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There is a need for increased nosological knowledge to enable rational trials in Alzheimer’s disease (AD) and related disorders. The ongoing Gothenburg mild cognitive impairment (MCI) study is an attempt to conduct longitudinal in-depth phenotyping of patients with different forms and degrees of cognitive impairment using neuropsychological, neuroimaging, and neurochemical tools. Particular attention is paid to the interplay between AD and subcortical vascular disease, the latter representing a disease entity that may cause or contribute to cognitive impairment with an effect size that may be comparable to AD. Of 664 patients enrolled between 1999 and 2013, 195 were diagnosed with subjective cognitive impairment (SCI), 274 with mild cognitive impairment (MCI), and 195 with dementia, at baseline. Of the 195 (29%) patients with dementia at baseline, 81 (42%) had AD, 27 (14%) SVD, 41 (21%) mixed type dementia (=AD + SVD = MixD), and 46 (23%) other etiologies. After 6 years, 292 SCI/MCI patients were eligible for follow-up. Of these 292, 69 (24%) had converted to dementia (29 (42%) AD, 16 (23%) SVD, 15 (22%) MixD, 9 (13%) other etiologies). The study has shown that it is possible to identify not only AD but also incipient and manifest MixD/SVD in a memory clinic setting. These conditions should be taken into account in clinical trials.

Aim: To explore patterns of cerebral blood flow in patients with mild cognitive impairment (MCI), who (1) eventually deteriorate into overt dementia, with no particular focus on the type of dementia, or (2) do not appear to further deteriorate in their cognitive functions. Methods: Thirty-seven MCI patients, with or without vascular pathology, were studied prospectively. The patients underwent 99mTc-HMPAO SPECT analysis at baseline. Possible clinical conversion into dementia within a 2-year period was assessed. Results: Nineteen patients had progressive MCI (PMCI), while 18 patients were considered clinically stable (SMCI). PMCI patients had more often abnormally low cerebral blood flow in at least one of the frontal, temporal, parietal or occipital lobes compared to SMCI patients (12/19 vs. 5/18; p = 0.049). At least one of the temporal regions was found to be abnormal in 9 PMCI patients in contrast to only 1 SMCI patient (p = 0.008). More specifically, blood flow in the medial portion of the left temporal region was abnormal in 8 PMCI patients, a pattern seen in 1 SMCI patient only (p = 0.019). Conclusion: The results suggest that blood flow reductions particularly in the left medial temporal region indicate an elevated risk of further cognitive decline in MCI patients.

Background: Mild cognitive impairment (MCI) is a heterogeneous condition suggested as a prodromal state of Alzheimer’s disease (AD) and subcortical vascular dementia (SVD). Recent findings suggest that white matter lesions (WML) may be associated with hippocampal atrophy. The objective of the study was to examine hippocampal and WML volumes in MCI patients and to examine if WML were linked to hippocampal atrophy. Methods: The Gothenburg MCI study is a clinically based longitudinal study with biennial clinical assessments. The participants (n = 166) consist of 92 patients with stable MCI, 30 patients with converting MCI, and 44 healthy controls. WML volumes was measured manually using MRIcron. Automated segmentation of hippocampal and total white matter volumes was performed using FreeSurfer. Results: The patients converting from MCI to dementia had reduced hippocampal volume. Stable MCI patients had fewer WML and converting MCI patients had more WML compared to controls. Hippocampal volume was only correlated to WML volume (ρ = 0.57; p < 0.01) in the quartile (n = 42) with the most WML. Conclusions: Hippocampal atrophy is present in both AD and SVD. Hippocampal volume was associated with WML volume only in the high WML quartile, suggesting that the WML volume must reach a threshold before hippocampal atrophy is seen.

Background/Aim: Detection of cerebrospinal fluid (CSF) biomarker deviations improve prediction of progression from mild cognitive impairment (MCI) to dementia. However, it is not settled whether the same pattern exists in patients progressing from very mild to more pronounced MCI. Given that neurodegenerative processes occur very early in the disease course, we also expected to find biomarker deviations in these patients. Methods: A total of 246 memory clinic patients with non-progressive (n = 161), progressive (n = 19), or converting (n = 66) MCI, 67 with stable dementia, and 80 controls were followed for 24 months. At baseline, CSF total tau (T-tau), β-amyloid 1–42 (Aβ42) and the light subunit of neurofilament protein (NFL) were determined. Results: Patients with converting MCI and stable dementia had lower CSF Aβ42 concentrations and higher T-tau concentrations and NFL in comparison with controls and non-progressive/progressive MCI (p < 0.0005). No differences were found between progressive and non-progressive MCI. Conclusion: As expected, biomarker deviations predicted progression from MCI to dementia. Contrary to our hypothesis, progression from very mild MCI to more pronounced MCI was not reflected by biomarker deviations. The results suggest that the measured biomarkers are not early disease markers, or alternatively Alzheimer or vascular pathology is not the underlying cause in this patient group.

