Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer’s disease?

Adult patients with Niemann-Pick disease type C (NPC) usually develop cognitive impairment progressing to dementia, whose pathophysiology remains still unclear. Noteworthy parallels exist in cognitive impairment and cellular pathology of NPC and Alzheimer’s disease (AD). In particular, alterations of cholinergic system, which represent one of the pathological hallmarks and contribute to cognitive deterioration in AD, have recently been demonstrated in a human brain autopsy and in an experimental model of NPC. This finding raised the issue that central cholinergic circuits dysfunction may contribute to pathophysiology of cognitive impairment in NPC as well, and prompted us to evaluate the cholinergic functional involvement in NPC patients by applying a neurophysiologic technique, named short-latency afferent inhibition (SAI). We describe clinical, biochemical, molecular and neuropsychological features, and SAI findings in three patients affected by NPC. Diagnosis of NPC was assessed by molecular analysis of the NPC1 gene in all patients. In two of them, biochemical analysis of intracellular accumulation of unesterified cholesterol was also performed. The main clinical features were cerebellar ataxia, vertical supranuclear gaze palsy and a variable degree of cognitive impairment ranging from only memory impairment to severe dementia. Electrophysiological evaluation revealed a reduced SAI in all three patients. Our SAI findings provide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic alterations may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD.     

Cortical afferent inhibition reflects cognitive impairment in obstructive sleep apnea syndrome: a TMS study

ObjectivesPatients with obstructive sleep apnea syndrome (OSAS) show neurocognitive impairment, but the exact mechanisms that cause cognitive dysfunctions remain unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this exploratory study was to test the hypothesis that impaired cognitive performances in OSAS patients are associated with a dysfunction of the cholinergic system, as assessed by SAI.MethodsWe applied SAI technique in a group of 13 patients with OSAS and compared the data with those from a group of 13 age-matched healthy subjects. All the patients underwent a sleep study, an extensive neuropsychological evaluation, and TMS examination.ResultsMean SAI was significantly reduced in our OSAS patients when compared with controls. The neuropsychological evaluation showed impairments in most cognitive areas in the OSAS patients. SAI values were strongly correlated with the neuropsychological test scores.ConclusionsThese findings suggest that the cognitive deficits in OSAS may be, at least in part, secondary to alterations in cholinergic neurotransmission, presumably caused by nocturnal hypoxemia. TMS studies may shed light on the pathophysiological mechanisms of the cognitive disturbances in OSAS patients.     

Cholinergic dysfunction in subcortical ischaemic vascular dementia: a transcranial magnetic stimulation study

Little is known about the neurochemical pathology of vascular dementia (VD); it was suggested that cholinergic mechanisms play a role in the pathogenesis of VD, as well as been established for Alzheimer's disease (AD). A recently devised test of motor cortex excitability, the short latency afferent inhibition (SAI), has been proven to depend upon the activity of cholinergic circuits in the human brain. To evaluate, in vivo, the functional role of the cholinergic system in the cognitive dysfunction associated with VD, we used this test in 20 patients with subcortical ischemic VD (SIVD) and in 25 control subjects. Mean SAI was significantly reduced in the SIVD patients; however, individual data varied widely, with SAI responses ranging from normal to markedly reduced values. These findings provide physiological evidence for an important role for cholinergic mechanisms in the pathogenesis of VD. The evaluation of SAI, similar to that described in AD patients, could help in identifying those patients who are more likely to respond to treatment with cholinergic drugs.     

