Normal brain aging and Alzheimer's disease are associated with lower cerebral pH: an in vivo histidine 1H-MR spectroscopy study.

It is unclear whether alterations in cerebral pH underlie Alzheimer's disease (AD) and other dementias. We performed proton spectroscopy after oral administration of histidine in healthy young and elderly persons and in patients with mild cognitive impairment and dementia (total N = 147). We measured cerebral tissue pH and ratios of common brain metabolites in relation to phosphocreatine and creatine (Cr) in spectra acquired from the hippocampus, the white matter (WM) of the centrum semiovale, and the cerebellum. Hippocampal pH was inversely associated with age in healthy participants but did not differ between patients and controls. WM pH was low in AD and, to a lesser extent, mild cognitive impairment but not in frontotemporal dementia spectrum disorders and pure vascular dementia. Furthermore, WM pH provided incremental diagnostic value in addition to N-acetylaspartate to Cr ratio. Our study suggests that in vivo assessment of pH may be a useful marker for the differentiation between AD and other types of dementia.

Nonpharmacological Modulation of Chronic Inflammation in Parkinson's Disease: Role of Diet Interventions.

Neuroinflammation is increasingly recognized as an important pathophysiological feature of neurodegenerative diseases such as Parkinson's disease (PD). Recent evidence suggests that neuroinflammation in PD might originate in the intestine and the bidirectional communication between the central and enteric nervous system, the so-called "gut-brain axis," has received growing attention due to its contribution to the pathogenesis of neurological disorders. Diet targets mediators of inflammation with various mechanisms and combined with dopaminergic treatment can exert various beneficial effects in PD. Food-based therapies may favorably modulate gut microbiota composition and enhance the intestinal epithelial integrity or decrease the proinflammatory response by direct effects on immune cells. Diets rich in pre- and probiotics, polyunsaturated fatty acids, phenols including flavonoids, and vitamins, such as the Mediterranean diet or a plant-based diet, may attenuate chronic inflammation and positively influence PD symptoms and even progression of the disease. Dietary strategies should be encouraged in the context of a healthy lifestyle with physical activity, which also has neuroimmune-modifying properties. Thus, diet adaptation appears to be an effective additive, nonpharmacological therapeutic strategy that can attenuate the chronic inflammation implicated in PD, potentially slow down degeneration, and thereby modify the course of the disease. PD patients should be highly encouraged to adopt corresponding lifestyle modifications, in order to improve not only PD symptoms, but also general quality of life. Future research should focus on planning larger clinical trials with dietary interventions in PD in order to obtain hard evidence for the hypothesized beneficial effects.

Optic nerve sheath diameter: present and future perspectives for neurologists and critical care physicians.

BACKGROUND: Estimation of intracranial pressure (ICP) may be helpful in the management of neurological critically ill patients. It has been shown that ultrasonography of the optic nerve sheath diameter (ONSD) is a reliable tool for non-invasive estimation of increased intracranial pressure (ICP) at hospital admission or in intensive care. Less is known about the estimation of increased ICP and usefulness of ONSD in the prehospital setting. The aim of this review was to elucidate both prevailing and novel applications of ONSD for neurologists and critical care physicians. METHODS: In this review, we discuss the technique and the novel approach of ONSD measurement, the clinical applications of ONSD in neurology and critical care patients. RESULTS: ONSD measurement is simple, easy to learn, and has diverse applications. ONSD has utility for ICP measurement in intracranial hemorrhage and ischemic stroke, meningitis and encephalitis, and idiopathic intracranial hypertension (IIH). It is also valuable for lesser known syndromes, where an increase of ICP is postulated, such as acute mountain sickness and posterior reversible encephalopathy syndrome. ONSD changes develop in inflammatory or ischemic optic neuropathies. Some papers demonstrate the usefulness of ONSD studies in symptomatic intracranial hypotension. CONCLUSIONS: ONSD is a safe and low-cost bedside tool with the potential of screening patients who need other neuroimaging and those who may need an invasive measurement of ICP.

Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging.

Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure-function relationship of alien/anarchic limb was investigated in multi-centric structural magnetic resonance imaging (MRI) data. Whole-group and single-subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture.

FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations.

C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.

