Vortioxetine Treatment for Depression in Patients with Prodromal vs Mild Alzheimer's Disease: A Six-Month, Open-Label, Observational Study.

BACKGROUND: Depressive symptoms are common in Alzheimer disease (AD) from the prodromal stage. The benefits of antidepressants have been investigated in patients with AD dementia with mixed results. OBJECTIVES: This study aimed to compare the efficacy of vortioxetine in prodromal and mild-to-moderate AD patients with depression, and to assess the comparative effect on secondary measures, including behavioral disturbances, cognitive function, and activities of daily living. PARTICIPANTS: All subjects with AD at a single-center dementia center underwent a standard evaluation with mini-mental state examination (MMSE), basic and instrumental activities of daily living (BADL and IADL), geriatric depression scale (GDS), neuropsychiatric inventory (NPI), and clinical evaluation every six months. MEASUREMENTS: The study specifically assessed patients on vortioxetine with available six-month follow-up data. The changes in GDS, NPI, MMSE, BADL/IADL at six months in the entire AD population and mild-to-moderate AD vs prodromal population were analyzed using repeated measure multivariate analyses. Linear regression analyses were implemented to evaluate baseline demographics and clinical characteristics associated with depressive and cognitive improvements at six months. RESULTS: Out of 680 AD patients, 115 were treated with vortioxetine, and 89 with six-month follow-up data were included in the analyses. A significant improvement at follow-up was observed for GDS, NPI total and sub score items (mood, anxiety, apathy, sleep disturbances, eating abnormalities). Both mild-to-moderate and prodromal AD showed a positive GDS response, whereas mild-to-moderate AD showed a better improvement on total NPI and apathy/nighttime behaviors subitems compared to prodromal AD. Higher baseline GDS score was the only variable associated with higher responses in linear regression analyses. MMSE showed a significant improvement at six months in the entire cohort, with a greater effect in prodromal vs mild-to-moderate AD. Cognitive improvement (i.e., MMSE changes) was associated with cognitive status at baseline but independent of the antidepressant/behavioral changes (i.e., GDS/NPI). CONCLUSIONS: Our results suggest that vortioxetine is highly tolerable and clinically effective in both prodromal and mild-to-moderate AD with depression. Patients with mild-to-moderate AD benefited more from a wide range of behavioral disturbances. The study also showed significant improvement in global cognitive measures, especially in prodromal AD subjects. Further studies are needed to investigate the independent beneficial effect of vortioxetine on depression and cognition in AD.

Neuropsychiatric symptoms in amnestic and nonamnestic mild cognitive impairment.

BACKGROUND: The information regarding neuropsychiatric symptoms in the subtypes of mild cognitive impairment (MCI) is inadequate. OBJECTIVE: To describe the behavioral neuropsychiatric symptoms of MCI in two subgroups of MCI patients with different neuropsychological characteristics. METHODS: MCI patients are classified as amnestic (aMCI) if they have a prominent memory impairment, either alone or with other cognitive impairments (multiple domains with amnesia), or nonamnestic (naMCI) if a single nonmemory domain is impaired alone or in combination with other nonmemory deficits (multiple domains without amnesia). The Neuropsychiatric Inventory (NPI) was administrated to detect behavioral and psychological disturbances observed by the caregiver. RESULTS: 120 subjects were analyzed: 94 were classified as aMCI and 26 as naMCI. Subjects with aMCI were more compromised than those with naMCI on global cognitive functions. About 85% of MCI patients had some neuropsychiatric symptoms evaluated with the NPI and the most prevalent symptom was depression, followed by anxiety. A significantly higher prevalence of hallucinations and sleep disorders has been observed in the naMCI group in comparison with the aMCI group. CONCLUSION: Neuropsychiatric symptoms occur in the majority of persons with MCI and may be the earliest manifestation of different diseases, each one associated with different clinical profiles at the stage of MCI.

The Italian version of the pain assessment in advanced dementia (PAINAD) scale.

Pain is an unpleasant sensory and emotional experience. It's recognized to be modified by individual memory, expectation, and emotion. The most accurate evidence of pain and its intensity is based on patient's description and self-report. One of the main problems in assessing pain in dementia concerns with the impairment of communication and memory. Unfortunately, the most used tools to evaluate pain have been developed for normal aging people, requiring verbal and cognitive skills. Therefore, proper instruments are urged to be developed, tested, and validated to assess pain in a cognitively impaired population. The purpose of this study was to assess the validity of the PAINAD in the Italian version as a reliable tool for measuring pain in demented people.

Volume reduction in cerebral blood flow in patients with Alzheimer's disease: a sonographic study.

Neuroimaging techniques such as PET and SPECT demonstrated a consistent reduction of cerebral blood flow (CBF) in Alzheimer's disease (AD). The aim of the study was to assess the potential role of ultrasonography for CBF measurement in AD patients and whether the CBF volume correlates positively with disease severity. Fifty patients who met the diagnostic criteria of probable AD (NINDS-ADRDA) were compared to 50 age-matched healthy elderly volunteers. The extracranial internal carotid arteries (ICAs) and the vertebral arteries (VAs) of the patients and controls were examined. Angle-corrected time-averaged flow velocity (TAV) and the diameter of the vessel were measured. Intravascular flow volumes were calculated as the product of TAV and the cross-sectional area of the circular vessel. CBF volume was calculated as the sum of flow volumes in the ICAs and VAs of both sides. All subjects underwent the MMSE. The mean global CBF (474.87 +/- 94.085 vs. 744.26 +/- 94.082 ml/min; p < 0.0001) was lower in AD patients than in healthy volunteers. A significant decline in global flow volumes (r = 0.48; p < 0.0007) with the degree of cognitive impairment was also present. The ability of ultrasonography to characterize flow decreases makes such a technique an attractive tool for the study of AD, for the evaluation of pharmacological therapies and, possibly, for early diagnosis.

Transcranial Doppler and risk of recurrence in patients with stroke and patent foramen ovale.

The importance of patent foramen ovale (PFO) in stroke of unknown cause remains disputed, as PFO may be present in up to 20% of normal people and in a high proportion of patients with non-vascular disorders. Recent evidence suggests that the amount of right-to-left shunt (RLS) may be the crucial factor for stroke occurrence and relapse. The aim of the study was to assess predictors of recurrence in PFO-related stroke patients with particular emphasis on amount of shunting. Patients less than 61 years old who had been admitted for a PFO-related stroke within the previous 5 years, were re-evaluated on a follow-up visit. The clinical syndrome, residual disability, vascular risk factors and number of relapses as the index event were assessed. RLS sizing was semi-quantitatively performed with saline-enhanced transcranial Doppler (TCD), by assuming a cut-off of more or less 10 bubbles recorded in the cerebral vessels as a criterion to discriminate large versus small shunt, respectively. Thereafter patients were prospectively followed-up for a median time of 23 months. Total follow-up was 61 months. Fifty-nine patients (M/F = 23/36, mean age 43 +/- 13) were studied. Overall there were 23 relapses in 13 patients. The amount of shunting was the only significant independent variable associated with relapse: at the end of the follow-up period the recurrence rate was 0.66 and 8.2% per patient per year in patients with small and large shunt, respectively. This difference was statistically significant (chi2 = 10.39, P = 0.0012; OR 17.05, 95% CI 2.10-755.22). In patients with PFO-related stroke, the amount of RLS as assessed with TCD is the only independent predictor of relapse. PFO sizing is mandatory in patients with PFO.

Transient global amnesia: a clinical and sonographic study.

BACKGROUND: The aetiology of transient global amnesia (TGA) is still unknown. The aim of this study was to identify potential risk factors for TGA, vascular risk factors, the role of patent foramen ovale (PFO) and of retrograde jugular venous flow. METHODS: 138 subjects entered the study, including 48 patients with TGA, 42 age-matched patients with transient ischaemic attack (TIA) and 48 controls. PFO was studied by contrast transcranial duplex sonography. Retrograde jugular venous flow was tested with air contrast ultrasound venography (ACUV). RESULTS: TGA patients and controls showed a lower prevalence for vascular risk factors than TIA patients. No statistical difference was found between the 3 groups with regard to PFO. ACUV detected jugular valve incompetence in 72.9% TGA, 35.7% TIA and 39.5% controls (TGA vs. TIA and TGA vs. controls p < 0.01). CONCLUSIONS: TGA patients have fewer vascular risk factors than TIA patients. Paradoxical embolism due to PFO as a cause of TGA is not confirmed in our study. Cerebral venous hypertension due to incompetence of the internal jugular valve may play a role in the pathogenesis of TGA.

