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Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n=74), VaD (n=33), mixed AD/VaD (n=31), or FTD (n=52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales.

The overall aim was to evaluate to what extent the diagnosis of dementia subtypes, obtained by three clinical rating scales, concurred with postmortem neuropathologic (NP) diagnosis of Alzheimer disease (AD), frontotemporal dementia (FTD), vascular dementia (VaD) and mixed AD/VaD.A prospective longitudinal clinical work-up with postmortem NP examination.Two hundred nine patients with dementia referred for clinical evaluation and follow-up.The diagnostic scores in a set of three short clinical rating scales for AD, FTD, and VaD were evaluated against NP diagnoses.The sensitivity and specificity of the AD scale were 0.80 and 0.87, respectively, of the FTD scale 0.93 and 0.92, respectively, and of the Hachinski Ischemic Score (HIS, VaD diagnosis) 0.69 and 0.92, respectively. Cases with mixed AD/VaD generally presented a combination of high AD and ischemic scores. A preferred cutoff score of six was identified for both the AD and FTD scales.All three clinical rating scales showed a high sensitivity and specificity, in close agreement with final NP diagnosis-for the HIS a moderate sensitivity. These scales may thus be considered good diagnostic tools and are recommended for clinical and research center settings.

Background: Attempts to retrieve absolute values of cerebral blood flow (CBF) by dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) have typically resulted in overestimations. Purpose: To improve DSC-MRI CBF estimates by calibrating the DSC-MRI-based cerebral blood volume (CBV) with a corresponding T1-weighted (T1W) steady-state (ss) CBV estimate. Material and Methods: 17 volunteers were investigated by DSC-MRI and 133Xe SPECT. Steady-state CBV calculation, assuming no water exchange, was accomplished using signal values from blood and tissue, before and after contrast agent, obtained by T1W spin-echo imaging. Using steady-state and DSC-MRI CBV estimates, a calibration factor K = CBV(ss)/CBV(DSC) was obtained for each individual. Average whole-brain CBF(DSC) was calculated, and the corrected MRI-based CBF estimate was given by CBF(ss) = K×CBF(DSC). Results: Average whole-brain SPECT CBF was 40.1±6.9 ml/min·100 g, while the corresponding uncorrected DSC-MRI-based value was 69.2±13.8 ml/min·100 g. After correction with the calibration factor, a CBF(ss) of 42.7±14.0 ml/min·100 g was obtained. The linear fit to CBF(ss)-versus-CBF(SPECT) data was close to proportionality ( R = 0.52). Conclusion: Calibration by steady-state CBV reduced the population average CBF to a reasonable level, and a modest linear correlation with the reference 133Xe SPECT technique was observed. Possible explanations for the limited accuracy are, for example, large-vessel partial-volume effects, low post-contrast signal enhancement in T1W images, and water-exchange effects.

Clinical vascular features, either as manifest vascular disease or as cardiovascular risk factors were compared in AD with and without neuropathological white matter disease (WMD). The aim of the study was to investigate whether the presence of WMD and the severity of either AD pathology or WMD were associated with different cardiovascular profiles. A total of 44 AD cases were retrospectively studied. All the cases were neuropathologically diagnosed as AD with WMD (n = 22) and as AD without WMD (n = 22), respectively. The patients' medical records were studied with regard to their medical history and to somatic and neurological findings including arrhythmia, congestive heart failure, angina, myocardial infarctions, signs of TIA/stroke, diabetes mellitus, and blood pressure abnormalities, such as hypertension and orthostatic hypotension. In AD-WMD, hypertension, orthostatic hypotension as well as dizziness/unsteadiness were significantly more common than in AD without WMD. Cardiovascular symptoms were more frequent in AD-WMD than in the other group, though the difference did not reach statistical significance. Hypothetically, abnormal and unstable blood pressure levels underlie recurrent cerebral hypoperfusion, which may in turn leave room for the development of WMD. Furthermore, dizziness/unsteadiness may be a symptom reflecting the presence of WMD. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Background and purpose Vascular dementia (VaD) has occasionally been associated with cerebral amyloid angiopathy (CAA), but the prevalence and significance of this counterintuitive relationship are poorly known. Therefore, we investigated the presence and characteristics of CAA in brains of VaD cases. Methods We examined temporal and parietal regions of the cerebral cortex of 26 consecutive VaD cases from the Lund Longitudinal Dementia Study. We carried out immunohistochemistry and routine stainings, determined Apolipoprotein E (ApoE) genotypes, and obtained clinical characteristics on the studied group for retrospective analysis. Results CAA was marked in eight out of 26 cases, and correlated strongly with the presence of cortical microinfarcts, both in the temporal lobe and in the parietal lobe. Based on comparisons with eight age-matched VaD cases without CAA, the clinical records suggested that VaD cases with CAA as a group exhibited less pronounced neurological symptoms. A clear contribution of the ApoE genotype could not be identified. Conclusions Based on a combination of the clinical and pathological data, we suggest that microinfarcts in the cerebral cortex associated with severe CAA may be the primary pathological substrate in a significant proportion of VaD cases. Future studies should be undertaken to confirm or dismiss the hypothesis that these cases exhibit a different symptom profile than VaD cases without CAA.