Background: Alterations in interrelated endocrine axes may be related to the pathogenesis of mild cognitive impairment (MCI) and dementia. Methods: Salivary cortisol before and after a 0.5-mg dexamethasone test, and serum levels of thyroid-stimulating hormone, total thyroxine (T4), free T4, total triiodothyronine (TT3), estradiol, testosterone and insulin-like growth factor 1 were measured in 43 MCI cases and 26 healthy controls. All participants underwent a comprehensive neuropsychological test battery covering the cognitive domains of speed/attention, memory, visuospatial functions, language and executive functions. Results: The MCI group did not differ in basal levels of endocrine markers compared to controls. Among those with MCI, TT3 levels were inversely associated with cognitive performance across all domains. After stratifying MCI cases according to TT3 levels, those with relatively high TT3 levels showed impairment in memory as well as in visuospatial and executive functions. Those with TT3 levels at or below the lower boundary of the normal range performed comparably to healthy controls. Other endocrine markers were not related to cognitive performance. Conclusions: Among those with MCI, TT3 was associated with a neuropsychological profile typical of prodromal Alzheimer’s disease. While the mechanisms remain unclear, optimal levels of thyroid hormone under a compromising condition such as MCI and related neuropathology need reconsideration.

Background: Mild cognitive impairment (MCI) is a heterogeneous condition, and the prognosis differs within the group. Recent findings suggest that hippocampal volumetry and CSF biomarkers can be used to predict which MCI patients have an underlying neurodegenerative disorder. Objective: To examine the combined predictive value of hippocampal volume and CSF levels of total tau (T-tau) and β-amyloid42 (Aβ42) in stable and converting MCI patients. The participants (n = 68) included patients with MCI at baseline and who converted to dementia by the time of the 2-year follow-up (n = 21), stable MCI patients (n = 21) and healthy controls (n = 26). Methods: The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually, based on data from the 0.5-tesla MRI investigations at baseline. Baseline CSF levels of T-tau and Aβ42 were measured using commercially available, enzyme-linked immunosorbent assays. Results: The converting MCI group had significantly smaller left hippocampi, lower CSF Aβ42 and higher T-tau compared to both the stable MCI group and the healthy controls. Multivariate analysis revealed that a combination of the variables outperformed the prognostic ability of the separate variables. Conclusions: Hippocampal volumes supplement the prognostic accuracy of CSF Aβ42 and T-tau in MCI.

Objective: To study which cognitive profiles of incipient dementia strongest predict the conversion to Alzheimer’s disease (AD) and mixed dementia (MD)/vascular dementia (VaD). Methods: 260 subjects with mild cognitive impairment (MCI) were included in the study and 209 (79%) were followed up after 2 years. At baseline, the subjects were assessed with a neuropsychological battery covering the cognitive domains speed/attention, memory, visuospatial, language and executive functions. Results: After 2 years, 9 subjects were considered normal, 148 had stationary MCI and 47 (23%) had converted to dementia. Twenty subjects were diagnosed with AD, 15 with MD and 9 with VaD. The others were 2 with unspecified dementias and 1 with primary progressive aphasia. Dementia converters had a high proportion of impairment in all cognitive domains. The profiles of incipient AD and MD/VaD differed, with memory, visuospatial and language symptoms preceding AD, and executive and speed/attention symptoms preceding MD/VaD. Conclusions: The risk of converting to dementia is increased when domains in addition to memory are impaired. The incipient AD and MD/VaD profiles differed quite clearly. Considering that the vascular group consisted of a majority of patients with MD, the differences are convincing – vascular disease seems to have an essential impact on cognition.

Background and purpose: White matter lesions (WMLs) caused by small vessel disease are common in elderly people and contribute to cognitive impairment. There are no established biochemical markers for WMLs. We aimed to study the relation between degree of WMLs rated on magnetic resonance imaging of the brain and cerebrospinal fluid (CSF) levels of structural biomarkers associated with Alzheimer’s disease (AD) and subcortical vascular dementia. Methods: Fifty-three non-demented elderly individuals with WMLs were subjected to lumbar puncture. Degree of WMLs was rated using the Fazekas scale. Volumetric assessment of WMLs was performed. CSF samples were analyzed for the 40 and 42 amino acid fragments of amyloid β, α- and β-cleaved soluble amyloid precursor protein, total tau (T-tau), hyperphosphorylated tau (P-tau181), neurofilament light protein (NFL), sulfatide and CSF/Serum-albumin ratio. Results: Fifteen subjects had mild, 23 had moderate and 15 had severe degree of WMLs. CSF-NFL levels differed between the groups (P