A review of transcranial magnetic stimulation in the in vivo functional evaluation of central cholinergic circuits in dementia

Central cholinergic circuits of human brain can be tested non-invasively by coupling electrical peripheral stimulation with transcranial magnetic stimulation (TMS) of the motor cortex. The short-latency afferent inhibition (SAI) is reduced in cholinergic forms of dementia, such as Alzheimer disease (AD) and dementia with Lewy bodies, while it is normal in non-cholinergic forms of dementia, such as frontotemporal dementia. This finding suggests that this method can be used as a non-invasive additional tool for discriminating between cholinergic and non-cholinergic forms of dementia. Interestingly, SAI was also found to be significantly smaller in early AD patients. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs. In patients with vascular dementia, SAI responses varied widely; the number of patients with abnormal SAI conceivably reflects the percentage of subjects with a significant cholinergic dysfunction. It has recently been demonstrated that brain microbleeds have an impact on SAI that is independent of the extent of associated white matter changes and ischemic stroke. Since SAI can be increased by acetylcholinesterase inhibitors, TMS may help in identifying the patients who would be suitable for long-term treatment with cholinergic agents.     

In vivo functional evaluation of central cholinergic circuits in vascular dementia

OBJECTIVE: Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation of motor cortex. This test, named short latency afferent inhibition (SAI) has been shown in healthy subjects to be sensitive to the blockage of muscarinic acetylcholine receptors and it is impaired in Alzheimer disease (AD) patients, a cholinergic form of dementia, while it is normal in non-cholinergic forms of dementia such as fronto-temporal dementia. The objective of present study was to evaluate central cholinergic circuits in patients with Vascular Dementia (VaD). METHODS: We evaluated SAI in a group of patients with VaD and compared the data with those from a group of AD patients and a control group of age-matched healthy individuals. RESULTS: Mean SAI was normal in VaD patients while it was significantly reduced in AD patients. The analysis of individual data showed abnormal SAI in 75% of AD and in only 25% of VaD. CONCLUSIONS: SAI is normal in most of VaD patients in contrast with AD patients. This test might be used for the functional evaluation of central cholinergic circuits in VaD patients. SIGNIFICANCE: SAI testing may represent a useful additional tool for the evaluation of patients with VaD however, further studies are required in order to evaluate whether this method can be used for the differential diagnosis between pure VaD and different forms of dementia.     

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.     

Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer’s disease

Summary. To determine whether a peculiar neurophysiological profile may contribute to characterize dementia with Lewy bodies (DLB) vs. Alzheimer disease (AD), we used transcranial magnetic stimulation to examine the excitability of two different inhibitory systems of the motor cortex, short latency intracortical inhibition (SICI) and short latency afferent inhibition (SAI) in 10 patients with DLB, in 13 patients with AD and in 15 healthy subjects. SICI and SAI were significantly reduced in AD patients, while both were not significantly different from the controls in DLB patients. The differential pattern of SICI and SAI exhibited by AD vs. DLB may have diagnostic significance in discriminating DLB from AD. Furthermore, this technique may help to clarify the pathophysiological entity of DLB; since SAI is a cortical phenomenon that depends on central cholinergic activity, our findings suggest that the mechanisms of cholinergic depletion in DLB may be different from that in AD, while normal SICI may reflect a less pronounced dysregulation of the intracortical GABAergic inhibitory circuitries in DLB.     

Cortical afferent inhibition is reduced in patients with idiopathic REM sleep behavior disorder and cognitive impairment: a TMS study

ObjectivesImpaired cognitive profile and electroencephalography (EEG) slowing have been reported in patients with REM sleep behavior disorder (RBD), but the neurobiological significance of these findings remains unknown. The cholinergic system is known to play a key role in all attentional processes and cognitive functions. A transcranial magnetic stimulation (TMS) protocol may give direct information about the function of some cholinergic circuits in the human brain; this technique relies on short latency afferent inhibition (SAI) of the motor cortex. The objective of this study was to test the hypothesis that cognitive performance and cortical activation in RBD patients are associated with a dysfunction of the cholinergic system.MethodsWe applied the SAI technique in a group of 10 patients with idiopathic RBD (iRBD) and compared the data with those from a group of 15 age-matched healthy subjects. All the iRBD patients and the control subjects also underwent an extensive neuropsychological evaluation.ResultsMean SAI was significantly reduced in patients with iRBD when compared with controls. Neuropsychological examination showed mild cognitive impairment in six out of the 10 iRBD patients. SAI values correlated strongly with tests measuring episodic verbal memory and executive functions.ConclusionsThese results support the hypothesis of cholinergic dysfunction in some patients with iRBD who develop cognitive impairment. Our findings raise the possibility that the presence of SAI abnormalities may indicate increased risk of cognitive impairment in patients diagnosed with iRBD.     