Aims To study cardio-cerebrovascular disease and clinical features, such as falls, dizziness/unsteadiness, urinary incontinence, hallucinations/delusions and delirium in neuropathologically defined subgroups of vascular Dementia (VaD): pure Small Vessel Dementia (SVD), combined SVD and Alzheimer's disease (SVD-AD), pure Large Vessel Dementia (LVD) and pure Hypoxic Hypoperfusive Dementia (HHD), and to analyse the clinical differences between these groups. Materials and Methods From 175 consecutive cases with neuropathologically verified VaD cases with pure SVD (n = 36) and SVD-AD (n = 38) with varying severity of AD pathology were selected and studied with respect to cardio-cerebrovascular and other clinical features. Furthermore, a comparison between pure SVD, pure LVD (n = 7) and pure HHD (n = 6) was made. Results Neither cardiovascular symptoms, hypertension, Transitoric Ischemic Attacks (TIA) nor complete cerebrovascular lesions (CVL) differed significantly between the pure SVD and SVD-AD groups. However, a wide variation of clinical features were reported. The prevalence of cardiovascular features varied markedly in the pure groups, with the highest prevalence consistently found in the LVD group. Hypertension was common in the pure LVD and SVD-groups, while it was a rare finding in the HHD-group. TIA and/or CVL were, as expected, most common in the LVD-group. Conclusion In conclusion, this longitudinal and retrospective study of VaD shows important clinical similarities as well as differences between pathologically defined subgroups. Hopefully these findings will contribute to a better understanding of etiopathogenetic and diagnostic issues and form a solid basis for possible treatment strategies in VaD. Copyright © 2006 John Wiley & Sons, Ltd.

Based on a retrospective study of 19 neuropathologically verified cases with frontotemporal dementia (FTD), neuropsychiatric symptoms related to behavioral disturbances and their psychosocial consequences were studied. The results indicate that frontotemporal dementia is often misdiagnosed early in the clinical course. Behavioural features with impaired social interactions, impaired personal regulation, and loss of insight were seen in all patients. The psychosocial consequences reported in this paper challenge future research in frontotemporal dementia.

All vascular dementia (VaD) cases, neuropathologically verified in a longitudinal prospective dementia project, were classified according to the vascular brain lesion type and related to the dementia type and cardiovascular pathology. From 1976 to 1995, there were 175 VaD cases, 49 of which were pure, without Alzheimer pathology and only one type of cerebrovascular lesion. Furthermore, it was found that 6 cases suffered hypoxic hypoperfusive disease, while 7 were found to have large vessel disease and 36 small vessel disease. In addition to Alzheimer pathology, more than one type of vascular brain pathology was found in the remaining 126 cases. In these cases, diagnosed in accordance with the predominant type of VaD, hypoxic-hypoperfusive lesions were found in 55, large vessel lesions in 50 and small vessel lesions in 110 cases. It should be stressed that 87% of all cases with hypoxic hypoperfusive lesions also had Alzheimer pathology. Cardiovascular and aortic pathologies were more prevalent in small vessel dementia than in the other VaD groups. Clinically diagnosed arterial hypertension was significantly associated with small vessel dementia, but not with hypoxic-hypoperfusive dementia. Cardiovascular symptoms varied considerably in frequency between different dementia groups. VaD is a heterogeneous group regarding lesions caused by different pathophysiological mechanisms and with different combinations of brain pathologies. It is therefore necessary to identify the various types of vascular brain lesions for a correlation with clinical symptoms and for diagnostic purposes in the search for risk factors and therapeutic strategies.

Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders.

Objectives To find associations between predictors and survival in frontotemporal dementia (FTD). Methods 96 patients with FTD, here defined as Dementia in Pick's disease, were studied. The predictors included psychiatric/behavioural features, language impairment and neurological deficits present up to the time of diagnosis. The influence on mortality was studied by means of Cox regression analyses. Results Most of the behavioural/psychiatric features were associated with longer survival. Among these features, anxiety and suicidal ideation were associated with a statistically significant decreased mortality. Semi-mutism/mutism and neurological deficits were associated with a statistically significant increased mortality. Analyses of the dementia-specific mortality strengthened the already significant results and revealed dysphagia as significantly related to increased mortality. Conclusions Two groups of predictors with different influence on survival were identified in FTD. Most behavioural/psychiatric features were associated with longer survival. These features may indicate a slower disease progress and a better preserved cerebral function. By contrast, semi-mutism/mutism, neurological deficits and dysphagia were associated with shorter survival, indicating an aggressive, degenerative process. Copyright © 2003 John Wiley & Sons, Ltd.

Objectives To retrospectively evaluate pre-diagnostic clinical features (predictors) of mortality in frontotemporal dementia (FTD). The main aim was to investigate if there were indications against interpreting missing data as signs of absence. Material and methods 96 cases with FTD, here defined as Dementia in Pick's disease according to ICD-10. The predictors were behavioural/psychiatric features, language impairment and neurological deficits up to the date of diagnosis. Each predictor was rated as present (Yes), absent (No) or not recorded (Missing), and evaluated according to its distribution and mortality pattern: if a feature was not recorded because it was absent, the mortality of the Missing and the No-category should hypothetically be close. Statistical methods included Kaplan-Meier survival curves and Cox regression analyses. Results Neurological deficits and language impairments were frequently recorded as present or absent, while non-recordings were more prevalent among the behavioural/psychiatric features. Some features were excluded as predictors because they showed too little variation. Analyses of the survival pattern indicated that in some features, the observations of the Missing-category could be interpreted as absence of the symptoms. In other features these observations had to be regarded as truly missing. Conclusions In the retrospective evaluation of predictors of mortality a method for treating missing data was applied. The interpretation of non-recordings as signs of absence was supported by the analyses of the survival patterns in some of the studied features. However, the study underscores the importance of systematic estimations of pre-diagnostic clinical features in dementia. Copyright © 2003 John Wiley & Sons, Ltd.