The applause sign in frontotemporal lobar degeneration and related conditions.

The applause sign, i.e., the inability to execute the same amount of claps as performed by the examiner, was originally reported as a sign specific for progressive supranuclear palsy (PSP). Recent research, however, has provided evidence for the occurrence of the applause sign in various conditions. The aim of this study was to determine the prevalence of the applause sign and correlate its presence with neuropsychological and MRI volumetry findings in frontotemporal lobar degeneration and related conditions. The applause sign was elicited with the three clap test (TCT), with a higher score indicating poorer performance. Data were recorded from 272 patients from the cohort of the German consortium for frontotemporal lobar degeneration (FTLDc): 111 with behavioral variant frontotemporal dementia (bvFTD), 98 with primary progressive aphasia (PPA), 30 with progressive supranuclear palsy Richardson's syndrome, 17 with corticobasal syndrome (CBS) and 16 with amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). For comparison, 29 healthy elderly control subjects (HC) were enrolled in the study. All subjects underwent detailed language and neuropsychological assessment. In a subset of 156 subjects, atlas-based volumetry was performed. The applause sign occurred in all patient groups (40% in PSP, 29.5% in CBS, 25% in ALS/FTD, 13.3% in PPA and 9.0% in bvFTD) but not in healthy controls. The prevalence was highest in PSP patients. It was significantly more common in PSP as compared to bvFTD, PPA and HC. The comparison between the other groups failed to show a significant difference regarding the occurrence of the applause sign. The applause sign was highly correlated to a number of neuropsychological findings, especially to measures of executive, visuospatial, and language function as well as measures of disease severity. TCT scores showed an inverse correlation with the volume of the ventral diencephalon and the pallidum. Furthermore the volume of the ventral diencephalon and pallidum were significantly smaller in patients displaying the applause sign. Our study confirms the occurrence of the applause sign in bvFTD, PSP and CBS and adds PPA and ALS/FTD to these conditions. Although still suggestive of PSP, clinically it must be interpreted with caution. From the correlation with various cognitive measures we suggest the applause sign to be indicative of disease severity. Furthermore we suggest that the applause sign represents dysfunction of the pallidum and the subthalamic nucleus, structures which are known to play important roles in response inhibition.

Molecular links between endothelial dysfunction and neurodegeneration in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a progressive decline of cognitive functions and represents the most common form of dementia and a major cause of morbidity and mortality in the modern, westernized societies. There is accumulating evidence to support the hypothesis that a primary cerebral vascular dysfunction initiates a cascade of events that lead to neuronal injury in Alzheimer's dementia. The endothelium, in specific, constitutes a part of the blood brain barrier, the dysfunction of which is thought to play an important role to disturbed amyloid-ß homeostasis and infiltration of the brain parenchyma with circulating toxic molecules in the disease. Furthermore, the endothelium itself is under certain conditions capable of producing neurotoxic and inflammatory factors, whereas common growth factors regulate the development and maintenance of both neurons and blood vessels. Reliance of both endothelial and neuronal cells on mitochondrial integrity and common molecular pathways for apoptosis also imply that there is a link between vascular pathology and neurodegeneration. The present article intends to review available evidence on molecular players implicated in the above mechanisms with the potential to develop biomarkers or novel therapeutic targets.

Increased self-report of obsessive-compulsive behaviors among hemodialysis patients: a case-control study.

BACKGROUND: Patients with end-stage renal insufficiency undergoing hemodialysis show important psychiatric morbidity, particularly increased depression and anxiety. Obsessive-compulsive symptoms, however, are much less frequently investigated. The purpose of the present study was thus to assess obsessive-compulsive symptoms in hemodialysis patients. METHOD: Patients treated at an outpatient hospital hemodialysis unit (July 2007) were compared with controls on scores on the Maudsley Obsessional-Compulsive Inventory (MOCI) and its checking, cleaning, slowness, and doubting components as well as on measures of emotional (Beck Depression Inventory-Fast Screen), anxiety (Beck Anxiety Inventory), and cognitive (Trail Making Test) status. Student t tests, analyses of covariance, or nonparametric tests were used. Correlations were applied between behavioral outcomes and demographic, clinical, and laboratory data of patients. RESULTS: Patients showed more obsessive traits than controls on the MOCI total score (P < .001) and on the checking, cleaning, and doubting subscales. Significant differences between groups occurred also in Beck Depression and Anxiety Inventories (P ≤ .001). The MOCI total score did not correlate with marital status, education level, duration of hemodialysis, or the other psychological instrument scores in patients. By contrast, the MOCI total score was associated with the level of creatinine, and it showed an inverse correlation with the urea reduction ratio in patients (P < .05). CONCLUSIONS: Obsessive-compulsive symptoms may constitute an important aspect of the psychiatric profile of patients undergoing hemodialysis. Potential interpretation involves disease- and treatment-associated factors or adaptive responses to emergence of otherwise uncontrollable stress.