Plasma amyloid-β as a function of age, level of intellectual disability, and presence of dementia in Down syndrome

Adults with Down syndrome (DS) are at risk for developing Alzheimer's disease (AD). While plasma amyloid-β (Aβ) is known to be elevated in DS, its relationship to cognitive functioning is unknown. To assess this relationship, samples from two groups of subjects were used. In the first group, nondemented adults with DS were compared to: 1) a group of young and old individuals without DS and 2) to a group of patients with AD. Compared to these controls, there were significantly higher levels of plasma Aβ in nondemented adults with DS while AD patients showed lower levels of plasma Aβ. A larger second group included demented and nondemented adults with DS, in order to test the hypothesis that plasma Aβ may vary as a function of dementia and Apolipoprotein E (ApoE) genotype. Plasma Aβ levels alone did not dissociate DS adults with and without dementia. However, in demented adults with DS, ApoE4 was associated with higher Aβ40 but not Aβ42. After controlling for level of intellectual disability (mild, moderate, severe) and the presence or absence of dementia, there was an improved prediction of neuropsychological scores by plasma Aβ. In summary, plasma Aβ can help predict cognitive function in adults with DS independently of the presence or absence of dementia.     

Down syndrome, Alzheimer's disease and seizures

Neuropathologically, Alzheimer-type abnormalities are demonstrated in patients with Down syndrome (DS), both demented and nondemented and more than a half of patients with DS above 50 years develop Alzheimer's disease (AD). The apolipoprotein E epsilon4 allele, oestrogen deficiency, high levels of Abeta1-42 peptide, elevated expression of BACE2, and valine polymorphism of prion protein gene are associated with earlier onset of dementia in DS individuals. Advanced AD alone may be an important risk factor for new-onset seizures in older adults and age above 60 years is a recognized risk factor for poor outcome from convulsive and nonconvulsive status epilepticus. DS patients aged over 45 years are significantly more likely to develop Alzheimer's disease than those less than 45 years and up to 84% demented individuals with DS develop seizures. Late-onset epilepsy in DS is associated with AD, while early-onset epilepsy is associated with an absence of dementia. In AD patients with a younger age of dementia onset are particularly susceptible to seizures. DS adults with epilepsy score significantly higher overall on the adaptive behaviour profile. Language function declined significantly more rapidly in AD patients with seizures and there is a good correlation between the severity of EEG abnormalities and cognitive impairment whereas in DS slowing of the dominant occipital rhythm is related to AD and the frequency of the dominant occipital activity decreases at the onset of cognitive deterioration.     

Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.     

