Apathy: a complex symptom specific to the clinical pattern of presentation of Parkinson's disease?

There is currently no consensus on the nosological position of apathy in clinical practice, although many different articles indicate that apathy is a common, behavioral disturbance in the general Parkinson's disease (PD) population, often related to severe motor symptoms, hypothesizing that the dysfunction of the nigrostriatal pathway may play an important role in its pathophysiology. However, not all patients with PD become apathetic, indicating that apathy should not entirely be considered a dopamine-dependent syndrome in PD. The aim of this study was to examine the prevalence and clinical correlates of apathy in a representative community-based sample of patients within 2 variants of the PD: akinetic-rigid type and tremor-dominant type. Specifically, we wanted to investigate whether these 2 variants of PD would present with apathy as a primary behavioral disorder and whether apathy could be associated with different cognitive and behavioral disorders. Apathy is present in both the groups but significantly more evident in the akinetic-rigid group associated with frontal impairment but not related to motor impairment or depression. We discuss the results, starting with anatomical and physiological brain studies.

The on-freezing phenomenon: cognitive and behavioral aspects.

Freezing of gait is a warning sign of Parkinson's disease. One could distinguish off-freezing, which is associated with dopaminergic therapy and to its titration, and it is clinically related to wearing-off phenomenon. Differently, the on-freezing phenomenon seems to be related to a neural disruption of the frontal-parietal-basal ganglia-pontine projections; clinically, it does not respond to therapy modifications or to different drug titration. In a group of patients with on-freezing, we have detected an alteration of focusing attention, an impairment of set-shifting, in addition to poor abstract reasoning and a reduction of planning. These aspects have been even more evident, when compared with the results obtained by a group of PD patients, without freezing.

Depression in vascular pathologies: the neurologist's point of view.

The coexistence of depression and cardiovascular disease (CVD) is regularly discussed, and much debated. There is strong evidence that there are pathophysiological mechanisms, particularly endothelial dysfunction, altered platelet aggregation, and hyperactivation of the thrombosis cascade, which coexist with hypothalamic-pituitary-adrenocortical axis dysfunction, and link depression to CVD. Therefore, depression should not be automatically considered to be a consequence of life impairment due to myocardial infarction or major stroke. Probably, it should be considered as one of the many other stressful events, or "genetic reactions to life", which are risk factors for CVD development. This review will examine the significance of depression in clinical daily practice, its pathophysiology as a determinant in vascular events, and its real importance in, before, and after many CVD events.

Gait and equilibrium in subcortical vascular dementia.

Subcortical vascular dementia is a clinical entity, widespread, even challenging to diagnose and correctly treat. Patients with this diagnosis are old, frail, often with concomitant pathologies, and therefore, with many drugs in therapy. We tried to diagnose and follow up for three years more than 600 patients. Study subjects were men and women, not bedridden, aged 68-94 years, outpatients, recruited from June, 1st 2007 to June, 1st 2010. We examined them clinically, neurologically, with specific consideration on drug therapies. Our aim has been to define gait and imbalance problem, if eventually coexistent with the pathology of white matter and/or with the worsening of the deterioration. Drug intake interference has been detected and considered.

Risk factors for vascular dementia: hypotension as a key point.

Physiologically, the cerebral autoregulation system allows maintenance of constant cerebral blood flow over a wide range of blood pressure. In old people, there is a progressive reshape of cerebral autoregulation from a sigmoid curve to a straight line. This implies that any abrupt change in blood pressure will result in a rapid and significant change in cerebral blood flow. Hypertension has often been observed to be a risk factor for vascular dementia (VaD) and sometimes for Alzheimer disease although not always. Indeed, high blood pressure may accelerate cerebral white matter lesions, but white matter lesions have been found to be facilitated by excessive fall in blood pressure, including orthostatic dysregulation and postprandial hypotension. Many recent studies observed among other data, that there was a correlation between systolic pressure reduction and cognitive decline in women, which was not accounted for by other factors. Baseline blood pressure level was not significantly related to cognitive decline with initial good cognition. Some researchers speculate that blood pressure reduction might be an early change of the dementing process. The most confounding factor is that low pressure by itself might be a predictor of death; nevertheless, the effect of low blood pressure on cognition is underestimated because of a survival bias. Another explanation is that clinically unrecognized vascular lesions in the brain or atherosclerosis are responsible for both cognitive decline and blood pressure reduction. We discuss the entire process, and try to define a possible mechanism that is able to explain the dynamic by which hypotension might be related to dementia.