This study was undertaken in order to compare regional cerebral blood flow (rCBF) and EEG findings of patients with clinically diagnosed dementia with Lewy bodies (clinDLB) and Alzheimer's disease (clinAD). Furthermore, within the clinDLB group to compare cases with and without neuropathologically verified Lewy bodies (LBs). When we studied 200 dementia cases in a prospective longitudinal dementia study, 48 had clinDLB and 45 clinAD in retrospective analyses. EEG information was analysed in 34 clinDLB and 28 clinAD patients and cerebral blood flow, measured with the Xe 133 inhalation method, in 26 clinDLB and 25 clinAD. There were no differences in EEG between the clinDLB and clinAD groups or between the cases with and without LBs. The rCBF patterns in the clinDLB and clinAD groups showed similar reductions in the temporoparietal areas. The rCBF in cases with LBs showed heterogeneous pathology. The imaging results in clinDLB and clinAD were strikingly similar. The EEG and rCBF could not differentiate between cases with or without LB. The study illustrates the lack of specific changes of EEG and rCBF in cases with LB pathology.

Background:Frontotemporal dementia (FTD) constitutes a spectrum of neurodegenerative disorders associated with degeneration of, predominantly, the frontal and temporal lobes. The clinical heterogeneity is evident, and early diagnosis is a challenge. The primary objectives were to characterize psychotic symptoms, initial clinical diagnoses and family history in neuropathologically verified FTD-patients and to analyze possible correlations with different neuropathological findings.Methods:The medical records of 97 consecutive patients with a neuropathological diagnosis of frontotemporal lobar degeneration (FTLD) were reevaluated. Psychotic symptoms (hallucinations, delusions, paranoid ideas), initial diagnosis and family history for psychiatric disorders were analyzed.Results:Psychotic symptoms were present in 31 patients (32%). There were no significant differences in age at onset, disease duration or gender between patients with and without psychotic symptoms. Paranoid ideas were seen in 20.6%, and hallucinations and delusions in 17.5% in equal measure. Apart from a strong correlation between psychotic symptoms and predominantly right-sided brain degeneration, the majority of patients (77.4%) were tau-negative. Only 14.4% of the patients were initially diagnosed as FTD, while other types of dementia were seen in 34%, other psychiatric disorders in 42%, and 9.2% with other cognitive/neurological disorders. The patients who were initially diagnosed with a psychiatric disorder were significantly younger than the patients with other initial clinical diagnoses. A positive heredity for dementia or other psychiatric disorder was seen in 42% and 26% of the patients respectively.Conclusions:Psychotic symptoms, not covered by current diagnostic criteria, are common and may lead to clinical misdiagnosis in FTD.

The aim of the study was to investigate arterial blood pressure (BP) and the use of pharmacological treatment in patients with Lewy body dementia (cLBD) and Alzheimer's disease (cAD) diagnosed on clinical grounds. BP and pharmacological treatment was analysed based on the medical records of 200 deceased dementia patients. Forty-eight cases with LBD and 45 AD were diagnosed using clinical criteria. The patients, who died between 1985 and 1994, were part of a prospective longitudinal dementia project. The majority of the cases were examined and cared for at the psychogeriatric and psychiatric departments. BP levels were very similar at an early stage of dementia but there was a marked decrease during the course of dementia in cAD and cLBD. The cLBD cases became hypotensive during the course of dementia to a significantly greater extent and also had a more pronounced drop in systolic BP at orthostatic testing compared to the cAD cases. cLBD and cAD were prescribed neuroleptics and medication potentially associated with hypotension to the same extent. The total number of these drugs was however higher in cLBD than in cAD. Antiparkinsonian treatment was, as expected, more common in cLBD compared to cAD. The findings suggest that insufficient BP regulation and drug treatment could affect the clinical picture of dementia, particularly in cLBD patients.

OBJECTIVE: To study the prevalence of patients fulfilling the clinical consensus criteria for dementia with Lewy bodies (DLB) in a dementia population followed up with postmortem examination. To compare the clinical and neuropathological findings in the clinical Lewy body dementia (LBD) group with findings in a clinically defined group with Alzheimer's disease (AD). DESIGN: Medical records from 200 patients were studied retrospectively. Clinical consensus criteria for DLB and clinical criteria for other dementias were applied. SETTING: The majority of the cases were examined and cared for in psychogeriatric and psychiatric departments. PATIENTS: The patients, who died between 1985 and 1994, were part of a longitudinal dementia project. Each case was neuropathologically examined. Main outcome measures Prevalence of clinical signs and neuropathology was compared between the clinical groups. RESULTS: Forty-eight (24%) patients fulfilled the clinical criteria for DLB while 45 (22%) fulfilled the clinical criteria for Alzheimer's disease. The clinical LBD group had a higher Hachinski score compared to the clinical AD group. They also showed a tendency towards a 'frontal profile' with disinhibition, confusion, personality change and vocally disruptive behaviour. More than 80% of the AD and LBD groups respectively exhibited Alzheimer pathology. The LBD group had frontal white matter pathology and degeneration of the substantia nigra more often than the clinical AD group. Both LBD and AD groups showed a progressive and marked increase in severity of dementia and decrease in ADL capacity according to an evaluation based on the Berger scale and Katz index. The condition of the LBD group was significantly worse earlier in dementia. CONCLUSION: The results of this study indicate that patients fulfilling the clinical criteria for DLB also exhibit clinical features of possible vascular origin and a frontal profile. Subcortical vascular pathology, nigral degeneration and AD pathology in this group could partly explain the clinical features used to define DLB. (Less)

In order to evaluate the functional significance of synaptic pathology, synaptic density was quantitated and related to clinical symptomatology and regional cerebral blood flow (rCBF) in 8 patients with frontal lobe degeneration of non-Alzheimer type (FLD) and 19 patients with Alzheimer’s disease (AD). Synaptic density was measured in all layers of prefrontal and parietal cortex. The clinical picture of FLD was dominated by a frontal lobe syndrome with changes in personality and behavior, while AD was dominated by temporoparietal symptoms. This parallels the finding of frontal rCBF reductions in FLD patients and temporoparietal reductions in AD patients. Synaptic density was significantly decreased in both FLD and AD, with a regional severity which closely correlated with that of the degeneration, symptomatology and rCBF deficit. The results suggest that synaptic pathology is a likely cause of clinical symptoms and regional metabolic decrement in dementia.

