Navigated and individual α-peak-frequency-guided transcranial magnetic stimulation in male patients with treatment-refractory schizophrenia.

BACKGROUND: Previous electroencephalography (EEG) studies have indicated altered brain oscillatory α-band activity in schizophrenia, and treatment with repetitive transcranial magnetic stimulation (rTMS) using individualized α-frequency has shown therapeutic effects. Magnetic resonance imaging-based neuronavigation methods allow stimulation of a specific cortical region and improve targeting of rTMS; therefore, we sought to study the efficacy of navigated, individual α-peak-frequency-guided rTMS (αTMS) on treatment-refractory schizophrenia. METHODS: We recruited medication-refractory male patients with schizophrenia or schizoaffective disorder in this doubleblind, sham-controlled study. We randomized patients to a 3-week course of either active αTMS or sham stimulation applied to the left dorsolateral prefrontal cortex (DLPFC). We assessed participants with the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Scale (CGI) at baseline and after treatment. We conducted a follow-up assessment with the PANSS 3 months after intervention. RESULTS: We included 44 patients. After treatment, we observed a significantly higher PANSS total score (p = 0.029), PANSS general psychopathology score (p = 0.027) and PANSS 5-factor model cognitive-disorganized factor score (p = 0.011) in the αTMS group than the sham group. In addition, the CGI-Improvement score was significantly higher among those who received αTMS compared with sham stimulation (p = 0.048). LIMITATIONS: The limited number of study participants included only male patients. Depression was not formally evaluated. CONCLUSION: Navigated αTMS to the left DLPFC reduced total, general psychopathological, and cognitive-disorganized symptoms of schizophrenia. These results provide evidence for the therapeutic efficacy of individual α-peak-frequency-guided rTMS in treatment-refractory schizophrenia. CLINICAL TRIAL REGISTRATION: NCT01941251; ClinicalTrials.gov.

The Progression of Alzheimer's Disease Can Be Assessed with a Short Version of the CERAD Neuropsychological Battery: The Kuopio ALSOVA Study.

BACKGROUND/AIMS: Measuring and predicting Alzheimer's disease (AD) progression is important in order to adjust treatment and allocate care resources. We aimed to identify a combination of subtests from the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) that best correlated with AD progression in follow-up as well as to predict AD progression. METHOD: A total of 236 participants with very mild [Clinical Dementia Rating (CDR) = 0.5] or mild AD (CDR = 1.0) at baseline were followed up for 3 years. The CERAD-NB and Mini-Mental State Examination (MMSE) were used to assess cognition, and the CDR scale sum of boxes (CDR-sb) was employed to evaluate AD progression. Generalized estimating equations were used to develop models to predict and follow up disease progression. RESULTS: Performance declined on all CERAD-NB subtests. The ability of the separate subtests to distinguish between groups (baseline CDR = 0.5 or 1.0) diminished during follow-up. The best combination of subtests that explained 62% of CDR-sb variance in follow-up included verbal fluency, constructional praxis, the clock drawing test, and the MMSE. Baseline values of the same combination predicted 37% of the CDR-sb change. CONCLUSION: A short version of the CERAD-NB subtests provides a promising and time-efficient alternative for measuring cognitive deterioration during AD follow-up. Although the initial signs of AD include memory difficulties, it may be useful to assess non-memory tasks in follow-up.

Word list learning in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy.

BACKGROUND/AIMS: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare hereditary disease that is characterized by a combination of progressive presenile dementia and sclerosing leukoencephalopathy with bone cysts. No quantitative information on verbal memory functioning in PLOSL patients compared with control subjects is available. METHODS: 23 patients with PLOSL and 23 control subjects were examined with a version of the 10-word list-learning task. Learning curves were compared between the patients and the matched control subjects. RESULTS: Compared with the control subjects, PLOSL patients with moderate or severe dementia were impaired in both learning trials and delayed recall on the 10-word list-learning test. CONCLUSION: Progressive degeneration of brain structures affecting the hippocampus and the medial temporal lobe with advanced PLOSL disease contributes to an inefficient verbal learning process.

Cognitive and Neuropsychiatric Symptom Differences in Early Stages of Alzheimer's Disease: Kuopio ALSOVA Study.

