Cause of death in demented and non-demented elderly inpatients; an autopsy study of 308 cases

Few studies evaluated cause of death (COD) in elderly demented and non-demented people, the majority based on death certificates alone. The present study is based on autopsy reports with neuropathological examination of 308 inpatients (58.1% female) over age 60 years (mean: 83.5, SD: +/-8.6). CODs were classified into seven groups. The most common were bronchopneumonia (n=117; 38%) and cardiovascular disease (n=116, 37.7%). In 176 patients (57.1%) neuropathology was indicative for dementia: 76.7% Alzheimer disease (AD), 4.5% vascular dementia, 4.0% mixed type dementia (AD + vascular dementia), and 14.8% other dementias. Main COD significantly differed in demented and non-demented patients: bronchopneumonia (45.5% in demented versus 28.0% in non-demented), cardiovascular disease (46.2% in non-demented versus 31.3% in demented). Whereas there were significant differences in COD between AD patients and non-demented ones (bronchopneumonia versus cardiovascular disease), no differences were seen between the latter and patients with other types of dementia than AD. Our data emphasize the high incidence of bronchopneumonia as a COD in patients suffering from AD.     

Insulin,glucose and glycated hemoglobin in Alzheimer’s and vascular dementia with and without superimposed Type II diabetes mellitus condition

Summary. Increased concentrations of insulin, glucose and glycohemoglobin are associated with Type II diabetes mellitus (DM) and recognized as characteristic markers of the disease; in Alzheimer’s (AD), Vascular dementia (VaD), and both dementia’s with superimposed diabetes (AD + DM, VaD + DM) the knowledge is scarce. The sample (n = 122; males = 60; mean age = 73 ± 7) comprised DM, AD, VaD, AD + DM, and VaD + DM patients, and healthy controls (C). The ANOVA’s yielded significant differences between groups: Insulin p = 3.7 × 10⁻³; Glucose p < 10⁻¹²; Glycohemoglobin p = 9.2×10⁻⁴. Comparisons between groups (DM vs. C, AD + DM vs. AD, VaD + DM vs. VaD, and demented DM vs. non-demented DM) resulted significant for all variables (Bonferroni’s statistic, α = 0.05). Diabetic and diabetic demented patients presented significant increases largely different from controls (0.01 < p < 0.001), unlike the non-significant changes in their non-diabetic counterparts; linear relationships were found across all groups. The correlation’s insulin/glucose and insulin/glycohemoglobin change to positive within demented groups, indicating a different performance of insulin in demented and non-demented subjects. Integrated by the following medical degrees (MD) and psychologists (Ps) from the Neurology Service and the Diabetes Unit of the Hospital General de Agudos Juan A. Fernández, Hospital Sirio-Libanés and the FACENE: Eduardo L. Bartolomé MD, Silvia González MD, Graciela D’Abraccio MD, Marcela Arata Ps, Liliana Oudkerk Ps, Laura Garau MD, Fernando Krinsky MD, Edith Labos Ps, Cecilia Ruiz Ps, Gustavo Frechtel MD, Alejandra Arana MD, and Silvia Lovecchio MD. Correspondence: Jorge A. Serra, Laboratorio de Estrés Oxidativo, PRALIB-CONICET, Facultad de Farmacia y Bioquímica, UBA; Junín 954; C1113AAD Buenos Aires, Argentina     

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).     

Cognitive Functioning in Alzheimer's Disease and Vascular Dementia: Further Evidence for Similar Patterns of Deficits

The purpose of the present study was to examine possible differences in patterns of cognitive performance between population-based samples of Alzheimer's disease (AD; n = 51) and vascular dementia (VaD; n = 14) patients between 75 and 96 years of age. The two demented groups were comparable in age, years of education, gender distribution, and severity of dementia. The selection of cognitive tasks (letter and category fluency, Block design, Clock reading and setting, and episodic face recognition) was thought to address some of the inconsistencies in previous research. The main finding was that AD and VaD patients were comparable on most tasks, although robust dementia-related deficiencies were found when comparing the results of the demented participants with those of the control participants. These findings suggest that AD and VaD may affect several basic cognitive functions in an equal manner.     