The concentrations of the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (HMPG) in the cerebrospinal fluid (CSF) of patients with clinical frontotemporal dementia (FTD; n = 30), early onset Alzheimer's disease (EAD; n = 33), late onset Alzheimer's disease (LAD, n = 27) and normal controls (n = 31) were determined using HPLC. ANCOVA showed no significant effect of neuroleptic medication, extrapyramidal signs, myoclonia or gender on the CSF levels of the monoamine metabolites. Homovanillic acid was significantly reduced in all diagnostic groups (FTD, p = 0.0002; EAD, p = 0.016; LAD, p = 0.013). 5-Hydroxyindoleacetic acid was significantly reduced in EAD (p = 0.013) and in LAD (p = 0.0014), and HMPG was reduced in LAD only (p = 0.020). HMPG was significantly higher in FTD compared to EAD (p = 0.0005) and LAD (p = 0.0003). CSF-5-HIAA was significantly reduced in patients with antidepressant medication (p = 0.006). ANCOVA within the FTD group showed no significant effect of neuroleptic or antidepressant medication, extrapyramidal signs, myoclonia, gender or FTD subtype on the CSF levels of the monoamine metabolites. The results suggest that CSF-HMPG might differentiate FTD from EAD and LAD, but not from normals.

Frontotemporal dementia (FTD) is associated with a broad spectrum of clinical characteristics. The objective of this study was to analyze the prevalence of unexplained somatic complaints in neuropathologically verified FTD. We also examined whether the somatic presentations correlated with protein pathology or regional brain pathology and if the patients with these somatic features showed more depressive traits. Ninety-seven consecutively neuropathologically verified FTLD patients were selected. All 97 patients were part of a longitudinal study of FTD and all medical records were systematically reviewed. The somatic complaints focused on were headache, musculoskeletal, gastro/urogenital and abnormal pain response. Symptoms of somatic character (either somatic complaints and/or abnormal pain response) were found in 40.2%. These patients did not differ from the total group with regard to gender, age at onset or duration. Six patients showed exaggerated reactions to sensory stimuli, whereas three patients showed reduced response to pain. Depressive traits were present in 38% and did not correlate with somatic complaints. Suicidal behavior was present in 17 patients, in 10 of these suicidal behavior was concurrent with somatic complaints. No clear correlation between somatic complaints and brain protein pathology, regional pathology or asymmetric hemispherical atrophy was found. Our results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration. Somatic complaints are not covered by current diagnostic criteria for FTD, but need to be considered in diagnostics and care. The need for prospective studies with neuropathological follow up must be stressed as these phenomena remain unexplained, misinterpreted, bizarre and, in many cases, excruciating.

OBJECTIVE: To determine the prevalence of orthostatic hypotension (OH), low blood pressure and dizziness, falls and fractures in patients with organic dementia. DESIGN: We prospectively studied 151 patients, assessing the prevalence of OH, hypertension, heart disorders, diabetes mellitus and the use of medication possibly associated with OH. SETTING: The patients were admitted to our psychogeriatric clinic as part of routine clinical investigation of their dementia. PATIENTS: Forty-six patients with Alzheimer's disease (AD), 28 patients with frontotemporal dementia (FTD) and 77 patients with vascular dementia (VaD) were investigated. MAIN OUTCOME MEASURE: Due to the paucity of information about the prevalence of OH in organic dementia, this study is mainly explorative in nature, thus preventing explicit hypothesis formulation. However, clinical impressions indicated a higher prevalence of OH in organic dementia than normally seen in healthy elderly. RESULTS: OH/low blood pressure was present in 39-52% of the patients. The majority reached their maximum systolic decrease within 5 minutes of standing, but in 20-30% the maximum blood pressure drop occurred after 5 minutes or later. In 38%, the systolic blood pressure drop was more than 40 mm Hg. Hypertension and heart disease was found only in AD and VaD, with no difference between those with and without OH/low blood pressure. Falls and fractures were common in orthostatic and hypotensive patients, with an incidence of more than 50% in AD and VaD. CONCLUSIONS: The results support our clinical impressions that OH and low blood pressure is common and an important factor in organic dementia.

Patterns of functional cortical activation were studied by means of regional cerebral blood flow measurements, performed during rest and during a word fluency task in normal subjects (n = 22), in patients with Alzheimer's disease (n = 17), and in patients with frontotemporal dementia (n = 15). Although all groups showed a significant activation of the Broca's area during word production, the activation of the dorsolateral prefrontal cortex was clearly subnormal in both dementia groups. The frontal dysfunction was not explained by number of words produced, illness duration, or age. Thus, the results demonstrate that the word fluency task is a sensitive measure of frontal lobe function, and its incorporation in imaging studies may facilitate the detection of subtle functional impairment of the frontal lobes in organic dementia.