Different responses to rivastigmine in subcortical vascular dementia and multi-infarct dementia.

Vascular dementia (VaD) is associated with a large amount of heterogeneity, as it groups together a broad category of patients in whom various manifestations of cognitive decline are attributed to cerebrovascular or cardiovascular disease. Thus, a study was designed to determine the effects of rivastigmine on cognitive function, global daily living performance, and behavioral disorders in VaD patients versus an active control (nimodipine), stratifying patients according to the type of VaD, subcortical vascular dementia (sVAD), and multi-infarct dementia (MID). The trial was a prospective study. This study shows that long-term treatment with rivastigmine, at dosages approved for therapeutic use in Alzheimer's disease, produces significant improvement in all behavioral symptoms in 2 forms of VaD, MID and sVaD, except delusions. It also suggests that rivastigmine may enable a reduction in concomitant neuroleptics and benzodiazepines in VaD, especially in MID. The results are discussed with an overview of the literature.

Rivastigmine and Parkinson dementia complex.

Patients suffering from Parkinson's disease dementia (PDD) have a movement disorder, but it can be difficult to determine whether the functional impairment, which is critical in making the assessment of whether a patient has achieved the threshold for a diagnosis of dementia, is due to the dementia or the underlying Parkinson's disease. Although the cognitive impairment found in nondemented patients with Parkinson's disease is very dysexecutive in nature, the DSM IV (Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association IV) diagnosis of PDD has memory impairment as the defining characteristic of PDD. Severe deficits in cortical, cholinergic, excitatory, neuromodulatory input mean that memory impairment is not always due to encoding and retrieval strategy deficits, but it may also be amnesic without being related to concomitant Alzheimer's disease pathology. Patients with PDD have a high mortality, especially when they develop hallucinations and/or are admitted to nursing homes. Of interest is the reduction in mortality that was more marked in the subgroup with visual hallucinations at baseline. The increased mortality in PD may be due to autonomic failure, evidenced by the reductions in heart rate variability in these patients. This reduction is greater in patients with hallucinations. Rivastigmine is a dual inhibitor of brain acetyl- and butyrylcholinesterases that has been evaluated in the symptomatic treatment of patients with mild-to-moderate dementia associated with idiopathic Parkinson's disease. Although there is a need for more studies using pragmatic measures, such as time to residential care facility and both patient and carer quality of life assessments, rivastigmine appears to improve cognition and activities of daily living in patients with PDD, resulting in a clinically meaningful benefit in a large number of cases.

Peripheral neuropathy in hepatitis C virus-related mixed cryoglobulinaemia: existing treatments and a positive symptomatic response to oxcarbazepine.

Peripheral neuropathy is the most common symptom in patients with hepatitis C virus (HCV) associated mixed cryoglobulinaemia, in whom it may be the first clinical manifestation. Very frequently, the medical therapy proposed to treat HCV and cryoglobulinaemia causes an exacerbation of the disabling neuropathy. Therefore, other neuropathy treatments have been proposed, such as alternative immunosuppressive agents (steroids or cyclosporine) and plasma exchange, which, according to case reports, have yielded inconsistent results and presumably exert only temporary effects as they do not promote clearance of HCV. We present five cases of cryoglobulinaemia-related neuropathy resistant to steroids and gabapentin. Oxcarbazepine was introduced and produced moderate and persistent relief of symptoms without side effects.

Atypical neuroleptics as a treatment of agitation and anxiety in Alzheimer's disease: risks or benefits.

Behavioral problems produce excess disability that can be potentially devastating in cognitively impaired patients. These behavioral symptoms can be a major cause of stress, anxiety and concern for caregivers. While psychotropic drugs are frequently used to control these symptoms, they have the potential for significant side effects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonism and akathisias. On examination of the consequences of adverse events, somnolence, as well as postural instability and postural hypotension, have been noted. All patients with Alzheimer's disease (AD) and other progressive dementias will advance through stages of moderate-to-severe AD unless effective treatments suspend transition from mild deterioration to dementia, or competitive mortality truncates survival. Treatment trials suggest that these patients respond to both disease-modifying (such as inhibitors of cholinesterase and butirrylcholinesterase) and symptomatic (such as neuroleptics) agents. Relatively few studies have been conducted in this patient population, and more information regarding the type of behavioral disturbances exhibited, how best to measure them in this disabled population and their optimum treatment are urgently needed.

Positivity of cytomegalovirus antibodies predicts a better clinical and radiological outcome in multiple sclerosis patients.