Neuropathological evaluation of mixed dementia

Mixed dementia (MD) refers to a combination of definite Alzheimer disease (AD) and vascular encephalopathy, but the distinction between both disorders is controversial. For the diagnosis of MD the clinical/neuroimaging criteria of possible AD plus cerebrovascular disease (CVD) as separate entities are used, but causal relations between vascular brain lesions and dementia are unclear. We proposed the combination of autopsy-proven AD with multiple vascular or ischemic lesions with about 30-50 ml of infarcted/damaged brain tissue. The population-based prevalence of MD is unknown. In retrospective and prospective autopsy studies, it ranges from 2 to 58% with reasonable means of 6-12%. In a consecutive autopsy series of 1500 demented elderly subjects, 830 of which with clinically probable AD, in Vienna, Austria, 41.5 to 52.0% showed "pure" AD, 7% atypical AD, 16-20% AD plus cerebrovascular lesions, and 9% AD plus Lewy body pathology; MD was diagnosed in 4.6 and 2.4%, and "pure" vascular dementia (VaD) in 11 and 2.0%, respectively, while 16.3/6.1% were other dementing disorders, and 1% showed no specific pathology. Like the MRC-CFAS and other studies, this indicates frequent coexistence of AD with multiple cerebrovascular lesions in cognitively impaired patients. In both AD and VaD, vascular lesions frequently involved subcortical regions (basal ganglia, thalamus, hippocampus, and white matter) or were multiple microinfarcts, whereas in MD, large/hemispheral infarcts and multiple microinfarcts were more frequent, suggesting different pathogenic mechanisms. In early/mild AD, critically located small vascular lesions may induce/promote cognitive decline, but in full-blown AD they appear of minor importance. Discussion of the major pathogenic factors inducing AD, VaD and MD suggests synergistic relations between these disorders. However, currently available morphological criteria for AD and VaD are of limited value for the diagnosis of MD and generally accepted and validated histopathological criteria for the diagnosis of VaD and MD are currently not available. Therefore, more distinct and critically evaluated clinico-pathological criteria are warranted.     

The Pocket Smell Test: successfully discriminating probable Alzheimer's dementia from vascular dementia and major depression

The present study extended previous work on olfactory dysfunction (odor identification deficits) by using the Pocket Smell Test (PST) to discriminate between groups of patients with Alzheimer's disease (AD), vascular dementia (VaD), and major depression (MD). Sixty patients meeting the DSM-IV criteria for either AD, VaD, or MD (20 per group) underwent assessment with the PST, a three-item screening measure of odor identification, and the Mini-Mental State Examination (MMSE). Patients with AD scored significantly lower than patients with either VaD or MD on the PST, even after controlling for MMSE scores. A PST score of > or =1 (i.e., 1 or 0 correct) discriminated between patients with and without AD with a classification accuracy of 95% (sensitivity 100%, specificity 92.5%). Olfactory assessment may be of diagnostic utility in the differential diagnosis of AD versus VaD versus MD in elderly patients.     

Diagnosis and treatment of mixed dementia

Vascular dementia (VaD)--secondary to cerebrovascular disease (CVD)--has been traditionally distinguished from Alzheimer's disease (AD), which is a purely neurodegenerative form of dementia. However, CVDs such as lacunes and white matter lesions are common in patients with AD, whereas certain pathological changes of AD, including senile plaques and tangles, are observed in elderly patients with VaD. These findings indicate that mixed vascular-degenerative dementia (MD) is the most common cause of dementia in the elderly. In the treatment and prevention of dementia, the accurate diagnosis of each individual type of dementia is vital. However, recognizing the distinction between these diseases can be difficult in clinical practice. This article provides an overview of MD, including the incidence, diagnosis, and treatment. In particular, we emphasize that functional brain imaging, including perfusion single photon emission computed tomography and benzodiazepine receptor binding measurement, in combination with morphological imaging (such as magnetic resonance imaging) is useful for distinguishing AD, VaD and MD. In addition to antiplatelet medications, cholinesterase inhibitors and N-methyl-D-aspartic acid antagonists may be effective in treating MD. Moreover the vascular risk factors also should be treated appropriately. The article describes the need for further studies to develop a better understanding of MD.     

Elevated levels of fragmented DNA nucleosomes in native and activated lymphocytes indicate an enhanced sensitivity to apoptosis in sporadic Alzheimer's disease. Specific differences to vascular dementia

Apoptotic cell death is thought to be the most likely mechanism of cell death contributing to neurodegeneration in Alzheimer's disease (AD). Here, we provide evidence that in sporadic AD cases the vulnerability of peripheral cells to undergo apoptosis is increased compared to non-demented elderly controls and, very importantly, to patients with subcortical vascular encephalopathy (SVE) as another, but demented control group. Quiescent 'native' and 'activated' lymphocytes from AD patients that were predisposed to commit apoptotic cell death by priming the cells with interleukin-2, are shown to accumulate apoptosing cells to a significantly higher extent in spontaneous and in oxidative stress-induced in vitro apoptosis. Our results demonstrate robust differences in cell death sensitivity between AD and vascular dementia. In none of the conditions investigated, lymphocytes from SVE patients were significantly different from non-demented controls. The comparable findings of a higher extent of apoptotic features in neurons and in peripheral blood cells of AD patients are remarkable and may suggest a rather general modulation of apoptotic mechanisms by the disease, which even can be picked up at the level of peripheral lymphocytes under specific in vitro conditions.     

Blood-brain barrier in Alzheimer dementia and in non-demented elderly

Summary Peroxidase-antiperoxidase staining of formalin-fixed brain was employed to compare the blood-brain barrier (BBB) function in five patients with Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) and three patients with AD/SDAT combined with multi-infarct dementia (MID/SDAT) with that of six non-demented aged controls. The diffusion of serum proteins through the BBB was visualized with antisera to albumin, prealbumin, immunoglobulin, C1q, C3c and to fibrinogen. A similar patterns of diffusion was seen in AD/SDAT and non-demented aged individuals. Neuron and glial cells were stained with different antisera in the vicinity of the diffusion. Senile (neuritic) plaques were occasionally visualized with antisera to IgG, C1q and C3c but not with antisera to albumin, prealbumin and fibrinogen in both demented and non-demented aged individuals. Neurofibrillary tangles were not labelled with any of the antisera studied. These results indicate that the BBB is compromised equally in AD/SDAT and in the non-demented elderly.Supported by grants from the Swedish Medical Research Council, King Gustaf V. and Queen Victoria's Foundation, Osterman's, Pfannestill's, Mångberg's and Thuring's foundations and NIH grants NS 18105 and NS 17487     

Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds

Deposition of beta-amyloid (Abeta) is an early pathogenic event in Alzheimer's disease (AD). We measured Abeta42 and Abeta40 in cerebrospinal fluid (CSF) in a population-based sample of 85-year-olds, 27 demented and 35 non-demented. During the following 3 years, 7 of the 35 non-demented individuals had developed dementia, while 28 remained non-demented. Reduced CSF levels of both Abeta42 (p = 0.001) and Abeta40 (p = 0.0001) were found in patients with manifest AD and vascular dementia at the age of 85. Non-demented individuals who developed dementia during follow-up had lower levels of CSF- Abeta42 (p = 0.003), but not CSF-Abeta40 (p = 0.96), than those who remained non-demented. The odds ratio for development of dementia was 8.2 (p = 0.027) for individuals in the lower 50th percentile of CSF-Abeta42, while none of those in the highest 33rd percentile of CSF-Abeta42 developed dementia during follow-up. There were no significant differences between carriers and non-carriers of the apolipoprotein E epsilon4 allele regarding CSF-Abeta42 or CSF-Abeta40. Our study suggests that low CSF-Abeta42 is found also in an unselected population-based sample of old demented patients and provides the first evidence of a disturbance in the metabolism of Abeta, specifically involving Abeta42, before the onset of clinical symptoms in AD.     