Background: Mild cognitive impairment (MCI) is an etiologically unclear disorder. Cerebrospinal fluid (CSF) biomarkers are potentially useful for the differentiation between various MCI etiologies. Aim: The aim of the study was to assess whether baseline CSF hyperphosphorylated tau (P-tau), total tau (T-tau), amyloid β 1–42 (Aβ42) and neurofilament light (NF-L) in patients with MCI could predict subcortical vascular dementia (SVD) and Alzheimer’s disease (AD) at follow-up. Methods: Biomarker levels were assessed by Luminex xMAP technology and ELISA. Results: Increased baseline concentrations of NF-L significantly separated MCI-SVD from stable MCI. The MCI-SVD patients were inseparable from stable MCI but separable from patients developing AD (MCI-AD) on the basis of Aβ42, T-tau and P-tau181 levels. Conclusion: A combination of the biomarkers Aβ42, T-tau, P-tau181 and NF-L has the potential to improve the clinical separation of MCI-SVD patients from stable MCI and MCI-AD patients.

This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p0.01), while baseline Abeta(1-42) levels were lower (p0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.

Background: This study focuses on the effect of psycho-educative family therapy on the self-assessed burden in families in which one member has suffered from relapse of schizophrenia or a schizoaffective syndrome. The impact on the family's self-assessed attitude towards continuing to take care of the patient was also evaluated. Burden and attitude were assessed continuously during a period that contained no further relapse episodes. Methods: Included were 31 families in which one family member suffered from schizophrenia or a schizoaffective syndrome. Of these, 14 families underwent a psycho-educative intervention programme called BFT (Behavioural Family Therapy). The remaining 17 families, i. e. the contrast group, received conventional family support. The intervention was initiated within 24 h after the patient/family member was admitted to a psychiatric ward due to relapse of the psychotic disorder. The intervention continued until the patient was discharged from hospital. Falloon's Distress Scale and Attitude Scale were used in the families' self-assessments of burden and attitude towards continuing to take care of the patient, respectively. The self-assessments were performed on three occasions: 1) on the day of admission to the ward, or the day after; 2) 4–5 weeks after admission; and 3) on the day of discharge, or the day after. Medication doses were registered upon admission and at the time of discharge. Finally, the rates of re-occurring relapses within 1 year after discharge from hospital were determined, i. e. 1 year after the completion of the family treatment programme. The BFT families had access to the therapist for questions after the programme had been completed, when needed. The patients and families in the contrast group had access to physicians and therapists in the outpatient care. Results: The self-assessed family burden was significantly lower for the BFT families at the time of discharge, compared to the contrast group, and the self-assessed attitude towards continuing to take care of the patient was significantly more positive for the BFT families at the time of discharge, compared to the contrast families. One patient in the BFT group relapsed within 1 year, whereas 13 patients relapsed in the contrast group. The dosages of neuroleptics were significantly lower on discharge than on admission for the patients in the BFT group. Conclusions: The results suggest that BFT, when provided to schizophrenic patients and their families during a hospitalisation period caused by a psychotic relapse, reduces the feeling of burden in these families. Likewise, the families' attitude towards continuing to take care of the patients was influenced in a positive way.

Objectives The aim of the present study was to elucidate a possible relationship between depressive symptomatology and regional brain symptomatology in demented patients. Methods 170 consecutive inpatients were studied. They suffered from Alzheimer's disease (103 patients), vascular dementia (48 patients), or frontotemporal dementia (19 patients). The patients underwent a neuropsychiatric investigation, which included assessments of (1) depression, and (2) regional brain symptomatology. Depressive symptomatology was assessed as presence of (a) depressed mood, and (b) anxiety. In the further statistical analysis, the presence of depressed mood and/or anxiety was also evaluated. The principle of the regional symptom analysis was the successive aggregation of observable symptom variables, leading to the final determination of four possible regional brain syndromes (frontal, subcortical, parietal and global), by way of the Stepwise comparative status analysis (STEP). The possible correlations between regional brain symptomatology and depressive symptomatology were analysed by means of (a) χ2 statistics, and (b) a logistic regression analysis in which confounding factors were included (age, degree of dementia, duration). Results The subcortical syndrome correlated with depressed mood (χ2, p = 0.002; logistic regression, p = 0.002). A negative correlation was noted between the parietal syndrome and depressed mood (p = 0.010 and p = 0.013, respectively). No other significant correlations between presence of regional brain syndrome and presence of depressive symptomatology could be seen. Conclusions Demented patients with a clinically established subcortical dysfunction appear to be more susceptible to depressive symptomatology. The results of this study also suggest that posterior brain dysfunction in dementia is not correlated with depressive symptomatology. Copyright © 2002 John Wiley & Sons, Ltd.