OBJECTIVES: To establish the relationship between the presence and titer of virus-specific serum- and cerebrospinal fluid (CSF)-antibodies in multiple sclerosis (MS) patients and disease severity measured with different quantitative magnetic resonance imaging (MRI) techniques. METHODS: We investigated an association between clinical and MRI measures of disease activity and the presence and titer of IgG antibodies against seven common viruses (measles, rubella, herpes simplex virus type 1 and 2, varicella zoster virus, cytomegalovirus (CMV) and Epstein-Barr virus). One hundred and forty (90 female/50 male) patients with definite MS and 131 age and sex-matched controls participated in the study. Antibody positivity and titer were ascertained by the enzyme linked immunosorbent assay (ELISA) technique and clinical assessment was performed by evaluating the expanded disability status scale (EDSS) score and the lifetime relapse rate (LRR). T1- and T2-lesion loads (LL) and the brain parenchymal fraction (BPF) were calculated. RESULTS: Multiple analyses showed that there was an association between antibody positivity against CMV and higher titer and better clinical and MRI outcomes. The cluster analyses indicated that patients positive for antibodies against CMV had significantly older age at onset (uncorr p = 0.001 and corr p = 0.009), lower LRR (uncorr p = 0.003 and corr p = 0.03) and higher BPF (uncorr p = 0.004 and pcorr p = 0.04). CMV-positive patients who had higher antibody titer showed lower T2-LL (uncorr p = 0.003 and corr p = 0.03) and higher BPF (uncorr p = 0.006 and corr p = 0.05). DISCUSSION: Surprisingly, our results focused attention on the 'protective' role of a particular virus. CMV is probably capable of triggering some immunomodulating/immune evasion mechanisms which may decrease immune reactivity in MS patients. Further studies are needed to confirm and elucidate our study results on a larger sample of MS patients and in animal model studies.

Behavioral alterations and vascular dementia.

BACKGROUND: Vascular dementia is one of the most frequent forms of dementia, where behavioral and cognitive symptoms coexist. Negative signs, such as apathy, abulia, opposition, and agnosia, are badly tolerated and dramatically experienced by caregivers, even worse than the other signs of cognitive decline. REVIEW SUMMARY: We have studied 120 subjects affected by subcortical vascular dementia (group A) and 120 subjects suffering from multiinfarct dementia (group B) for 24 months. The main outcomes of the study were the global performance, the global behavioral symptoms, the caregiver stress, the depression status, and the insight in their clinical situation. CONCLUSIONS: Group A manifested a reduction of depression, agitation and suicidal ideation during follow-up, with a constant tendency to refer somatic pain, to exhibit anxiety, and an evident increase in apathy, cognitive abulia, social withdrawal, and loss of insight. On the contrary, group B showed a constant tendency to manifest depression, somatic pain, anxiety, agitation, cognitive abulia, social withdrawal, and suicide ideations; they manifested a decrease of apathy and an increase in delusions, hallucinations, craving for food, and loss of insight and awareness. Their behavioral alterations were stronger than those exhibited by group A, and that was reflected by an increment of caregivers' burden score. Even from a behavioral perspective, multiinfarct dementia is not the same as subcortical vascular dementia. This opinion must be taken into account to find more suitable and tailored therapy to specific pathologies and not to a single, generic entity.

Cognitive impairment in the lateralized phenotype of corticobasal degeneration.

Corticobasal degeneration (CBD) is a rare disorder, which normally includes a combination of neurobehavioural features, movement disorders and other manifestations. It is now recognized that CBD patients usually present with two phenotypes: the lateralized phenotype and the dementia phenotype. The aim of our work was to determine the nature and the progression of cognitive and behavioural impairment in 10 lateralized CBD patients. In our patients, the most salient aspects of cognitive impairment were: an evident alteration of rapid alternating operative strategies, associated with the evident impairment of set shifting, of executive operations, of operative and sequential procedure and of implementation of judgement and abstract reasoning. The self-activation of retrieval processes is partly preserved in CBD. As all the other types of subcortical impairments, even CBD encompasses both cognitive impairment as well as a wide range of behaviour disturbances, such as progressive alterations of sleep, depression, and of anxiety (with a remarkable incidence of somatic pain). This suggests that in addition to neuropsychological assessment, quantification of the personality behaviour disorder is important for standardizing the diagnosis of subcortical vascular dementia and distinguishing it from any other dementias.

Olanzapine as a possible treatment of behavioral symptoms in vascular dementia: risks of cerebrovascular events. A controlled, open-label study.