In vivo neurochemical imaging of olfactory dysfunction in Parkinson’s disease

Olfactory dysfunction is common in Parkinson’s disease (PD) and has been attributed to early deposition of α-synuclein pathology in olfactory areas. The pathophysiology of olfactory dysfunction in PD, however, remains poorly understood. Changes in odor identification suggest in part impairment in odor memory, possibly due to hippocampal dysfunction. Olfactory dysfunction occurs also in Alzheimer’s disease (AD) and increases with severity of dementia. Cholinergic degeneration is not only a feature of AD but can also occur in PD, at least in a subset of patients with cognitive changes. We reported previously that impaired odor identification in early PD is more closely correlated with hippocampal dopaminergic than nigrostriatal dopaminergic denervation. Results of our multi-tracer PET studies show that odor identification deficits in PD are best predicted by cholinergic denervation and to a lesser extent by dopaminergic denervation. These results suggest that olfactory dysfunction in PD may have multiple components including hippocampal dysfunction secondary to cholinergic and dopaminergic denervations. Olfactory dysfunction in PD may be the most marked in subjects at risk of incipient dementia, and may reflect the transition of PD toward a stage with more heterogeneous multi-system neurodegenerations. Our preliminary imaging data do not support a significant contribution of amyloidopathy or serotoninergic denervation to abnormal olfactory functions in PD, at least in the absence of dementia. We outline how progressive changes in olfaction may be used as a biomarker of cholinergic denervation and cognitive decline in PD patients. We will discuss also the utility of olfactory testing as an early screening test for neurodegeneration.     

Functional evaluation of central cholinergic circuits in patients with Parkinson’s disease and REM sleep behavior disorder: a TMS study

Central cholinergic dysfunction has been reported in patients with Parkinson?s disease (PD) and hallucinations by evaluating short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain. REM sleep behavior disorder (RBD) was also found to be associated with cognitive impairment in PD patients. The objective of the study was to assess the cholinergic function, as measured by SAI, in PD patients with RBD (PD-RBD) and PD patients without RBD (PD-nRBD). We applied the SAI technique in 10 PD-RBD patients, in 13 PD-nRBD patients and in 15 age-matched normal controls. All PD patients and control subjects also underwent a comprehensive battery of neuropsychological tests. Mean SAI was significantly reduced in PD-RBD patients when compared with PD-nRBD patients and controls. Neuropsychological examination showed mild cognitive impairment in 9 out of the 10 PD-RBD patients, and in 5 out of the 13 PD-nRBD. SAI values correlated positively with neuropsychological tests measuring episodic verbal memory, executive functions, visuoconstructional and visuoperceptual abilities. Similar to that previously reported in the idiopathic form of RBD, SAI abnormalities suggest a cholinergic dysfunction in PD patients who develop cognitive impairment, and present findings indicate that RBD is an important determinant of MCI in PD.     

Cholinergic neurotransmission and olfactory function in obstructive sleep apnea syndrome: a TMS study

Background/objectiveOdor identification and discrimination are reduced in subjects with obstructive sleep apnea syndrome (OSAS), but the pathophysiology of the olfactory dysfunction in OSAS is still poorly understood. Experimental evidence suggests that olfactory impairment could be related to central cholinergic dysfunction. Short latency afferent inhibition (SAI) is a paired-pulse transcranial magnetic stimulation (TMS) protocol that gives the opportunity to test an inhibitory cholinergic circuit in the human cerebral motor cortex. The objective of the study was to assess the cholinergic function, as measured by SAI, in OSAS patients with olfactory impairment.MethodsWe applied SAI technique in 20 patients with OSAS and in 20 healthy control subjects; SAI values were correlated with the Sniffin' Sticks olfactory test results.ResultsSAI was reduced in OSAS patients when compared with control subjects. We also found a strong negative correlation between olfactory parameters and SAI.ConclusionsThese findings suggest that cholinergic dysfunction is a robust determinant of hyposmia also in OSAS patients. Reduced SAI values and presence of olfactory impairment might indicate an increased risk of cognitive decline in patients with OSAS.     

Abnormal short latency afferent inhibition in early Alzheimer’s disease: a transcranial magnetic demonstration

The pathogenesis of Alzheimer's disease (AD) appears to involve several different mechanisms, the most consistent of which is an impairment of cholinergic neurotransmission; however, there is controversy about its relevance at the early stage of disease. A transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with motor cortex TMS (short latency afferent inhibition, SAI) may give direct information about the function of some cholinergic pathways in the human motor cortex. We evaluated SAI in a group of patients with early diagnosis of AD and compared the data with that from a control group. The amount of SAI was significantly smaller in early AD patients than in controls. This study first provides physiological evidence that a central cholinergic dysfunction occurs in the earlier stages of AD. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs.     

Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: a role for intraneuronal amyloid

The amyloid Abeta-peptide (Abeta) is suspected to play a critical role in the cascade leading to AD as the pathogen that causes neuronal and synaptic dysfunction and, eventually, cell death. Therefore, it has been the subject of a huge number of clinical and basic research studies on this disease. Abeta is typically found aggregated in extracellular amyloid plaques that occur in specific brain regions enriched in nAChRs in Alzheimer's disease (AD) and Down syndrome (DS) brains. Advances in the genetics of its familiar and sporadic forms, together with those in gene transfer technology, have provided valuable animal models that complement the traditional cholinergic approaches, although modeling the neuronal and behavioral deficits of AD in these models has been challenging. More recently, emerging evidence indicates that intraneuronal accumulation of Abeta may also contribute to the cascade of neurodegenerative events and strongly suggest that it is an early, pathological biomarker for the onset of AD and associated cognitive and other behavioral deficits. The present review covers these studies in humans, in in vitro and in transgenic models, also providing more evidence that adult 3xTg-AD mice harboring PS1M146V, APPSwe, tauP301L transgenes, and mimicking many critical hallmarks of AD, show cognitive deficits and other behavioral alterations at ages when overt neuropathology is not yet observed, but when intraneuronal Abeta, synaptic and cholinergic deficits can already be described.     

Cognitive profiles differ in autopsy-confirmed frontotemporal dementia and AD

BACKGROUND: Frontotemporal dementia (FTD) is currently distinguished from AD primarily on the basis of behavioral features because studies of cognition have shown negligible or inconsistent differences. However, the poor discriminability of cognitive measures may relate to reliance on imprecise clinically diagnosed groups. Therefore, a retrospective examination of neuropsychological test performance in autopsy-confirmed patients is warranted. OBJECTIVE: To compare the pattern of cognitive deficits exhibited by patients with autopsy-confirmed FTD and AD. METHODS: The profiles of cognitive deficits exhibited by patients with neuropathologic diagnosis of FTD (n = 14) or AD (n = 28) were compared. The Mattis Dementia Rating Scale (MDRS), letter and category fluency tests, Wechsler Intelligence Scale for Children-Revised block design test, Boston naming test, and clock drawing test were administered. RESULTS: Multivariate analysis of covariance controlling for age, education, and level of dementia revealed that patients with FTD performed significantly worse than patients with AD on letter and category fluency tests but significantly better on the MDRS memory subscale, block design test, and clock drawing test. A logistic regression model, validated in an independent clinical sample, used letter fluency, MDRS memory, and block design scores to correctly classify 91% of AD patients and 77% of FTD patients. CONCLUSIONS: A double dissociation in the pattern of cognitive deficits exhibited by FTD and AD patients was demonstrated. The FTD patients were more impaired than AD patients on word generation tasks (i.e., verbal fluency) that are sensitive to frontal lobe dysfunction but less impaired on tests of memory and visuospatial abilities sensitive to dysfunction of medial temporal and parietal association cortices.     

Absence of cholinergic deficits in "pure" vascular dementia

Choline acetyltransferase in temporal cortex was evaluated as a marker of cholinergic function in autopsied dementia cases (9 vascular dementia [VaD] cases, 12 "mixed" VaD and Alzheimer disease [AD] cases, 10 AD cases, 12 control subjects). Patients with AD (t = 2.5, p = 0.02) and "mixed" VaD and AD (t = 3.8, p = 0.001) had greater cholinergic deficits than age-matched control subjects and patients with "pure" VaD. The absence of cholinergic deficits in "pure" VaD may be relevant to the pharmacologic treatment of these patients.     

A noradrenergic lesion exacerbates neurodegeneration in a Down syndrome mouse model

Individuals with Down syndrome (DS) acquire Alzheimer's-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies.