Tau PET and relative cerebral blood flow in dementia with Lewy bodies: A PET study.

PURPOSE: Alpha-synuclein often co-occurs with Alzheimer's disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [18F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB. METHODS: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [18F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BPND) and R1, reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [18F]flortaucipir BPND and R1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [18F]flortaucipir BPND, R1 and performance on ten neuropsychological tests. RESULTS: Regional [18F]flortaucipir BPND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p < 0.05). Occipital and lateral parietal R1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R1 was associated with impaired performance on digit span forward (standardized beta, stß = 0.72) and category fluency (stß = 0.69) tests. Lower parietal R1 was related to lower delayed (stß = 0.50) and immediate (stß = 0.48) recall, VOSP number location (stß = 0.70) and fragmented letters (stß = 0.59) scores. Lower occipital R1 was associated to worse performance on VOSP fragmented letters (stß = 0.61), all p < 0.05. CONCLUSION: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET.

Serotonergic deficits in dementia with Lewy bodies with concomitant Alzheimer's disease pathology: An 123I-FP-CIT SPECT study.

PURPOSE: To study the influence of concomitant Alzheimer's disease (AD) pathology in dementia with Lewy bodies (DLB) on dopamine transporter (DAT) and serotonin transporter (SERT) availability, using 123I-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (123I-FP-CIT) single photon emission computed tomography (SPECT). METHODS: Based on their cerebrospinal fluid biomarker profile, fifty-two patients with probable DLB were divided in a group with (DLB/AD+, N = 15) and without concomitant AD-pathology (DLB/AD-, N = 37). We conducted atrophy-corrected region of interest (ROI) analyses comparing binding ratios (BRs) in the DAT-rich striatal and SERT-rich extrastriatal brain areas (amygdala, hippocampus, thalamus, midbrain and pons). RESULTS: DLB/AD+ patients had significantly lower 123I-FP-CIT BRs in the left amygdala, and a trend was seen in the right hippocampus. Groups did not differ significantly in striatal 123I-FP-CIT BRs, neuropsychiatric or motor symptoms. Motor symptoms correlated negatively with striatal DAT BRs. CONCLUSIONS: DLB/AD+ patients may have lower SERT binding in limbic brain regions than DLB/AD- patients, possibly indicating faster neurodegeneration in mixed pathology.

Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

Directional information flow in patients with Alzheimer's disease. A source-space resting-state MEG study.

In a recent magnetoencephalography (MEG) study, we found posterior-to-anterior information flow over the cortex in higher frequency bands in healthy subjects, with a reversed pattern in the theta band. A disruption of information flow may underlie clinical symptoms in Alzheimer's disease (AD). In AD, highly connected regions (hubs) in posterior areas are mostly disrupted. We therefore hypothesized that in AD the information flow from these hub regions would be disturbed. We used resting-state MEG recordings from 27 early-onset AD patients and 26 healthy controls. Using beamformer-based virtual electrodes, we estimated neuronal oscillatory activity for 78 cortical regions of interest (ROIs) and 12 subcortical ROIs of the AAL atlas, and calculated the directed phase transfer entropy (dPTE) as a measure of information flow between these ROIs. Group differences were evaluated using permutation tests and, for the AD group, associations between dPTE and general cognition or CSF biomarkers were determined using Spearman correlation coefficients. We confirmed the previously reported posterior-to-anterior information flow in the higher frequency bands in the healthy controls, and found it to be disturbed in the beta band in AD. Most prominently, the information flow from the precuneus and the visual cortex, towards frontal and subcortical structures, was decreased in AD. These disruptions did not correlate with cognitive impairment or CSF biomarkers. We conclude that AD pathology may affect the flow of information between brain regions, particularly from posterior hub regions, and that changes in the information flow in the beta band indicate an aspect of the pathophysiological process in AD.

Alzheimer's disease: The state of the art in resting-state magnetoencephalography.

Alzheimer's disease (AD) is accompanied by functional brain changes that can be detected in imaging studies, including electromagnetic activity recorded with magnetoencephalography (MEG). Here, we systematically review the studies that have examined resting-state MEG changes in AD and identify areas that lack scientific or clinical progress. Three levels of MEG analysis will be covered: (i) single-channel signal analysis, (ii) pairwise analyses over time series, which includes the study of interdependencies between two time series and (iii) global network analyses. We discuss the findings in the light of other functional modalities, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Overall, single-channel MEG results show consistent changes in AD that are in line with EEG studies, but the full potential of the high spatial resolution of MEG and advanced functional connectivity and network analysis has yet to be fully exploited. Adding these features to the current knowledge will potentially aid in uncovering organizational patterns of brain function in AD and thereby aid the understanding of neuronal mechanisms leading to cognitive deficits.