Behavioral problems produce excess disability, potentially devastating in cognitively impaired patients. These behavioral symptoms can be a major cause of stress, anxiety and concern for caregivers. While psychotropic drugs are frequently used to control these symptoms, they have the potential for significant side effects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonism and akathisia. We followed up (for 12 months) a group of 346 consecutive outpatients, with a diagnosis of subcortical vascular dementia or multi-infarctual dementia. Patients eligible for this open-label study were required to have behavioral problems (BPSD). Patients were divided into two groups, Group A received olanzapine 2.5-7.5 mg/day while Group B received typical antipsychotics. Patients in both groups were allowed to continue any previous therapy. Patients in both groups were significantly improved in their BPSD. Our patients had a host of medical conditions and received numerous concomitant medications. Given the potential complications associated with these therapeutic agents, these patients tolerated olanzapine quite well. On examination of consequences of adverse events, particularly somnolence, postural instability, and postural hypotension, it appeared that cerebrovascular events were not present. Moreover, no anticholinergic effect was recorded. These findings suggest that olanzapine could be a safe and effective treatment even for elderly population in suitable doses and receiving the adequate follow-up.

Frontal lobe dementia and subcortical vascular dementia: a neuropsychological comparison.

We compared the performance of 40 patients with frontal lobe dementia to that of 40 patients with subcortical vascular dementia (80 patients including, 46 men and 34 women) in a set of tasks assessing attentional, executive, and behavioural tasks. The frontal lobe dementia represents an important cause for degenerative disruption and is increasingly recognised as an important form (up to 25%) of degenerative dementia among individuals of late-middle-age. The main involvement is the frontal-subcortical pathway, which is the final target of impairment even in subcortical vascular dementia. A wider involvement of the cortical (decisional) layers in frontal dementia, in contrast with the prominent and widespread involvement of the subcortical pathways (refinement and corrections programs) creates the different profiles of the two groups. Frontal patients have more difficulties in abstract reasoning, focusing attention, and implementing strategies to solve problems. They exhibit more profound behavioural alterations in personality and social conduct and show only moderate depression, and a total lack of insight concerning their dinical condition. In contrast, the patients with subcortical vascular dementia have poor general cognitive functions, high insight, and important depression and apathy as the principal and most salient characteristic of their behavioral conduct.

Neuropsychological evaluation of late-onset post-radiotherapy encephalopathy: a comparison with vascular dementia.

It is known that radiotherapy (RT) may cause cerebral injury. The most frequent neurotoxic effect of RT at any age is diffuse cerebral injury. Brain injury by therapeutic irradiation has traditionally been classified according to its time of onset into acute, early delayed, and late forms. The latter is not reversible. The neurocognitive sequelae of cranial irradiation can be mediated through vascular injury. Because the pathologic changes are most profound in the white matter, we compared a group of patients treated by RT (n=34) with a group of patients affected by subcortical vascular dementia (sVaD, n=34). Patients with a total radiation does <35 cGy did not show any sign of cognitive impairment. All the patients with a total irradiation dose >45 cGy did show profound cognitive and behavioural alteration. The patients who received a total dose of brain radiation comprised between 35 and 45 cGy did show slowness of executive function, and profound alterations of frontal functions, such as attention focusing, mentation control, analogical judgement and insight. The patients who suffered from the consequences of RT had slowness of executive functions, and profound alterations of frontal functions, such as attention focusing, mentation control, analogical judgement and insight, similar to those obtained by the patients suffering from subcortical vascular dementia. High dose RT might result in a severely demented, bedridden patient, who "has been cured" from his primary disease, the brain tumour. This constellation demands serious consideration before RT is given.

Use of the ten-point clock test to compare executive functioning across 24 months in patients with subcortical vascular dementia.

The Ten-point Clock Test can be used to identify early forms of Alzheimer's disease because it is reliable, well accepted, and easily administered at the bedside. Nevertheless, its clinical role in the detection of early dementia and its correlations with other cognitive processes is still under investigation. Vascular dementia is an uncertain nosological entity, in which unevenly distributed patterns of cognitive deficits comprising slowing of cognitive processing and impairment of executive function occur. The present study assessed how the Clock Test scores correlated with a number of other neuropsychological and functional tests in a sample of 144 patients with vascular dementia, who were followed for a period of 24 mo. At baseline, at 12 mo. and at 24 mo. subjects were administered a battery of tests, including the Mini-Mental State Examination, word fluency, visuospatial skills, an evaluation of hetero- and autotopognosia (knowledge of self), the Proverbs Test, and the Ten-point Clock Test. For these patients scores on the Clock Test correlated significantly with semantic abilities, with abstract reasoning capacities, visuospatial perception, and with right and left recognition.