BACKGROUND/AIM: Alzheimer's disease (AD) causes impairment in memory and other cognitive functions as well as neuropsychiatric symptoms and limitations in the activities of daily living (ADL). The aim of this study was to examine whether demographic variables, dementia severity, ADL and neuropsychiatric symptoms are associated with cognition in very mild or mild AD. METHODS: We analyzed the baseline data of 236 patients with very mild or mild AD participating in a prospective AD follow-up study (ALSOVA). The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery total score was used in the evaluation of the global cognitive performance. RESULTS: Cognition was associated with dementia severity and ADL but not with neuropsychiatric symptoms. ADL functions were associated with both cognitive performance and neuropsychiatric symptoms. CONCLUSION: Even patients with very mild or mild AD may exhibit neuropsychiatric symptoms not related to cognitive impairment. The results of this study emphasize the importance of taking a multidimensional approach to the diagnostic and prognostic evaluation of AD patients already in the early stages of the disease.

Neuropsychiatric symptoms and quality of life in patients with very mild and mild Alzheimer's disease.

BACKGROUND: Neuropsychiatric symptoms (NPS) are common manifestations of Alzheimer' s disease (AD). OBJECTIVE: To examine the prevalence and significance of NPS in very mild and mild AD patients with emphasis on their influence on the well-being of the patients and their caregivers. METHODS: The participants were 240 patient-caregiver dyads who participated in a prospective, controlled rehabilitation study (ALSOVA). Three Quality of Life (QoL) instruments were used; generic 15D, disease-specific QoL-AD and Visual Analog Scale (VAS). The disease-specific QoL-AD was both self-rated and caregiver rated. Other scales used were Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), ADCS-ADL, Neuropsychiatric Inventory (NPI) and Beck Depression Inventory (BDI). RESULTS: NPS were present in 76.5% of patients with very mild AD (CDR 0.5) and in 84.9% of patients with mild to moderate AD (CDR 1). The most frequent symptoms were apathy, depression, irritability, and agitation. The strongest predictor of self-reported QoL-AD scores was depressive symptoms whereas functional decline and presence of NPS predicted poor caregiver ratings of patients' QoL. However, caregiver depression also influenced significantly their ratings. CONCLUSION: NPS are common even in the early stages of AD. NPS were significantly associated with caregiver assessment of the patient's QoL but not with patients' self-assessed QoL. Depression decreases QoL, but may remain unrecognized in AD patients, emphasizing the need for careful and structured assessment of NPS before deciding on the appropriate treatment.

Olfactory identification in non-demented elderly population and in mild cognitive impairment: a comparison of performance in clinical odor identification versus Boston Naming Test.

Performance in olfactory identification was studied in mild cognitive impairment (MCI), using slightly expanded standard clinical approach to study the olfactory nerve. Four hundred and eighty-six cognitively normal individuals and 72 individuals with MCI underwent spontaneous and cued odor identification and delayed odor recall. Performance in these was compared with the performance in the CERAD version of the Boston Naming Test (BNT). The individuals with MCI scores significantly worse in all tests compared with controls, but the performance in tests assessing odor were less impaired than performance in the BNT. Standard assessment of olfactory nerve function is not sufficient to study cognitive impairment in MCI.

MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study.

The concept of mild cognitive impairment (MCI) has been proposed to represent a transitional stage between normal aging and dementia. We studied the predictive value of the MRI-derived volumes of medial temporal lobe (MTL) structures, white matter lesions (WML), neuropsychological tests, and Apolipoprotein E (APOE) genotype on conversion of MCI to dementia and AD. The study included 60 subjects with MCI identified from population cohorts. During the mean follow-up period of 34 months, 13 patients had progressed to dementia (9 to Alzheimer's disease (AD)). In Cox regression analysis the baseline volumes of the right hippocampus, the right entorhinal cortex and CDR sum of boxes predicted the progression of MCI to dementia during the follow-up. In a bivariate analysis, only the baseline volumes of entorhinal cortex predicted conversion of MCI to AD. The Mini-Mental State Examination (MMSE) score at baseline, WML load, or APOE genotype were not significant predictors of progression. The MTL volumetry helps in identifying among the MCI subjects a group, which is at high risk for developing AD.

Voxel-based morphometry to detect brain atrophy in progressive mild cognitive impairment.