Background: Frontotemporal dementia (FTD) is recognised as a clinically and morphologically heterogeneous group of interrelated neurodegenerative conditions. One of the subtypes within this disease spectrum is the behavioural variant FTD (bvFTD). This is known to be a varied disorder with a mixture of tau-positive and tau-negative underlying pathologies. The other subtypes include semantic dementia (SD), which generally exhibits tau-negative pathology, and progressive non-fluent aphasia (PNFA), which is usually tau-positive. As the clinical presentation of these subtypes may overlap, a specific diagnosis can be difficult to attain and today no specific biomarker can predict the underlying pathology. Neurofilament light chain protein (NFL), a cytoskeletal constituent of intermediate filaments, is thought to reflect neuronal and axonal death when appearing in the cerebrospinal fluid (CSF). NFL has been shown to be elevated in CSF in patients with FTD compared with AD and controls. Our hypothesis was that the levels of NFL also differ between the subtypes of FTD and may indicate the underlying pathological subtype. Methods: We retrospectively analysed data from previous CSF analyses in 34 FTD cases (23 bvFTD, seven SD, four PNFA), 20 AD cases, and 26 healthy controls. A separate group of 10 neuropathologically verified and subtyped FTD cases (seven tau-negative, three tau-positive) were also analysed. Result: NFL levels were significantly higher in FTD compared with both AD (p

BackgroundThis study examines relations between regional cerebral blood flow (rCBF) and neuropsychological test results, age at onset and duration of disease in patients with frontotemporal-type dementia (FTD).MethodSixteen patients with a diagnosis of probable FTD were examined using single photon emission computerised tomography (SPECT) with 99mTc-HMPAO as the tracer. The rCBF of 14 regions of interest relative to cerebellar blood flow was calculated. Psychological tests assessing language, verbal fluency, memory and visuospatial constructive ability were given.ResultsCorrelations were demonstrated between a global impairment score and relative blood flow in lateral frontal, medial frontal and left orbital frontal areas. Verbal fluency scores correlated with left lateral frontal medial frontal and left anterior inferior temporal blood flow. No relationships between decrease in CBF and age at onset or duration of disease, or between impaired cognitive function and age at onset or duration of disease, were found.ConclusionsThe present study demonstrates a close coupling between reduced rCBF and specific neuropsychological deficits in FTD.

Regional cerebral blood flow was measured in 35 patients with organic dementia (Alzheimer's disease, n = 13, vascular dementia, n = 17, frontotemporal dementia, n = 5) and orthostatic hypotension. Measurements were performed during supine rest and during head-up tilt (60 degrees). Despite marked blood pressure falls, few patients had symptoms of orthostatic hypotension. All three dementia groups had a decrease in regional cerebral blood flow in the frontal lobes during head-up tilt, but no change in mean hemispheric flow. All patients had a consistent drop in their systolic blood pressure upon head-up tilt, with a wide variation over time. The findings suggest that orthostatic hypotension needs to be considered, and actively sought for, in organic dementia as many patients may lack the typical symptoms of orthostatic hypotension, despite a marked fall in blood pressure.

The aim of this study was to analyze the medical history, with regards to previous remote depression, in patients with neuropathologically verified Alzheimer's disease (AD), vascular dementia (VaD) and mixed AD/VaD. The 201 patients included (115 AD, 44 VaD and 42 mixed AD/VaD) had been referred to the Psychogeriatric/Psychiatric Department, Lund University Hospital, for psychogeriatric investigation and were followed-up with clinical records and detailed information on psychiatric history prior to the onset of dementia. Depression was considered to exist when the patient had consulted a psychiatrist or physician and had been diagnosed with a "depressive episode" or "depression" and when anti-depressants and/or other specific treatments had been prescribed. Twenty patients (10%) had suffered from depression earlier in life well before the onset of dementia. Eight of the 9 AD patients with a previous diagnosis of depression had suffered from only one depressive episode and all had responded well to treatment, with complete recovery. In the VaD group, 8 out of 9 patients suffered two or more depressive episodes and only two recovered completely. Events with a possible significant relationship to depression were seen in 8 of the 9 AD patients but in only 1 of the 9 VaD patients. Psychotic symptoms were more common in VaD than in the AD group. The treatment modality of depression was similar in the groups. In conclusion, a history of depression prior to dementia is more common and more therapy-resistant in VaD than in AD.

The present study examined the utility of the Word Fluency Test (WFT) as a frontal-lobe-activating test in brain imaging. Regional cerebral blood flow (rCBF) was measured during rest and during the WFT in 49 healthy volunteers and in 15 patients with frontal lobe dementia (FLD). The results showed a highly significant frontal lobe activation in 85% of the normal subjects. This finding was not related to age or to the level of performance on the WFT. A significant frontal activation was seen in 13 of the 15 FLD patients. The frontal flow increase did not reach normal levels, and was not related to age, illness duration or severity of clinical symptoms. The results suggest that the WFT is an ideal test to use in conjunction with functional imaging in normals as well as in patients with organic dementia.

The aims were to evaluate the cognitive performance and clinical diagnosis in patients (

Udgivelsesdato: 2010 White matter (WM) changes are frequently seen on structural imaging in AD but the clinical relevance of these changes is uncertain. Frontal WM pathology is often observed upon neuropathological examination in AD. Since frontal cortical/sub-cortical pathology is known to relate to executive dysfunction, the aim was to elucidate if frontal WM changes in AD correlated with executive dysfunction. In all, 15 AD patients and 15 age-matched control cases were investigated in the study, which covered conventional magnetic resonance imaging (MRI), DTI, neuropsychiatric and neuropsychological examinations. Reduced performance on neuropsychological testing of executive function correlated significantly with an increasing degree of frontal WM changes detected by DTI in the AD group, while no such correlation was observed for the controls. Conventional semi-quantitative MRI assessment did not correlate with results on neuropsychological testing of executive function in any of the groups. The structural correlate to certain dimensions of executive dysfunction in AD patients could be related to changes in the deep frontal WM. DTI appears to be more sensitive in the detection of clinically significant WM alterations than conventional semi-quantitative MRI.