Elevated plasma homocysteine concentration in elderly patients with mental illness is mainly related to the presence of vascular disease and not the diagnosis

BACKGROUND: Plasma total homocysteine (tHcy) is often elevated in patients with mental illness. Since patients with mental illness and vascular disease exhibit a higher plasma tHcy concentration than patients without vascular disease, it is possible that elevated plasma tHcy in mental illness is mainly due to concomitant vascular disease. METHODS: We have investigated plasma tHcy, cobalamin/folate status, renal function and the presence of vascular disease in patients with vascular dementia (VaD, n = 501), Alzheimer's disease (AD, n = 300), depression (n = 259) and in healthy subjects (n = 144) stratified according to age (below and above 75 years). RESULTS: Plasma tHcy concentration showed the highest increase in patients with VaD compared to patients with AD or depression. After the exclusion of patients with cobalamin/folate deficiencies and increased serum creatinine, patients with AD or depression above 75 years with vascular disease showed a similar elevation of plasma tHcy concentration as patients with VaD. Furthermore, patients with AD and depression without vascular disease showed a similar plasma tHcy concentration to healthy subjects. CONCLUSION: The findings imply that elevated plasma tHcy concentration in elderly patients with mental illness is mainly associated with the presence of vascular disease and is not related to the specific psychogeriatric diagnosis.     

Length of stay in skilled nursing facilities is longer for patients with dementia

Studies estimate prolonged stays in acute and sub-acute facilities for patients with dementia. Actuarial projections suggest prolonged stays in long term care facilities for patients with dementia. To test these predictions, we assessed whether patients with dementia stay in skilled nursing facilities (SNF) longer than patients without dementia. We obtained medical records of 5,373 residents discharged from a SNF between 1996 and 2001. Residents were identified as having dementia by ICD-9 codes. Age, sex and length of stay (LOS), measured in days from admission to discharge or death, were gathered. Mean LOS for patients with dementia (92.7 +/- 313.0, n = 758) was significantly longer than non-demented patients (29.7 +/- 136.8, n = 4615, p < 0.001). In a subset of individuals who stayed until death, the mean LOS for patients with dementia (202.9 +/- 528.6, n = 195) also was significantly longer than for non-demented patients (91.8 +/- 300.5, n = 610, p < 0.001). LOS was increased for demented patients even within age groups. Thus, patients with dementia stay in SNFs significantly longer from entry until discharge or death. It is likely that demented patients enter for non-physical, cognitive related reasons. These results may help families and institutions plan for long-term care.     

Apolipoprotein E genotypes in hospitalized elderly patients with vascular dementia

BACKGROUND: Polymorphism in the apolipoprotein E (APOE) gene is the major genetic risk factor associated with late-onset Alzheimer's Disease (AD). However, it is still unclear if a relationship exists between the APOE epsilon4 allele and vascular dementia (VaD) in elderly subjects. OBJECTIVES: To evaluate the prevalence of APOE alleles in elderly patients with VaD compared to AD patients and to control subjects with no cognitive impairment (NoCI). PATIENTS AND METHODS: We evaluated 396 consecutive patients aged > or =65 years with definite or suspected cognitive impairment with a clinical (Mini-Mental State Examination, Clinical Dementia Rating, Geriatric Depression Scale), functional (Activities of Daily Living, Instrumental Activities of Daily Living), comorbidity (Cumulative Illness Rating Scale) and instrumental (CT scan, NMR) assessment. Diagnosis of dementia was made according to NINCDS-ADRDA and NINDS-AIREN Work Group and the DSM-IV. APOE genotypes were analyzed by a recently described method resulting in positive/negative chain reaction products for each APOE genotype. Statistical analysis was carried out using the Pearson chi(2), the Kruskal-Wallis test and the ANOVA post hoc comparisons. RESULTS: A total of 287 elderly patients (males = 138, females = 149, mean age = 77.8 +/- 6.9 years, range = 65-98) with diagnoses of VaD (n = 97), AD (n = 82) or NoCI (n = 108) were included in the study. A significantly higher APOE epsilon4 allele frequency was observed in AD patients compared to VaD and/or NoCI subjects, while no differences were found between VaD patients and subjects with NoCI (AD = 24.3%, VaD = 10.3, NoCI = 8.7, p < 0.05). Furthermore, a significantly lower APOE epsilon3 allele frequency was observed in AD patients compared to VaD and/or NoCI subjects but not between VaD and NoCI patients (AD = 71.3%, VaD = 80.9, NoCI = 83.4, p < 0.05). No significant differences were observed in the APOE epsilon2 allele (VaD = 8.8%, AD = 4.4, NoCI = 7.9, p = n.s.) among the 3 groups. CONCLUSIONS: In this population, the frequency of the APOE epsilon4 allele is lower in VaD than in AD.     