The objective of this study was to compare cerebrospinal fluid (CSF) levels of the light subtype of the neurofilament proteins (NFL), tau, and beta-amyloid42 (Abeta42) in individuals with moderate or severe white matter changes (WMC) and in those with mild or no WMC. Twenty-two patients with Alzheimer's disease (AD), nine patients with subcortical vascular dementia (SVD), and 20 normal controls were included in the study. The occurrence of WMC was evaluated by a neuroradiologist using the Blennow-Wallin scale. Thirty-seven subjects had no or only punctate WMC; 14 had moderate to severe WMC. Both diagnostic group and WMC, but not gender or apolipoproteinE E4 inheritance, contributed to the variance in the CSF levels of tau, NFL, and Abeta42. In patients with moderate to severe WMC, CSF NFL (P < 0.01), but not CSF tau or CSF Abeta42, was increased also after correction for age, gender, and degree of cognitive impairment. A comparison between patients and controls with any signs of WMC and those without such signs yielded a similar result: CSF NFL (P < 0.001) was increased in the group with signs of WMC. As in numerous previous studies, we found that CSF tau was increased in AD (P < 0.001) compared with controls. Furthermore, CSF NFL was increased in both AD and SVD compared with controls (P < 0.001 for both). Although diagnostic group seems to be a stronger predictor of the variance found in CSF NFL, a clear association between the presence of WMC and increased CSF NFL was found. Because NFL is located mainly in large myelinated axons, increased CSF NFL in individuals with WMC probably reflects axonal degeneration.

Today, cognitive impairment can be successfully treated with acetylcholine esterase inhibitors (AChE-I) in many, but not all, patients with Alzheimer's disease (AD). To investigate the relation between tacrine treatment, inheritance of ApoE epsilon4 alleles, and rate of progression, the differences in MMSE and CIBIC scores (efficacy parameters) after 6 and 12 months of tacrine (an AChE-I) treatment were investigated in 145 AD patients. Of these, 84 were ApoE epsilon4-positive (ApoE4) and 61 were ApoE epsilon4-negative (ApoE2-3). No differences were found after 6 months of treatment, but after 12 months the CIBIC scores revealed that the ApoE4 patients had declined more than the ApoE2-3 patients (p < 0.05). No differences were found for the last 6 months of treatment. The results primarily suggest a faster rate of decline in the ApoE4 AD compared to the ApoE2-3, but may also reflect that ApoE epsilon4 genotype inheritance is a negative predictor of treatment effect of tacrine in AD patients.

Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and β-amyloid42 (Aβ42) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer’s disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration.

Occurrence of delirium is known to be related to, among other things, organic brain disorder, somatic disease and old age. It has been hypothesized that delirium is also associated with stress. Disturbances of the hypothalamic-pituitary-adrenal (HPA) system have been found in delirious patients in various studies. The aim of the present study was to determine the activity in the HPA axis in demented patients to ascertain whether the stress regulating system was more disturbed in patients with delirium than in those without delirium. Demented inpatients with no acute medical illness were included in the study. Basal cortisol levels in serum were measured and dexamethasone suppression test (DST) was performed. The most important finding of the study was a strong relationship between delirium and DST pathology irrespective of age and severity of dementia. It is suggested that certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.

The aim was to study the frequently found white-matter changes on computerized tomography (CT) in patients with dementia and to relate these changes to clinical regional brain symptomatology, vascular factors, albumin ratio [indicator of blood-brain barrier (BBB) function] and other CT changes. The study included 85 patients, average age 71 ± 8, with Alzheimer’s disease (n = 56) and vascular dementia (n = 29), who underwent CT (Siemens Somatome DR 1) of the brain. They were inpatients in a psychiatric department specialized in dementia investigations. The degree of CT white-matter changes (absence, mild-moderate, severe) was the basis for the division of the patients into three groups. As the patients without white-matter changes were significantly younger than those with such changes, all statistical analyses were controlled for age. Subcortical symptomatology was significantly more frequent in the group with severe white-matter changes, whereas the reverse was true for parietal symptomatology. Diabetes mellitus, hypertension, ischemic cardiac disease and lacunas were significantly more common in patients with white-matter changes, whereas the freqeuncy of transient ischemic attack/stroke episodes did not differ significantly between the groups. The albumin ratio was significantly higher in the groups with white-matter changes and highest in the group with severe white-matter changes. The findings indicate that white-matter changes in demented patients are at least partially an age- and stroke-independent disease manifestation of the vascular system and is associated with a specific symptom pattern. BBB dysfunction may be the link between the vasculature and the tissue damage.

