Camillo Marra

The Mental Deterioration Battery: Normative Data, Diagnostic Reliability and Qualitative Analyses of Cognitive Impairment

This study aimed at investigating the clinical usefulness of the Mental Deterioration Battery (MDB) in the neuropsychological diagnosis and characterization of the dementia syndrome. In this paper, we report: (a) normative data for various test scores derived from the analysis of performance of 340 normal subjects living in urban areas; (b) an evaluation of the reliability of the single tests and of the battery as a whole in differentiating normal subjects from patients affected by cognitive deterioration derived from the analysis of performance of 130 normal subjects living in rural areas and 134 patients affected by probable Alzheimers dementia; (c) a cluster analysis of performances of the 340 normal subjects in the standardization group to evaluate possible criteria of homogeneity according to which the various MDB scores tend to aggregate; (d) an analysis of performance profiles of 183 patients with right monohemispheric focal lesions, 159 patients with left unilateral lesions with aphasia and 131 left-lesioned nonaphasic patients to evaluate the specificity of the single tests of the battery in documenting a selective impairment of one of the two cerebral hemispheres. Results confirm the reliability of the MBD in discriminating between normal and demented patients and provide indications for use of the battery in differentiating qualitative patterns of cognitive impairment.

Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation

BackgroundA recently devised test of motor cortex excitability (short latency afferent inhibition) was shown to be sensitive to the blockade of muscarinic acetylcholine receptors in healthy subjects. The authors used this test to assess cholinergic transmission in the motor cortex of patients with AD. MethodsThe authors evaluated short latency afferent inhibition in 15 patients with AD and compared the data with those of 12 age-matched healthy controls. ResultsAfferent inhibition was reduced in the patients (mean responses ± SD reduced to 85.7% ± 15.8% of the test size) compared with controls (mean responses ± SD reduced to 45.3% ± 16.2% of the test size;p < 0.001, unpaired t-test). Administration of a single oral dose of rivastigmine improved afferent inhibition in a subgroup of six patients. ConclusionsThe findings suggest that this method can be used as a noninvasive test of cholinergic pathways in AD. Future studies are required to evaluate whether short latency afferent inhibition measurements have any consistent clinical correlates.

Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease

Objectives: Recent transcranial magnetic stimulation (TMS) studies demonstrate that motor cortex excitability is increased in Alzheimer’s disease (AD) and that intracortical inhibitory phenomena are impaired. The aim of the present study was to determine whether hyperexcitability is due to the impairment of intracortical inhibitory circuits or to an independent abnormality of excitatory circuits. Methods: We assessed the excitability of the motor cortex with TMS in 28 patients with AD using several TMS paradigms and compared the data of cortical excitability (evaluated by measuring resting motor threshold) with the amount of motor cortex disinhibition as evaluated using the test for motor cortex cholinergic inhibition (short latency afferent inhibition) and GABAergic inhibition (short latency intracortical inhibition). The data in AD patients were also compared with that from 12 age matched healthy individuals. Results: The mean resting motor threshold was significantly lower in AD patients than in controls. The amount of short latency afferent inhibition was significantly smaller in AD patients than in normal controls. There was also a tendency for AD patients to have less pronounced short latency intracortical inhibition than controls, but this difference was not significant. There was no correlation between resting motor threshold and measures of either short latency afferent or intracortical inhibition (r = −0.19 and 0.18 respectively, NS). In 14 AD patients the electrophysiological study was repeated after a single oral dose of the cholinesterase inhibitor rivastigmine. Resting motor threshold was not significantly modified by the administration of rivastigmine. In contrast, short latency afferent inhibition from the median nerve was significantly increased by the administration of rivastigmine. Conclusions: The change in threshold did not seem to correlate with dysfunction of inhibitory intracortical cholinergic and GABAergic circuits, nor with the central cholinergic activity. We propose that the hyperexcitability of the motor cortex is caused by an abnormality of intracortical excitatory circuits.