Psychiatric diagnoses underlying the phenocopy syndrome of behavioural variant frontotemporal dementia.

INTRODUCTION: The frontotemporal dementia (FTD) consortium criteria (2011) emphasise the importance of distinguishing possible and probable behavioural variant FTD (bvFTD). A significant number of possible patients with bvFTD do not show functional decline and remain with normal neuroimaging over time, thus exhibiting the bvFTD phenocopy syndrome. A neurodegenerative nature is unlikely but an alternative explanation is missing. Our aim was to detect psychiatric conditions underlying the bvFTD phenocopy syndrome after extensive evaluation. METHODS: We included patients with the bvFTD phenocopy syndrome whereby patients with probable bvFTD served as a control group. Patients had to have undergone both neurological and psychiatric evaluation. Their charts were reviewed retrospectively. Using both qualitative and quantitative methods, psychiatric and psychological conditions associated with the clinical syndrome were determined in both groups and their relative frequencies were compared. RESULTS: Of 181 suspected bvFTD cases, 33 patients with bvFTD phenocopy syndrome and 19 with probable bvFTD were included. Recent life events, relationship problems and cluster C personality traits were the most prevalent psychiatric/psychological conditions. The frequency of these conditions was higher in the group of patients with the bvFTD phenocopy syndrome (n=28) compared to the probable bvFTD group (n=9) (χ(2) p<0.05). CONCLUSIONS: This is the first study thoroughly exploring psychiatric causes of the bvFTD phenocopy syndrome, revealing that in most cases multiple factors played a contributory role. Our study gives arguments for neurological and psychiatric collaboration when diagnosing bvFTD. Prompt diagnosis of treatable psychiatric conditions is to be gained.

[Atypical pain in the mandible caused by trigeminal neuralgia]. / Een patiënt met een atypische pijnklacht in de onderkaak.

A 58-year-old woman came to her dentist with atypical pain on the right side of the mandible. The pain diminished with the use of carbamazepine, paracetamol and diclofenac, and eventually disappeared completely. Magnetic resonance imaging, undertaken at the advice of a neurologist, showed no structural lesions and confirmed the diagnosis of idiopathic trigeminal neuralgia. Trigeminal neuralgia is a condition which often can be diagnosed on the basis of the clinical history and the specific symptoms. The condition can be divided into idiopathic and symptomatic trigeminal neuralgia. It is important to consider a possible trigeminal neuralgia in case of atypical pain in the oral region in order to prevent unnecessary dental procedures.

Global dynamical analysis of the EEG in Alzheimer's disease: frequency-specific changes of functional interactions.

OBJECTIVE: EEG coherence is decreased in Alzheimer's disease (AD), suggesting decreased interaction between brain areas. Nonlinear EEG analysis in AD points to decreased complexity of brain dynamics, implicating increased interaction. To clarify these apparently paradoxical findings from linear and nonlinear analysis, we calculated global coherence and global correlation dimension (D2), a nonlinear measure, in the EEG of patients with probable AD and controls. Our hypothesis is that these measures are related to each other when calculated in a comparable way. METHODS: From 15 patients with probable AD (mean age 63.1 years; SD 6.3) and 21 age-matched controls with subjective memory complaints (mean age 62.8; SD 12.0), band filtered EEG data were analysed in six frequency bands. For each frequency band average coherence and multichannel D2 were determined. RESULTS: ANOVA for repeated measures showed for D2 an interaction between band and group, but not for coherence. In the beta band and upper alpha band, D2 was higher in patients with probable AD compared to controls, while global coherence tended to be lower in these frequency bands in patients with probable AD. In the frequency range from theta to beta, coherence and D2 were inversely correlated without group differences. CONCLUSIONS: When calculated in comparable ways, global correlation dimension and coherence are related measures. In AD, these measures change especially in the higher frequency ranges, both pointing to decreased functional cortical connectivity. SIGNIFICANCE: Both global coherence and global correlation dimension seem to measure global connectivity, but nonlinear measures may be more sensitive. In AD, connectivity measures are not equally impaired in all frequency ranges, possibly reflecting differentiated affection of the dynamical processes responsible for the different frequency bands.

Reduced resting-state brain activity in the "default network" in normal aging.