Cognitive dysfunction in multiple sclerosis: the effect of pharmacological interventions.

Research has recently focused on cognitive dysfunction in multiple sclerosis (MS). Cognitive deficits are frequently encountered in patients and account for important impairment in quality of life, therefore posing a major therapeutic challenge for the disease. We presently review studies on cognitive effects of pharmacological treatments in MS. There is evidence for a possible beneficial effect of immunomodulatory treatments, particularly of interferons, and also of acetylcholinesterase inhibitors on cognition in MS, which, however, requires evaluation in larger, multi-centre, longitudinal studies. Methodological issues and future prospects regarding the investigation of this issue are also discussed.

Assessment and rehabilitation of cognitive impairment in multiple sclerosis.

Patients with multiple sclerosis (MS) have a substantial risk of cognitive dysfunction, even in the earliest stages of the disease, where there is minimum physical disability. Despite the high prevalence rates and the significant impact of cognitive dysfunction on quality of life in this population, cognitive functions are not routinely assessed due to the high cost and time consumption. This article provides an overview of the current state of knowledge related to cognition in MS and on the optimal approach to neuropsychological assessment of this population. It then focuses on the pharmacological and other treatment options available for MS patients with, or at risk for developing, cognitive impairment. The available immune-modulating agents may reduce the development of new lesions and therefore prevent or minimize the progression of cognitive decline. However, there is currently insufficient evidence concerning the efficiency of symptomatic treatment in MS. There is also currently no optimal non-pharmacological treatment strategy for cognitive decline in MS, as the studies published to date report heterogeneous results. Nevertheless, non-pharmacological treatments such as cognitive rehabilitation may benefit some MS patients. As cognition is increasingly recognized as a major feature of MS, its assessment and rehabilitation will become a greater priority.

Neuropsychological functioning in buprenorphine maintained patients versus abstinent heroin abusers on naltrexone hydrochloride therapy.

RATIONALE: Methadone and buprenorphine are among the most widely employed pharmacological treatments currently available for opioid addiction. Cognitive effects of buprenorphine in abstinent heroin abusers are nevertheless far from being understood. METHODS: Neuropsychological performance of 18 buprenorphine-maintained patients (BMP) was evaluated relative to that of 32 currently abstinent heroin abusers on naltrexone hydrochloride therapy (FHAN), and 34 non-drug dependent controls. The three groups were demographically balanced. Clinical groups reported histories of similar patterns of drug use and had increased periods of abstinence from any illicit substance use including heroin. RESULTS: The BMP group performed poorer than controls on the RAVLT (encoding and delayed recall of verbal information), CTT (conceptual flexibility, executive functions) and the RBANS figure copy (visual perception) and delayed recall of visual information. There were no significant differences in any of the cognitive measures between the BMP and FHAN groups or between the FHAN group and controls. Furthermore, the non-differing percentage of abnormal cases between the two patient groups led us to infer that treatment with either BPM or FHAN is not accompanied by qualitative differences in the cognitive profiles of these patients. CONCLUSION: Overall, results suggest that treatment with naltrexone in abstinent heroin abusers may result in less impairment of cognitive functions compared to treatment with buprenorphine. These findings are relevant for improved prognosis and treatment strategies in opioid dependence.

Neuropsychological functions and rCBF SPECT in Parkinson's disease patients considered candidates for deep brain stimulation.