Recent research has shown an increased rate of conversion to dementia in subjects with mild cognitive impairment (MCI) compared to controls. However, there are no specific methods to predict who will later develop dementia. In the present study, 22 controls and 56 MCI subjects were followed on average for 37 months (max. 60 months) and studied with magnetic resonance imaging (MRI) at baseline to assess changes in brain structure associated to later progression to dementia. Voxel-based morphometry (VBM) was used to investigate gray matter atrophy. During the follow-up, 13 subjects progressed to dementia. At baseline, no differences were detected in age or education between the control and MCI subjects, but they differed by several neuropsychological tests. The stable and progressive MCI subjects differed only by CDR sum of boxes scores and delayed verbal recall, which were also significant predictors of conversion to dementia. At the baseline imaging, the MCI subjects showed reduced gray matter density in medial temporal, temporoparietal as well as in frontal cortical areas compared to controls. Interestingly, the progressive MCI subjects showed atrophy in the left temporoparietal and posterior cingulate cortices and in the precuneus bilaterally, and a trend for hippocampal atrophy when compared to the stable MCI subjects. We conclude that widespread cortical atrophy is present already two and a half years before a clinical diagnosis of dementia can be set.

The effect of apolipoprotein polymorphism on brain in mild cognitive impairment: a voxel-based morphometric study.

We investigated the effect of apolipoprotein E (ApoE) on the whole brain in 51 individuals with mild cognitive impairment using voxel-based morphometry. Between cases heterozygous for the ApoE epsilon4 (n = 15) and those who were ApoE epsilon4 noncarriers (n = 28), only the right parahippocampal gyrus, with the entorhinal cortex included, reached the level of statistical significance. In cases homozygous for the epsilon4 allele (n = 8) versus noncarriers, the greatest atrophy was located in the right amygdala followed by the right parahippocampal gyrus, the left amygdala and the left medial dorsal thalamic nucleus.

Hippocampus and entorhinal cortex in mild cognitive impairment and early AD.

Magnetic resonance imaging (MRI) has been suggested as a useful tool in early diagnosis of Alzheimer's disease (AD). Based on MRI-derived volumes, we studied the hippocampus and entorhinal cortex (ERC) in 59 controls, 65 individuals with mild cognitive impairment (MCI) and 48 patients with AD. The controls and individuals with MCI were derived from population-based cohorts. Volumes of the hippocampus and ERC were significantly reduced in the following order: control > MCI > AD. Stepwise discriminant function analysis showed that the most efficient overall classification between controls and individuals with MCI subjects was achieved with ERC measurements (65.9%). However, the best overall classification between controls and AD patients (90.7%), and between individuals with MCI and AD patients (82.3%) was achieved with hippocampal volumes. Our results suggest that the ERC atrophy precedes hippocampal atrophy in AD. The ERC volume loss is dominant over the hippocampal volume loss in MCI, whereas more pronounced hippocampal volume loss appears in mild AD.

Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects.

BACKGROUND: Mild cognitive impairment (MCI) has attracted considerable interest as a potential predictor of Alzheimer's disease (AD). Both the apolipoprotein E (ApoE) epsilon4 allele and vascular factors have been associated with a higher risk for AD, recently they have also been linked to the risk of MCI. OBJECTIVES: To estimate the incidence of MCI among cognitively healthy elderly subjects during a 3-year follow-up, and to evaluate the impact of demographic and vascular factors as well as the ApoE epsilon4 allele on the conversion to MCI. METHODS: At baseline, the cognitive abilities of 806 out of 1,150 eligible subjects (aged 60-76 years) from a population-based sample were examined. Cognitively intact subjects (n = 747) were followed for an average of 3 years. RESULTS: 66 subjects (8.8%) had converted to MCI. The global incidence rate of MCI was 25.94/1,000 person-years. Persons with higher age (OR 1.08, 95% CI 1.01-1.16), ApoE epsilon4 allele carriers (OR 2.04, 95% CI 1.15-3.64) and persons with medicated hypertension (OR 1.86, 95% CI 1.05-3.29) were more likely to convert to MCI than those individuals of lower age and without an ApoE epsilon4 allele or medicated hypertension. Persons with high education (OR 0.79, 95% CI 0.70-0.89) were less likely to convert to MCI than persons with low or no education. In subjects with both the ApoE epsilon4 allele and medicated hypertension, the crude OR for conversion was 3.92 (95% CI 1.81-8.49). In subjects with cardiovascular disease, the crude OR for conversion was 2.13 (95% CI 1.26-3.60). Gender, elevated blood pressure, diabetes or cerebrovascular disease had no significant effect on the conversion to MCI. CONCLUSION: Higher age, the presence of at least one ApoE epsilon4 allele and medicated hypertension are independent risk factors, but high education is a protective factor for MCI. The results suggest that vascular factors may have an important role in the pathogenesis of MCI.