This paper presents the Swedish translation of stepwise comparative status analysis (STEP), which is a clinical method for identifying regional brain syndromes in dementia, developed by Wallin and colleagues. Added are guidelines with regard to the order in which the items can be assessed and a checklist including those items that require information from relatives or nursing staff to be correctly assessed (such as items connected with the patient's premorbid personality). The analysis is made in three steps, including evaluation of primary, compound, and complex status variables. The primary variables represent single symptoms and signs (for example, memory disturbance, apraxia, and mental slowness). The compound variables represent symptom constellations that suggest damage to certain brain regions (for example, instrumental difficulties). Scores on the presence and intensity of the primary and compound variables form the basis of the evaluation of the complex variables. These represent regional brain s...

Objective. Our hypothesis was that patients with vascular dementia and a dominating frontal lobe syndrome have a symptomatology that reflects a more widespread lesion compared with patients with frontotemporal dementia. Design. Patients with vascular dementia and a dominating frontal lobe syndrome (VAD-F; N=11) were compared with regard to clinical symptoms and imaging features on CT scans of the brain with patients with frontotemporal dementia (FTD; N=21). Setting. A neuropsychiatric diagnostic ward. Patients. Thirty-two inpatients, aged 48–78 years, with frontotemporal dementia or vascular dementia. Measures. Relatives were questioned about the initial symptoms. At the clinical investigation, mental and neurological symptoms and signs were recorded using the STEP method (stepwise comparative status analysis). CT scan features of the brain were evaluated by a trained neuroradiologist. The GBS-i (Gottfries–Bra3ne–Steen, intellectual variables) scale was used to measure the degree of dementia. Results. At the onset of dementia, loss of memory (p

A method for clinical examination of patients with dementia, stepwise comparative status analysis (STEP), is presented. It combines psychiatric and neurologic status examination methods to identify certain common dementia symptoms by which the patient's regional brain symptom profile can be determined. Fifty status variables (items) are estimated with respect to occurrence and severity. The analysis is performed in three steps. The scores on the primary variables reflect observations of single dementia symptoms. These scores form the basis for the assessment of the ‘compound’ variables, which in turn form the basis for evaluation of the ‘complex’ variables, one of which describes the patient's regional (predominant) brain syndrome (subcortical, frontosubcortical, frontal, frontoparietal, parietal, or global). In 96 mildly and moderately demented inpatients, the global (42%) and frontosubcortical (31%) were the most common. Ninety-one percent of the patients with vascular dementia had a predominant frontal and/or subcortical symptomatology

The levels of the monoamine metabolites 5-hydroxy-indoleacetic acid (5-HIAA), homovanillic acid (HVA), and 4-hydroxy-3-methoxyphenylglycol (HMPG) were determined in lumbar cerebrospinal fluid (CSF) of 56 patients with vascular dementia (VAD) and 57 healthy controls. Despite CSF sampling under standardized conditions, the variability in values was wide among both patients and controls. This suggests that yet unknown factors affect the lumbar CSF concentrations of monoamine metabolites. The VAD group showed significantly lower mean concentrations of 5-HIAA (p < .001) and HVA (p < .001) than the control group. These low concentrations appear to be no disease-specific phenomenon, but may be attributable to subcortical white-matter changes or a decreased production of monoamines, which are dependent on oxygen for their synthesis.

BACKGROUND: Mild cognitive impairment (MCI) is a condition with increased risk for further cognitive decline. A considerable challenge lies in predicting which patients will eventually convert to dementia. OBJECTIVE: To study prediction of dementia in MCI using neuropsychological tests, commonly used cerebrospinal fluid (CSF) biomarkers, and hippocampal volume. METHODS: Twenty-one MCI patients converting to dementia, 21 stable MCI patients, and 26 controls were included in the study with a follow-up time of two years. The study participants underwent comprehensive examinations at inclusion: a neuropsychological assessment comprising 20 tests, MRI scanning with subsequent hippocampal volumetry, and CSF analyses of T-tau, P-tau, and Aβ42. RESULTS: Neuropsychological tests, hippocampal volume, and the CSF markers Aβ42, P-tau, and T-tau all predicted conversion from MCI to dementia. A combination of all classes of markers was the most successful at predicting dementia (AUC 0.96) with a memory test (RAVLT) as the best individual predictor (AUC 0.93). Similar findings are reported for the prediction of Alzheimer's disease. CONCLUSION: Neuropsychological tests were the best individual predictors of dementia. A combination of markers improved the predictive ability with the combination of neuropsychological tests, CSF, and hippocampal volume as the best predictors of dementia.