Early stages of probable Alzheimer disease are associated with changes in platelet amyloid precursor protein forms.

Previous findings demonstrated an altered pattern of amyloid precursor protein (APP) forms in platelets of Alzheimer disease (AD) patients, compared both with healthy control subjects or patients with non-Alzheimer-type dementia. The present study aims to evaluate whether platelet APP form ratio (APPr) is altered in patients with early stage AD. We selected 40 patients with early stage AD and 40 age-matched healthy controls. Compared with controls (mean+/-SD=0.91+/-0.3), mean APPr was decreased in AD (mean+/-SD=0.46+/-0.26, p<0.0001). Sixteen very mild AD patients (clinical dementia rating=0.5), identified among the AD group, showed a significant decrease of APPr values (mean+/-SD=0.50+/-0.3, p<0.0001). These findings indicate that alteration of APP processing in platelets is an early event and suggest that this assay might be of diagnostic value in differentiating mild AD from normal ageing.

Amyloid precursor protein in platelets of patients with Alzheimer disease: effect of acetylcholinesterase inhibitor treatment.

BACKGROUND: Amyloid precursor protein (APP) forms with apparent molecular weights of 130, 110, and 106 kd are present in human platelets. It has been demonstrated that Alzheimer disease (AD) is specifically associated with a decreased APP forms ratio in platelets. OBJECTIVE: To investigate whether acetylcholinesterase (AChE) inhibitor treatment modifies the ratio of platelet APP forms in patients with AD. PATIENTS AND METHODS: From a large sample of patients with probable AD, 30 with mild to moderate AD were selected. Each patient underwent a clinical evaluation including the Mini-Mental State Examination (MMSE) and platelet APP forms analysis at baseline and after 30 days. During this interval, 20 of 30 patients with AD were treated with donepezil hydrochloride (5 mg/d), a piperidine phosphate-based cholinesterase inhibitor. Platelets were subjected to Western blot analysis using monoclonal antibody (22C11). The ratio between the immunoreactivity of the higher-molecular-weight APP form (130 kd) and the lower forms (106 and 110 kd) was measured. RESULTS: All patients taking donepezil completed the 30 days of treatment without adverse effects. The platelet APP forms ratio at baseline did not differ between the 2 AD groups (mean +/- SD optical density ratio: untreated AD, 0.47 +/- 0.12; treated AD, 0.38 +/- 0.18), whereas a significant difference was found at follow-up (mean +/- SD optical density ratio: untreated AD, 0.45 +/- 0.17; treated AD, 0.77 +/- 0.29; P<.001). A significant improvement in MMSE scores in treated AD patients was observed from baseline (16.9 +/- 3.8) to 30 days (18.9 +/- 4.42) (P<.009, 30 days vs baseline), but no significant correlation was found in treated AD patients between MMSE score improvement and APP forms/ratio increase (P =.09). CONCLUSIONS: Administration of AChE inhibitors increases the ratio of APP forms in platelets of patients with AD, suggesting a potential effect of AChE inhibitors on APP trafficking or processing in a peripheral cell.

Amyloid precursor protein in platelets: a peripheral marker for the diagnosis of sporadic AD.

BACKGROUND: An altered pattern of amyloid precursor protein (APP) forms consisting in a reduced ratio between the upper (130 kDa) and the lower (106 to 110 kDa) immunoreactivity bands has been described in platelets of patients with AD. OBJECTIVE: To evaluate the sensitivity and the specificity of platelet APP forms' ratio (APPr) as a marker for AD. METHODS: Eighty-five patients with probable AD and 95 control subjects (CON), including healthy individuals and neurologic patients, entered the study. Platelet APPr was evaluated by means of Western Blot analysis and immunostaining in the whole platelet homogenate, and calculated by the ratio between the optical density (OD) of the upper (130 kDa) and the lower (106 to 110 kDa) APP immunoreactive bands. RESULTS: Mean APPr levels were decreased in AD patients (mean OD +/- SD = 0.35 +/- 0.18) compared with the CON group (mean OD +/- SD = 0.92 +/- 0.38) (DF 1, 178, p < 0.0001). Accuracy levels measured by Receiver Operating Curve analysis showed that a cut-off level of 0.57 resulted in a sensitivity of 88.2% and a specificity of 89.4%, with an area under the curve of 0.945. APPr levels were significantly associated with disease severity (mild AD versus moderate AD: p < 0.0001; moderate AD versus severe AD: p < 0.05). CONCLUSION: Platelet APPr allowed to differentiate AD from normal aging and other dementing disorders with high sensitivity and specificity. These findings suggest that platelet APPr may be of help as an adjunctive diagnostic tool in clinical practice.

