methods for evaluation of premorbid functioning, instruments for assessment of executive functions, and personality characteristics in dementia. Furthermore, brain-behavior studies are needed to learn more about the relation between neuropsychological measures vs neuropathology, neurochemistry, and neuroimaging.

Skin vessel reactivity is impaired in Alzheimer's disease.

Fifteen patients with Alzheimer's disease (AD) and 16 age-matched controls underwent skin vessel reactivity tests employing three vasodilating substances with different modes of action: acetylcholine (ACh), nitroprusside, and isoprenaline. The substances were iontophoresed into the skin and the results were mapped through a newly developed laser Doppler perfusion imager. The skin vascular responses of the patients to ACh and isoprenaline but not nitroprusside were significantly attenuated compared to those of the controls. The differences between patient and control groups concerning skin vessel reactivity might be due to receptor/signal transduction abnormalities but might in addition indicate an attenuated endothelium-dependent vasodilation in AD. The results of this study support the hypothesis that AD might be a systemic disease. They suggest that tests of skin vessel reactivity might be of help in the antemortem diagnosis of AD.

Quantitative electroencephalography in mild cognitive impairment: longitudinal changes and possible prediction of Alzheimer's disease.

The present study evaluated the clinical course of patients with mild cognitive impairment (MCI), the pattern of electroencephalography (EEG) changes following cognitive deterioration, as well as the potential of neurophysiological measures in predicting dementia. Twenty-seven subjects with MCI were followed for a mean follow up period of 21 months. Fourteen subjects (52%) progressed (P MCI) to clinically manifest Alzheimer's disease (AD), and 13 (48%) remained stable (S MCI). The two MCI subgroups did not differ in baseline EEG measures between each other and the healthy controls (n = 16), but had significantly lower theta relative power at left temporal, temporo-occipital, centro-parietal, and right temporo-occipital derivation when compared to the reference AD group (n = 15). The P MCI baseline alpha band temporo-parietal coherence, alpha relative power values at left temporal and temporo-occipital derivations, theta relative power values at frontal derivations, and the mean frequency at centro-parietal and temporo-occipital derivations overlapped with those for AD and control groups. After the follow-up, the P MCI patients had significantly higher theta relative power and lower beta relative power and mean frequency at the temporal and temporo-occipital derivations. A logistic regression model of baseline EEG values adjusted for baseline Mini-Mental Test Examination showed that the important predictors were alpha and theta relative power and mean frequency from left temporo-occipital derivation (T5-O1), which classified 85% of MCI subjects correctly.

Olfactory dysfunction for pyridine and dementia progression in Alzheimer disease.

OBJECTIVE: To investigate whether odor detection sensitivity for pyridine, suggested by previous research not to be affected, is impaired in Alzheimer disease (AD) and whether an association exists between odor threshold and both degree of dementia and rate of dementia progression in AD. METHOD: The method of constant stimuli was used to determine odor thresholds for pyridine in 18 patients with AD (Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria) and 16 healthy elderly control subjects. All participants were carefully examined with medical and neuropsychological tests. RESULTS: Six patients with AD but none of the controls were anosmic (total olfactory loss) to pyridine, and the 12 nonanosmic patients had significantly higher detection thresholds (50% probability for detection, 323 parts per billion [ppb]) than did the controls (50% probability for detection, 105 ppb). In addition, an association was found between odor threshold and both degree of dementia and rate of dementia progression in AD. CONCLUSIONS: In contrast to previous findings, our results provide evidence that odor sensitivity in AD is impaired for pyridine. Odor sensitivity, in addition to other suggested predictors of progression rate, may be of interest for defining subgroups of AD or for clinical prognostic judgments of single patients.

Detection of mild dementia in community surveys. Is it possible to increase the accuracy of our diagnostic instruments?

OBJECTIVE: To investigate the accuracy of cognitive tests and clinical dementia diagnosis in distinguishing between mildly demented and nondemented subjects. DESIGN: Three-year longitudinal follow-up of a community-based cohort sample. Using the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised as criterion variable, subjects were classified as demented and nondemented based on the results of cognitive test performance at time 1. These subjects were then examined prospectively for development of dementia at time 2. PARTICIPANTS: The sample consisted of 63 mildly demented (Mini-Mental State Examination score > 18 < 24) and 398 nondemented subjects at time 1. At follow-up, due to death and refusal of participation, the sample consisted of 108 demented and 217 nondemented subjects. RESULTS: The group of subjects who were considered to be demented according to the results of the cognitive tests and nondemented by the clinical diagnosis at time 1 had a higher incidence of dementia at time 2 than did the subjects who were considered to be nondemented according to both cognitive tests and clinical diagnosis. Among the incident dementia cases, subjects considered to be demented according to the cognitive tests but nondemented by the clinical diagnosis performed at a lower level on most cognitive tests were older, had less education, and consisted of more women than did the group of subjects who were considered to be demented by the clinical diagnosis and nondemented by the cognitive tests at time 1. CONCLUSIONS: A combination of cognitive tests, especially tasks assessing episodic memory, can detect many subjects in a preclinical state of dementia who could be missed in the clinical diagnostic procedure due to subjects' relatively high age, low education, and female sex. However, cognitive tests also may miss a sizable proportion of prevalent dementia cases due to possible insensitivity to the same demographic variables. These findings indicate the need of integration between clinical and cognitive data to increase the accuracy in detecting dementia in an early phase.