Aggressive behavior in dementia often has a severe impact on the quality of life of the patient and the caregivers, and is therefore important to handle. The strategy of treatment should be broad. Nonpharmacological interventions, including environmental adjustments and supporting and training the caregivers, should always be considered. Pharmacological treatment of aggressive behavior in patients with dementia often includes the use of neuroleptics. The atypical compounds clozapine, risperidone, and olanzapine have been shown to have an effect on aggressive behavior at low dosage with limited extrapyramidal side effects. The anticonvulsants carbamazepine and sodium valproate are further alternatives. In treatment-resistant cases, buspirone or lithium may be tried, although the effect of these substances on aggressive behavior in dementia has not been well established. In the end, however, a considerable degree of aggressive behavior sometimes remains after careful treatment trials, particularly in patients with severe aggressive behavior. In addition, treatment is sometimes limited by side effects.

Background/Aims: Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging. Methods: CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS). Results: 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0–2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015). Conclusion: The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer’s disease.

Alzheimer's disease (AD) and vascular dementia (VaD) are intertwined by mixed dementia (MD) harboring varying degrees of AD pathology in combination with cerebrovascular disease. The aim was to assess whether there is a difference in the cerebrospinal fluid (CSF) profile, of selected proteins, between patients with VaD and MD with subcortical vascular disease (SVD), AD, and healthy controls that could contribute in the separation of the groups. The study included 30 controls, 26 SVD patients (9 VaD and 17 MD) and 30 AD patients. The protein panel included total tau (T-tau), hyperphosphorylated tau 181 (P-tau(181)), amyloid β 1-42 (Aβ(1-42)), neurofilament light (NF-L), myelin basic protein (MBP), heart fatty acid binding protein (H-FABP), matrix metalloproteinases (MMP-1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinases (TIMP-1 and -2). Immunochemical methods were utilized for quantification of the proteins in CSF and data analysis was performed with a multivariate discriminant algorithm. The concentrations of MBP, TIMP-1, P-tau(181), NF-L, T-tau, MMP-9, Aβ(1-42), and MMP-2 contributed the most to the separation between SVD and AD, with a sensitivity of 89% and a specificity of 90% (AUC = 0.92). MBP and NF-L performed the best in discriminating SVD from controls, while T-tau and Aβ(1-42) contributed the most in segregating AD from controls. The CSF biomarkers reflecting AD pathology (T-tau, P-tau(181), and Aβ(1-42)), white matter lesions (NF-L and MBP) and matrix remodeling (MMP-9 and TIMP-1) perform well in differentiating between SVD and AD patients.

Objective Cerebral white-matter changes (WMCs) are frequently found in dementia and have been proposed to be related to vascular factors and a certain symptomatological profile. However, few studies have included both vascular factors and a broad spectrum of cognitive, neurological and psychiatric symptoms, easily detectable by the physician in the everyday clinical work. The objective was to study the relationships between WMCs on MRI/CT and neuropsychiatric symptoms and vascular factors in patients with cognitive impairment. Methods One hundred and seventy-six patients with Alzheimer's disease, vascular dementia, mixed dementia, and mild cognitive impairment were included. All patients underwent a standardized examination including medical history, clinical examinations, laboratory tests and brain imaging (CT or MRI). The identification and severity degree of WMCs was assessed blindly to clinical findings, using a semi-quantitative scale. For statistical analyses, patients were grouped based on absence or presence of WMCs. Significant variables in bivariate analyses were included as predictors in stepwise multiple logistic regression analyses. Results Bivariate analyses showed significant associations between WMCs and age, gender, blood pressure, hypertension, ischaemic heart disease and TIA/RIND. Furthermore, there were significant associations between WMCs and apathy, mental slowness, disinhibition, gait disturbance and focal neurologic symptoms. The multivariate logistic model revealed apathy, mental slowness and age as the most consistent predicting factors for WMCs, together with MRI as a radiological method for the detection of WMCs. Conclusions The findings indicate that WMCs in patients with dementia are associated with a dysexecutive-related behavioural symptom profile, vascular factors related to small and large vessel diseases and age. Copyright © 2009 John Wiley & Sons, Ltd.

Background: It is unknown whether HPA-axis dysfunction is present in patients with mild cognitive impairment (MCI). The aim of the present study was to investigate whether cortisol levels are elevated among patients with MCI and/or whether the individuals have adequate feedback control of their HPA axis. Material and Methods: 27 patients with MCI and 15 healthy controls were included in the study. Saliva samplings were performed 5 times a day before intake of 0.5 mg dexamethasone, and 5 times a day after intake of dexamethasone, respectively. Results: Significantly higher cortisol levels were found 15 min after awakening among patients with MCI in comparison with the controls, both before and after dexamethasone administration (p < 0.05). Also, the ratio between cortisol at awakening time and 15 min after awakening was lower in the patient group after dexamethasone administration (p < 0.05). There were no significant differences in basal cortisol levels before or after dexamethasone between groups. Conclusion: The results indicate that there is an HPA-axis disturbance, with normal basal cortisol levels and increased awakening response among patients with MCI. The dissociation between basal values and the awakening response may be of pathophysiological importance for the cognitive impairment.