SPECT findings in Alzheimer's disease and Parkinson's disease with dementia

We examined, with single photon emission tomography (SPECT) and (^99mTc)-HMPAO, 18 patients with idiopathic Parkinson's disease and no dementia (PD), 12 patients with PD and dementia, 24 patients with probable Alzheimer's disease (AD) and 14 controls. While the three patient groups showed significantly lower perfusion in frontal inferior and temporal inferior areas as compared to controls, both demented groups showed significantly more severe bilateral hypoperfusion in superior frontal, superior temporal and parietal areas as compared to non-demented PD patients and controls. On the other hand, no significant differences in cerebral perfusion were found between patients with AD and patients with PD and dementia. In conclusion, our findings demonstrated specific but similar cerebral perfusion deficits in demented patients with either AD or PD.     

Extrapyramidal features in advanced Down''s syndrome: clinical evaluation and family history.

Extrapyramidal, frontal release, and other neurological signs were studied in 54 demented and non-demented patients with Down's syndrome (DS). Fourteen patients were demented and five showed extrapyramidal signs, mainly of the rigid-hypokinetic spectrum and similar to Parkinsonian features in advanced Alzheimer's disease (AD). None of the non-demented patients had Parkinsonian signs. The mean age of the demented DS patients with extrapyramidal signs was significantly higher than that of the patients without. Frontal release signs were present in demented and non-demented patients. A questionnaire showed no increase in either the proportion of early- or senile-onset dementia or Parkinsonism among first- and second-degree relatives of DS patients. Parkinsonian signs appear to be present at a lower frequency in DS than in advanced AD. A speculative hypothesis about a gene dosage effect of Cu/Zn-superoxide dismutase in preventing toxic radical formation in the substantia nigra of DS patients is presented.     

Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow change on SPECT in young onset patients with Alzheimer's disease, frontotemporal dementia and vascular dementia

OBJECTIVES: Alzheimer's disease (AD), frontotemporal dementia (FTD) and vascular dementia (VaD) are the three most common causes of young onset dementias. Most neuroimaging studies of these disorders have involved comparisons with normal controls. The aims of this study were to examine the clinical diagnostic value of magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT) (in combination and in isolation) in the differentiation of one form of dementia from another from amongst a group of AD, FTD and VaD. METHODS: T1 weighted MRI images and 99mTc-HMPAO SPECT images were obtained from consecutive patients with FTD (n=21), AD (n=23) and VaD (n=20) and rated visually by experienced neuroradiologists and nuclear medicine physicians. RESULTS: Asymmetrical atrophy was seen only in FTD. Frontotemporal dementia patients were the most atrophic whereas severe atrophy was rarely observed in VaD. Severe frontal atrophy (unilaterally or bilaterally) and/or asymmetrical atrophy on MRI is highly diagnostic (sensitivity 0.71, specificity 0.93, LR 10.24) of FTD from within a group of FTD and non-FTD (AD, VaD) patients. Mild or severe parietal atrophy with severe reduction in parietal regional cerebral blood flow on SPECT is diagnostic (sensitivity 0.71, specificity 0.76, LR 3.02) of AD from within a group of AD and non-AD (VaD, FTD) patients. CONCLUSION: Anatomical (MRI) and functional (SPECT) imaging provide different information and a combination of these modalities improves diagnostic specificity.     

Lifetime symptoms of depression in Alzheimer's disease.

INTRODUCTION: Depression is common in Alzheimer's disease (AD). The symptomatology of depression in dementia may differ from depression alone. Consequently, the reports on lifetime depressive symptoms were compared in AD patients and age-matched non-demented participants. METHODS: Seventy-six AD patients, 109 elderly from the general population and their 189 siblings were examined using the Composite International Diagnostic Interview (CIDI). The presence of individual lifetime depressive symptoms was compared between 76 AD patients, 29 AD patients with comorbid depression, and different control groups using chi(2) statistics and logistic regression analysis. RESULTS: Lifetime depressive symptoms were significantly more frequent in 76 AD patients than in 109 age-matched elderly from the general population. These 76 AD patients complained more about thinking and concentration disturbances, and less about depressed mood or appetite disturbance than the 298 non-demented participants matched for the lifetime presence of major depression (MD). In agreement, the 29 patients comorbid for lifetime diagnoses of AD and MD reported less about depressed mood than the 114 age-matched elderly with MD only. Feelings of worthlessness and suicidal ideas were related to the severity of cognitive decline. CONCLUSION: AD influences the reports on lifetime depressive symptoms. This may be caused by additional neurodegeneration, by an overlap of symptoms of depression and dementia or by an altered perception of mood disturbances in AD. Further studies should investigate these alternatives.     

The tropicamide eye drop test in Parkinson's disease

The dementia of Parkinson's disease (PD) and Alzheimer's disease (AD) share neurochemical and neuroanatomical characteristics. Pupillary supersensitivity to dilute pilocarpine and to the cholinergic antagonist tropicamide were described in AD, although the specificity has been debated. In the present work we examine whether a similar supersensitivity of the pupil exists in PD patients with and without dementia.

PD patients (n = 36,13 demented) and 14 neurologically healthy age-matched controls were examined. The pupil size was determined at baseline and 30 min after the instillation of 0.01% tropicamide, and measured using the Goldmann perimeter. All 13 demented PD patients, but only eight of the 23 non-demented patients (35%), had a mydriatic response to dilute tropicamide. Among controls, only 2/14 (14%) had mydriaris (p < 0.001). This supersensitivity of the pupil of demented PD patients to a cholinergic antagonist may reflect either a reduced parasympathetic tone or an artifact of increased corneal permeability and decreased lacrimation and blinking. We conclude that the tropicamide eye drop test is not useful as a diagnostic tool for dementia in PD.     

Cerebrospinal fluid phospho-tau,total tau and beta-amyloid(1-42) in the differentiation between Alzheimer's disease and vascular dementia

The two most frequently examined biomarkers in the diagnosis of dementia are cerebrospinal fluid (CSF) tau and beta-amyloid(1-42) (Abeta(1-42)). An assay for tau phosphorylated at threonine 181 (phospho-tau) has recently been developed. We studied these three markers in patients with possible Alzheimer's disease (AD; n = 23), probable AD (n = 50), AD with relevant cerebrovascular disease (AD with CVD; n = 14), possible vascular dementia (VaD; n = 39), probable VaD (n = 36), cognitively impaired (n = 13) and 27 neurologically healthy controls. Compared with the controls, tau levels were significantly increased in possible AD, probable AD, AD with CVD and probable VaD. Abeta(1-42) was decreased in all dementia groups compared with the controls. In contrast, phospho-tau levels were increased only in probable AD compared with the controls. From the results of the present study, it is concluded that neither measurement of phospho-tau, tau nor Abeta(1-42) in CSF can discriminate entirely between dementia and cognitively non-disturbed controls or between dementia of different aetiologies in the clinical diagnostic procedure.     

Neuropsychiatric symptoms and functional status in Alzheimer's disease and vascular dementia patients

Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimer's Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.