Neurophysiological predictors of long term response to AChE inhibitors in AD patients

Background: In vivo evaluation of cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with motor cortex TMS (short latency afferent inhibition, SAI). SAI is reduced in Alzheimer’s disease (AD) and drugs enhancing cholinergic transmission increase SAI. Methods: We evaluated whether SAI testing, together with SAI test-retest, after a single dose of the acetylcholinesterase (AChE) inhibitor rivastigmine, might be useful in predicting the response after 1 year treatment with rivastigmine in 16 AD patients. Results: Fourteen AD patients had pathologically reduced SAI. SAI was increased after administration of a single oral dose of rivastigmine in AD patients with abnormal baseline SAI, but individual responses to rivastigmine varied widely, with SAI change ranging from an increase in inhibition of ∼50% of test size to no change. Baseline SAI and the increase in SAI after a single dose of rivastigmine were correlated with response to long term treatment. A normal SAI in baseline conditions, or an abnormal SAI in baseline conditions that was not greatly increased by a single oral dose of rivastigmine, were invariably associated with poor response to long term treatment, while an abnormal SAI in baseline conditions in conjunction with a large increase in SAI after a single dose of rivastigmine was associated with good response to long term treatment in most of the patients. Conclusions: Evaluation of SAI may be useful for identifying AD patients likely to respond to treatment with AChE inhibitors.

Cognitive Impairment in chronic obstructive pulmonary disease: a neuropsychological and spect study

Abstract. Some analogy exists between cognitive impairment in hypoxemic patients with chronic obstructive pulmonary disease (COPD) and Alzheimers disease (AD). We purposed to verify whether the analogy extends to the cerebral perfusion pattern. Ten normal subjects, 15 COPD patients with and 18 without hypoxemia, and 15 patients with mild AD matched for age and educational level underwent brain perfusion single photon emission computed tomography (SPECT) and neuropsychological assessment. Normal subjects and non hypoxemic COPD patients had comparable perfusion patterns. The average perfusion decreased from non hypoxemic to hypoxemic COPD and, then, to AD patients. Hypoperfusion of associative areas was the hallmark of AD, whereas the average perfusion of anterior cortical and subcortical regions did not distinguish AD and hypoxemic COPD patients. Both COPD groups scored higher than AD patients (p ≤ 0.01) in 13 cognitive tests but below the normal in selected tests of verbal attainment, attention and deductive thinking. Perfusion of anterior cortical and subcortical regions of the dominant hemisphere was directly correlated with the number of correctly performed neuropsychologic tests. In conclusion, anterior cerebral hypoperfusion and selected neuropsychological dysfunctions characterized hypoxemic COPD patients and could herald frontal-type cognitive decline with the worsening of the hypoxemia.

A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease

Background and aims: Epidemiological studies have examined the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of Alzheimer’s disease (AD). Recently, a variety of experimental studies indicates that a subset of NSAIDs, such as ibuprofen or flurbiprofen, also have Aβ-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. In this trial, we evaluated whether the non-selective NSAID ibuprofen slows disease progression in patients with mild to moderate AD. Methods: This was a 12-month multicenter, randomized, double-blind, placebo-controlled, parallel group trial. Participants with mild-moderate AD (Mini-Mental State Examination score >15, <26; Clinical Dementia Rating= 0.5–1), 65 years or older, with reliable caregivers, were recruited between April 2003 and September 2004. Seven AD Outpatient Treatment Centers screened 530 patients, 132 of whom were enrolled. Interventionconsisted of 400 mg ibuprofen twice a day or placebo, together with 20 mg once a day of esomeprazol, or placebo. The primary measure was any one-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary measures included changes in MMSE, CDR, Basic and Instrumental Activities of Daily Living scales, and Neuropsychiatry Inventory (NPI). Results: Fifty-one patients (77%) in the ibuprofen vs 46 (70%) in the placebo group completed the protocol (p>0.20). In intention-to-treat analysis, ADAS-Cog score worsening was similar in the two groups (p=0.951, treatment difference= 0.1, CI-2.7; 2.9). No differences were found for any secondary outcomes. In a subsample of genotyped patients, ApoE ε4 carriers treated with ibuprofen (n=27) were the only group without significant cognitive decline. Conclusions: Ibuprofen, if used for relatively short periods of time and although well tolerated thanks to gastroprotection, does not seem to be effective in tertiary prevention of mild-moderate AD. Our results suggest the need to examine whether differences in the response to NSAIDs exist, based on ApoE ε4 carrier status.

Sensitivity and specificity of some neuropsychological markers of Alzheimer dementia.