BACKGROUND: Little solid information is available on the possible risks for neuronal injury in amateur boxing. OBJECTIVE: To determine whether amateur boxing and severity of hits are associated with elevated levels of biochemical markers for neuronal injury in cerebrospinal fluid. DESIGN: Longitudinal study. SETTING: Referral center specializing in evaluation of neurodegenerative disorders. PARTICIPANTS: Fourteen amateur boxers (11 men and three women) and 10 healthy male nonathletic control subjects. INTERVENTIONS: The boxers underwent lumbar puncture 7–10 days and 3 months after a bout. The control subjects underwent LP once. MAIN OUTCOME MEASURES: Neurofilament light protein, total tau, glial fibrillary acidic protein, phosphorylated tau, and beta-amyloid protein 1–40 (Abeta([1–40])) and 1–42 (Abeta([1–42])) concentrations in cerebrospinal fluid were measured. RESULTS: Increased levels after a bout compared with after 3 months of rest from boxing were found for two markers for neuronal and axonal injury, neurofilament light protein (mean±SD, 845±1140 vs 208±108 ng/L; P=0.008) and total tau (mean±SD, 449±176 vs 306±78 ng/L; P=0.006), and for the astroglial injury marker glial fibrillary acidic protein (mean±SD, 541±199 vs 405±138 ng/L; P=0.003). The increase was significantly higher among boxers who had received many hits (>15) or high-impact hits to the head compared with boxers who reported few hits. In the boxers, concentrations of neurofilament light protein and glial fibrillary acidic protein, but not total tau, were significantly elevated after a bout compared with the nonathletic control subjects. With the exception of neurofilament light protein, there were no significant differences between boxers after 3 months of rest from boxing and the nonathletic control subjects. CONCLUSIONS: Amateur boxing is associated with acute neuronal and astroglial injury. If verified in longitudinal studies with extensive follow-up regarding the clinical outcome, analyses of cerebrospinal fluid may provide a scientific basis for medical counseling of athletes after boxing or head injury.

Objective The aim of the present study was to investigate if depressive symptoms in demented patients are associated with white matter changes (WMCs) in the brain. Background WMCs are frequently found in patients with dementia, as well as among elderly nondemented patients with depressive symptoms. However, it is less established whether or not WMCs are related to depressive symptoms in demented patients. Methods 67 (26 men, 41 women) patients with primary degenerative dementia (Alzheimer's disease, frontotemporal dementia), vascular dementia (VaD), or mixed Alzheimer/VaD dementia were included in the study. The patients were young-old (mean 68.1, SD 7.3). All patients underwent a standardized examination procedure and MRI of the brain. The degree of WMCs was visually rated, blindly. Depressive symptoms were rated according to the Gottfries-Brane-Steen scale (anxiety, fear-panic, depressed mood). Results No significant relationship was found between WMCs and depressive symptoms in the demented patients. Conclusion The possible involvement of WMCs in the pathogenesis of depressive symptoms in dementia is unclear. A link between disruptions of frontal-subcortical pathways, due to WMCs, and depressive symptomatology in dementia has been hypothesised from earlier findings, which would imply common elements of pathogenesis for depressive symptomatology and cognitive impairment in dementia. However, the results of the present study do not add further support to this hypothesis. Copyright © 2006 John Wiley & Sons, Ltd.

The aim of the study was to elaborate a method to estimate the degree of cognitive impairment in Alzheimer’s disease from the EEG quantitative indicators. We examined 38 unmedicated patients with a diagnosis of Alzheimer’s disease, with various stages (mild, moderate, and severe) of dementia. The EEG recordings were evaluated both visually and by means of computer analysis. The EEG spectra and coherences in 6 frequency bands were calculated in 16 EEG derivations. Among various EEG indicators, a decrease in the alpha coherence and an increase in the delta coherence was found to be most significantly correlated to the degree of dementia. Combining 6 variables from the spectrum and coherence analysis by means of the multiple regression model, a high correlation (r = 0.87) between a set of EEG variables and the Mini-Mental State Examination score could be obtained. The results suggest that the EEG can supplement the clinical examination by providing an independent assessment of the degree of dementia. The results also suggest that the EEG coherences are of particular interest in dementia, being an indicator of the signal transfer between various parts of the brain cortex.