Potential source of cerebral embolism in migraine with aura: a transcranial Doppler study.

BACKGROUND: The recently found association between patent foramen ovale (PFO) and transient global amnesia (TGA) has suggested that paradoxical microembolization in the terminal vertebrobasilar territory might underlie at least some TGA cases. Migraine with visual aura is another paroxysmal disturbance in which a sudden dysfunction of cortical areas fed by the terminal branches of the basilar artery is believed to trigger the attack. Therefore we investigated the prevalence of PFO in a consecutive unselected cohort of migraine patients. OBJECTIVE: To investigate the prevalence of PFO in a consecutive unselected cohort of migraine patients to search for a possible mechanism for the reported association of migraine with stroke. METHODS AND RESULTS: A total of 113 patients, consecutively referred by the Headache Outpatient Clinic for migraine with aura (MA+, mean age 34+/-12 years) were compared with 53 patients with migraine without aura (MA-, mean age 36+/-13 years) and with 25 age-matched nonmigraine subjects (mean age 31+/-10 years) selected from the hospital staff. PFO was assessed with transcranial Doppler sonography with IV injection of agitated saline, a technique that is 90% sensitive and 100% specific. The prevalence of PFO was 48% (54/113) in MA+ patients, 23% (12/53) in MA- patients, and 20% (5/25) in control subjects. The difference between MA+ and MA- patients was significant (odds ratio [OR] = 3.13, 95% confidence interval [CI] = 1.41 to 7.04, chi2 = 9.52,p = 0.002) as was the difference between MA+ patients and controls (OR = 3.66, 95% CI = 1.21 to 13.25, chi2 = 6.46, p = 0.01), whereas MA- patients did not differ from controls (OR = 1.17, 95% CI = 0.32 to 4.45, chi2 = 0.07). MRI was negative in 22 MA+ and 8 MA- patients. CONCLUSIONS: Patency of the foramen ovale is associated with migraine with aura but not with migraine without aura. The increased risk of stroke found in epidemiologic studies in patients with migraine with aura may be explained by an increased propensity to paradoxical cerebral embolism.

Behavioral syndromes in Alzheimer's disease: description and correlates.

INTRODUCTION: Behavioral disturbances in patients with Alzheimer's disease (AD) are ill-defined conditions. We hypothesize that the many behavioral disturbances hitherto described and studied might be grouped into few syndromes with separate determinants and correlates. PATIENTS AND METHODS: 162 consecutive patients with probable AD admitted to a dementia unit were assessed by the UCLA Neuropsychiatric Inventory (NPI). RESULTS: Factor analysis was carried out on NPI subscales, leading to three syndromes: 'mood', 'psychotic' and 'frontal'. Patients with the 'psychotic' syndrome were older, had older age at dementia onset, had poorer cognition, were more often males, and had faster rate of dementia progression. Patients with the 'frontal' syndrome had higher education, longer disease duration, and slower rate of progression. DISCUSSION: Some combinations of behavioral disturbances occur more frequently together and might represent separate behavioral syndromes. Different clinical correlates of the syndromes suggest separate etiologies.

Behavioral disorders in Alzheimer disease: a transcultural perspective.

OBJECTIVES: To compare 2 samples of patients with Alzheimer disease (AD), from Italy and the United States, in order to determine transcultural differences in the manifestation of noncognitive symptoms. To analyze the concurrent validity, internal consistency reliability, between-rater reliability, and test-retest reliability of the Neuropsychiatric Inventory Scale (NPI). METHODS: The NPI was given to 50 Italian and 50 US patients with AD. To demonstrate the validity and reliability of the Italian version of the instrument, several different methods of analysis were used. The total score on the NPI and the score of single items in the different stages of the disease were compared in the 2 samples of patients. RESULTS: A high level of internal consistency reliability was confirmed, the between-rater reliability was very high, and the test-retest reliability was significantly correlated. Apathy was the most frequently recorded behavior in the Italian sample. Five of 10 NPI item scores showed a significant relation with the Mini-Mental State Examination scores in both samples. The Italian patients showed an increasing and significantly higher mean NPI total score at all levels of dementia severity when compared with the US patients. The scores on some NPI subscales, such as apathy, aberrant motor behavior, disinhibition, and agitation, were significant higher in Italian patients at different levels of severity covarying with educational level. CONCLUSIONS: These results indicate that NPI is a reliable instrument with which to study transcultural differences in the presentation of neuropsychiatric disturbances in patients with AD. The described similar pattern of behaviors between Italians and US patients with AD suggests a biological origin of the disorders. However, cultural influences must be taken in account when the focus of the study is on psychopathological aspects of dementia.