Background Clinical dementia diagnoses are not always consistent with neuropathological findings. As correct diagnosis is important for treatment and care, new diagnostic possibilities for dementia are in demand. Cerebrospinal fluid biomarkers should ideally be able to identify ongoing processes in the brain, but need to be further compared with neuropathological findings for evaluation of their diagnostic validity. Methods This study included 43 patients with a clinical dementia disorder. All patients were neuropathologically examined at the University Hospital in Lund, Sweden, during the years 2001-2008, and all had a lumbar puncture carried out as part of the clinical investigation during the time of cognitive impairment. Results Of eight patients, five with Alzheimer's disease had elevated total tau protein (T-tau) and decreased amyloid beta 1-42 protein (Aβ42), while both values for the other three patients were normal. Slightly elevated T-tau and/or decreased Aβ42 were also seen in several patients with other dementia diagnoses such as Lewy body disease, frontotemporal lobar degeneration and vascular dementia. Furthermore, T-tau levels did not differ markedly between patients with morphologically tau-positive and tau-negative frontotemporal lobar degeneration. Also, seven of nine patients with Creutzfeldt-Jacob disease exhibited pronounced elevation in T-tau concentration. Conclusion From this rather limited study, being the first of its kind in Sweden, we may conclude that there is no perfect concordance between cerebrospinal fluid biomarker levels and pathological findings, which should be taken into account in the clinical diagnostic setting.

The objectives of this study were to examine potential clinical and neuropsychological changes over time in non-demented patients with subjective memory complaints (≤70 years) and to compare the patients with objective memory impairment (OMI) with those who suffer from subjective memory impairment (SMI). OMI and SMI patients did not differ regarding duration of memory problems, age or education. At baseline no differences were revealed between the OMI and SMI patients regarding self-reported cognitive deficits, self-reported worry about deficits, and symptoms of anxiety or depression. None of the patients had converted to dementia at follow-up. Eighty percent of the OMI patients and 61% of the SMI patients reported cognitive deficits to the same degree at follow-up as at baseline. Despite a significant reduction of depressive symptoms in the OMI patients, a considerable portion of both OMI and SMI patients scored above the cut off score on both anxiety and depression subscales at baseline as well as at follow-up. Our study reveals close points of similarity between patients with memory complaints, verified by test, and patients with memory complaints, not verified by test, as well as stability over time regarding important clinical aspects.

Objective To compare the time taken to establish a clinical diagnosis of Frontotemporal dementia (FTD) relative to a diagnosis of early onset Alzheimer's dementia (AD). Methods The data came from 89 patients under the age of 65 years, 52 of whom met the Manchester-Lund criteria for Frontotemporal dementia; 20 of these came from Lund University Hospital in Sweden. The other 32 patients with FTD along with 37 subjects who fulfilled the ICD-10 criteria for early onset Alzheimer's disease were recruited from four memory clinics and two neurology departments in Norway. Results For FTD patients in Norway it took 59.2 months (SD 36.1) from the onset of illness until a clinical FTD diagnosis was made. The corresponding time period for FTD patients in Sweden is 49.5 months (SD 24.5) and for AD patients in Norway 39.1 months (SD 19.9). The time from the first visit to a medical doctor until a diagnosis was made for the FTD patients in Norway was 34.5 months (SD 22.6), for the Swedish FTD patients 23.1 months (SD 22.4) and for the AD patients 25.9 months (SD 13.1). In all, 71% of FTD patients and 30% of AD patients initially received a non-dementia diagnosis. Conclusion More knowledge about early presenting cognitive and behavioural signs of FTD is needed in both primary and secondary health care to reduce the time period needed to establish a clinical diagnosis of FTD. Copyright (C) 2008 John Wiley & Sons, Ltd. (Less)

We investigated the distribution of neuropathologically defined dementia subtypes among individuals with dementia disorder. The neuropathological reports were studied on all patients (n=524; 55.3% females; median age 80, range 39-102 years) with clinically diagnosed dementia disorder who underwent complete autopsy including neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1974-2004. The neuropathological diagnosis was Alzheimer's disease (AD) in 42.0% of the cases, vascular dementia (VaD) in 23.7%, dementia of combined Alzheimer and vascular pathology in 21.6%, and frontotemporal dementia in 4.0% of the patients. The remaining 8.8% of the patients had other dementia disorders, including combinations other than combined Alzheimer and vascular pathology. The registered prevalence of dementia subtypes depends on many variables, including referral habits, clinical and neuropathological judgments and diagnostic traditions, all of these variables potentially changing over time. This, however, does not seem to obscure the delineation of the major dementia subgroups. In this material of 30 years from Lund in the south of Sweden, AD by far dominated among dementia subtypes, while cerebrovascular pathology corresponded with the dementia disorder, either entirely or partly, in almost half of the demented patients.

The aims are to study personality characteristics of patients with memory complaints and to assess the presence of objective (OMI) versus subjective (SMI) memory impairment, the affective status, as well as potential gender differences. The patients were assessed by means of a neuropsychiatric examination and a neuropsychological test-battery. The Swedish version of the revised NEO Personality Inventory (NEO PI-R) and the Hospital Anxiety and Depression Scale (HADS) were used. The 57 patients (38 women, 19 men, mean age 56.9) differed from the Swedish normative group in three of the five personality factors: neuroticism, extraversion and agreeableness. This was mainly because of the scores of the female patients. Approximately half of the patients had OMI. No differences regarding personality factors or affective status were found between OMI and SMI patients. The female patients scored significantly higher than the male patients on symptoms of anxiety and depression. Neuroticism and symptoms of depression interacted with memory performance and gender. Our findings demonstrate the importance of applying an objective assessment of memory functions and a gender perspective when studying patients with memory complaints. (JINS, 2007, 13, 911–919.)