Carbamazepine-10,11-epoxide in epilepsy. A pilot study.

The effects of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, were evaluated in seven outpatients with frequent epileptic seizures. The study included an initial 4-week period with the carbamazepine dose optimized for each patient. Patients were then crossed over, dose by dose, to carbamazepine-10,11-epoxide and followed up for another 4 weeks. Dosing was single blind. The evaluation of the anticonvulsant effect was hampered by marked fluctuations in plasma levels during treatment with carbamazepine-10,11-epoxide. There was, however, no significant change in seizure control. During epoxide treatment, no subjective side effects were reported despite epoxide plasma concentrations up to 57 mumol/L. Neuropsychological assessment revealed a significant improvement in finger motor speed and logical reasoning during the carbamazepine-10,11-epoxide period. Subnormal serum sodium levels in two patients were normalized after switching from carbamazepine to the epoxide. Continued investigations with this active metabolite of carbamazepine in epilepsy are therefore justified.

Cerebrospinal fluid levels of alpha-secretase-cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation.

OBJECTIVE: To explore the relationship between possible biological markers of Alzheimer disease that are related to amyloid metabolism and mental functions. PARTICIPANTS: Twelve individuals from a Swedish family with Alzheimer disease and a double mutation at codons 670/671 of the amyloid precursor protein gene participated in the study. DESIGN: Cerebrospinal fluid levels of alpha-secretase cleaved soluble amyloid precursor protein (alpha-sAPP), total sAPP, and amyloid beta-peptide were correlated with data on multiple cognitive functions that covered the whole range of human performance. SETTING: The Alzheimer's Disease Research Centre, Department of Clinical Neuroscience, Section of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden. RESULTS: There were highly significant linear correlations between low levels of alpha-sAPP and poor performance on neuropsychological tests that assessed intelligence, verbal and visuospatial functions, memory, and attention. Within the group of nonmutation carriers, significant correlations were also obtained between the levels of alpha-sAPP and cognitive functions. A less striking association was seen between the levels of total sAPP and cognition. No association was found between the levels of amyloid beta-peptide and cognition. CONCLUSIONS: The strong relationship between alpha-sAPP levels and cognition in both patients with Alzheimer disease and normal-aging persons may imply that alpha-sAPP is involved in basic protective brain processes. Alternatively, less amyloid beta-peptide amounts are produced, leading to diminished plaque formation, when alpha-sAPP is generated.

Bilateral temporal lobe volume reduction parallels cognitive impairment in progressive aphasia.

BACKGROUND: Patients with isolated aphasia in the absence of other cognitive abnormalities have been the focus of several studies during the past decade. It has been called primary progressive aphasia (PPA), and the typical features of this syndrome are marked atrophy of the left temporal lobe according to the radiological examination and a language disorder as the initial symptom. In previous studies of PPA, the selection of the patients was based mainly on linguistic symptoms. Now, when computed tomography or magnetic resonance imaging scans are part of the routine investigation of cognitive impairment and suspected dementia, the patients with lobar atrophy will be found at an earlier stage. In the present study, we used a new approach and defined the study group by selecting patients with obvious left temporal lobe atrophy, assessed by MRI, and we referred to them as patients with temporal lobe atrophy (TLA). OBJECTIVE: To identify the features that distinguish TLA from other primary neurodegenerative disorders. PATIENTS: Six patients with TLA were compared with patients with Alzheimer disease (AD), patients with frontal lobe dementia (FLD), and healthy control subjects. METHODS: The investigations included magnetic resonance imaging volumetry, single photon emission computed tomography, and neuropsychologic and linguistic evaluations. RESULTS: In the TLA group, the mean volume of the left temporal lobe was 35% smaller than the right, while in the AD and FLD groups, the atrophy was symmetrical and bilateral. In the TLA group, the absolute volumes of the temporal lobes were significantly smaller on the left side compared with the AD and FLD groups, whereas there was no difference on the right side. The cerebral blood flow pattern in TLA was asymmetric and differed from that in the other study groups. All patients with TLA had a history of progressive Wernicke-type aphasia, ranging from 2 to 6 years. They showed primary verbal memory impairment but had preserved visuospatial functions. The clinical condition of all patients with TLA deteriorated during the study period; severe aphasia developed, and the patients exhibited signs of frontal lobe dysfunction. Serial volumetric measurements in 4 of 6 patients showed an annual 8% to 9% decrease of both left and right temporal lobes. CONCLUSIONS: The initial marked asymmetry in cognitive function found in patients with TLA contrasts with the general decline found in patients with AD. The bilateral degenerative process evident in patients with TLA paralleled the clinical deterioration, indicating TLA to be a non-AD lobar atrophy that develops into generalized cognitive dysfunction and dementia.