Object and action naming in Alzheimer's disease and frontotemporal dementia [see comment].

To assess noun and verb processing in different dementia types, we tested object and action naming in three groups of subjects: probable Alzheimer's disease (AD) with mild to moderate dementia; age- and education-matched normal subjects; and a group of frontotemporal dementia (FTD) patients. AD and FTD patients were impaired in naming compared with control subjects; action naming was more severely impaired. However, the discrepancy between object and action naming was significantly greater in FTD than in AD patients, independent of the severity of dementia or of overall language impairment. The latter finding is compatible with the hypothesis that the frontal lobe plays a crucial role in action naming. A relatively selective impairment in action naming might be a characteristic neuropsychological feature of FTD.

Validity of direct assessment of functional status as a tool for measuring Alzheimer's disease severity.

OBJECTIVE: to assess the validity of the Direct Assessment of Functional Status (DAFS) performance-based functional scale for the staging of dementia severity by comparing it with established clinical, functional and cognitive scales. PATIENTS AND METHODS: 93 consecutive Alzheimer's disease patients underwent DAFS. Socio-demographic variables, cognitive status (Mini-Mental State Examination; MMSE), global disease severity (Clinical Dementia Rating; CDR), disease duration, physical performance (Physical Performance Test, PPT) and functional status (as reported by the primary caregiver) were also recorded and basic (B) and instrumental (I) activities of daily living (ADL) assessed. RESULTS: a significant correlation was found between DAFS and MMSE (Pearson's r = 0.60; P < 0.01), PPT (r = 0.54; P < 0.01) and CDR (Spearman correlation coefficient: -0.48; P < 0.01). A mild, significant correlation was found between DAFS score and daily function as reported by the primary caregiver (r = -0.30 for BADL and r = - 0.27 for IADL). On multiple regression analysis, only MMSE and PPT were independently associated with the DAFS score, explaining 56% of DAFS total variance. ADL scales did not independently contribute to DAFS variance. A multivariate regression model of the association of DAFS with CDR showed that the association was significant even after adjustment for MMSE and PET, suggesting that DAFS scores provide additional information on dementia severity. CONCLUSION: DAFS is a valid tool for the assessment of dementia severity, capturing cognitive and physical aspects of disability.

Procedural memory stimulation in Alzheimer's disease: impact of a training programme.

The study evaluates the efficacy of a procedural memory stimulation programme in mild and mild-moderate Alzheimer's disease (AD). Twenty basic and instrumental activities of daily living have been selected, and divided into two groups, comparable for difficulty. Ten normal elderly subjects (age 68.0 +/- 4.8 years; MMSE score: 28.7 +/- 0.9; education: 7.6 +/- 3.5 years) were asked to perform the two groups of daily activities and the time required to perform the tasks of each group was recorded and used as a reference. Ten mild and mild-moderate AD patients (age 77.2 +/- 5.3 years; MMSE score: 19.8 +/- 3.5; education: 7.3 +/- 4.7 years) without major behavioural disturbances constituted the experimental group. Patients were evaluated in all 20 daily activities and the time employed was recorded at baseline and after a 3-week training (1 h/d, 5 d/week) period. Five patients were trained during the 3 weeks on half of the 20 daily activities and the other five patients were trained on the remainder. This procedure was adopted in order to detect separately the improvement in "trained" and "not trained" activities, allowing to control better the effects of the intervention. The assessment of the functional impact of the training was directly measured, through the variation of time employed to perform tasks before and after training. After 3 weeks of training a significant improvement was observed for the trained activities, from 3.6 to 1.9 standard deviations below the performance of the normal elderly controls (P < 0.05). AD patients improved also in not-trained activities from 3.5 to 2.7 standard deviations below the controls' performance (P < 0.05). The rehabilitation of activities of daily living through developing procedural memory strategies may be effective in mild and mild-moderate AD patients.