Normal aging is associated with cognitive decline. Functions such as attention, information processing, and working memory are compromised. It has been hypothesized that not only regional changes, but also alterations in the integration of regional brain activity (functional brain connectivity) underlie the observed age-related deficits. Here, we examined the functional properties of brain networks based on spontaneous fluctuations within brain systems using functional magnetic resonance imaging. We hypothesized that functional connectivity of intrinsic brain activity in the "default-mode" network (DMN) is affected by normal aging and that this relates to cognitive function. Ten younger and 22 older subjects were scanned at "rest," that is, lying awake with eyes closed. Our results show decreased activity in older versus younger subjects in 2 resting-state networks (RSNs) resembling the previously described DMN, containing the superior and middle frontal gyrus, posterior cingulate, middle temporal gyrus, and the superior parietal region. These results remain significant after correction for RSN-specific gray matter volume. The relevance of these findings is illustrated by the correlation between reduced activity of one of these RSNs and less effective executive functioning/processing speed in the older group.

CSF biomarkers and medial temporal lobe atrophy predict dementia in mild cognitive impairment.

OBJECTIVE: To study CSF biomarkers, beta-amyloid(1-42) (Abeta(1-42)) and tau, and medial temporal lobe atrophy (MTA) on MRI in their ability to predict dementia in patients with mild cognitive impairment (MCI). METHODS: Fifty-nine MCI patients (49% male, mean age 69+/-8), follow-up 19 months, were included. Baseline CSF levels of Abeta(1-42), tau and MTA-score were dichotomized. RESULTS: Thirty-three (56%) of the MCI patients progressed to dementia, 30 of which had Alzheimer's disease. Lower CSF Abeta(1-42) level, higher CSF-tau and higher MTA-scores at baseline were found in progressed patients. Cox proportional hazards models revealed that abnormal CSF Abeta(1-42), CSF tau and MTA were significantly associated with dementia at follow-up (hazard ratio (95% confidence interval): 4.0 (1.3-12.1), 5.9 (1.6-21.7) and 2.1 (1.0-4.6)). A fourfold higher risk was found for patients with both abnormal CSF biomarkers and MTA compared to patients with either test abnormal. Ninety-four percent of patients with both abnormalities converted to dementia. CONCLUSIONS: These findings suggest an added value of CSF to MRI in the diagnostic work up of patients presenting at a memory clinic.

Small-world networks and functional connectivity in Alzheimer's disease.

We investigated whether functional brain networks are abnormally organized in Alzheimer's disease (AD). To this end, graph theoretical analysis was applied to matrices of functional connectivity of beta band-filtered electroencephalography (EEG) channels, in 15 Alzheimer patients and 13 control subjects. Correlations between all pairwise combinations of EEG channels were determined with the synchronization likelihood. The resulting synchronization matrices were converted to graphs by applying a threshold, and cluster coefficients and path lengths were computed as a function of threshold or as a function of degree K. For a wide range of thresholds, the characteristic path length L was significantly longer in the Alzheimer patients, whereas the cluster coefficient C showed no significant changes. This pattern was still present when L and C were computed as a function of K. A longer path length with a relatively preserved cluster coefficient suggests a loss of complexity and a less optimal organization. The present study provides further support for the presence of "small-world" features in functional brain networks and demonstrates that AD is characterized by a loss of small-world network characteristics. Graph theoretical analysis may be a useful approach to study the complexity of patterns of interrelations between EEG channels.

Simple versus complex assessment of white matter hyperintensities in relation to physical performance and cognition: the LADIS study.

BACKGROUND: White matter hyperintensities (WMH) on MRI are associated with disorders of gait and balance and with cognitive impairment. The most suitable method to assess WMH in relation to the clinical evaluation of disturbances in these areas has not yet been established. AIM: To compare a simple visual rating scale, a detailed visual rating scale and volumetric assessment of WMH with respect to their associations with clinical measures of physical performance and cognition. METHODS: Data were drawn from the multicentre, multinational LADIS study. Data of 574 subjects were available. MRI analysis included assessment of WMH using the simple Fazekas scale, the more complex Scheltens scale and a semi-automated volumetric method. Disturbances of gait and balance and general cognitive function were assessed using the Short Physical Performance Battery (SPPB) and the Mini Mental State Examination (MMSE), respectively. RESULTS: Irrespective of the method of measuring WMH, subjects with disturbances of gait and balance (SPPB < or = 10) had more WMH than subjects with normal physical performance. Subjects with mild cognitive deficits (MMSE < or = 25) had more WMH than subjects with normal cognition. Correlations between clinical measures and WMH were equal across methods of WMH measurement (SPPB: Spearman r = -0.22, -0.25, -0.26, all p < 0.001; MMSE: Spearman r = -0.11, -0.10, -0.09, all p < 0.05, for Fazekas scale, Scheltens scale and volumetry, respectively). These associations remained significant and comparable after correcting for age, gender and education in multivariate linear regression analyses. CONCLUSION: Simple and complex measures of WMH yield comparable associations with measures of physical performance and cognition. This suggests that a simple visual rating scale may be sufficient, when analyzing relationships between clinical parameters and WMH in a clinical setting.