PURPOSE: In the present study, we examined relationships between neuropsychological functions and brain single photon emission computed tomography (SPECT) regional cerebral blood flow (rCBF) observed at presurgical evaluation for deep brain stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinson's disease (PD) patients. METHODS: Twenty advanced non-demented PD patients, candidates for DBS surgery, underwent perfusion brain SPECT study and neuropsychological assessment prior to surgery (range: 30-50 days). Patients were further assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (H&Y) scale. During all assessments patients were "on" standard medication. NeuroGam software, which permits voxel by voxel analysis, was used to compare the brain perfusion of PD patients with a normal database adjusted for sex and age. Neuropsychological scores were compared to age, education and sex-adjusted normative databases. RESULTS: Our results indicated that the distribution of rCBF showed significant differences when compared to an age- and sex-adjusted normative database. We found impaired blood flow in 17 (85%) of our patients in the left prefrontal lobe, in 14 (70%) in the right prefrontal lobe and in 11 (55%) in the left frontal and right parietal lobes. Neuropsychological testing revealed that 18 (90%) of our patients had significant impairments in measures of executive functions (set-shifting) and 15 (75%) in response inhibition. Furthermore, we found significant correlations between measures of visual attention, executive functions and the right frontal lobe region. CONCLUSION: The presence of widespread blood flow reduction was observed mainly in the frontal lobes of dementia-free patients with advanced PD. Furthermore, performance on specific cognitive measures was highly related to perfusion brain SPECT findings.

Benton Visual Retention Test performance in normal adults and acute stroke patients: demographic considerations, discriminant validity, and test-retest reliability.

We examined relationships between demographic variables and Benton Visual Retention Test performance in 352 healthy Greek adults, aged 18-84 years. We derived norms for BVRT total number correct and error scores adjusted for variables that contributed significantly to the variance. We also investigated BVRT performance in 28 acute stroke patients M = 6.14 days after insult. Age, education, and IQ, but not gender, were significantly associated with BVRT performance in healthy participants. However, only age contributed significantly to BVRT performance in acute stroke patients. Test-retest reliability was moderate (.782) for number correct and low for number error (.596) scores. Practice effects were noted only for number correct score. The test appears to discriminate adequately between acute stroke patients and matched healthy controls.

Communicating the diagnosis of multiple sclerosis: results of a survey among Greek neurologists.

In the frame of current treatment options for multiple sclerosis (MS) and recommendations for early intervention, we investigated the practice and attitudes of neurologists towards MS-diagnosis communication in Greece. We constructed and sent out a 22-item questionnaire to neurologists practising in different employment settings and geographic regions in Greece. Overall, 217 (37.41 %) of 580 neurologists replied. The vast majority (94.9 %) informs the patient of a definite MS diagnosis, and 73.6 % do so immediately, but only 41.7 % use the term multiple sclerosis. Furthermore, neurologists strongly agreed that timing of diagnosis communication depends to a large extent on the individual patient's personality (62.5 %) and mental state (52.3 %). Most neurologists (78.7 %) inform relatives about the diagnosis, but only in the presence of the patient. In cases where disclosure was delayed, 59.5 % noted that they did not observe any changes as regards the trust or confidence of their patients towards them. Most neurologists also noted that education level (72 %) and mental state (51.9 %), at the time of disclosure influenced patients who did not fully understand the meaning of their diagnosis. This survey provided some useful new findings with respect to MS diagnosis communication; however, the questions of how and possibly how much to communicate warrant further cross-cultural investigation.

Multiple sclerosis, cannabinoids, and cognition.

There is increasing interest in the therapeutic potential of cannabis-based medicinal extracts in multiple sclerosis. Cognitive deficits that have been attributed to long-term heavy recreational use of cannabis are not necessarily extended to controlled pharmaceutical use of cannabis-based medicinal extracts. Available data indicate that after relatively short-term administration of cannabis-based medicinal extracts no significant cognitive decline occurs. Due to the absence of large scale long-term systematic clinical trials of cannabis-based medicinal extracts in multiple sclerosis therapeutics, however, many issues remain unresolved, including the possible adverse effects of cannabis-based medicinal extracts on cognition. This article critically reviews the current literature and considers the potential for cognitive adverse effects of long-term cannabinoid use in multiple sclerosis therapeutics.