White-matter hyperintensity and neuropsychological functions in dementia and healthy aging.

The relationship between quantitative measurements of brain white-matter hyperintensity (WMH), assessed by magnetic resonance imaging and neuropsychological functions, was explored in demented patients and healthy aged individuals with and without WMH in 12 brain regions. The prevalence of WMH was significantly higher in vascular dementia compared with Alzheimer's disease, especially in posterior periventricular regions. Results showed no difference in any neuropsychological measurement between healthy aged adults with and without WMH. The demented patients with WMH were more impaired in tests of visuoconstruction, attention, finger-motor speed, and latency of tactile identification of objects compared with patients without WMH. These impairments were related mainly to posterior periventricular WMH. There was no relationship between WMH and global cognitive functioning in the demented patients. The degree of WMH was related to age and blood pressure. The data suggest that specific regional WMH may result in specific neuropsychological impairments.

Clinical characteristics of a chromosome 17-linked rapidly progressive familial frontotemporal dementia.

OBJECTIVE: To describe symptoms, signs, neuroimaging results, and neuropathologic findings in patients from a family with chromosome 17q21-linked autosomal dominant frontotemporal dementia. DESIGN: Multiple case report with genetic investigations. SUBJECTS: The disease was observed in a Swedish family and documented in 3 generations. Four siblings are described in this article. RESULTS: A rapidly progressive dementia with genetic linkage to chromosome 17q21 was observed. The mean age of onset was 51 years and the average duration of disease to death was 3 years. Two patients started with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia and akinesia and muscular rigidity, and in 1 patient reckless driving was the first symptom. Loss of spontaneous speech developed later in all patients and emotional bluntness in 3 of the patients. Cerebral perfusion was decreased in the frontal areas in all patients. In the person with apraxia as the onset symptom, the cerebral blood flow was also diminished in the left hemisphere, where a slight atrophy was detected on magnetic resonance imaging scans. At the postmortem examination, slight gliosis of the parietal lobes was observed in this patient. In all patients there was a frontocentral degeneration of the cortex with discrete microvacuolation and gliosis. CONCLUSION: Clinical features of frontotemporal dementia, parkinsonism, an early age of onset, a rapid disease progression, and variable onset symptoms were seen in these patients. Two other clinically distinct diseases, dementia with pallido-ponto-nigral degeneration and a disinhibition-dementia-parkinsonism-amyotrophy complex, have recently been mapped to chromosome 17q21. In the family described in this article, genetic linkage was detected to the same region, suggesting the possibility that these diseases may originate from pathogenic mutations in the same gene.

Brain regions associated with episodic retrieval in normal aging and Alzheimer's disease.

OBJECTIVE: To examine patterns of brain activation during verbal episodic retrieval in normal elderly subjects and patients in an early phase of AD. BACKGROUND: It is established that 1) a profound episodic memory impairment is a cardinal symptom of AD; and 2) some of the earliest brain changes in this disease occur in regions critical to episodic memory, such as the hippocampus and neighboring regions. Yet, it remains largely unknown whether the episodic memory deficit seen in AD is paralleled by concomitant alterations in brain activity during actual task performance in these or other brain areas. METHODS: Using PET, blood flow was assessed in normal elderly subjects and patients with early AD during two retrieval conditions involving completion of word stems: baseline and cued recall. RESULTS: The patients with AD showed a marked performance deficit in cued recall, although the two groups were indistinguishable in the baseline task condition. Both groups showed bilateral activity in orbital and dorsolateral prefrontal cortex, left precuneus, and right cerebellum, as well as decreased activity in distinct left temporal regions during cued recall. The normal elderly alone activated the left parietal cortex and the left hippocampal formation during episodic retrieval. By contrast, AD-related increases in activity during cued recall were observed in the left orbital prefrontal cortex and left cerebellum. CONCLUSIONS: The similar patterns of activations in the two groups suggest that a large distributed network involved in episodic memory retrieval functions relatively normally in early AD. Those retrieval activations seen in the normal elderly, as opposed to the patients, may reflect AD-related failures in semantic processing and successful recollection of the target information, respectively. Finally, the AD-related increases in activity were interpreted in terms of compensatory reactions to the difficulties in performing the episodic memory task.