A standardized neuropsychological test battery was administered to 167 patients with different forms of mild-to-moderate dementia: probable Alzheimer dementia (AD: n = 49), multi-infarct dementia (n = 43), idiopathic Parkinson disease with dementia (n = 35), depressive pseudodementia (n = 26), and progressive supranuelear palsy (n = 14). Results obtained were used (a) to analyze the profiles of cognitive impairment shown by the different dementia groups; (b) to assess the incidence of some neuropsychological patterns that we hypothesized to be more characteristic of AD, in the various groups; and hence (c) to evaluate the reliability of these patterns as diagnostic markers of AD. Four of the patterns investigated were derived from a verbal learning task (Reys Auditory Verbal Learning test): (1) absence of the primacy effect; (2) tendency to produce intrusion errors during free recall of a word list; (3) absolute decay of memory trace; and (4) tendency to produce false alarms during delayed recognition of the same word list. Two additional patterns were derived from visual-spatial tasks (copying drawings and Ravens Coloured Progressive Matrices): (5) occurrence of the closing-in phenomenon in copying drawings; and (6) tendency to choose globalistic or odd responses in Ravens matrices. Though all the six patterns were somewhat useful for identifying AD patients, no pattern met the criteria of being both highly sensitive and highly specific, which should characterize an ideal marker. In fact, intrusions and false alarms were observed in many AD patients, but also in patients affected by other forms of dementia. The absence of the primacy effect, the closing-in phenomenon, and the absolute decay of memory trace were more specific, but could be observed in only one-third of AD patients. We also computed the number of positive patterns shown by each patient and assumed the presence of two or more patterns as a global index suggestive of a dementia of the Alzheimer type. With this cumulative method, a higher level of sensitivity and specificity was achieved in the identification of AD patients.

Does cognitive dysfunction conform to a distinctive pattern in obstructive sleep apnea syndrome

Obstructive sleep apnea (OSA) is a recognized cause of cognitive dysfunction. By using a cross‐sectional comparative study, we aimed to verify whether neuropsychological performance of untreated OSA patients conforms to a distinctive pattern. Forty‐nine newly diagnosed, untreated OSA patients, 27 with multi‐infarctual dementia (MID), 31 with mild to moderate dementia of Alzheimer type (DAT) and 63 with severe chronic obstructive pulmonary disease (COPD), all free from major comorbid dementing conditions were chosen for the study. The groups were matched for age and education. We found a bimodal distribution of cognitive performance in OSA group, which was therefore divided into two clusters having better (OSAb, n = 35) and worse (OSAw, n = 14) performance on a battery of 10 cognitive indexes. Cognitive performances of OSAb, OSAw, MID, DAT and COPD were compared by discriminant analysis. OSAb performed better than OSAw in all but one test. Deductive thinking and verbal attainment were more severely impaired in OSAw than in COPD patients. Constructive ability, deductive thinking and both verbal attainment and immediate memory were comparably impaired in OSAw and DAT. The mean neuropsychological scores of OSAw and MID were comparable, but 71% of OSAw patients had a distinctive cognitive profile, i.e. a group specific pattern of cognitive dysfunction, according to discriminant analysis. One of four newly diagnosed OSA patients had a severe and distinctive neuropsychological dysfunction mainly involving inductive and deductive thinking, and constructive ability. Some analogy with cognitive pattern of MID suggests that a mainly subcortical damage underlies this dysfunction.

In vivo cholinergic circuit evaluation in frontotemporal and Alzheimer dementias

The test of short latency afferent inhibition (SAI) of the motor cortex is helpful in demonstrating dysfunction of central cholinergic circuits in Alzheimer disease (AD). The authors evaluated SAI in 20 patients with frontotemporal dementia (FTD) and compared data with those from 20 patients with AD and 20 controls. SAI was normal in FTD, whereas it was reduced in AD. SAI may represent an additional tool to discriminate FTD from AD.

Some aspects of memory disorders clearly distinguish dementia of the Alzheimer's type from depressive pseudo-dementia

Two groups of patients affected by mild dementia of the Alzheimers type (n = 42) or by depressive pseudo-dementia (n = 26) were given a modified version of the Reys Auditory Verbal Learning Test. The two groups were roughly matched for overall level of cognitive impairment. The main purpose of the research was to determine if some aspects of their memory disorders distinguished the two diagnostic groups. Comparison between results obtained on recall and on recognition measures was of little diagnostic usefulness in distinguishing dementia of the Alzheimers type (DAT) from depressive pseudo-dementia (DPD). A marked prevalence of the recency over the primary effect in immediate recall, a high rate of forgetting, and the presence of many intrusion errors on delayed recall were observed more frequently in DAT than in DPD patients. None of these indices, however, was sensitive and specific enough to allow a confident diagnostic discrimination at the individual case level. The memory measure which best distinguished DAT from DPD patients was the presence of several false positive errors on delayed recognition because DAT patients adopted a very liberal response bias, endorsing many false recognition errors, whereas DPD patients adopted a conservative criterion and tended to miss real stimuli, rather than making false recognition errors.