[Role of the cerebellum in the control of distal motor activities in patients with akinetic-rigid Parkinson disease]. / Ruolo del cervelletto nel controllo dell'atto motorio distale in pazienti con malattia di Parkinson acinetico-rigida.

Using f-MRI, we have studied the changes induced by the performance of a complex sequential motor task in the cortical areas of nine akinetic PD patients and compared to that of healthy volunteers. Compared with normal subjects, PD patients showed a reduction of activation of motor and SMA areas, an increase of activation of parietal areas and a bilateral activation of cerebellar hemispheres, which are likely to participate in the attempt to recruit parallel motor circuits in order to overcome the striatocortical defective loop.

Rivastigmine in frontotemporal dementia: an open-label study.

OBJECTIVE: This preliminary open-label study aims to investigate the effects of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in 20 patients diagnosed with frontotemporal dementia (FTD). PATIENTS AND METHODS: Study subjects were men and women 60-75 years of age diagnosed with probable FTD. The rivastigmine group received doses of 3-9 mg/day. The control group included matched patients receiving antipsychotics, benzodiazepines and selegiline (deprenyl). All patients completed a 12-month follow-up period. RESULTS: Rivastigmine treatment was well tolerated. At 12 months, there was a general amelioration of behavioural changes as demonstrated by reductions in Neuropsychiatric Inventory (p<0.001 vs baseline and control), Behavioral Pathology in Alzheimer's Disease Rating Scale (p<0.001 vs baseline and control) and Cornell Scale for Depression in Dementia scores (p<0.05 vs baseline, p<0.001 vs control) in the rivastigmine group. Caregiver burden was reduced, as shown by reduced Relative Stress Scale scores (p<0.001 vs baseline and control). Mean scores on outcome measures evaluating executive function stabilised in the rivastigmine group (p<0.05 vs controls). Rivastigmine did not prevent the disease-related deterioration of cognition as assessed using the Mini-Mental State Examination. CONCLUSION: In this open-label study, rivastigmine-treated patients were less behaviourally impaired, and caregiver burden was reduced, at 12 months, compared with baseline. The use of cholinesterase inhibitors in FTD warrants further research.

Vitamin B12 and folate depletion: clinical evidence in a neurological population.

In cross-sectional studies, low levels of folate and vitamin B12 have been associated with poor cognition and dementia. Results are quite controversial and a debate continues in the literature. Still not completely understood are the differential roles of folate and vitamin B12 in memory acquisition and cognitive development. More intriguing and not fully understood is the rule that treating a vitamin B12-deficient patient with folate may exacerbate the neurological consequences of either deficiency. Starting from these quite confusing perspectives, the aim of this study was to define a possible role of vitamin B12 and folate in cognitive disruption. Data were collected among a cohort of people, admitted to the Neurology Clinic of the University of Trieste, in a period between November 1,2000, and November 1, 2002. We examine potential risk factors, concomitant drug-therapies, and cognitive global performance and correlate these parameters with folate and vitamin B 12 serum levels.We discuss the results with an overview of the literature.

Vitamin B12 and folate depletion in cognition: a review.

In cross-sectional studies, low levels of folate and B12 have been shown to be associated with cognitive decline and dementia Evidence for the putative role of folate, vitamin B12 in neurocognitive and other neurological functions comes from reported cases of severe vitamin deficiencies, particularly pernicious anemia, and homozygous defects in genes that encode for enzymes of one-carbon metabolism. The neurological alterations seen in these cases allow for a biological role of vitamins in neurophysiology. Results are quite controversial and there is an open debate in literature, considering that the potential and differential role of folate and B12 vitamin in memory acquisition and cognitive development is not completely understood or accepted. What is not clear is the fact that vitamin B12 and folate deficiency deteriorate a pre-existing not overt pathological situation or can be dangerous even in normal subjects. Even more intriguing is the interaction between B12 and folate, and their role in developing hyperhomocysteinemia. The approach to the rehabilitation of the deficiency with adequate vitamin supplementation is very confusing. Some authors suggest it, even in chronic situations, others deny any possible role. Starting from these quite confusing perspectives, the aim of this review is to report and categorize the data obtained from the literature. Despite the plausible biochemical mechanism, further studies, based on clinical, neuropsychological, laboratory and (lastly) pathological features will be necessary to better understand this fascinating biochemical riddle.