Objectives/Methods Ten patients with neuropathologically verified frontotemporal dementia (FTD) were analysed for neuropathological features in relation to first presenting and dominating symptoms, age at onset and duration of dementia, as well as to EEG/quantitative EEG. Results Cases with a late onset (> 65 years) initially presented language disturbances, while the early onset group (

Frontal lobe degenerative dementias, the second largest degenerative dementia group after Alzheimer's disease, is dominated by frontal lobe degeneration of non-Alzheimer type. It is classified in a group also containing Pick's disease, progressive aphasia and dementia in motor neuron disease. Frontal lobe degeneration of non-Alzheimer type is clinically marked by frontal lobe symptoms and frontotemporal reduction of blood flow. From a histopathological point of view it is characterized by gliosis, microvacuolation, neuronal atrophy-loss and 40–50% loss of synapses in three superficial cortical laminae of the frontal convexity and anterior temporal cortex, while the deeper laminae are little or not changed. The structural changes of Alzheimer's disease including amyloid, Levy body dementia and Pick's disease are entirely lacking. A strong heredity points to a genetic cause as yet undefined.

This study describes the clinical, neuropsychological, neuroimaging and genetic characteristics in two generations of a Swedish family affected by presenile dementia. The pedigree includes 5 cases (mother and 4 of 5 children) of progressive dementia with onset between 54 and 62 years. The clinical picture is characterized by insidious onset and progressive decline in episodic memory without spatial impairment or dyspraxia, followed by changes in personality and behaviour, with signs of disinhibition, irritability, impulsivity and loss of social awareness. Three siblings, examined after 10 years of duration, showed moderate language deficits but preserved spatial function and praxis. CT and MRI showed progressive bilateral temporal atrophy and moderate frontal white matter changes. Regional cerebral blood flow measurements showed hypoperfusion in temporal areas bilaterally. Quantitative EEG was normal within 5 years after symptom onset and thereafter showed a moderate increase in relative theta power. Sequencing of the tau gene (chromosome 17) revealed the previously described R406W mutation in exon 13 as a likely cause of the disease. This mutation was identified in all affected cases. The clinical picture of this family shows striking similarities not only to frontotemporal dementia but also to Alzheimer’s disease.

A novel mutation in exon 9 of tau, I260V, is associated with a clinical syndrome consistent with frontotemporal dementia with extensive tau pathology; however, neurofibrillary tangles and Pick bodies are absent. Significantly, Sarkosyl-insoluble tau extracted from affected brain tissue consisted almost exclusively of four-repeat isoforms. Consistent with these findings, in vitro biochemical assays demonstrated that the I260V mutation causes a selective increase in tau aggregation and a decrease in tau-induced microtubule assembly with four-repeat isoforms only. The contrasting pathology and biochemical effects of this mutation suggest a different disease mechanism from the other exon 9 mutations and demonstrates the critical role for the first microtubule-binding domain in tau-promoted microtubule assembly and the pathogenic aggregation of tau.

The aim of this study was to evaluate cognitive impairment, psychiatric symptoms and cerebral blood flow (CBF) patterns in middle-aged (35–64 years) and younger old patients (65–74 years) with subjective experience of memory deficits. The study group was heterogeneous with patients fulfilling criteria for dementia, as well as patients with mild cognitive impairment (MCI) and with non-verified cognitive impairment (non-MCI). Seventy per cent of the non-MCI patients reported long-lasting experiences of psychosocial stress tentatively causing the memory problems. The MCI patients were subdivided into two groups: MCI type 1 included patients with isolated memory impairment, while MCI type 2 included patients with memory impairment together with slight verbal and/or visuospatial impairments. CBF measurements comparing the two MCI groups with the non-MCI group were performed. The MCI type 2 showed reduced CBF in the left anterior medial temporal lobe as well as in parts of the posterior cingulate gyrus. The CBF pattern in MCI type 2 concurs with the pathophysiological process of Alzheimer’s disease. The results indicate that it is important to make a subdivision of MCI patients regarding the presence of isolated memory impairments or memory impairments together with other slight cognitive deficits.

The clinical picture with its pathological correlate was analysed in 16 patients fulfilling consensus criteria for dementia with Lewy bodies (DLB). The cases were part of a larger cohort (n = 200) of patients within a prospective longitudinal study of dementing disorders. Six cases exhibited not only Lewy bodies (LBs) but also other brain pathologies such as Alzheimer changes, multiple infarcts or complete and incomplete white matter infarcts. Degeneration of the nucleus basalis of Meynert and substantia nigra was also seen. The 10 cases without LBs all had Alzheimer changes. In 7 cases, these changes were combined with mainly incomplete frontal white matter infarcts. However, the degeneration of brain stem nuclei was less pronounced in these cases. Symptoms such as fluctuations in cognition, falls and episodic confusion appeared in association with arterial hypotension, which developed during the course of dementia in almost all the 16 cases. The majority of the cases were treated with neuroleptics and other potentially hypotensive medication. This study shows that multiple and different pathological features may contribute to a clinical symptom constellation as in DLB. The case study approach reveals the complexity of the clinico-pathological relationships in dementia that might otherwise be lost in the analysis of larger group data.

The etiology of frontal lobe dementia of non-Alzheimer type (FLD) is still unknown. There is strong evidence of genetic factors with positive heredity. In this paper, a Swedish family, with several generations affected by FLD is described. In 3 patients typical FLD was confirmed postmortem. The clinical and neuropathological similarities between the patients are impressive.