Brain aging in very old men with type 2 diabetes: the Honolulu-Asia Aging Study.

OBJECTIVE: Type 2 diabetes leads to cognitive impairment and dementia, which may reflect microvascular and macrovascular complications as well as neurodegenerative processes. There are few studies on the anatomical basis for loss of cognitive function in type 2 diabetes. The objective of this study was to investigate the association between type 2 diabetes and markers of brain aging on magnetic resonance images, including infarcts, lacunes, and white matter hyperintensities as markers of vascular damage and general and hippocampal atrophy as markers of neurodegeneration in Japanese-American men born between 1900 and 1919 and followed since 1965 in the Honolulu-Asia Aging Study. RESEARCH DESIGN AND METHODS: Prevalent and incident dementia was assessed. Associations between magnetic resonance imaging markers and diabetic status were estimated with logistic regression, controlling for sociodemographic and other vascular factors. RESULTS: The prevalence of type 2 diabetes in the cohort is 38%. Subjects with type 2 diabetes had a moderately elevated risk for lacunes (odds ratio [OR] 1.6 [95% CI 1.0-2.6]) and hippocampal atrophy (1.7 [0.9-2.9]). The risk for both hippocampal atrophy and lacunes/infarcts was twice as high in subjects with compared with those without type 2 diabetes. Among the group with type 2 diabetes, those with the longest duration of diabetes, those taking insulin, and those with complications had relatively more pathologic brain changes. CONCLUSIONS: There is evidence that older individuals with type 2 diabetes have an elevated risk for vascular brain damage and neurodegenerative changes. These pathological changes may be the anatomical basis for an increased risk of cognitive impairment or dementia in type 2 diabetes.

Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer's Disease.

Mild cognitive impairment (MCI) was proposed as a nosological entity referring to elderly people with mild cognitive deficit but no dementia. MCI is a heterogeneous clinical entity with multiple sources of heterogeneity. The concept of MCI was reviewed and a diagnostic procedure with three different stages was proposed by the European Consortium on Alzheimer's Disease Working Group on MCI. Firstly, MCI should correspond to cognitive complaints coming from the patients or their families; the reporting of a relative decline in cognitive functioning during the past year by a patient or informant; cognitive disorders as evidenced by clinical evaluation; absence of major repercussions on daily life; and absence of dementia. These criteria, similar to those defined during an international workshop in Stockholm, make it possible to identify an MCI syndrome, which is the first stage of the diagnostic procedure. Secondly, subtypes of MCI had to be recognised. Finally, the aetiopathogenic subtype could be identified. Identifying patients at a high risk for progression to dementia and establishing more specific and adapted therapeutic strategies at an early stage, together with more structured overall management, is made possible by the diagnostic procedure proposed.

Corpus callosum size correlates with asymmetric performance on a dichotic listening task in healthy aging but not in Alzheimer's disease.

Alzheimer's disease (AD) involves not only gray matter but also white matter pathology, as reflected by atrophy of the corpus callosum (CC). Since decreased CC size may indicate reduced functional interhemispheric connectivity, differences in callosal size may have cognitive consequences that may become specifically apparent in neuropsychological tasks that tap hemispheric laterality. In the present study, we examined callosal functioning with a dichotic listening task in 25 Alzheimer patients, 20 healthy elderly and 20 healthy elderly with subjective memory complaints. We found decreased performance, increased ear asymmetry, and decreased callosal size in the AD group compared to healthy elderly. As expected, in the healthy elderly, we found significant negative correlations between ear asymmetry and callosal size, specifically in the anterior and posterior callosal subareas. While the association with the posterior subareas (isthmus and splenium) points at involvement of temporal areas mediating language processing, the association with the anterior subarea (the rostrum and genu) points at involvement of frontal areas mediating attention and executive functions. Remarkably however, in contrast to the healthy elderly, callosal size was not related to ear asymmetry in the AD group. The absence of an association between callosal atrophy and ear asymmetry implies that other pathological processes, next to reduced callosal functioning, attribute to ear asymmetry in AD. Difficulties to attend specifically to the left ear during dichotic listening in some of the AD patients, points at decreased attention and executive functions and suggests that pathology of specifically the frontal areas is involved.

Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior.

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

Disturbed fluctuations of resting state EEG synchronization in Alzheimer's disease.

OBJECTIVE: We examined the hypothesis that cognitive dysfunction in Alzheimer's disease is associated with abnormal spontaneous fluctuations of EEG synchronization levels during an eyes-closed resting state. METHODS: EEGs were recorded during an eyes-closed resting state in Alzheimer patients (N=24; 9 males; mean age 76.3 years; SD 7.8; range 59-86) and non-demented subjects with subjective memory complaints (N=19; 9 males; mean age 76.1 years; SD 6.7; range: 67-89). The mean level of synchronization was determined in different frequency bands with the synchronization likelihood and fluctuations of the synchronization level were analysed with detrended fluctuation analysis (DFA). RESULTS: The mean level of EEG synchronization was lower in Alzheimer patients in the upper alpha (10-13Hz) and beta (13-30Hz) band. Spontaneous fluctuations of synchronization were diminished in Alzheimer patients in the lower alpha (8-10Hz) and beta bands. In patients as well as controls the synchronization fluctuations showed a scale-free pattern. CONCLUSIONS: Alzheimer's disease is characterized both by a lower mean level of functional connectivity as well as by diminished fluctuations in the level of synchronization. The dynamics of these fluctuations in patients and controls was scale-free which might point to self-organized criticality of neural networks in the brain. SIGNIFICANCE: Impaired functional connectivity can manifest itself not only in decreased levels of synchronization but also in disturbed fluctuations of synchronization levels.

[Alzheimer's disease and treatment of vascular risk factors]. / De ziekte van Alzheimer en behandeling van vasculaire risicofactoren.

There is increasing evidence that vascular risk factors including hypertension, high cholesterol, hyperhomocysteinaemia and diabetes mellitus are connected to the risk of Alzheimer's disease (AD). The risk of AD may be reduced by the treatment of hypertension prior to onset of cognitive impairment. One small randomised clinical trial has provided some evidence of beneficial effects on cognition of cholesterol-lowering drugs such as the statins in patients with AD. Treatment of hypertension, hyperhomocysteinaemia and diabetes mellitus with the aim of halting the progression of cognitive decline in AD is still under study and results are awaited. For the time being findings from the trials carried out thus far should be interpreted with care due to methodological shortcomings, both in study design and execution. In order to investigate the role of vascular risk factors both in the aetiology and treatment of AD, large prospective randomised trials with long-term follow-up of AD patients who have been diagnosed using revised uniform diagnostic criteria that take the heterogeneity of the disease into account, are necessary.

[Cognitive disorders appearing before the age of 65 in patients of the Alzheimer Centre of the VU Medical Centre: diagnoses and clinical characteristics]. / Cognitieve stoornissen optredend vóór de leeftijd van 65 jaar bij patiënten van het Alzheimercentrum van het VU Medisch Centrum: diagnosen en klinische kenmerken.

OBJECTIVE: To obtain a profile of the causes and clinical characteristics of cognitive disorders in patients referred to a memory clinic before the age of 65 years. DESIGN: Retrospective case-note study. METHOD: Data were collected from 127 subjects with objective cognitive disorders who visited the Alzheimer Centre of the VU Medical Centre in Amsterdam, the Netherlands, in the period from 1 January 2001 to 31 December 2003 with an onset of complaints before the age of 65. Besides the diagnoses, we investigated the clinical presentations, the occurrence of cardiovascular risk factors, the family history, and the presence of noncognitive neurological signs. RESULTS: The most common causes of cognitive decline under the age of 65 were Alzheimer's disease (46%) and frontotemporal dementia (23%). Vascular dementia was seen in 5% and dementia with Lewy bodies in 2%; 9% had mild cognitive impairment but no dementia. Hypertension and a positive family history for dementia were each present in 40% of the patients. Non-cognitive neurological abnormalities were found only in cases of non-Alzheimer dementia. During the period under investigation, the number of patients with objective cognitive disorders increased more than did the number without a cognitive disorder. CONCLUSION: Within the population of a memory clinic, Alzheimer's disease was the most frequent cause of cognitive decline under the age of 65, followed by frontotemporal dementia. The distribution differed from causes of dementia at an older age, where vascular dementia had the second place.