We investigated the clinical and biological effects of cholesterol-lowering treatment with a statin in 19 patients with Alzheimer’s disease. They received simvastatin 20 mg/day for 12 weeks in an open trial. Primary efficacy parameters were the changes after 12 weeks in the cerebrospinal fluid (CSF) levels of β-amyloid42 (Aβ42), α-secretase-cleaved amyloid precursor protein (α-sAPP), β-secretase-cleaved APP (β-sAPP), tau, phospho-tau and the plasma levels of Aβ42. A secondary efficacy parameter was the change in the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-cog) score. After 12 weeks, CSF α-sAPP and CSF β-sAPP were significantly reduced (p < 0.001), but the CSF levels of tau, phospho-tau, Aβ42 and the plasma levels of Aβ42 were unchanged. The ADAS-cog score was slightly increased (p < 0.05). The results suggest that simvastatin acts directly on the processing of APP by inhibiting both the α- and the β-secretase pathways.

The alertness level of 143 patients with dementia was investigated. The patients were examined clinically and electroencephalographically, and the results were compared with 21 healthy volunteers. Regional brain syndromes were determined clinically. For the assessment of the EEG, a method was employed that distinguishes alertness-related slow wave activity from abnormal slow activity. The shifts of the EEG power were monitored during the 5-min examination. The short-term variations were considered to be caused by changes in alertness, whereas the basal level was supposed to reflect the EEG abnormality. It was found that a decrease in alertness occurred more often in the demented patients than in the controls. The intensity of this decrease was proportional to the degree of the dementia. The alertness disturbance was found to be particularly associated with the parietal brain syndrome.

An inter-rater reliability test of the Stepwise Comparative Status Analysis (STEP) is presented. The STEP is a pro tocol for the clinical examination of patients with dementia, within the scope of a neuropsychiatric investigation. It combines psychiatric and neurologic bedside examination methods. The analysis is made in three steps where primary, observable symptom variables are successively aggregated via compound variables to the final determi nation of one of seven possible dominant regional brain syndromes (global, frontal, subcortical, parietal, frontosubcortical, frontoparietal, other), here also called complex variables. In the present study, two senior physi cians assessed 50 patients independently and simultaneously. None of the patients was known to both physicians. In 42 patients (84%), the same dominant brain syndrome was determined by the two clinicians. The probability (P value) of this (or better) agreement was calculated at 2.0 × 10-12. Kappa coefficients were calculated as a measure of assessment agreement regarding the 50 STEP variables. For 20 variables, the coefficient was 0.75 or above, indi cating excellent agreement; for 22 variables, the coefficient was below 0.75 and above 0.40, indicating moderate agreement; and for 4 variables, the value was 0.40 or below, indicating poor agreement. Kappa calculations regard ing the assessments of four variables were either not possible or were considered inappropriate. (J Geriatr Psychiatry Neurol 2001; 14:140-144).

The aim of this study was to investigate to what extent the examination of regional syndromes can improve EEG diagnostics in dementia. The study was based on 77 patients, aged between 47 and 83 years, with a dementia disease in accordance with the DSM-III-R criteria. The clinical examination was refined using a so-called stepwise clinical status analysis to estimate the occurrence and intensity of the parietal lobe syndrome, the frontal lobe syndrome, the subcortical syndrome and the less-regionalised global syndrome. In the same time period, the patients were examined electroencephalographically and the recordings were assessed both visually and by means of spectrum analysis. It was found that the intensity of the parietal lobe syndrome was correlated more strongly to the EEG slow activity as compared to the other regional syndromes. Thus, it can be expected that the EEG will be most valuable in the early-onset type of Alzheimer's disease, in which the parietal syndrome is dominant, giving information regarding the degree of dementia and suggesting a possible interference with depression. The results of the study can probably explain some discrepancies between the EEG findings and the results of clinical examination in other forms of dementia.

EEG slow-wave activity was correlated with the regional brain syndrome profile in 74 patients with dementia. The EEGs were visually assessed using a semiquantitative rating scale. The intensities of four regional brain syndromes (parietal, frontal, subcortical, global) and the degree of dementia were rated. The patients were examined twice with a 1-year interval. A significant relationship was found between the increase in EEG slow-wave activity and the increase in intensity of the parietal brain syndrome. A somewhat lower significance was found for the relation between increase in slow-wave activity and increase in dementia degree. The results suggest that the EEG deterioration in dementia mainly reflects the gradual decline of parietal brain function.

EEG indicators were correlated with clinical items in 174 patients with dementia diagnoses based on the DSM-III-R criteria. The patients'' clinical symptomatologies were presented as regional brain syndromes, i.e. parietal lobe, frontal lobe, subcortical and global (nonregional) syndromes. The EEGs were abnormal in 87% of the cases. The typical abnormalities consisted of diffusely distributed slow wave activity. A significant correlation was found between the degree of slow wave abnormality and the degree of dementia. The results of the statistical analysis also suggest that EEG slow wave activity in dementia primarily reflects parietal lobe dysfunction. No association seems to exist between EEG slow wave activity and frontal lobe dysfunction.