OBJECTIVES: To analyse the neuropathological changes behind clinically defined dementia with Lewy bodies (clinDLB) compared with clinically diagnosed Alzheimer's disease (clinAD). METHODS: The prevalence of neuropathological findings in 48 clinDLB and 45 clinAD cases was compared. Sixteen clinDLB and 10 clinAD cases were reassessed with alpha-synuclein staining for Lewy bodies (LB). RESULTS: Alzheimer pathology was found in 81% of the clinDLB and 93% of the clinAD cases. The clinDLB group had a higher prevalence of frontal white matter pathology, mostly of ischemic type, and a more severe degeneration of the substantia nigra compared with the clinAD group. In hematoxylin-eosin staining, LBs were identified in seven (15%) of the clinDLB and in four (9%) of the clinAD group. In alpha-synuclein staining, 38% of the clinDLB and 40% of the clinAD cases exhibited LBs. The cases without LBs, in the clinDLB group, had AD pathology in combination with frontal white matter disease. Vascular pathology of significant degree was prevalent in more than 40% of all the cases with verified LBs regardless of clinical diagnosis. CONCLUSION: Consecutive dementia cases, fulfilling the clinical consensus criteria for DLB, may exhibit combinations of neuropathological changes which in themselves can explain the clinical picture of DLB even when LBs are absent. (Less)

Frontotemporal dementia (FTD) is the second most common primary degenerative dementia with early onset and constitutes about 9% of dementia cases examined post mortem. The clinical picture is related to the distribution and severity of the degenerative changes. This chapter analyzes neuropathologically verified cases of Pick’s disease (PiD) and frontal lobe degeneration of non-Alzheimer type (FLD) with regard to heredity and clinical features. When the two groups were compared, there was a female dominance in the PiD group, whereas the FLD group showed a stronger load of heredity concerning similar dementia disorders. A general impression was that symptoms were more prevalent and severe in the PiD group, which is consistent with the more severe atrophy in these cases. In frontotemporal dementia (FTD), as in other dementias, there is a need for a multidimensional classification system, keeping apart etiological, morphological, and clinical aspects. This approach allows flexibility and new combinations that facilitates study and understanding of the nature of FTD.

The magnetic resonance imaging (MRI) and computed tomography findings in 28 patients with the clinical diagnosis of frontotemporal dementia (FTD) were compared with the findings in a control group of 76 individuals without dementia or stroke. A pattern of frontal and temporal atrophy with predominantly frontal white matter changes was found in the FTD patients, and this was significantly different from the radiological findings in the control group. Six of the FTD patients have undergone autopsy. Histopathological evaluation showed a primary cortical degenerative disease (frontal lobe degeneration of non-Alzheimer type) in 3 of them, and primary white matter disorder, mainly frontal, of basically ischemic type (selective incomplete white matter infarction) in 3 of them. MRI could be a helpful tool to support the clinical diagnosis FTD, especially in young patients. MRI may also be helpful for the differentiation of a primary neurodegenerative from a mainly ischemic-vascular type of dementia.

Measurements of regional cerebral blood flow (rCBF) were performed in 16 women suffering from spider phobia. The non-invasive 133Xe inhalation method, giving information about the blood flow of superficial areas, was used. The subjects were studied under three conditions: during resting, when exposed to a videotape showing nature scenery, and finally when watching a video with living spiders. During the rCBF measurements the subjects' behaviour was registered systematically and respiration, blood pressure, Pco2, and heart rate were monitored. Eight subjects who showed and reported severe panic during the spider exposure had marked rCBF decreases in frontal areas, especially in the right hemisphere. The remaining eight subjects displayed a more efficient control of their emotions and became frightened, but not panic-stricken, during the spider exposure. These showed a consistent rCBF increase in the right frontal area compared to neutral stimulation. Thus, results revealed significant functional changes in the frontal cortex in subjects with spider phobia during phobogenic exposure. It seems likely that these frontal changes are related to the experience and control of phobic anxiety.

Analysis of the serum concentrations of free thyroid hormones (fT3, fT4) and thyrotropin (TSH) in 173 psychogeriatric patients (94 females and 79 males, mean age 79 +/- 8 years) disclosed that the hormone levels were related to sex, psychiatric diagnosis, medication and the presence of nonthyroid illness (NTI). Subnormal concentrations of thyroid hormones and/or TSH were found in 25% of the patients. In addition, fT3 and fT4 concentrations were significantly lower (p < 0.05 and p < 0.001, respectively) in demented males compared with demented females although the levels were within the reference limits. Strongly negative correlations between fT3 and age (p < 0.001), and between fT3 and the sedimentation rate (SR) (p < 0.01) were found in demented but not in non-demented patients. These correlations were most pronounced in (age) or restricted to (SR) demented males. In addition, the correlation between fT3 and Hb was strongly positive (p < 0.001) in demented as well as in nondemented patients, particularly in males. The concentration of fT4 was positively correlated to Hb in demented males (p < 0.001), whereas TSH concentration was positively correlated to Hb in demented females (p < 0.05). The results show that TSH is not sufficient as the sole screening assay for evaluation of possible thyroid dysfunction in psychogeriatric patients. In addition, central (hypothalamic?) hypothyroidism may be present in a substantial amount of psychogeriatric patients, as we found an adequate TSH response to exogenous thyrotropin-releasing hormone (TRH) also in patients with decreased fT3/fT4 and no signs of non thyroid diseases. Furthermore, there was an apparent lack of correlation between thyroid hormone levels and dementia (or subgroups of dementia), even though thyroid hormone abnormalities seemed to be rather common in frontotemporal dementia (38%) and non specified dementia (36%).

Frontotemporal dementia (FTD) as an important clinical entity was rediscovered in Lund and Manchester in the early 1990s. Here we show that the large Lund pedigree with behavioral variant of frontotemporal dementia previously described with this disorder has an expansion in the recently described C9ORF72 locus on chromosome 9.